CN111116567B

CN111116567B - Zanamivir and ranamivir intermediates and synthesis method thereof

Info

Publication number: CN111116567B
Application number: CN201910532524.8A
Authority: CN
Inventors: 马大为; 田峻山; 钟建康; 潘强彪; 李运生
Original assignee: Lianhe Chemical Technology Taizhou Co ltd; Shanghai Institute of Organic Chemistry of CAS
Current assignee: Lianhua Angjian Zhejiang Pharmaceutical Co ltd; Shanghai Institute of Organic Chemistry of CAS
Priority date: 2013-09-09
Filing date: 2014-09-09
Publication date: 2023-10-10
Anticipated expiration: 2034-09-09
Also published as: CN111018901A; CN111018901B; CN104418876B; CN111116567A; CN111116533B; CN111116533A; CN104418876A; WO2015032357A1

Abstract

The invention discloses an intermediate of zanamivir and ranamivir and a synthesis method thereof. The invention provides a synthesis method of a compound 8, which comprises the following steps: in the presence of a base, a catalyst and a catalyst ligand in an aprotic solvent, the compound 10 and the compound 9 are reacted to obtain the compound 8. The synthesis method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, short steps, high total yield, low production cost, good product purity, high chiral purity and good prospect of industrial production.

Description

Zanamivir and ranamivir intermediates and synthesis method thereof

Technical Field

The invention relates to an intermediate of zanamivir and ranamivir and a synthesis method thereof.

Background

Zanamivir (Zanamivir) is a first class of neuraminidase inhibitors synthesized based on drug design, and Oseltamivir (Oseltamivir) is currently a very few of two drugs approved for the treatment of influenza A and B viruses on the market. It was discovered by the scientist of Biota in 1989 and was licensed to the gram company of ghatti in 1990 for clinical treatment. 1999 FDA approval and marketing in the united states.

In 1994, university of Meng Nashen in australia m.v. itzstein was first completed for the first synthesis of zanamivir (carbohydro.res., 1994,259,301-305). They start from N-acetylneuraminic acid, introduce the required nitrogen atom by azide para-oxazoline ring opening, hydrogenate azide and then convert to zanamivir through several steps.

This method only provides mg-scale product for clinical studies. The explosion hazards presented by the azide, reagents and intermediates present a hazard to large scale industrial processes. In addition, the raw material N-acetylneuraminic acid is not easily available, and the application of the method is limited.

In 1995, J.Scheigetz et al, merck, canada found that the above reaction was not well reproducible. They used the same starting materials and similar strategies and optimized the zanamivir synthesis process to improve yields and reproducibility (org.prep.proc.int., 1995,27,637-644). DPPA is used to replace explosive reagents such as lithium azide and the like. Although they synthesized only milligram-scale products, they lay the foundation for later human studies.

In 1995, M.Chandler et al, from the company Gelanin Shike, UK, reported for the first time the Wei Deke-level synthesis of zanami (J.chem. Soc., perkin Trans. I,1995, 1173-1180). They also used N-acetylneuraminic acid as the starting material, and obtained the key oxazoline intermediate in 3 steps very efficiently. Using TMSN ₃ The product can be obtained by 5 steps of conversion after being used as a nitrogen source.

Although they obtained 1.28 grams of zanamivir, all of their multi-step reactions required preparation on a scale of hundreds of grams, including the azide substitution reaction on a scale of 600 grams, and required multi-step ion exchange resin desalting. The overall yield of the 9-step reaction is 8.3%, and there are still many places where improvement is required.

The former work was done to structurally modify N-acetylneuraminic acid and the synthesis of zanamivir was also reported by the Yao Zhoujun professor of the Shanghai organic institute in China (Org. Lett.,2004,6,2269-2272). Unlike the former, they use cheap gluconolactone as raw material, and use one-step key azide to introduce nitrogen atom needed in zanamivir for aziridine ring-opening reaction, and then hydrogenate azide and make subsequent conversion to complete their synthesis.

However, despite its very inexpensive starting material, its 24-step reaction, a total yield of 0.2% makes the process very difficult to industrialize.

In 2012, the professor m.shiasaki, university of tokyo, japan, also reported the synthesis of zanamivir by their group (angelw.chem.int.ed., 2012,51,1644-1647). They constructed two key chiral centers using asymmetric Henry reactions developed by their group and synthesized key oxazoline intermediates using novel 3, 3-sigma rearrangement reactions. As in the Yao Zhoujun teaching, they also completed their synthesis in 24 steps with a total yield of 1.2%. Although the reaction is quite novel, the lengthy linear steps and low yields also make the process difficult to industrialize.

However, with the advent of drug resistant strains, the development of some novel NA inhibitors has been accelerated. Laninavir (Ranamivir) is a neuraminidase inhibitor developed by the company Biota Pharmaceuticals and Daiichi Sankyo and is useful for the treatment of influenza virus infections which are resistant to oseltamivir. The average recovery time of the person taking Laninavir is longer than 60 hours before the average recovery time of the person taking Dafein. Laninavir was approved in 2010 for sale in Japan under the Inavir name. Its octanoate CS-8958 is also marketed in Japan in the same year.

In 2002, the synthesis of laninavir was first completed by Daiichi Sankyo company T.Honda et al (US 6340702). They obtained an Aldol reaction precursor from benzyl-protected sugar by literature methods, then constructed their core skeleton with Aldol reaction enzyme, and then transformed into laninavir in 11 steps.

In the same year, daiichi Sankyo company T.Honda et al, japan improved the synthesis of laninavir (bioorg. Med. Chem. Lett.,2002,12,1921-1924). Starting from the known cheaper pyranose compounds, they obtained an Aldol reaction precursor by a few simple transformations, then constructed their core skeleton by Aldol reaction enzymes and obtained laninavir by 8 transformations.

The method has the advantages that N-acetylneuraminic acid serving as a raw material is not easy to obtain in large quantity, and the application of the method is limited.

In 2002, improved synthesis of ranamivir was reported by Daiichi Sankyo, japan, Y.Kawaoka et al (bioorg. Med. Chem. Lett.,2002,12,1925-1928). They start from N-acetylneuraminic acid, firstly protect two hydroxyl groups near the terminal position by acetonylidene and methylate the required hydroxyl groups, convert the hydroxyl groups into amine groups, and then convert the amine groups into the ranamivir through a plurality of steps.

In 2008, daiichi Sankyo corporation Y.Nakamura et al perfected the synthesis of ranamivir and filed a world patent (WO 2008/126943). They also used N-acetylneuraminic acid as the starting material, and obtained the key oxazoline intermediate in 3 steps very efficiently. Using TMSN ₃ The product can be obtained by 5 steps of conversion after being used as a nitrogen source.

It is desirable to develop more efficient synthetic methods for synthesizing important intermediates of zanamivir in order to make the overall synthetic route more economical and simpler to operate.

Disclosure of Invention

The invention aims to overcome the defects of long route, low total yield, poor atom economy, operation danger, high production cost, inapplicability to industrial production and the like of the conventional zanamivir Wei Gecheng, and provides an intermediate of zanamivir and ranamivir and a synthesis method thereof. The synthesis method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, short steps, high total yield, low production cost, good product purity, high chiral purity and good prospect of industrial production.

The invention provides a preparation method of a compound 2, which can adopt a method 1 or a method 2,

the method 1 comprises the following steps: carrying out a reaction of removing protecting groups on the compound 3 to obtain a compound 2;

wherein R is hydrogen or methyl; r is R ¹ Is Trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), methoxymethyl (MOM), methyl or hydrogen;

R ² and R is ⁵ Each independently is methyl, ethyl or propyl; r is R ⁴ Is an amino protecting group, such as t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or p-toluenesulfonyl (Ts).

The method 2 comprises the following steps: carrying out hydrolysis reaction on the compound 35 to obtain a compound 2;

r is hydrogen or methyl.

Method 1 for preparing compound 2 may employ conventional methods of such deprotection reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention: in an aprotic solvent, under the condition of acid, carrying out a reaction of removing a protecting group on the compound 3 to obtain a compound 2;

in the method 1 for producing the compound 2, the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably methylene dichloride.

In the method 1 for producing the compound 2, the volume/mass ratio of the aprotic solvent to the compound 3 is preferably 0.1 to 5mL/mg, more preferably 0.1 to 1mL/mg.

In process 1 for preparing compound 2, the acid is preferably an inorganic acid and/or an organic acid; the mineral acid is preferably hydrochloric acid; the organic acid is preferably trifluoroacetic acid; the hydrochloric acid can be a conventional commercial hydrochloric acid reagent in the field, preferably 10-37% of hydrochloric acid by mass percent, and the mass percent refers to the percentage of the mass of hydrogen chloride in the total mass of the hydrochloric acid reagent.

In the process 1 for preparing the compound 2, the molar ratio of the compound 3 to the acid is preferably 1:1 to 1:100, more preferably 1:30 to 1:50.

In the method 1 for producing the compound 2, the temperature of the reaction for removing the protecting group is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the method 1 for preparing the compound 2, the progress of the deprotection reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 20 hours, more preferably 8 to 10 hours, generally taking the disappearance of the compound 3 as the reaction end point.

The process 1 for preparing compound 2 further comprises the steps of, in process 1 for preparing compound 2, when R ¹ In the case of Trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), methoxymethyl (MOM) or methyl, said compound 3 may be prepared by the following method one; when R is ¹ In the case of hydrogen, the compound 3 can be prepared by the following method II; when R is ¹ In the case of Trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), methoxymethyl (MOM), methyl or hydrogen, said compound 3 may be prepared by the following method III;

the method comprises the following steps: in a protonic solvent, under an acidic condition, carrying out an oxidation reaction on the compound 4 and an oxidant to obtain a compound 3;

the second method is as follows: in an aprotic solvent, carrying out a reduction reaction on the compound 12 and a reducing agent to obtain a compound 3;

and a third method: carrying out hydrolysis reaction on the compound 34 to obtain a compound 3;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ The definitions of which are as described above.

Methods for preparing compound 3-conventional methods of this type of oxidation reaction in the art can be employed, and the following reaction methods and conditions are particularly preferred in the present invention:

In the first method for preparing the compound 3, the protic solvent is preferably an alcohol solvent and/or water; the alcohol solvent is preferably tert-butanol; when a mixed solvent of tert-butanol and water is used, the volume ratio of tert-butanol to water in the mixed solvent of tert-butanol and water is preferably 10:1 to 1:1, more preferably 5:1 to 3:1.

In the first method for preparing the compound 3, the volume/mass ratio of the protic solvent to the compound 4 is preferably 20mL/g to 300mL/g, more preferably 120mL/g to 300mL/g.

In the first method for preparing the compound 3, the oxidant is preferably chlorous acid; the chlorous acid is preferably obtained by reacting sodium chlorite with sodium dihydrogen phosphate.

In the first method for producing the compound 3, the molar ratio of the compound 4 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:3 to 1:4.

In process one of the preparation of compound 3, the acidic condition is preferably achieved by the addition of a strong basic salt of a weak acid, preferably sodium dihydrogen phosphate. When a strong basic weak acid salt is used to achieve acidic conditions, the molar ratio of said strong basic weak acid salt to said compound 4 is preferably 1:1 to 20:1, more preferably 5:1 to 10:1.

In the first method for producing compound 3, the acidic condition is preferably a pH of 2 to 5.

In the first method for producing Compound 3, the temperature of the oxidation reaction is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the first method for preparing compound 3, the progress of the oxidation reaction may be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 24 hours, more preferably 2 to 8 hours, generally with the disappearance of compound 4 as the reaction end point.

The process for preparing compound 3 is preferably carried out in the presence of a radical scavenger, preferably 2-methylbutene or phenol. The molar ratio of the radical scavenger to the compound 4 is preferably 0.5:1 to 3:1, more preferably 1:1 to 2:1.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method 1 for preparing the compound 3, the compound 4 can be prepared by the following steps: in an aprotic solvent, carrying out oxidation reaction on the compound 5 and an oxidant to obtain a compound 4;

The process for preparing compound 4 may employ conventional methods of this type of oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

In the process for preparing compound 4, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably 1, 4-dioxane.

In the method for producing Compound 4, the volume/mass ratio of the aprotic solvent to the Compound 5 is preferably 20mL/g to 300mL/g, more preferably 150mL/g to 300mL/g.

In the process for preparing compound 4, the oxidizing agent is preferably selenium dioxide.

In the process for preparing compound 4, the molar ratio of compound 5 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.

In the process for producing compound 4, the temperature of the oxidation reaction is preferably 30 to 100 ℃, more preferably 60 to 100 ℃, still more preferably 35 to 80 ℃, and most preferably 40 to 80 ℃.

In the method for preparing compound 4, the progress of the oxidation reaction may be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 5 hours, more preferably 2 to 3 hours, generally with the disappearance of compound 5 as the reaction end point.

The process for preparing compound 4 is preferably carried out under the protection of an inert gas, preferably one or more of nitrogen, argon and helium.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 4, the compound 5 can be prepared by the following steps: in a solvent, under the existence of alkali, carrying out nucleophilic substitution reaction on the compound 6 and an acetylating reagent to obtain the compound 5;

The method for preparing compound 5 may employ a conventional method of such nucleophilic substitution reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the method for preparing the compound 5, the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the organic base is preferably one or more of pyridine, piperidine and triethylamine.

In the process for preparing compound 5, the base is preferably an organic base, and the organic base is preferably one or more of pyridine, piperidine and triethylamine.

In the process for preparing compound 5, the molar ratio of compound 6 to the base is preferably 1:3 to 1:6, more preferably 1:4 to 1:5.

In the method for preparing the compound 5, the acetylating reagent is an acetylating reagent with acetyl groups commonly used in nucleophilic substitution reaction of the type, preferably acetyl halide and/or acetic anhydride; the acetyl halide is preferably acetyl chloride or acetyl bromide.

In the process for preparing compound 5, the molar ratio of compound 6 to the acetylating reagent is preferably 1:1 to 1:20, more preferably 1:1 to 1:3, still more preferably 1:1 to 1:1.1.

In the method for producing compound 5, the temperature of the nucleophilic substitution reaction is preferably 0℃to 100℃and more preferably 0℃to 60 ℃.

In the method for preparing compound 5, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 24 hours, more preferably 2 to 3 hours, generally with the end point of the reaction when compound 6 disappears.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 5, the compound 6 can be prepared by the following steps: carrying out reduction reaction on the compound 7 in an aprotic solvent under the condition of the action of acid and a reducing agent to obtain the compound 6;

In the process for preparing compound 6, the aprotic solvent is preferably an ester solvent; the ester solvent is preferably ethyl acetate.

In the method for producing Compound 6, the volume/mass ratio of the aprotic solvent to the Compound 7 is preferably 20mL/g to 200mL/g, more preferably 90mL/g to 120mL/g.

In the process for preparing compound 6, the acid is preferably an organic acid; the organic acid is preferably glacial acetic acid.

In the process for preparing compound 6, the molar ratio of the acid to the compound 7 is preferably 10:1 to 100:1, more preferably 60:1 to 100:1.

In the method for producing compound 6, the reducing agent is preferably one or more of zinc, iron and aluminum.

In the process for preparing compound 6, the molar ratio of the reducing agent to the compound 7 is preferably 10:1 to 100:1, more preferably 60:1 to 100:1.

In the method for producing Compound 6, the temperature of the reduction reaction is preferably 0℃to 40℃and more preferably 10℃to 30 ℃.

In the method for preparing compound 6, the progress of the reduction reaction may be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 20 hours, more preferably 10 to 15 hours, with the disappearance of compound 7 as the reaction end point.

The process for preparing compound 6 preferably employs the following steps: and (3) adding a reducing agent and an acid into a solution formed by the compound 7 and the aprotic solvent in sequence, and carrying out reduction reaction to obtain a compound 6.

The process for preparing compound 6 preferably comprises the following work-up steps: after the reaction, adding alkali to adjust the pH to about 7, extracting, concentrating, and separating by column chromatography to obtain the compound 6. The alkali is preferably organic alkali, and the organic alkali is preferably ammonia water; the ammonia water can be a conventional commercial ammonia water reagent, the mass percentage concentration of the ammonia water reagent is preferably 5-50%, more preferably 15-40%, and the mass percentage refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution. The solvent used for the extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The column chromatography separation method can be performed by a method conventional in the art for such an operation.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 6, the compound 7 can be prepared by the following steps: in an organic solvent, in the presence of alkali, carrying out dehydration reaction on the compound 8 and a dehydrating agent to obtain a compound 7;

The process for preparing compound 7 may employ conventional methods of such dehydration reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the method for producing compound 7, the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent and an aromatic hydrocarbon solvent; further preferred are ether solvents and/or halogenated hydrocarbon solvents; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the aromatic solvent is preferably toluene.

In the method for producing Compound 7, the volume/mass ratio of the organic solvent to the Compound 8 is preferably 20mL/g to 200mL/g, more preferably 100mL/g to 150mL/g.

In the process for preparing compound 7, the base is preferably an organic base; the organic base is preferably triethylamine and/or pyridine.

In the process for preparing compound 7, the molar ratio of the base to the compound 8 is preferably from 100:1 to 1:1, more preferably from 50:1 to 1:1.

In the method for producing the compound 7, the dehydrating agent is preferably one or more of thionyl chloride, methanesulfonyl chloride and Burgess reagent (Burgess reagent means methyl N- (triethylammonium sulfonyl) carbamate, CAS: 29684-56-8).

In the process for preparing compound 7, the molar ratio of compound 8 to the dehydrating agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.

In the process for producing compound 7, the temperature of the dehydration reaction is preferably from 0℃to 40℃and more preferably from 10℃to 30 ℃.

In the method for preparing compound 7, the progress of the dehydration reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1h to 5h, more preferably 1h to 3h, generally taking the disappearance of compound 8 as the reaction end point.

The process for preparing compound 7 is preferably carried out in the presence of a catalyst, preferably 4-Dimethylaminopyridine (DMAP). The molar ratio of the catalyst to the compound 8 is preferably 1:1 to 1:10, more preferably 1:1 to 1:5.

The process for preparing compound 7 preferably employs the following steps: and (3) adding a catalyst and a dehydrating agent into a solution formed by the compound 8, the alkali and the organic solvent in sequence to carry out dehydration reaction to obtain the compound 7.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 7, the compound 8 can be prepared by the following steps: reacting compound 10 with compound 9 in the presence of a base, a catalyst and a catalyst ligand in an aprotic solvent to obtain compound 8;

The process for preparing compound 8 may employ conventional methods of such reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound 8, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the method for producing Compound 8, the volume/mass ratio of the aprotic solvent to the Compound 9 is preferably 1mL/g to 50mL/g, more preferably 1mL/g to 10mL/g.

In the process for preparing compound 8, the base is preferably an inorganic base; the inorganic base is preferably one or more of cesium carbonate, sodium carbonate, potassium carbonate and potassium tert-butoxide.

In the process for preparing compound 8, the molar ratio of compound 9 to the base is preferably 1:1 to 10:1, more preferably 1:1 to 3:1.

In the process for preparing compound 8, the catalyst is preferably an inorganic copper salt and/or an organic copper salt; the inorganic copper salt refers to salt formed by the reaction of copper and inorganic acid; the organic copper salt refers to a salt formed by the reaction of copper and an organic acid. The inorganic copper salt is preferably one or more of cupric chloride, cuprous bromide, cupric bromide and cuprous iodide, and further preferably cupric bromide and/or cupric chloride; the organic copper salt is preferably copper acetate.

In the process for preparing compound 8, the molar ratio of compound 9 to the catalyst is preferably 1:1 to 10:1, more preferably 3:1 to 10:1.

In the process for preparing compound 8, the molar ratio of said compound 10 to said compound 9 is preferably 1:1 to 5:1, more preferably 2:1 to 5:1.

In the process for preparing compound 8, the catalyst ligand is preferably a pyrrolidine-phenol catalyst; the pyrrolidine-phenol catalyst is preferably

In the process for preparing compound 8, the molar ratio of the catalyst ligand to the compound 9 is preferably 1:10 to 3:10, more preferably 2:10 to 3:10.

In the process for preparing compound 8, the temperature of the reaction is preferably-20℃to 40℃and more preferably-20℃to 30 ℃.

In the method for preparing compound 8, the progress of the reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 24 to 96 hours, more preferably 24 to 48 hours, generally taking the disappearance of compound 9 as the reaction end point.

In the process for preparing compound 8, the catalyst ligandCan be synthesized by the method reported in chem. Eur. J.2012,18,12357.

In the preparation of compound 8, compound 9 may be synthesized by the method reported in reference to Tetrahedron, asymmetry 1998,9, 1359-1367.

The second method for preparing compound 3 may employ a conventional method of this type of reduction reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the second method for preparing the compound 3, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the second method for producing the compound 3, the volume/mass ratio of the aprotic solvent to the compound 12 is preferably 10mL/g to 500mL/g, more preferably 400mL/g to 500mL/g.

In the second method for preparing the compound 3, the reducing agent is preferably zinc borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride or lithium borohydride.

In the second method for producing the compound 3, the molar ratio of the compound 12 to the reducing agent is preferably 1:1 to 1:5, more preferably 1:1 to 1:3.

In the second method for producing Compound 3, the temperature of the reduction reaction is preferably-78℃to 40℃and more preferably 20℃to 30 ℃.

In the second method for preparing compound 3, the progress of the reduction reaction may be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 12 hours, more preferably 4 to 10 hours, generally with the disappearance of compound 12 as the reaction end point.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method two for preparing the compound 3, the compound 12 can be prepared by the following methods: in a protonic solvent, under an acidic condition, carrying out an oxidation reaction on the compound 13 and an oxidant to obtain a compound 12;

The process for preparing compound 12 may employ conventional methods of this type of oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

In the process for preparing compound 12, the protic solvent is preferably an alcoholic solvent and/or water; the alcohol solvent is preferably tert-butanol; when a mixed solvent of tert-butanol and water is used, the volume ratio of tert-butanol to water in the mixed solvent of tert-butanol and water is preferably 10:1 to 1:1, more preferably 5:1 to 3:1.

In the method for producing compound 12, the volume/mass ratio of the protic solvent to compound 13 is preferably 20 to 300mL/g, more preferably 200 to 300mL/g.

In the process for preparing compound 12, the oxidizing agent is preferably chlorous acid; the chlorous acid is preferably obtained by reacting sodium chlorite with sodium dihydrogen phosphate.

In the process for preparing compound 12, the molar ratio of compound 13 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.

In the process for preparing compound 12, the acidic condition is preferably achieved by adding a strong basic salt of a weak acid, preferably sodium dihydrogen phosphate. When a strong base weak acid salt is used to achieve acidic conditions, the molar ratio of the strong base weak acid salt to the compound 13 is preferably 1:1 to 20:1, more preferably 5:1 to 10:1.

In the process for preparing compound 12, the acidic condition, preferably the pH is 2 to 5.

In the method for producing compound 12, the temperature of the oxidation reaction is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 12, the progress of the oxidation reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1h to 24h, more preferably 2h to 8h, generally taking the disappearance of compound 13 as the reaction end point.

The process for preparing compound 12 is preferably carried out in the presence of a radical scavenger, preferably 2-methylbutene or phenol. The molar ratio of the radical scavenger to the compound 13 is preferably 0.5:1 to 3:1, more preferably 1:1 to 2:1.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 12, the compound 13 can be prepared by the following steps: oxidizing compound 14 with an oxidant in an aprotic solvent to obtain compound 13;

wherein R is ² 、R ⁴ And R is ⁵ The definitions of which are as described above.

The method for preparing compound 13 may employ a conventional method of this type of oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

In the process for preparing compound 13, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably 1, 4-dioxane.

In the method for producing compound 13, the volume/mass ratio of the aprotic solvent to the compound 14 is preferably 20mL/g to 300mL/g, more preferably 150mL/g to 300mL/g.

In the process for preparing compound 13, the oxidizing agent is preferably selenium dioxide.

In the process for preparing compound 13, the molar ratio of compound 14 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.

In the process for producing compound 13, the temperature of the oxidation reaction is preferably 80℃to 150℃and more preferably 100℃to 140 ℃.

In the method for preparing compound 13, the progress of the oxidation reaction may be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 5 hours, more preferably 2 to 4 hours, with the disappearance of compound 14 being the reaction end point.

The process for preparing compound 13 is preferably carried out under the protection of an inert gas, preferably one or more of nitrogen, argon and helium.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 13, the compound 14 can be prepared by the following steps: subjecting compound 15 to oxidation reaction to obtain said compound 14;

Methods for preparing compound 14 may employ conventional methods of this type of oxidation in the art, with Ley's oxidation being particularly preferred in the present invention; the Ley's oxidation reaction may be a conventional method of this type in the art, and the following reaction methods and conditions are particularly preferred in the present invention: in the presence of a catalyst, carrying out the Leachi oxidation reaction of the compound 15 and an oxidant in an organic solvent to obtain a compound 14.

In the method for producing the compound 14, the organic solvent is preferably a halogenated hydrocarbon solvent and/or a nitrile solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the nitrile solvent is preferably acetonitrile; the organic solvent is further preferably a mixed solvent of dichloromethane and acetonitrile; when a mixed solvent of dichloromethane and acetonitrile is adopted, the volume ratio of dichloromethane to acetonitrile in the mixed solvent of dichloromethane and acetonitrile is preferably 20:1-1:1, and more preferably 15:1-10:1.

In the method for producing the compound 14, the volume/mass ratio of the organic solvent to the compound 15 is preferably 20mL/g to 200mL/g, more preferably 150mL/g to 200mL/g.

In the process for preparing compound 14, the oxidizing agent is preferably N-methylmorpholine oxide (CAS: 7529-22-8, english name 4-Methylmorpholine N-oxide).

In the process for preparing compound 14, the molar ratio of compound 15 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:1 to 1:2.

In the process for preparing compound 14, the catalyst is preferably tetra-n-propyl ammonium perruthenate (TPAP).

In the process for preparing compound 14, the molar ratio of compound 15 to the catalyst is preferably 20:1 to 5:1, more preferably 10:1 to 15:1.

In the process for producing compound 14, the temperature of the Leaching oxidation reaction is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 14, the progress of the Leaching oxidation reaction may be monitored by conventional test methods in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 5 to 20 hours, more preferably 8 to 12 hours, generally taking the disappearance of compound 15 as the reaction end point.

PreparationThe process of compound 14 is preferably carried out in the presence of a molecular sieve; the molecular sieve is preferablyMolecular sieves. The mass molar ratio of the molecular sieve to the compound 15 is preferably 1g/mol to 5g/mol, more preferably 1g/mol to 2g/mol.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 14, the compound 15 can be prepared by the following steps: in a solvent, carrying out a reaction of removing hydroxyl protecting groups on the compound 16 and a fluorinating reagent to obtain a compound 15;

wherein R is ² 、R ⁴ And R is ⁵ Is as defined above; r is R ³ Is a hydroxy protecting group such as Trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS) or methoxymethyl (MOM).

The method for preparing compound 15 may employ a conventional method of this kind of reaction for removing hydroxyl protecting groups in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound 15, the solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 15, the volume/mass ratio of the solvent to the compound 15 is preferably 1mL/g to 100mL/g, more preferably 50mL/g to 100mL/g.

In the process for preparing compound 15, the fluorinating agent is preferably tetrabutylammonium fluoride and/or potassium fluoride.

In the process for preparing compound 15, the molar ratio of compound 16 to the fluorinating agent is preferably 1:1 to 1:5, more preferably 1:1 to 1:2.

In the method for producing compound 15, the reaction temperature for removing the hydroxyl protecting group is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 15, the progress of the reaction for removing the hydroxyl protecting group can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 5 hours, more preferably 2 to 3 hours, generally taking the disappearance of compound 16 as the reaction end point.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 15, the compound 16 can be prepared by the following method: in a solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on the compound 17 and an acetylating reagent to obtain the compound 16;

wherein R is ² 、R ³ 、R ⁴ And R is ⁵ The definitions of which are as described above.

In the method for preparing the compound 16, the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the organic base is preferably one or more of pyridine, piperidine and triethylamine.

In the process for preparing compound 16, the base is preferably an organic base, and the organic base is preferably one or more of pyridine, piperidine and triethylamine.

In the process for preparing compound 16, the molar ratio of compound 17 to the base is preferably 1:1 to 1:5, more preferably 1:1 to 1:4.

In the method for preparing the compound 16, the acetylating reagent is an acetylating reagent commonly used in nucleophilic substitution reaction of the type and having an acetyl group, preferably acetyl halide and/or acetic anhydride, and further preferably acetic anhydride; the acetyl halide is preferably acetyl chloride or acetyl bromide.

In the method for preparing the compound 16, the molar ratio of the compound 17 to the acetylating reagent is preferably 1:1-1:20; when the acetylating agent is acetyl halide, the molar ratio of the compound 17 to the acetylating agent is preferably 1:1 to 1:3, more preferably 1:1 to 1:1.5.

In the method for producing compound 16, the temperature of the nucleophilic substitution reaction is preferably 0℃to 100℃and more preferably 0℃to 60 ℃.

In the method for preparing compound 16, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 24 hours, more preferably 8 to 12 hours, generally with the end point of the reaction when compound 17 disappears.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 16, the compound 17 can be prepared by the following steps: carrying out reduction reaction on the compound 18 in an aprotic solvent under the condition of the action of acid and a reducing agent to obtain the compound 17;

In the process for preparing compound 17, the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably methylene dichloride.

In the method for producing compound 17, the volume/mass ratio of the aprotic solvent to the compound 18 is preferably 1mL/g to 200mL/g, more preferably 30mL/g to 50mL/g.

In the process for preparing compound 17, the acid is preferably an organic acid; the organic acid is preferably glacial acetic acid.

In the process for preparing compound 17, the molar ratio of the acid to the compound 18 is preferably 10:1 to 100:1, more preferably 40:1 to 100:1.

In the method of preparing compound 17, the reducing agent is preferably one or more of zinc, iron and aluminum.

In the process for preparing compound 17, the molar ratio of the reducing agent to the compound 18 is preferably 10:1 to 100:1, more preferably 40:1 to 100:1.

In the method for producing compound 17, the temperature of the reduction reaction is preferably 0℃to 40℃and more preferably 10℃to 30 ℃.

In the method for preparing compound 17, the progress of the reduction reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1h to 20h, more preferably 12h to 18h, generally taking the disappearance of compound 18 as the reaction end point.

The process for preparing compound 17 preferably employs the following steps: and (3) adding a reducing agent and an acid into a solution formed by the compound 18 and the aprotic solvent in sequence to perform a reduction reaction to obtain the compound 17.

The process for preparing compound 17 preferably comprises the following work-up steps: after the reaction, adding alkali to adjust the pH to about 7, extracting, concentrating, and separating by column chromatography to obtain the compound 17. The alkali is preferably organic alkali, and the organic alkali is preferably ammonia water; the ammonia water can be a conventional commercial ammonia water reagent, the mass percentage concentration of the ammonia water reagent is preferably 5-50%, more preferably 15-40%, and the mass percentage refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution. The solvent used for the extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The column chromatography separation method can be performed by a method conventional in the art for such an operation.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 17, the compound 18 can be prepared by the following steps: in an organic solvent, in the presence of alkali, carrying out dehydration reaction on the compound 19 and a dehydrating agent to obtain a compound 18;

The process for preparing compound 18 may employ conventional methods of such dehydration reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the method for producing the compound 18, the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent and an aromatic hydrocarbon solvent; further preferred are ether solvents and/or halogenated hydrocarbon solvents; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the aromatic solvent is preferably toluene.

In the method for producing the compound 18, the volume/mass ratio of the organic solvent to the compound 19 is preferably 20mL/g to 200mL/g, more preferably 100mL/g to 150mL/g.

In the method for producing the compound 18, the dehydrating agent is preferably one or more of thionyl chloride, methanesulfonyl chloride and Burgess reagent (Burgess reagent means methyl N- (triethylammonium sulfonyl) carbamate, CAS: 29684-56-8).

In the process for preparing compound 18, the molar ratio of compound 19 to the dehydrating agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.

In the process for preparing compound 18, the base is preferably an organic base; the organic base is preferably triethylamine and/or pyridine.

In the process for preparing compound 18, the molar ratio of said base to said compound 19 is preferably 1: 1-50:1; for example, 1:1 to 10:1, and more for example, 3:1 to 6:1.

In the method for producing compound 18, the temperature of the dehydration reaction is preferably 0℃to 40℃and more preferably 10℃to 30 ℃.

In the method for preparing compound 18, the progress of the dehydration reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1h to 20h, more preferably 8h to 15h, generally taking the disappearance of compound 19 as the reaction end point.

The process for preparing compound 18 is preferably carried out in the presence of a catalyst, preferably 4-Dimethylaminopyridine (DMAP, CAS:1122-58-3, english name 4-Dimethylaminopyridine). The molar ratio of the catalyst to the compound 19 is preferably 1:1 to 1:5, more preferably 1:3 to 1:4.

The process for preparing compound 18 preferably employs the following steps: and (3) adding 4-Dimethylaminopyridine (DMAP) and methanesulfonyl chloride into a solution formed by the compound 19, triethylamine and an organic solvent in sequence, and carrying out dehydration reaction to obtain the compound 18.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 18, the compound 19 can be prepared by the following steps: reacting compound 10 with compound 20 in the presence of an alkaline substance in an aprotic solvent to give said compound 19;

The process for preparing compound 19 may employ conventional methods of such reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the method for producing compound 19, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the method for producing compound 19, the volume/mass ratio of the aprotic solvent to the compound 10 is preferably 1mL/g to 50mL/g, more preferably 30mL/g to 50mL/g.

In the method of preparing compound 19, the basic substance may be a substance that is conventional in the art to be basic (i.e., a substance having a pH of greater than 7); preferably one or more of an inorganic base, an organic base, a basic oxide, a strong base weak acid salt and an ion exchange resin; the inorganic base is preferably sodium methoxide and/or potassium tert-butoxide; the organic base is preferably one or more of tetrabutylammonium hydroxide, 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU, CAS:6674-22-2, english name 1,8-Diazabicyclo [5.4.0] undec-7-ene), tetramethylguanidine (TMG, CAS:80-70-6, english name Tetramethylguanidine) and lithium diisopropylamide (LDA, CAS:4111-54-0, english name Lithium diisopropylamide). The alkaline oxide is preferably alkaline aluminum oxide; the strong base weak acid salt is preferably potassium acetate; the ion exchange resin is preferably Amberlite A-21.

In the process for producing compound 19, the molar ratio of the basic substance to the compound 10 is preferably 1:1 to 1:10, more preferably 1:1 to 1:5.

In the process for preparing compound 19, the temperature of the reaction is preferably from 0℃to 40℃and more preferably from 10℃to 30 ℃.

In the method for preparing compound 19, the progress of the reaction can be monitored by a conventional test method in the art (such as TLC or HPLC), and the reaction time is preferably 1 to 10 hours, more preferably 5 to 8 hours, with the end point of the reaction being generally when compound 20 disappears.

In the method for preparing compound 8 or 19, compound 10 may be synthesized by the method reported in angel. Chem. Int. Ed.,2010,49,4656-4660, the following reaction methods and conditions may also be employed:

the method 1 for preparing the compound 2 further comprises the following steps of carrying out Michael addition reaction on the compound 11 and acetone in the presence of an additive and a catalyst in an organic solvent to obtain the compound 10;

wherein R is ⁴ Is as defined above.

The process for preparing compound 10 may employ conventional methods of this type of Michael addition reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

In the method for producing compound 10, the organic solvent is preferably one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alkane solvent and a halogenated aromatic hydrocarbon solvent; the aromatic solvent is preferably toluene and/or mesitylene; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane and/or carbon tetrachloride; the ether solvent is preferably diethyl ether and/or anisole; the alkane solvent is preferably n-hexane; the halogenated aromatic solvent is preferably chlorobenzene and/or benzotrifluoride.

In the method for producing compound 10, the volume/mass ratio of the organic solvent to the compound 11 is preferably 0.1mL/g to 10mL/g, more preferably 0.1mL/g to 1mL/g.

In the process for preparing compound 10, the additive is preferably an organic acid; the organic acid is preferably one or more of benzoic acid, acetic acid, p-dibenzoic acid, p-hydroxybenzoic acid, p-nitrobenzoic acid, (+) -camphorsulfonic acid and p-toluenesulfonic acid.

In the process for preparing compound 10, the molar ratio of the additive to the compound 11 is preferably from 0.1:1 to 1:1, more preferably from 0.1:1 to 0.5:1.

In the process for preparing compound 10, the molar ratio of acetone to compound 11 is preferably 5:1 to 20:1, more preferably 5:1 to 10:1.

In the method for producing the compound 10, the catalyst is preferably any one of catalysts represented by the following formulas, and more preferably a Jacobsen catalyst;

in the process for preparing compound 10, the molar ratio of the catalyst to the compound 11 is preferably 0.01:1 to 0.1:1, more preferably 0.01:1 to 0.05:1.

In the process for producing compound 10, the temperature of the Michael addition reaction is preferably 0℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 10, the progress of the Michael addition reaction can be monitored by conventional test methods in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1d to 5d, more preferably 3d to 4d, with the disappearance of compound 11 as the reaction end point.

In the method of preparing compound 10, the Jacobsen catalyst may be synthesized by the reported method with reference to j.am.chem.soc.

The process for preparing compound 10 preferably comprises the steps of: and adding a catalyst, an additive and acetone into a solution of the compound 11 and an organic solvent in sequence, and performing Michael addition reaction to obtain the compound 10.

The process 1 for preparing compound 2 further comprises the step of, in the process for preparing compound 19, synthesizing the compound 20 as reported in the reference bioorg.med.chem.,2003,11,827-841. The following reaction methods and conditions are particularly preferred in the present invention: oxidizing compound 21 with an oxidizing agent in an aprotic solvent to obtain compound 20;

wherein R is ² 、R ³ And R is ⁵ The definitions of which are as described above.

The method for preparing compound 20 may employ conventional methods of this type of oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the method for producing the compound 20, the aprotic solvent is preferably an ether solvent and/or a halogenated hydrocarbon solvent; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent, and the chlorinated hydrocarbon solvent is preferably dichloromethane.

In the method for producing the compound 20, the volume/mass ratio of the aprotic solvent to the compound 21 is preferably 1mL/g to 50mL/g, more preferably 10mL/g to 30mL/g.

In the method of preparing compound 20, the oxidizing agent is preferably one or more of dess-martin oxidizing agent (CAS: 87413-09-0, english name 1,1-Triacetoxy-1,1-dihydro-1, 2-benzodox-3 (1H) -one), pyridinium chlorochromate (PCC) and Pyridinium Dichromate (PDC).

In the process for preparing compound 20, the molar ratio of compound 21 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:1 to 1:2.

In the method for producing compound 20, the temperature of the oxidation reaction is preferably 0℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 20, the progress of the oxidation reaction may be monitored by conventional test methods in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 10 hours, more preferably 1 to 3 hours, generally taking the disappearance of the compound 21 as the reaction end point.

The process for preparing compound 20 is preferably carried out in the presence of a base; the alkali is preferably an inorganic alkali; the inorganic base is preferably one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate. The molar ratio of the compound 21 to the base is preferably 1:1 to 1:5, more preferably 1:2 to 1:4.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 20, the compound 21 can be prepared by the following method: condensing compound 22 with ketone in the presence of catalyst to obtain compound 21;

The process for preparing compound 21 may employ conventional methods of this type of condensation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound 21, the catalyst is preferably montmorillonite; the montmorillonite is preferably conventional commercial montmorillonite, and further preferably K-10 montmorillonite.

In the process for preparing compound 21, the mass molar ratio of the catalyst to the compound 22 is preferably 100g/mol to 1000g/mol, more preferably 400g/mol to 600g/mol.

In the process for preparing compound 21, the ketone is preferably acetone, butanone, 2-pentanone or 3-pentanone.

In the method for producing compound 21, the volume/mass ratio of the ketone to the compound 22 is preferably 30mL/g to 100mL/g, more preferably 30mL/g to 50mL/g.

In the method for producing compound 21, the temperature of the condensation reaction is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 21, the progress of the condensation reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 5 to 20 hours, more preferably 8 to 15 hours, generally with the disappearance of compound 22 as the reaction end point.

The process for preparing compound 21 is preferably carried out in the presence of a molecular sieve; the molecular sieve is preferably a conventional commercially available molecular sieve, and more preferablyMolecular sieves.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 21, the compound 22 is preferably prepared by the following method: carrying out reduction reaction on the compound 23 and a reducing agent in an aprotic solvent to obtain the compound 22;

wherein R is ³ Is as defined above.

In the process for preparing compound 22, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 22, the volume/mass ratio of the aprotic solvent to the compound 23 is preferably 1mL/g to 50mL/g, more preferably 1mL/g to 10mL/g.

In the method of preparing compound 22, the reducing agent is preferably one or more of lithium borohydride, sodium borohydride, potassium borohydride, and zinc borohydride.

In the process for preparing compound 22, the molar ratio of the reducing agent to the compound 23 is preferably 1:1 to 5:1, more preferably 1:1 to 3:1.

In the method for producing compound 22, the temperature of the reduction reaction is preferably 0℃to 40℃and more preferably 10℃to 30 ℃.

In the method for preparing compound 22, the progress of the reduction reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1h to 20h, more preferably 10h to 15h, generally taking the disappearance of compound 23 as the reaction end point.

The process for preparing compound 22 preferably employs the following steps: and (3) dropwise adding a solution formed by the compound 23 and the aprotic solvent into a solution formed by the aprotic solvent and the reducing agent, and carrying out reduction reaction to obtain the compound 22.

The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 22, the compound 23 can be prepared by the following steps: in an organic solvent, in the presence of alkali, carrying out reaction of a hydroxyl protecting group on the D- (-) -diethyl tartrate 24 and a hydroxyl protecting reagent to obtain a compound 23;

wherein R is ³ Is as defined above.

The method for preparing compound 23 may employ conventional methods of such nucleophilic substitution reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the method for producing compound 23, the organic solvent is preferably an amide-based solvent; the amide solvent is preferably N, N-dimethylformamide.

In the method for producing compound 23, the volume/mass ratio of the organic solvent to the compound 6 is preferably 1mL/g to 50mL/g, more preferably 1mL/g to 10mL/g.

In the process for preparing compound 23, the base is preferably an inorganic base; the inorganic base is preferably sodium hydride; the sodium hydride is preferably a conventional commercial sodium hydride reagent; the mass percentage of the sodium hydride reagent is preferably 20-95%, and more preferably 50-85%; the mass percentage refers to the mass percentage of sodium hydride in the total mass of the sodium hydride reagent.

In the process for preparing compound 23, the molar ratio of the base to the diethyl D- (-) -tartrate 24 is preferably 1:1.

In the method for producing the compound 23, the hydroxyl-protecting agent is preferably one or more of t-butyldimethylsilyl chloride, trimethylchlorosilane, t-butyldiphenylchlorosilane, triisopropylchlorosilane and chloromethyl methyl ether.

In the method for producing compound 23, the reaction temperature of the upper hydroxyl protecting group is preferably 0℃to 40℃and more preferably 10℃to 30 ℃.

In the method for preparing compound 23, the progress of the reaction of the upper hydroxy protecting group may be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction is usually ended when D- (-) -diethyl tartrate 24 disappears, preferably for 1 to 24 hours, more preferably for 8 to 15 hours.

The process for preparing compound 23 preferably employs the following steps: and (3) dropwise adding a solution formed by the D- (-) -diethyl tartrate 24 and the organic solvent into a solution formed by the sodium hydride and the organic solvent, and dropwise adding a solution formed by a hydroxyl protecting reagent and the organic solvent, so as to carry out nucleophilic substitution reaction to obtain the compound 23.

In the present invention, the compound 11 can be referred to the literature, zhu, s; yu, s.; wang, y; prepared by the method reported in Ma, D.Angew.Chem., int.Ed.2010,49,4656.

The process 2 for preparing the compound 2 may employ conventional methods of such hydrolysis reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention: in an aprotic solvent, carrying out hydrolysis reaction on the compound 35 and alkali to obtain the compound 2;

in the method 2 for producing the compound 2, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the method 2 for producing the compound 2, the volume/mass ratio of the aprotic solvent to the compound 35 is preferably 0.1 to 5mL/mg, more preferably 0.1 to 1mL/mg.

In the method 2 for producing the compound 2, the base is preferably an inorganic base, and the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the sodium hydroxide, potassium hydroxide or lithium hydroxide may be conventional commercial reagents in the art. The inorganic base may participate in the reaction in the form of an aqueous solution thereof, and when the inorganic base participates in the reaction in the form of an aqueous solution thereof, the molar concentration of the inorganic base aqueous solution is preferably 1mol/L to 10mol/L, more preferably 5mol/L to 10mol/L, and the molar ratio concentration means a ratio of the number of moles of the inorganic base to the volume of the inorganic base aqueous solution.

In process 2 for preparing compound 2, the molar ratio of compound 35 to the base is preferably 1:1 to 1:100, more preferably 1:40 to 1:100.

In the method 2 for producing the compound 2, the temperature of the hydrolysis reaction is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.

In method 2 for preparing compound 2, the progress of the hydrolysis reaction can be monitored by conventional test methods in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1h to 20h, more preferably 1h to 5h, generally with the end of the reaction when compound 35 disappears.

The third method for preparing compound 3 may employ a conventional method of this type of hydrolysis reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention: in an aprotic solvent, carrying out hydrolysis reaction on the compound 34 and alkali to obtain the compound 3;

in the third method for preparing the compound 3, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the third method for producing Compound 3, the volume/mass ratio of the aprotic solvent to the compound 34 is preferably 0.1mL/mg to 5mL/mg, more preferably 0.1mL/mg to 1mL/mg.

In the third method for preparing the compound 3, the base is preferably an inorganic base, and the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the sodium hydroxide, potassium hydroxide or lithium hydroxide may be conventional commercial reagents in the art. The inorganic base may participate in the reaction in the form of an aqueous solution thereof, and when the inorganic base participates in the reaction in the form of an aqueous solution thereof, the molar concentration of the inorganic base aqueous solution is preferably 1mol/L to 10mol/L, more preferably 5mol/L to 10mol/L, and the molar ratio concentration means a ratio of the number of moles of the inorganic base to the volume of the inorganic base aqueous solution.

In the third process for preparing compound 3, the molar ratio of compound 34 to the base is preferably 1:1 to 1:100, more preferably 1:40 to 1:100.

In the third method for producing Compound 3, the temperature of the hydrolysis reaction is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the third method for preparing compound 3, the progress of the hydrolysis reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction is usually terminated when compound 34 disappears, preferably for 10 minutes to 20 hours, and more preferably for 30 minutes to 10 hours.

In the present invention, the method 1 for preparing the compound 2 further preferably comprises the steps of: the compound 34 is subjected to hydrolysis reaction with alkali in an aprotic solvent to obtain the compound 3, and then the compound 3 is subjected to deprotection reaction in the presence of acid without post-treatment to obtain the compound 2.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method 2 for preparing the compound 2, the compound 35 can be prepared by the following methods: carrying out a reaction of removing protecting groups on the compound 34 to obtain a compound 35;

therein, R, R ¹ 、R ² 、R ⁴ And R is ⁵ The definitions of which are as described above.

The process for preparing compound 35 may employ conventional methods of such deprotection reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention: in the presence of acid in an aprotic solvent, the compound 34 is subjected to a reaction of removing the protecting group to obtain the compound 35.

In the process for preparing compound 35, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 35, the volume/mass ratio of the aprotic solvent to the compound 34 is preferably 0.1mL/mg to 5mL/mg, more preferably 0.1mL/mg to 1mL/mg.

In the process for preparing compound 35, the acid is preferably an inorganic acid; the mineral acid is preferably hydrochloric acid; the hydrochloric acid can be a conventional commercial hydrochloric acid reagent in the field, preferably 1-10% of hydrochloric acid by mass percent, wherein the mass percent refers to the mass percent of hydrogen chloride in the total mass of the hydrochloric acid reagent.

In the process for preparing compound 35, the molar ratio of compound 34 to the acid is preferably 1:1 to 1:100, more preferably 1:30 to 1:50.

In the method for producing compound 35, the temperature of the reaction for removing the protecting group is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 35, the progress of the deprotection reaction can be monitored by conventional test methods in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 20 hours, more preferably 1 to 8 hours, generally taking the disappearance of compound 34 as the reaction end point.

Process 2 for preparing compound 2 preferably comprises the steps of: the compound 34 is subjected to a reaction of removing a protecting group in an aprotic solvent in the presence of acid, the compound 35 is prepared, and then the compound is subjected to a hydrolysis reaction in the presence of alkali without post-treatment, so that the compound 2 is obtained.

The method 1 or 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 35 or in the method for preparing the compound 3, the compound 34 can be prepared by the following methods: in a solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on the compound 33 and an acetylating reagent to obtain a compound 34;

The method for preparing compound 34 may employ conventional methods of such nucleophilic substitution reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound 34, the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably methylene dichloride. The organic base is preferably one or more of pyridine, diisopropylethylamine, piperidine and triethylamine.

In the process for preparing compound 34, the base is preferably an organic base, and the organic base is preferably one or more of pyridine, diisopropylethylamine, piperidine and triethylamine.

In the process for preparing compound 34, the molar ratio of compound 33 to the base is preferably 1:3 to 1:6, more preferably 1:4 to 1:5.

In the method for preparing the compound 34, the acetylating reagent is an acetylating reagent with acetyl groups commonly used in nucleophilic substitution reaction of the type, preferably acetyl halide and/or acetic anhydride; the acetyl halide is preferably acetyl chloride or acetyl bromide.

In the process for preparing compound 34, the molar ratio of the acetylating reagent to compound 33 is preferably 1:1 to 1:3, more preferably 1:1 to 1:1.1.

In the method for producing compound 34, the temperature of the nucleophilic substitution reaction is preferably 0℃to 100℃and more preferably 0℃to 30 ℃.

In the method for preparing compound 34, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 10min to 2h, more preferably 10min to 1h, generally with the disappearance of compound 33 as the reaction end point.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 34, the compound 33 can be prepared by the following method: subjecting compound 32 to reduction reaction in aprotic solvent under the condition of acid and reducing agent to obtain compound 33;

In the process for preparing compound 33, the aprotic solvent is preferably an ester solvent; the ester solvent is preferably ethyl acetate.

In the method for producing compound 33, the volume/mass ratio of the aprotic solvent to the compound 32 is preferably 20mL/g to 200mL/g, more preferably 90mL/g to 120mL/g.

In the process for preparing compound 33, the acid is preferably an organic acid; the organic acid is preferably glacial acetic acid.

In the process for preparing compound 33, the molar ratio of the acid to the compound 32 is preferably 10:1 to 100:1, more preferably 60:1 to 100:1.

In the method of preparing compound 33, the reducing agent is preferably one or more of zinc, iron and aluminum.

In the process for preparing compound 33, the molar ratio of the reducing agent to the compound 32 is preferably 10:1 to 100:1, more preferably 60:1 to 100:1.

In the method for producing compound 33, the temperature of the reduction reaction is preferably-10℃to 40℃and more preferably 0℃to 30 ℃.

In the method for preparing compound 33, the progress of the reduction reaction may be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 24 hours, more preferably 4 to 10 hours, with the disappearance of compound 32 being the reaction end point.

The process for preparing compound 33 preferably employs the following steps: the compound 32 is added with a reducing agent and an acid in sequence to a solution formed by an aprotic solvent for reduction reaction to obtain the compound 33.

The process for preparing compound 33 preferably comprises the following work-up steps: after the reaction, the mixture was filtered, extracted, concentrated and separated by column chromatography to give compound 33. The filtration is preferably carried out by using diatomaceous earth. The extraction is preferably performed by using an ester solvent, and the ester solvent is preferably ethyl acetate. The column chromatography separation method can be performed by a method conventional in the art for such an operation.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 33, the compound 32 can be prepared by the following steps: in an organic solvent, in the presence of alkali, carrying out dehydration reaction on the compound 31 and a dehydrating agent to obtain a compound 32;

The process for preparing compound 32 may employ conventional methods of such dehydration reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the method for producing the compound 32, the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent and an aromatic hydrocarbon solvent; further preferred are ether solvents and/or halogenated hydrocarbon solvents; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the aromatic solvent is preferably toluene.

In the method for producing the compound 32, the volume/mass ratio of the organic solvent to the compound 31 is preferably 1mL/g to 200mL/g, more preferably 20mL/g to 100mL/g.

In the process for preparing compound 32, the base is preferably an organic base; the organic base is preferably triethylamine and/or pyridine.

In the process for preparing compound 32, the molar ratio of the base to compound 31 is preferably 10:1 to 1:1, more preferably 8:1 to 5:1.

In the method for preparing the compound 32, the dehydrating agent is preferably thionyl chloride and/or methanesulfonyl chloride.

In the method for producing the compound 32, the molar ratio of the compound 31 to the dehydrating agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.

In the method for producing compound 32, the dehydration reaction is preferably carried out at a temperature of-78 to 30℃and more preferably at a temperature of-78 to 0 ℃.

In the method for preparing compound 32, the progress of the dehydration reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 0.1h to 5h, more preferably 0.5h to 2h, generally taking the disappearance of compound 31 as the reaction end point.

The process for preparing compound 32 preferably comprises the steps of: and adding a dehydrating agent into a solution formed by the compound 31, the alkali and the organic solvent, and carrying out dehydration reaction to obtain the compound 32.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 32, the compound 31 can be prepared by the following method: oxidizing the compound 30 in an aprotic solvent in the presence of an oxidant to obtain a compound 31;

The method for preparing compound 31 may employ a conventional method of this type of oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound 31, the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent, and the chlorinated hydrocarbon solvent is preferably dichloromethane.

In the method for producing the compound 31, the volume/mass ratio of the aprotic solvent to the compound 30 is preferably 20mL/g to 300mL/g, more preferably 50mL/g to 150mL/g.

In the process for preparing compound 31, the oxidizing agent is preferably a dessmartin oxidizing agent (CAS: 87413-09-0). The dessmartin oxidizing agent may be a conventional commercial agent in the art.

In the process for preparing compound 31, the molar ratio of compound 30 to the oxidizing agent is preferably 1:1 to 1:3, more preferably 1:1 to 1:2.

In the method for producing compound 31, the temperature of the oxidation reaction is preferably-30℃to 30℃and more preferably-20℃to 30 ℃.

In the method for preparing compound 31, the progress of the hydrolysis reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1h to 10h, more preferably 1h to 5h, generally taking the disappearance of compound 30 as the reaction end point.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 31, the compound 30 can be prepared by the following method: subjecting compound 29 to hydrolysis reaction in the presence of a base in a protic solvent to give said compound 30;

The method for preparing compound 30 may employ conventional methods of this type of hydrolysis reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound 30, the protic solvent is preferably an alcoholic solvent; the alcohol solvent is preferably methanol.

In the method for producing the compound 30, the volume/mass ratio of the protic solvent to the compound 29 is preferably 20mL/g to 300mL/g, more preferably 30mL/g to 100mL/g.

In the process for preparing compound 30, the base is preferably potassium carbonate and/or sodium methoxide, and more preferably sodium methoxide.

In the process for preparing compound 30, the molar ratio of said compound 29 to said base is preferably 3:1 to 1:1, more preferably 2:1 to 1:1.

In the method for producing compound 30, the temperature of the hydrolysis reaction is preferably 0℃to 50℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 30, the progress of the hydrolysis reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction is usually ended when compound 29 disappears, preferably for 1 hour to 1 day, and more preferably for 3 hours to 10 hours.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 30, the compound 29 can be prepared by the following method: reacting compound 28 with compound 9 in the presence of a base, a catalyst and a catalyst ligand in an aprotic solvent to give said compound 29;

The process for preparing compound 29 may employ conventional methods of such reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

In the process for preparing compound 29, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the method for producing compound 29, the volume/mass ratio of the aprotic solvent to the compound 9 is preferably 1mL/g to 50mL/g, more preferably 10mL/g to 30mL/g.

In the process for preparing compound 29, the base is preferably an inorganic base; the inorganic base is preferably cesium carbonate.

In the process for preparing compound 29, the molar ratio of compound 9 to the base is preferably 1:1 to 5:1, more preferably 2:1 to 4:1.

In the process for preparing compound 29, the catalyst is preferably an inorganic copper salt; the inorganic copper salt refers to a salt formed by the reaction of copper and inorganic acid. The inorganic copper salt is preferably one or more of cupric chloride, cuprous bromide, cupric bromide and cuprous iodide, and further preferably cupric bromide.

In the process for preparing compound 29, the molar ratio of compound 28 to the catalyst is preferably 1:1 to 10:1, more preferably 2:1 to 10:1.

In the process for preparing compound 29, the molar ratio of compound 28 to compound 9 is preferably 1:1 to 1:5, more preferably 1:1 to 1:2.

In the process for preparing compound 29, the catalyst ligand is preferably a pyrrolidine-phenol catalyst; the pyrrolidine-phenol catalyst is preferably

In the process for preparing compound 29, the molar ratio of the catalyst ligand to the compound 28 is preferably 1:10 to 3:10, more preferably 1:5 to 3:10.

In the process for preparing compound 29, the temperature of the reaction is preferably-20℃to 40℃and more preferably-20℃to 30 ℃.

In the method for preparing compound 29, the progress of the reaction can be monitored by conventional test methods in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 24 to 96 hours, more preferably 24 to 48 hours, generally at the end of the reaction when compound 28 disappears.

In the process for preparing compound 29, the catalyst ligandCan be synthesized by the method reported in chem. Eur. J.2012,18,12357.

In the preparation of compound 29, compound 9 may be synthesized by the method reported in reference to Tetrahedron, asymmetry 1998,9, 1359-1367.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 29, the compound 28 can be prepared by the following method: in an organic solvent, in the presence of alkali and a catalyst, carrying out a reaction of a hydroxyl protecting group on the compound 27 and a hydroxyl protecting reagent to obtain a compound 28;

Wherein R is ⁴ Is as defined above.

The method for preparing compound 28 may employ conventional methods in the art for the reaction of such hydroxy protecting groups, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound 28, the organic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

In the method for producing compound 28, the volume/mass ratio of the organic solvent to the compound 27 is preferably 1mL/g to 100mL/g, more preferably 10mL/g to 50mL/g.

In the process for preparing compound 28, the base is preferably an organic base; the organic is preferably triethylamine.

In the process for preparing compound 28, the molar ratio of the base to compound 27 is preferably 1:1 to 3:1.

In the process for preparing compound 28, the catalyst is preferably 4-dimethylaminopyridine.

In the process for preparing compound 28, the molar ratio of the catalyst to the compound 27 is preferably from 0.01:1 to 0.5:1, more preferably from 0.05:1 to 0.2:1.

In the method for producing the compound 28, the hydroxyl-protecting agent is preferably acetic anhydride, acetyl chloride, acetyl bromide, trifluoroacetyl chloride, trifluoroacetyl bromide, trimethylchlorosilane, trimethylbromosilane, t-butyldimethylchlorosilane, t-butyldimethylbromosilane, triethylchlorosilane, triethylbromosilane, benzyl chloride or benzyl bromide, and further preferably acetic anhydride.

In the method for producing compound 28, the reaction temperature of the upper hydroxyl protecting group is preferably 0℃to 40℃and more preferably 10℃to 30 ℃.

In the method for preparing compound 28, the progress of the reaction of the upper hydroxy protecting group may be monitored by conventional test methods in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 minute to 1 hour, more preferably 10 minutes to 30 minutes when compound 27 disappears as the reaction end point.

The process for preparing compound 28 preferably employs the following steps: and adding a catalyst into a solution formed by the compound 27 and an organic solvent, dropwise adding alkali and a hydroxyl protecting reagent, and carrying out a reaction of an upper hydroxyl protecting group to obtain the compound 28.

The process for preparing compound 28 further preferably employs the following steps: and adding a catalyst into a solution formed by the compound 27 and an organic solvent, then dropwise adding alkali and a hydroxyl protecting reagent in sequence, and carrying out a reaction of an upper hydroxyl protecting group to obtain the compound 28.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 28, the compound 27 can be prepared by the following method: subjecting compound 26 to reduction reaction with a reducing agent in a protic solvent to obtain said compound 27;

Wherein R is ⁴ Is as defined above.

The method for preparing compound 27 may employ a conventional method of this type of reduction reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound 27, the protic solvent is preferably an alcoholic solvent; the alcohol solvent is preferably methanol.

In the method for producing compound 27, the volume/mass ratio of the protic solvent to the compound 26 is preferably 1mL/g to 100mL/g, more preferably 20mL/g to 40mL/g.

In the process for preparing compound 27, the reducing agent is preferably an alkali metal borohydride, which refers to an alkali metal and BH ₄ ^- Salts formed, preferably sodium borohydride, potassium borohydride and lithium borohydrideThe sodium borohydride, potassium borohydride or lithium borohydride is a conventional commercial reagent.

In the process for preparing compound 27, the molar ratio of the reducing agent to the compound 26 is preferably from 0.4:1 to 10:1, more preferably from 0.4:1 to 1:1.

In the method for producing compound 27, the temperature of the reduction reaction is preferably 0℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 27, the progress of the reduction reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 10 minutes to 1 hour, more preferably 10 minutes to 30 minutes, with the disappearance of the compound 26 being the reaction end point.

The process for preparing compound 27 preferably comprises the steps of: sodium borohydride is added to a solution of the compound 26 and a protic solvent, and a reduction reaction is performed to obtain the compound 27.

The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 27, the compound 26 can be prepared by the following method: in the presence of a catalyst, carrying out Michael addition reaction on the compound 11 and methyl pyruvate to obtain a compound 26;

wherein R is ⁴ Is as defined above.

The method for preparing compound 26 may employ conventional methods of this type of Michael addition reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the method for producing the compound 26, the organic solvent is preferably one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alkane solvent and a halogenated aromatic hydrocarbon solvent; the aromatic solvent is preferably toluene and/or mesitylene; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane and/or trichloromethane; the ether solvent is preferably diethyl ether and/or anisole; the alkane solvent is preferably n-hexane.

In the method for producing compound 26, the volume/mass ratio of the organic solvent to the compound 11 is preferably 1mL/g to 100mL/g, more preferably 1mL/g to 10mL/g.

In the process for preparing compound 26, the molar ratio of methyl pyruvate to compound 11 is preferably 1:1 to 1:10, more preferably 1:3 to 1:10.

In the process for producing compound 26, the catalyst is preferably any one of the catalysts represented by the following formulas, and more preferably a Jacobsen catalyst:

in the process for preparing compound 26, the molar ratio of the catalyst to the compound 11 is preferably from 0.01:1 to 0.2:1, more preferably from 0.03:1 to 0.1:1.

In the process for preparing compound 26, the temperature of the Michael addition reaction is preferably-10℃to 40℃and more preferably 0℃to 30℃and still more preferably 20℃to 30 ℃.

In the method for preparing compound 26, the progress of the Michael addition reaction can be monitored by conventional test methods in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 12 hours to 5 days, more preferably 12 hours to 48 hours, generally at the end of the reaction when the compound methyl pyruvate disappears.

In the method of preparing compound 26, the Jacobsen catalyst may be synthesized by the reported method with reference to j.am.chem.soc.

The process for preparing compound 26 preferably comprises the steps of: the compound 26 is obtained by adding a catalyst and methyl pyruvate in this order to a solution of the compound 11 and an organic solvent, and performing a Michael addition reaction.

Compound 2 described in the present invention is preferably prepared using any one of the following routes:

route one:

route two:

route three:

route four

Compound 20 is preferably prepared using the following route:

compound 10 was prepared using the following route:

in the present invention, compound 1 may also be prepared after compound 2 is prepared, which comprises the steps of: in a solvent, carrying out nucleophilic substitution reaction on the compound 2 and a guanidine reagent to obtain a compound 1;

wherein R is methyl or hydrogen; compound 1 is Zanamivir (Zanamivir) when R is hydrogen; compound 1 is lanamivir (laninavir) when R is methyl.

The preparation of compound 1 can be carried out by the method reported in the literature J.chem.Soc., perkin Trans.I., 1995,1173-1180, or by methods conventional in the art for such nucleophilic substitution reactions, with the following reaction methods and conditions being particularly preferred in the present invention:

In the process for preparing compound 1, the solvent is preferably water.

In the method for producing Compound 1, the volume/mass ratio of the solvent to the Compound 2 is preferably 1mL/g to 100mL/g, more preferably 60mL/g to 90mL/g.

In the method for producing Compound 1, the guanidine reagent is preferably thiourea trioxide, N '-bis (t-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (N, N' -bis (tert-butoxycarbonyl) -1H-pyracle-1-carboxamidine, CAS: 152120-54-2), 1H-pyrazole-1-carboxamidine hydrochloride (1H-pyracle-1-carboximidinehydrochloride, CAS: 4023-02-3) or N, N '-Di-t-butoxycarbonyl thiourea (N, N' -Di-Boc-thiourea, CAS: 145013-05-04)

In the process for preparing compound 1, the molar ratio of compound 2 to guanidine reagent is preferably 1:1 to 1:30, more preferably 1:10 to 1:15.

In the method for producing compound 1, the temperature of the nucleophilic substitution reaction is preferably 10℃to 40℃and more preferably 20℃to 30 ℃.

In the method for preparing compound 1, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 18 to 36 hours, more preferably 30 to 36 hours, generally at the end of the reaction when compound 2 disappears.

The process for preparing compound 1 is preferably carried out in the presence of a base.

When the process for preparing compound 1 is carried out in the presence of a base, the base is preferably an inorganic base; the inorganic base is preferably potassium carbonate and/or sodium carbonate; the molar ratio of the inorganic base to the compound 2 is preferably 1:1 to 3:1, more preferably 1:1 to 2:1.

The process for preparing compound 1 preferably employs the following steps: and (3) adding alkali and guanidine reagent into a solution formed by the compound 2 and the solvent in batches in sequence, and carrying out nucleophilic substitution reaction to obtain the compound 1.

When R is methyl in the compound 1, the compound is the ranamivir, and after the ranamivir is prepared, the octanoate CS-8958 of the ranamivir can be prepared by referring to a method of patent (WO 2008/126943).

The invention also provides a synthesis method of the compound 3, when R is ¹ In the case of Trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), methoxymethyl (MOM) or methyl, said compound 3 may be prepared by the following method one; when R is ¹ In the case of hydrogen, the compound 3 can be prepared by the following method II; when R is ¹ In the case of Trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), methoxymethyl (MOM), methyl or hydrogen, said compound 3 may be prepared by the following method III;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described for the preparation of compound 3.

The invention also provides a synthesis method of the compound 4, which comprises the following steps: in an aprotic solvent, carrying out an oxidation reaction on the compound 5 and an oxidant to obtain a compound 4;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of Compound 4.

The invention also provides a synthesis method of the compound 5, which comprises the following steps: in a solvent, under the existence of alkali, carrying out nucleophilic substitution reaction on the compound 6 and an acetylating reagent to obtain a compound 5;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described for the preparation of Compound 5.

The invention also provides a synthesis method of the compound 6, which comprises the following steps: in an aprotic solvent, under the condition of the action of acid and a reducing agent, carrying out a reduction reaction on the compound 7 to obtain a compound 6;

Wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described for the preparation of Compound 6.

The invention also provides a synthesis method of the compound 7, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out dehydration reaction on the compound 8 and a dehydrating agent to obtain a compound 7;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 7.

The invention also provides a synthesis method of the compound 8, which comprises the following steps: in an aprotic solvent, reacting a compound 10 with a compound 9 in the presence of a base, a catalyst and a catalyst ligand to obtain a compound 8;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described for the preparation of compound 8.

The invention also provides a method for synthesizing the compound 10, which comprises the following steps: in an organic solvent, under the existence of an additive and a catalyst, carrying out Michael addition reaction on the compound 11 and acetone to obtain a compound 10;

wherein R is ⁴ Is as defined above; each reaction condition was as described above for the preparation of compound 10.

The invention also provides a method for synthesizing the compound 12, which comprises the following steps: in an aprotic solvent, under an acidic condition, carrying out an oxidation reaction on the compound 13 and an oxidant to obtain a compound 12;

wherein R is ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 12.

The invention also provides a synthesis method of the compound 13, which comprises the following steps: in an aprotic solvent, carrying out oxidation reaction on the compound 14 and an oxidant to obtain a compound 13;

wherein R is ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 13.

The invention also provides a method for synthesizing the compound 14, which comprises the following steps: oxidizing the compound 15 to obtain a compound 14;

wherein R is ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 14.

The invention also provides a synthesis method of the compound 15, which comprises the following steps: in a solvent, carrying out a reaction of removing hydroxyl protecting groups on the compound 16 and a fluorinating reagent to obtain a compound 15;

wherein R is ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was the same as that of the previous preparation of Compound 15 As described in the method.

The invention also provides a method for synthesizing the compound 16, which comprises the following steps: in a solvent, under the existence of alkali, carrying out nucleophilic substitution reaction on the compound 17 and an acetylating reagent to obtain a compound 16;

wherein R is ² 、R ³ 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 16.

The invention also provides a synthesis method of the compound 17, which comprises the following steps: in an aprotic solvent, under the condition of the action of acid and a reducing agent, carrying out a reduction reaction on the compound 18 to obtain a compound 17;

wherein R is ² 、R ³ 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 17.

The invention also provides a method for synthesizing the compound 18, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out dehydration reaction on the compound 19 and a dehydrating agent to obtain a compound 18;

wherein R is ² 、R ³ 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 18.

The invention also provides a synthesis method of the compound 21, which comprises the following steps: in the presence of a catalyst, performing condensation reaction on the compound 22 and ketone to obtain a compound 21;

Wherein R is ² 、R ³ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 21.

The invention also provides a method for synthesizing the compound 22, which comprises the following steps: in an aprotic solvent, carrying out a reduction reaction on the compound 23 and a reducing agent to obtain a compound 22;

R ³ is as defined above; each reaction condition was as described above for the preparation of compound 22.

The invention also provides a synthesis method of the compound 23, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out reaction of a hydroxyl protecting group on the D- (-) -diethyl tartrate 24 and a hydroxyl protecting reagent to obtain a compound 23;

R ³ is as defined above; each reaction condition was as described above for the preparation of compound 23.

The invention also provides a preparation method of the compound 35, which comprises the following steps: carrying out a reaction of removing protecting groups on the compound 34 to obtain a compound 35;

R、R ¹ 、R ² 、R ⁴ and R is ⁵ Is as defined above; under all reaction conditionsAs described above for the preparation of compound 35.

The invention also provides a process for the preparation of compound 34, comprising the steps of: in a solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on the compound 33 and an acetylating reagent to obtain a compound 34;

Wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 34.

The invention also provides a preparation method of the compound 33, which comprises the following steps: subjecting compound 32 to reduction reaction in aprotic solvent under the condition of acid and reducing agent to obtain compound 33;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 33.

The invention also provides a preparation method of the compound 32, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out dehydration reaction on the compound 31 and a dehydrating agent to obtain a compound 32;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition is as described above for the preparation of compound 32.

The invention also provides a preparation method of the compound 31, which comprises the following steps: oxidizing the compound 30 in an aprotic solvent in the presence of an oxidant to obtain a compound 31;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 31.

The invention also provides a preparation method of the compound 30, which comprises the following steps: subjecting compound 29 to hydrolysis reaction in the presence of a base in a protic solvent to give said compound 30;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition is as described above for the preparation of compound 30.

The invention also provides a process for the preparation of compound 29, comprising the steps of: reacting compound 28 with compound 9 in the presence of a base, a catalyst and a catalyst ligand in an aprotic solvent to give said compound 29;

wherein R is ¹ 、R ² 、R ⁴ And R is ⁵ Is as defined above; each reaction condition was as described above for the preparation of compound 29.

The present invention also provides a process for the preparation of compound 28, comprising the steps of: in an organic solvent, in the presence of alkali and a catalyst, carrying out a reaction of a hydroxyl protecting group on the compound 27 and a hydroxyl protecting reagent to obtain a compound 28;

wherein R is ⁴ Is as defined above; each reaction condition was as described above for the preparation of compound 28.

The invention also provides a preparation method of the compound 27, which comprises the following steps: subjecting compound 26 to reduction reaction with a reducing agent in a protic solvent to obtain said compound 27;

Wherein R is ⁴ T-butoxycarbonyl; each reaction condition was as described above for the preparation of compound 27.

The present invention also provides a process for the preparation of compound 26, comprising the steps of: in the presence of a catalyst, carrying out Michael addition reaction on the compound 11 and methyl pyruvate to obtain a compound 26;

wherein R is ⁴ Is as defined above; each reaction condition is as described above for the preparation of compound 26.

The invention also provides compounds 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35, which have the structural formula shown below:

wherein R is ¹ Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen; r is R ² And R is ⁵ Each independently is methyl, ethyl or propyl; r is R ⁴ Is an amino protecting group; the amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; r is R ³ The hydroxyl protecting group is trimethyl silicon base, tertiary butyl dimethyl silicon base, tertiary butyl diphenyl silicon base, triisopropyl silicon base or methoxymethyl.

Preferably, R ¹ Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl; or R is ³ Is hydrogen, R ² And R is ⁵ Each independently is methyl, R ⁴ Is tert-butyloxycarbonyl.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

In the invention, the room temperature refers to the ambient temperature of-20-40 ℃.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: the synthesis method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, short steps, high total yield, low production cost, good product purity, high chiral purity and good prospect of industrial production.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

"dr" in the present invention is an abbreviation of English diastereoisomer ratio, indicating the ratio of diastereomers; when the product is a pair of diastereomers, the two data before and after "& gt" represent the chemical shift value of hydrogen or carbon at the same position in the two isomers.

EXAMPLE 1 Synthesis of Compound 10

Nitro compound 11 (R) ⁴ Boc) (38.72 g,205.76 mmol) was dissolved in anhydrous toluene (13 mL), and then Jacobsen catalyst (4.01 g,10.27 mmol) benzoic acid (5.02 g,41.11 mmol) was added followed by acetone (152.3 mL,2056 mmol) and reacted at room temperature for 4d. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gives compound 10 (R ⁴ T-butoxycarbonyl) (42.6 g,84% ee). The product was recrystallized from petroleum ether/ethyl acetate=20:1 to give compound 10 (R ⁴ T-butoxycarbonyl) (37.1 g, 73% ee). [ alpha ]] _D ²⁰ ＝+1.83°(c 1.0,CHCl ₃ )； ¹ HNMR(400MHz,CDCl ₃ ):δ5.28(d,J＝5.6Hz,1H),4.72(dd,J＝12.4,5.6Hz,1H),4.55(dd,J＝12.4,5.2Hz,1H),4.48(m,1H),2.17(s,3H),1.41(s,9H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ216.17,154.87,80.47,76.94,45.28,44.08,30.38,28.25；ESI-MS(m/z):269([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₀ H ₁₈ N ₂ NaO ₅ ([M+Na] ⁺ ) 269.11052, experimental values: 269.11079.

nitro compound 11 (R) ⁴ Boc) (170 mg,0.90 mmol) was dissolved in dry toluene (30 uL), jacobsen catalyst (3.5 mg,0.009 mmol) and benzoic acid (1.1 mg,0.009 mmol) were added sequentially, acetone (670 uL,9.034 mmol) was added, and the mixture was reacted at room temperature for 4d. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gives compound 10 (R ⁴ T-butoxycarbonyl) (205 mg, 92% yield, 70% ee). [ alpha ]] _D ²⁰ ＝+0.75°(c 1.0,CHCl ₃ )； ¹ HNMR(400MHz,CDCl ₃ ):δ5.28(d,J＝5.6Hz,1H),4.72(dd,J＝12.4,5.6Hz,1H),4.55(dd,J＝12.4,5.2Hz,1H),4.48(m,1H),2.17(s,3H),1.41(s,9H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ216.17,154.87,80.47,76.94,45.28,44.08,30.38,28.25；ESI-MS(m/z):269([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₀ H ₁₈ N ₂ NaO ₅ ([M+Na] ⁺ ) 269.11052, experimental values: 269.11079.

preparation of compound 10 the reaction conditions are optimized under different catalysts as shown in table 1; preparation of compound 10 under the catalysis of catalyst 12 (cat.12), the reaction conditions are optimized as shown in table 2 under different organic solvent conditions; preparation of compound 10 under the catalysis of catalyst 12 (cat.12), under different additive conditions, the reaction conditions are optimized as shown in table 3; . Cat.1, cat.2 and Cat.3 are commercially available products. Cat.4 can be referred to: j.am.chem.soc.2012,134,20197; the reported methods were synthesized. Cat.5 may be referred to: angel.chem.int.ed.2012, 51,8838; the reported methods were synthesized. Cat.6 can be referred to: chem.commun.2012,48,5193; the reported methods were synthesized. Cat.7 can be referred to: org.lett.2007,9,599; the reported methods were synthesized. Cat.8 can be referred to: am.chem.soc.2006,128,9624; the reported methods were synthesized. Cat.9 can be referred to: eur.J.org.chem.2010,1849; the reported methods were synthesized. Cat.10 may be referred to: tetrahedron. Lett.2010,51,209; the reported methods were synthesized. Cat.11 can be referred to: org.lett.2010,12,1756; the reported methods were synthesized. Cat.12 can be referred to: am.chem.soc.2006,128,7170; synthesizing the reported method; cat.13 may be referred to: adv.synth.catalyst.2012, 354,740; the reported methods were synthesized.

Table 1 compound 10 synthesis catalyst screening

brsm (Based on Recovered Starting Materials) = yield calculated from recovered starting material

Table 2 Compound 10 synthetic organic solvent Screen (Cat.12)

Experiment number

Additive agent

Organic solvents

Temperature (temperature)

Time

Yield (%)

ee(％)

1

Benzoic acid

Benzene

Room temperature

4d

78

83

2

Benzoic acid

Mesitylene

Room temperature

4d

84

3

Benzoic acid

Chlorobenzene (Chlorobenzene)

Room temperature

4d

71

84

4

Benzoic acid

Benzotrifluoride (TFA)

Room temperature

4d

69

84

5

Benzoic acid

Anisole (anisole)

Room temperature

4d

77

84

6

Benzoic acid

N-hexane

Room temperature

4d

81

78

7

Benzoic acid

Diethyl ether

Room temperature

4d

81

82

8

Benzoic acid

Dichloromethane (dichloromethane)

Room temperature

4d

71

83

9

Benzoic acid

Carbon tetrachloride

Room temperature

4d

47

83

Table 3 Compound 10 synthetic additive Screen (Cat.12)

Experiment number

Additive agent

Organic solvents

Temperature (temperature)

Time

Yield (%)

ee(％)

1

Acetic acid

Toluene (toluene)

Room temperature

For 4 days

92

75

2

Para-dibenzoic acid

Toluene (toluene)

Room temperature

For 4 days

84

73

3

Para-hydroxybenzoic acid

Toluene (toluene)

Room temperature

For 4 days

89

79

4

P-nitrobenzoic acid

Toluene (toluene)

Room temperature

For 4 days

87

79

5

(+) -camphorsulfonic acid

Toluene (toluene)

Room temperature

For 4 days

77

84

6

Para-toluene sulfonic acid

Toluene (toluene)

Room temperature

For 4 days

64

84

The structure of the catalyst is as follows:

the structure of the Jacobsen catalyst (cat.12) is shown below:

example 2 Compound 8 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently methyl) synthesis

Compound 9 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently was methyl) (32.00 g,121.82 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) for further use. Weigh compound 10 (R) ⁴ Boc) (90.00 g,365.50 mmol), copper bromide (8.16 g,36.55 mmol), cesium carbonate (18.00 g,54.82 mmol), catalyst ligand(15.60 g,36.55 mmol) was placed in an egg-shaped bottle, anhydrous tetrahydrofuran (1500 mL) was added thereto, and the mixture was stirred at room temperature for 4 hours to give a small amount of a white solid, and then the compound was added at 0℃to give a solution of 9%R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently methyl) tetrahydrofuran solution, continuing to react for 36 hours at 0 ℃, extracting ethyl acetate after quenching reaction of saturated ammonium chloride solution, directly performing column chromatography after solvent spinning, and obtaining a compound 8 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (56.50 g, 80% yield), catalyst ligand +.>(12.10 g, yield 78%) with compound 10 (R) ⁴ T-butoxycarbonyl) (62.50 g, 69% yield). ¹ HNMR(400MHz,CDCl ₃ ):δ4.45～4.80(m,7H),4.17～4.22(m,1H),4.00～4.05(m,2H),3.67(m,1H),3.40(m,3H),2.17～2.23(m,1H),1.75～1.85(m,1H),1.50(m,3H),1.42(m,9H),1.39(m,3H)1.33(m,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ155.23,109.60,98.36,96.26,82.74,81.50,76.82,73.19,67.19,65.36,56.09,48.75,38.30,28.13,27.57,25.97,25.23；ESI-MS(m/z):473.3([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₄ N ₂ NaO ₁₀ ([M+Na] ⁺ ) 473.21057, experimental values: 473.21034.

the condition screening of the types and equivalent of the catalyst synthesized by the compound 8 is shown in tables 4 and 5, and the equivalent screening of the reaction substrate is shown in Table 6.

TABLE 4 screening of Compound 8 Synthesis catalyst species

^a (the ratio of the molar amount of the catalyst to the molar amount of Compound 9 was 0.2)

Table 5 screening of equivalent catalyst for compound 8 synthesis

TABLE 6 screening of equivalent reaction substrate for Synthesis 10 of Compound 8

Example 3 Compound 7 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 8 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (20 g,44.40 mmol) was dissolved in anhydrous dichloromethane (3.0L), pyridine (71.5 mL,888.00 mmol) and thionyl chloride (6.5 mL,88.80 mmol) were added sequentially at 0deg.C, reacted for 2h at 0deg.C, quenched with 18mL of water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=8:1, to give compound 7 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (13.44 g, 70% yield) (dr=8:1). [ alpha ]] _D ²⁰ ＝+27.95°(c0.75,CHCl ₃ )； ¹ H NMR(Pyridine-d ₅ Delta 8.24 (d, j=8.0 hz, 1H), 5.14 (t, j=7.6 hz, 1H), 5.04 (t, j= 9.6,1H), 4.69 (br, 1H), 4.62 (d, j=10.8 hz, 1H), 4.65 (dd, j=6.4, 2.4hz, 2H), 4.58 (d, j=6.4 hz, 1H), 4.51 (d, j=6.4 hz, 1H), 4.43 (s, 1H), 4.26 (q, j= 5.6,1H), 4.02 (dd, j=8.4, 6.0hz, 1H), 3.94 (dd, j=8.4, 6.4hz, 1H), 3.79 (d, j=4.8 hz, 1H), 3.00 (s, 3H), 1.45 (s, 3H), 1.22 (s, 1H), 4.43 (s, 1H), 4.26 (q, j= 5.6,1H), 4.02 (dd, j=8.0 hz, 1H), 3.94 (s, 3H). ¹³ CNMR(100MHz,Pyridine-d ₅ ) Delta 156.85,153.21,109.42,99.08,98.91,85.11,79.64,76.84,76.61,76.39,66.91,56.53,51.20,28.84,27.21,25.84,19.34; ESI-MS (m/z) :455.4([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₂ N ₂ NaO ₉ ([M+Na] ⁺ ) 455.20000, experimental values: 455.20090.

compound 8 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (100 mg,0.22 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), triethylamine (92. Mu.L, 0.66 mmol), DMAP (6 mg,0.04 mmol) and methanesulfonyl chloride (49. Mu.L, 0.22 mmol) were added in this order, and the reaction was continued at room temperature for 8 hours, with additional triethylamine (61. Mu.L, 0.44 mmol), DMAP (4 mg,0.03 mmol) and methanesulfonyl chloride (28. Mu.L, 0.13 mmol) and continued for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=8:1, to give compound 7 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (56 mg, 58% yield).

Compound 8 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (100 mg,0.22 mmol) was dissolved in anhydrous toluene (15 mL), and Burgess reagent (Burgess reagent means methyl N- (triethylammonium sulfonyl) carbamic acid methyl ester, CAS: 29684-56-8) (79 mg,0.33 mmol) was added and reacted at room temperature for 8 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=8:1, to give compound 7 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (41 mg, 43% yield).

Example 4 Compound 6 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 7 (R) ¹ Is methoxymethyl，R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (10 g,23.12 mmol) was dissolved in ethyl acetate (1.10L), and after cooling to 0deg.C, zinc powder (151 g,2312.00 mmol) and glacial acetic acid (133 mL,2312.00 mmol) were added sequentially and the reaction was continued at this temperature overnight. Excess zinc powder was removed by filtration, excess aqueous ammonia was added to the filtrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to give compound 6 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (7.91 g, 85% yield). [ alpha ]] _D ²⁰ ＝-15.58°(c 1.0,CHCl ₃ )； ¹ H NMR(CDCl ₃ ,400MHz):δ4.96(d,J＝6.8Hz,1H),4.74(d,J＝6.8Hz,1H),4.42(br,1H),4.39(s,1H),4.30(br,1H),4.24(m,1H),4.00～4.30(m,3H),3.67(d,J＝10.0Hz,1H),2.85(t,J＝9.6Hz,1H),1.71(s,3H),1.45(s,9H),1.39(s,3H),1.35(s,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ156.45,152.96,108.00,98.77,98.13,80.37,79.67,77.78,75.02,65.40,56.24,51.80,51.04,28.39,26.40,25.43,19.21；ESI-MS(m/z):403.4([M+H] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₅ N ₂ O ₇ ([M+H] ⁺ ) 403.24388, experimental values: 403.24551.

compound 7 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (1 g,2.31 mmol) was dissolved in ethyl acetate (110 mL), and after cooling to 0deg.C iron powder (12.95 g,231.20 mmol) and glacial acetic acid (13.3 mL,231.20 mmol) were added sequentially and the reaction was continued at that temperature overnight. Excess iron powder was removed by filtration, excess aqueous ammonia was added to the filtrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to give compound 6 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (510 mg, 55% yield).

Compound 7 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (1 g,2.31 mmol) in acetic acidTo ethyl ester (110 mL), aluminum powder (6.24 g,231.20 mmol) and glacial acetic acid (13.3 mL,231.20 mmol) were added sequentially after cooling to 0deg.C, and the reaction was continued at that temperature overnight. Excess aluminum powder was removed by filtration, excess ammonia water was added to the filtrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to give compound 6 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (316 mg, 34% yield).

Example 5 Compound 5 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 6 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (10 g,24.85 mmol) was dissolved in dichloromethane (1L), and triethylamine (14.0 mL,99.40 mmol) and acetyl chloride (1.77 mL,25.10 mmol) were added sequentially after cooling to 0deg.C and reacted at 0deg.C for 2h. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, to give compound 5 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (9.94 g, 90% yield). [ alpha ]] _D ²⁰ ＝+11.14°(c 1.1,CHCl ₃ )； ¹ H NMR(CD ₃ CN,400MHz):δ6.40(d,J＝8.4Hz,1H),5.29(d,J＝6.8Hz,1H),4.63～4.68(m,2H),4.45(s,1H),4.18～4.25(m,3H),4.08(dd,J＝8.8,6.0Hz,1H),4.04(dd,J＝8.8,6.0Hz,1H),3.86(t,J＝9.6Hz,1H),3.80(dd,J＝6.0,1.2Hz,1H),3.35(s,3H),1.88(s,3H),1.73(br,3H),1.42(s,9H),1.39(s,3H),1.33(s,3H)； ¹³ C NMR(100MHz,CD ₃ CN):δ170.17,155.64,151.44,107.97,98.17,97.46,78.13,76.13,76.00,75.24,65.79,55.17,49.94,48.19,27.35,25.71,24.21,22.21,18.08；ESI-MS(m/z):467.5([M+Na] ⁺ ),483.6([M+K] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₁ H ₃₆ N ₂ NaO ₈ ([M+Na] ⁺ ) 467.23639, experimental values: 467.23778.

compound 6 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1 g,2.49 mmol) was dissolved in pyridine (120 mL), acetic anhydride (5 mL) was added, and the reaction was allowed to proceed at 60℃for 12h. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gave compound 5 (0.91 g, yield 82%).

Compound 6 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1 g,2.49 mmol) was dissolved in piperidine (120 mL), acetic anhydride (5 mL) was added, and the reaction was allowed to proceed at 60℃for 12h. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gave compound 5 (0.82 g, yield 74%).

Example 6 Compound 4 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 5 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.0 g,2.25 mmol) was dissolved in anhydrous 1, 4-dioxane (300 mL) and selenium dioxide (500 mg,4.50 mmol) was added. Argon is introduced into the solution for 5min to remove oxygen in the solution, and the solution is reacted for 2h at 70 ℃ under the protection of argon. Suction filtration is carried out by a funnel with kieselguhr pad, and the filtrate is concentrated and then is directly subjected to column chromatography, wherein petroleum ether/ethyl acetate=1:1, and the compound 4 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (515 mg, yield 50%). [ alpha ]] _D ²⁰ ＝+54.55°(c 0.9,CHCl ₃ )； ¹ H NMR(400MHz,CDCl ₃ ):δ9.17(s,1H),6.08(d,J＝6.8Hz,1H),5.72(d,J＝2.5Hz,1H),5.14(d,J＝7.2Hz,1H),4.65～4.75(m,3H),4.28～4.38(m,2H),4.07～4.19(m,3H),3.83(d,J＝5.5Hz,1H),3.35(s,3H),1.98(s,3H),1.43(m,9H),1.39(s,3H),1.34(s,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ185.28,170.98,156.00,151.70,118.87,108.82,98.98,80.32,77.08,75.35,66.49,56.24,49.48,48.53,29.67,28.27,26.67,25.16,23.40；ESI-MS(m/z):481.5([M+Na] ⁺ ),513.6([M+MeOH+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₁ H ₃₄ N ₂ NaO ₉ ([M+Na] ⁺ ) 481.21565, experimental values: 481.21434.

compound 5 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.0 g,2.25 mmol) was dissolved in anhydrous 1, 4-dioxane (300 mL) and selenium dioxide (500 mg,4.50 mmol) was added. Argon is introduced into the solution for 5min to remove oxygen in the solution, and the solution is reacted for 2h at 100 ℃ under the protection of argon. Suction filtration is carried out by a funnel with kieselguhr pad, and the filtrate is concentrated and then is directly subjected to column chromatography, wherein petroleum ether/ethyl acetate=1:1, and the compound 4 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (309 mg, 30% yield).

Example 7 Compound 3 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 4 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.0 g,2.18 mmol) was dissolved in t-butanol (120 mL) and water (40 mL), 2-methylbutene (40 mL) and sodium dihydrogen phosphate (2.10 mg,17.44 mmol) were added sequentially, and finally sodium chlorite (789 mg,8.72 mmol) was added. The reaction was carried out at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then chromatographed on a column with dichloromethane/methanol=8:1 to give compound 3 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (827 mg, 80% yield). [ alpha ]] _D ²⁰ ＝+10.12°(c 0.43MeOH)； ¹ H NMR(CD ₃ OD,500MHz):δ5.71(d,J＝2.0Hz,1H),4.73(d,J＝6.5Hz,1H),4.68(d,J＝7.0,1H),4.37～4.46(m,2H),4.29(d,J＝8.4Hz,1H),4.20(dd,J＝6.4,4.8Hz,1H),4.07(dd,J＝7.2,4.8Hz,1H),3.99(t,J＝8.0Hz,1H),3.86(d,J＝5.5Hz,1H),3.38(s,3H),1.97(s,3H),1.44(s,9H),1.40(s,3H),1.34(s,3H)； ¹³ C NMR(125MHz,DMSO-d ₆ ):δ169.91,162.77,156.09,134.05,128.27,108.20,98.21,78.21,76.94,76.07,75.39,65.91,56.12,50.02,47.71,28.65,26.94,25.64,23.31；ESI-MS(m/z):473.4([M-H] ⁺ ) ESI-HRMS (m/z) calculated: c (C) ₂₁ H ₃₃ N ₂ O ₁₀ ([M-H] ⁺ ) 473.21407, experimental values: 473.21467.

EXAMPLE 8 Synthesis of Compound 2 (R is hydrogen)

Compound 3 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (100 mg,0.211 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (10 mL) was added and reacted at room temperature for 8h. After concentration of the system, the trifluoroacetate salt of compound 2 (R is hydrogen) (85 mg, yield 90%). [ alpha ]] _D ²⁰ ＝+20.13°(c 0.01,DMSO)； ¹ H NMR(D ₂ O,500MHz):δ5.85(d,J＝2.5Hz,1H),4.35(d,J＝11.0Hz,1H),4.26(dd,J＝10.5,9.5Hz,1H),4.10(dd,J＝9.5,2.5Hz,1H),3.88(ddd,J＝9.0,5.5,3.0Hz,1H),3.76(dd,J＝12.0,3.0Hz,1H),3.57(dd,J＝12.0,5.5Hz,1H),3.46(dd,J＝9.0,1Hz,1H),3.30(s,1H),1.98(s,1H)； ¹³ C NMR(125MHz,D ₂ O):δ174.55,164.72,146.71,104.12,77.23,75.73,69.52,62.27,60.32,50.44,45.43,22.13；ESI-MS(m/z):289.2([M-H] ⁺ ) ESI-HRMS (m/z) calculated: c (C) ₁₁ H ₁₇ N ₂ O ₇ ([M-H] ⁺ ) 289.10412, experimental values: 289.10520.

example 10 Compound 23 (R) ³ Tertiary butyl dimethylsilyl group)

24g of NaH (24 g,0.4mmol, 60% by mass of sodium hydride is the percentage of the total mass of the sodium hydride reagent) is weighed into a 2L three-necked flask, 600mL of N, N-dimethylformamide (DMF, CAS: 68-12-2) is added, the mixture is cooled to 0 ℃, 82.5g of D- (-) -diethyl tartrate 24 (82.5 g,0.4 mmol) is dissolved in 200mL of N, N-dimethylformamide (DMF, CAS: 68-12-2), and the mixture is slowly added dropwise to the suspension, and the reaction is completed for about half an hour, so that the system becomes clear. TBSCl (t-butyldimethylchlorosilane) (60.3 g,0.4 mmol) was added to the above solution, and the reaction was allowed to stand at room temperature overnight. Adding saturated NH ₄ After quenching the Cl solution, extracting 3 times with ethyl acetate, washing with saturated brine once, drying with anhydrous sodium sulfate, spin-drying the solvent, and column chromatography to give compound 23 (R ³ T-butyldimethylsilyl group) (128.2 g, 80% yield). [ alpha ]] _D ²⁰ ＝-29.17°(c 1.0,CHCl ₃ )； ¹ HNMR(400MHz,CDCl ₃ ):δ4.50(d,J＝1.6Hz,1H),4.45(dd,J＝10.0,1.6Hz,1H),4.00～4.24(m,4H),3.04(d,J＝10.0Hz,1H),1.20(q,J＝6.8Hz,6H),0.77(s,9H),0.01(s,3H),-1.0(s,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ171.30,170.36,73.59,73.16,61.77,61.34,25.41,18.08,14.05,13.96，-4.84，-5.92；ESI-MS(m/z):343([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₄ H ₂₈ NaO ₆ Si([M+Na] ⁺ ) 343.1546, experimental values: 343.15474.

example 11 Compound 22 (R) ³ Tertiary butyl dimethylsilyl group)

Weighing LiBH ₄ (13.72 g,0.63 mmol) in a three-necked flask, 630mL of anhydrous tetrahydrofuran was added, and the mixture was cooled to 0℃to obtain Compound 23 (R ³ Is tert-butyl dimethylsilyl group) (96.13 g,0.3 mmol) was dissolved in 200mL, and the solution was slowly added thereto, and the reaction was allowed to stand at room temperature overnight after the addition. Adding saturated NH ₄ After quenching in Cl solution, extraction with ethyl acetate was performed 3 times, saturated brine was washed once, and dried over anhydrous sodium sulfate. Spin-drying solvent followed by column chromatography with dichloromethane/methanol=15:1 to give compound 22 (R ³ T-butyldimethylsilyl group) (63.8 g, 90% yield). [ alpha ]] _D ²⁰ ＝-3.68°(c 1.0,CHCl ₃ )； ¹ HNMR(400MHz,CD ₃ CN):δ3.62(m,1H),3.44～3.50(m,2H),3.38～3.41(m,3H),2.77(t,J＝6.0Hz,1H),2.73(t,J＝5.6Hz,1H),2.68(d,J＝6.8Hz,1H),0.81(s,9H),0.01(s,3H),0.00(s,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ72.21,72.10,63.33,62.49,25.73,17.93,-4.62,-5.02.ESI-MS(m/z):259([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₀ H ₂₄ NaO ₄ Si([M+Na] ⁺ ) 259.13361, experimental values: 259.13304.

example 12 Compound 21 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently methyl) synthesis

Weigh compound 22 (R) ³ Is tert-butyl dimethylsilyl group) (31 g,0.131 mol) in an egg-shaped bottle, 78.6g of montmorillonite K-10, 31g are added in sequenceThe molecular sieve was reacted with 1500mL of acetone overnight at room temperature. Filtering with a layer of diatomite, washing the residue with ethyl acetate for 2 times, and spin-drying the solvent to obtain crude compound 21 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Methyl groups each independently) (36 g, 100% yield). [ alpha ]] _D ²⁰ ＝+13.65°(c 1.0,CHCl ₃ )； ¹ HNMR(400MHz,CDCl ₃ ):δ4.19(q,J＝6.8Hz,1H),3.98(dd,J＝8.0,6.8Hz,1H),3.83(dd,J＝8.4,6.8Hz,1H),3.81(t,J＝5.6Hz,1H),3.63～3.67(m,1H),3.50～3.56(m,1H),2.18(t,J＝6.4Hz,1H),1.42(s,3H),1.34(s,3H),0.89(s,9H),0.10(s,6H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ109.17,77.12,72.85,65.30,63.64,26.28,25.81,25.11,18.09,-4.68,-4.78.ESI-MS(m/z):299([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₃ H ₂₈ NaO ₄ Si([M+Na] ⁺ ) 299.16491, experimental values: 299.16474.

example 13 Compound 20 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently methyl) synthesis

Weigh compound 21 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently methyl) (45 g,0.163 mmol) was placed in an egg-shaped bottle, 800mL of anhydrous tetrahydrofuran was added, then cooled to 0 ℃, sodium bicarbonate (49.3 g,0.587 mmol) was added, dess-martin oxidant (CAS: 87413-09-0, english name 1,1-Triacetoxy-1,1-dihydro-1, 2-benzodoxol-3 (1H) -one) (82.96 g,0.196 mmol) was added, naturally warmed to room temperature after the reaction was completed for about 2 hours, the TLC plate was tracked to the end of the reaction, the pad silica gel was suction filtered and the residue was washed with dichloromethane, concentrated and then directly chromatographed, petroleum ether/ethyl acetate=20:1 to give compound 20 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Methyl groups each independently) (41.15 g, 92% yield). [ alpha ]] _D ²⁰ ＝-22.59°(c 1.0,CHCl ₃ )； ¹ HNMR(400MHz,CDCl ₃ ):δ9.68(d,J＝1.2Hz,1H),4.31(m,1H),4.06(dd,J＝8.4,6.8Hz,1H),4.04(dd,J＝4.8,1.2Hz,1H),3.93(dd,J＝8.4,6.0Hz,1H),1.41(s,3H),1.33(s,3H),0.91(s,9H),0.10(s,3H),0.08(s,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ201.88,109.42,77.45,76.11,64.79,25.72,25.38,24.81,17.93,-5.06,-5.40.ESI-MS(m/z):297([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₃ H ₂₆ NaO ₄ Si([M+Na] ⁺ ) 297.14926, experimental values: 297.1500.

weigh compound 21 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently methyl) (45 g,0.163 mmol) was placed in an egg-shaped bottle, 800mL of anhydrous dichloromethane was added, then cooled to 0 ℃, sodium bicarbonate (49.3 g,0.587 mmol) was added, dess-martin oxidant (CAS: 87413-09-0, english name 1,1-Triacetoxy-1,1-dihydro-1, 2-benzodoxol-3 (1H) -one) (82.96 g,0.196 mmol) was added, after the addition was naturally warmed to room temperature, after about 2 hours of reaction, the TLC plate was tracked to the end of the reaction, the pad was suction filtered with silica gel and the residue was washed with dichloromethane, concentrated and then directly chromatographed, petroleum ether/ethyl acetate=20:1 to give compound 20 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Methyl groups each independently) (42.94 g, 96% yield).

Example 15 Compound 19 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 10 (R) ⁴ Boc) (17.93 g,72.9 mmol) was dissolved in anhydrous tetrahydrofuran (600 mL), and sodium methoxide (790 mg,14.6 mmol) was added thereto and the mixture was stirred at room temperature for 30min. Adding 20 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently was methyl) (20.01 g,72.9 mmol) in 300mL of tetrahydrofuran was reacted at room temperature for 8 hours. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, recovery of starting material 10 (R ⁴ t-Butoxycarbonyl) (3.5 g, yield 19%) to give compound 19 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (29.3 g), and the yield (brsm: based on Recovered Starting Materials) after recovering the raw material was 96%. ¹ HNMR(400MHz,CDCl ₃ ):δ5.12(m,1H),4.83(m,1H),4.27(m,1H),4.08(m,1H),4.00(m,1H),3.93(m,1H),3.72(m,1H),3.61(m,1H),2.73～2.89(m,1H),1.85～2.05(m,1H),1.30～1.44(m,18H),0.87(m,9H),0.08(m,6H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ154.91,109.14,95.75,84.63,81.68,80.24,73.92,71.40,65.81,48.84,40.50,28.71,26.60,26.23,25.20,18.31,-4.63；ESI-MS(m/z):543([M+Na] ⁺ ),559([M+K] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₃ H ₄₄ N ₂ NaO ₉ Si([M+Na] ⁺ ) 534.2719, experimental values: 534.27083.

example 15 was repeated, except that sodium methoxide was replaced with the following base, compound 19 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ For t-butoxycarbonyl) is shown in Table 7.

TABLE 7 Synthesis of Compound 19 in the Presence of different bases

Example 16 Compound 18 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 19 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (130 mg,0.25 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), triethylamine (174. Mu.L, 0.75 mmol), 4-Dimethylaminopyridine (DMAP) (7 mg,0.05 mmol) and methanesulfonyl chloride (56. Mu.L, 0.25 mmol) were added sequentially, and the reaction was continued at room temperature for 8 hours, with additional triethylamine (90. Mu.L, 0.63 mmol), 4-Dimethylaminopyridine (DMAP) (4 mg,0.03 mmol) and methanesulfonyl chloride (28. Mu.L, 0.13 mmol) and continued for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=8:1, to give compound 18 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (89 mg, receivedRate 71%). [ alpha ]] _D ²⁰ ＝+9.13°(c 1.0,CHCl ₃ )； ¹ H NMR(CDCl ₃ ,400MHz):δ4.89(br,1H),4.35(m,2H),4.56～4.70(m,2H),4.50(s,1H),4.20(d,J＝7.2Hz,1H),4.03(dd,J＝8.0,6.8Hz,1H),3.95(dd,J＝8.4,5.2Hz,1H),4.50(s,1H),3.81(m,3H),3.66(t,J＝8.0Hz,1H),1.76(s,3H),1.42(s,9H),1.40(s,3H),1.30(s,3H),0.90(s,9H),0.12(s,3H),0.08(s,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ154.89,152.88,109.41,96.64,83.12,80.48,77.23,65.83,49.28,26.20,26.63,25.88,25.23,19.15,18.35,-4.51,-4.80；ESI-MS(m/z):503([M+H] ⁺ ),525([M+Na] ⁺ ),541([M+K] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₃ H ₄₂ N ₂ NaO ₈ Si([M+Na] ⁺ ) 525.2619, experimental values: 525.26027.

compound 19 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (28.6 g,54.9 mmol) was dissolved in anhydrous dichloromethane (1.1L), cooled to 0deg.C, pyridine (221 mL,2746.4 mmol) was added and stirred for 30min. Thionyl chloride (20 mL,274.6 mmol) was added at this temperature and the reaction was allowed to proceed naturally to room temperature for 2h. The reaction was quenched with small amounts of sodium hydroxide solids and filtered through celite. After concentration, column chromatography, petroleum ether/ethyl acetate=10:1, gives compound 18 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (22.4 g, 81% yield).

Compound 19 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (130 mg,0.25 mmol) was dissolved in anhydrous toluene (15 mL), and Burgess reagent (Burgess reagent means methyl N- (triethylammonium sulfonyl) carbamic acid methyl ester, CAS: 29684-56-8) (91 mg,0.38 mmol) was added and reacted at room temperature for 8 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=8:1, to give compound 18 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently of the otherIs methyl, R ⁴ T-butoxycarbonyl) (53 mg, 43% yield).

EXAMPLE 17 Compound 17 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 18 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.22 g,2.43 mmol) was dissolved in dichloromethane (50 mL) and zinc powder (6.35 g,97.10 mmol) was added sequentially to react with glacial acetic acid (5.55 mL,97.10 mmol) at room temperature for 18h. Excess zinc powder was removed by filtration, the filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=2:1 to give compound 17 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (1.00 g, 87% yield). [ alpha ]] _D ²⁰ ＝+11.96°(c 1.0,CHCl ₃ )； ¹ H NMR(CDCl ₃ ,400MHz):δ4.50(d,J＝7.6Hz,1H),4.35(m,2H),4.07(m,2H),3.94(d,J＝8.0Hz,1H),3.65(t,J＝8.0Hz,1H),3.40(d,J＝8.4Hz,1H),2.93(t,J＝8.8Hz,1H),1.68(s,3H),1.45(s,9H),1.40(s,3H),1.33(s,3H),0.91(s,9H),0.12(s,3H),0.09(s,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ156.41,152.60,109.05,97.39,81.21,79.49,78.24,77.93,66.21,51.39,28.36,26.67,25.92,25.50,19.25,18.36,-4.55,-4.74；ESI-MS(m/z):473([M+H] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₃ H ₄₅ N ₂ O ₆ Si([M+H] ⁺ ) 473.3056, experimental values: 473.30414.

compound 18 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.22 g,2.43 mmol) was dissolved in dichloromethane (50 mL) and zinc powder (159.8m g,2.43mmol) was added to the solution in sequence, followed by glacial acetic acid (148 uL,2.43 mmol) and reacted at room temperature for 24h. Filtering to remove excessive zinc powder, concentrating the filtrate, performing column chromatography, and petroleum ether/ethyl acetate Ethyl acetate=2:1 to give compound 17 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (0.52 g, 45% yield).

Compound 18 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (1.22 g,2.43 mmol) was dissolved in dichloromethane (50 mL), and iron powder (117.2m g,2.09mmol) and glacial acetic acid (148 uL,2.43 mmol) were added sequentially and reacted at room temperature for 24h. Excess iron powder was removed by filtration, the filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=2:1 to give compound 17 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (0.64 g, 55% yield).

Compound 18 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.22 g,2.43 mmol) was dissolved in dichloromethane (50 mL), followed by addition of aluminum powder (27.2 mg,1.01 mmol) and glacial acetic acid (148 uL,2.43 mmol) and reaction at room temperature for 24h. Excess iron powder was removed by filtration, the filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=2:1 to give compound 17 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (0.64 g, 55% yield).

Example 18 Compound 16 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 17 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.24 g,2.62 mmol) was dissolved in pyridine (120 mL), acetic anhydride (5 mL) was added, and the temperature was raised to 60℃for reaction for 12h. Direct column chromatography after solvent spinning is completed, petroleum ether/ethyl acetate=4:1, and compound 1 is obtained6(R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (1.20 g, 89% yield) [ α ]] _D ²⁰ ＝+4.4°(c 1.0,CHCl ₃ )； ¹ H NMR(CDCl ₃ ,400MHz):δ6.06(d,J＝7.6Hz,1H),5.35(d,J＝8.0Hz,1H),4.47(d,J＝1.6Hz,1H),4.04～4.21(m,3H),3.91～3.99(m,3H),3.72(t,J＝8.0Hz,1H),1.96(s,3H),1.73(s,3H),1.42(s,12H),1.36(s,3H),0.90(s,9H),0.10(s,3H),0.09(s,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ170.45,156.24,152.34,108.85,96.62,79.76,79.42,78.03,75.16,65.86,49.43,49.14,28.34,26.69,25.97,25.80,23.38,19.43,18.30,-4.479；ESI-MS(m/z):537([M+Na] ⁺ ),553([M+K] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₅ H ₄₆ N ₂ NaO ₇ Si([M+Na] ⁺ ) 537.2976, experimental values: 537.29665.

compound 17 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.24 g,2.62 mmol) was dissolved in pyridine (120 mL), acetic anhydride (5 mL) was added and reacted at 25℃for 12h. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gives compound 16 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (0.43 g, 32% yield).

Compound 17 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.24 g,2.62 mmol) was dissolved in piperidine (120 mL), acetic anhydride (5 mL) was added, and the mixture was heated to 60℃and reacted for 12h. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gives compound 16 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (0.74 g, 74% yield).

Compound 17 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.24 g,2.62 mmol) was dissolved in dichloromethane (120 mL) and addedTriethylamine (1.82 mL,13.10 mmol) and acetyl chloride (0.28 mL,3.92 mmol) were added and the temperature was raised to 25℃for 12h. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gives compound 16 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (0.84 g, 64% yield).

Example 19 Compound 15 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 16 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.20 g,2.33 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and a tetrahydrofuran solution (3.5 mL) of tetrabutylammonium fluoride (1M/L) was added to the solution, followed by reaction at room temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain compound 15 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (813 mg, yield 87%). [ alpha ]] _D ²⁰ ＝+15.96°(c 1.0,CHCl ₃ )； ¹ H NMR(CD ₃ OD,400MHz):δ6.32(br,1H),5.08(br,1H),4.49(s,1H),4.00～4.21(m,3H),3.82(m,1H),3.75(t,J＝8.0Hz,1H),3.68(m,1H),3.46(br,1H),1.94(s,3H),1.70(s,3H),1.38(s,12H),1.33(s,3H)； ¹³ CNMR(100MHz,CD ₃ OD):δ173.43,158.06,153.18,110.18,98.10,80.23,79.41,77.76,72.20,67.41,50.64,28.84,26.77,26.00,22.92,19.80；ESI-MS(m/z):423([M+Na] ⁺ ),439([M+K] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₂ N ₂ NaO ₇ ([M+Na] ⁺ ) 423.2106, experimental values: 423.21017.

compound 16 (R) ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1.20 g,2.33 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and potassium fluoride (1.35 g,2.66 mmol) was added and reacted at room temperature for 12h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain compound 15 (R ³ Is tert-butyldimethylsilyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (387 mg, 41% yield).

Example 20 Compound 14 (R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 15 (R) ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (400 mg,1.00 mmol) was dissolved in dry dichloromethane (60 mL) and acetonitrile (6 mL) and addedMolecular sieves (200 mg) and N-methylmorpholine oxide (203 mg,1.50 mmol) were stirred for 3min, and tetra-N-propyl ammonium perruthenate (TPAP) (35 mg,0.10 mmol) was added and reacted at room temperature for 12h. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=1:1, to give compound 14 (R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (238 mg, 64% yield). [ alpha ]] _D ²⁰ ＝-11.84°(c 1.0,CHCl ₃ )； ¹ H NMR(CDCl ₃ ,400MHz):δ5.92(d,J＝6.4Hz,1H),4.79(t,J＝6.8Hz,1H),4.67(d,J＝4.8Hz,1H),4.99(d,J＝3.2Hz,1H),4.45(br,2H),4.28(t,J＝8.4Hz,1H),4.28(t,J＝8.4Hz,1H),4.08(dd,J＝8.4,6.8Hz,1H),4.05(br,1H),1.94(s,3H),1.84(s,3H),1.49(s,3H),1.39(s,12H),1.38(s,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ202.86,170.23,155.58,153.60,112.13,95.29,80.19,78.32,66.17,49.59,47.10,29.67,28.25,25.62,25.22,23.10,19.62；ESI-MS(m/z):399([M+H] ⁺ ),421([M+Na] ⁺ ),437([M+K] ⁺ ) ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₀ N ₂ NaO ₇ ([M+Na] ⁺ ) 421.1962, experimental values: 421.19452.

compound 15 (R) ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (400 mg,1.00 mmol) was dissolved in anhydrous dichloromethane (60 mL), dess-Martin oxidant (CAS: 87413-09-0, english name 1,1-Triacetoxy-1,1-dihydro-1, 2-benzodoxol-3 (1H) -one) (636 mg,1.5 mmol) was added, and stirred at room temperature for 3H. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=1:1, to give compound 14 (R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (130 mg, 35% yield).

Example 21 Compound 13 (R) ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 14 (R) ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (160 mg,0.40 mmol) was dissolved in anhydrous 1, 4-dioxane (30 mL) and selenium dioxide (90 mg,0.80 mmol) was added. Argon is introduced into the solution for 5min to remove oxygen in the solution, and the solution is reacted for 4h at 130 ℃ under the protection of argon. Direct column chromatography after system concentration, petroleum ether/ethyl acetate=1:1, gives compound 13 (R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (74 mg, 45% yield). [ alpha ]] _D ²⁰ ＝+32.93°(c 1.0,CHCl ₃ )； ¹ H NMR(CDCl ₃ ,400MHz):δ9.24(d,J＝7.6Hz,1H),6.10(d,J＝8.4Hz,1H),5.82(d,J＝4.0Hz,1H),4.79～4.94(m,3H),4.63(m,1H),4.43(br,1H),4.27(t,J＝8.4Hz,1H),4.07(dd,J＝8.4,6.4Hz,1H),1.96(s,3H),1.49(s,3H),1.42(s,9H),1.38(s,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ203.01,185.39,170.51,155.50,151.34,118.43,111.28,80.60,79.42,78.58,65.93,48.84,47.33,28.24,25.62,24.99,22.96；ESI-MS(m/z):413([M+H] ⁺ ),435([M+Na] ⁺ ),467([M+MeOH+Na] ⁺ ),483([M+MeOH+K] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₂₈ N ₂ NaO ₈ ([M+Na] ⁺ ) 435.1738, experimental values: 435.1754.

compound 14 (R) ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (160 mg,0.40 mmol) was dissolved in anhydrous 1, 4-dioxane (30 mL) and selenium dioxide (90 mg,0.80 mmol) was added. Argon is introduced into the solution for 5min to remove oxygen in the solution, and the solution is reacted for 4h at 100 ℃ under the protection of argon. Direct column chromatography after system concentration, petroleum ether/ethyl acetate=1:1, gives compound 13 (R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (102 mg, 62% yield).

Example 22 Compound 12 (R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 13 (R) ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (74 mg,0.18 mmol) was dissolved in t-butanol (15 mL) and water (5 mL), 2-methylbutene (0.3 mL) and sodium dihydrogen phosphate (223 mg,1.43 mmol) were added sequentially, and finally sodium chlorite (65 mg,0.72 mmol) was added. The reaction was carried out at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=1:1, to give compound 12 (R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (48 mg, 63% yield). [ alpha ]] _D ²⁰ ＝+24.52°(c 1.0,Acetone)； ¹ H NMR(Acetone-d ₆ ,400MHz):δ7.18(d,J＝7.6Hz,1H),5.75(br,1H),4.78(dd,J＝7.6,6.8Hz,1H),4.76(d,J＝7.6Hz,1H),4.35(q,J＝7.2Hz,1H),4.23(m,1H),4.18(t,J＝8.4Hz,1H),3.99(dd,J＝8.4,6.4Hz,1H),1.76(s,3H),1.29(s,12H),1.22(s,3H)； ¹³ CNMR(Acetone-d ₆ ,100MHz):δ201.72,169.06,161.70,154.92,143.77,110.01,109.05,79.30,78.27,77.56,65.27,47.75,46.80,27.13,24.60,24.29,21.52；ESI-MS(m/z):427([M-H] ^- ) ESI-HRMS (m/z) calculated: c (C) ₁₉ H ₂₈ N ₂ NaO ₉ ([M+Na] ⁺ ) 451.1687, experimental values: 451.1670. example 23 Compound 3 (R ¹ Is hydrogen, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 12 (R) ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (12 mg,0.028 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and a tetrahydrofuran (0.5M) solution (100 uL) of zinc borohydride was added thereto to react at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain compound 3 (R ¹ Is hydrogen, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (9 mg, 75%).

Compound 12 (R) ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (12 mg,0.028 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), placed in a cold bath at-78deg.C, and a solution of lithium aluminum hydride (0.21 mmol) in tetrahydrofuran was slowly added dropwise thereto, followed by further reaction at this temperature for 1h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed (dichloromethane/methanol/water=100:20:1) to give compound 3 (R ¹ Is hydrogen, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (9.6 mg, 80% yield).

[α] _D ²⁰ ＝+22.56°(c 0.03,CHCl ₃ )； ¹ H NMR(CD ₃ OD,400MHz):δ5.58(s,1H),4.32(d,J＝10.0Hz,1H),4.24(m,1H),4.01～4.05(m,2H),3.86～3.94(m,2H),3.44(d,J＝8.4Hz,1H),1.87(s,3H),1.33(s,9H),1.26(s,3H),1.22(s,3H)； ¹³ CNMR(100MHz,CD ₃ OD):δ174.14,169.50,157.74,148.50,110.52,106.26,81.15,75.72,74.18,69.17,66.64,49.11,48.32,27.56,25.88,24.20,22.03；ESI-MS(m/z):429([M-H] ⁺ ) ESI-HRMS (m/z) calculated: c (C) ₁₉ H ₃₀ N ₂ NaO ₉ ([M+Na] ⁺ ) 453.1844, experimental values: 453.1843.

synthesis of Compound 3 under different reducing agent conditions

Example 23 was repeated except that the following reducing agents were used in place of zinc borohydride, and the experimental results are shown in table 8 below:

TABLE 8 Synthesis of Compound 3 under different reducing agent conditions

Reducing agent	NaBH ₄	KBH ₄	LiBH ₄	Mg(BH ₄ ) ₂
					Time	4h	4h	4h	4h
Yield (%)	52	45	32	63

EXAMPLE 24 Synthesis of Compound 2 (R is hydrogen)

Compound 3 (R) ¹ Is hydrogen, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (9 mg, 0.0070 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.1 mL) was added thereto and reacted at room temperature for 8h. Water (10 uL) was added thereto, and the mixture was reacted at room temperature for 1 hour. After concentration of the system, the trifluoroacetate salt of compound 2 (R is hydrogen) (10 mg, yield 90%). [ alpha ]] _D ²⁰ = +20.13 ° (c 0.01, DMSO). Adding a heavy aqueous solution of sodium hydroxide to adjust the pH to be alkalescent to obtain a compound 2 (R is hydrogen). ¹ H NMR(D ₂ O,400MHz):δ5.71(d,J＝2.4Hz,1H),4.38(m,2H),4.20(d,J＝8.0Hz,1H),3.99(ddd,J＝9.6,6.0,2.4Hz,1H),3.93(dd,J＝12.0,2.4Hz,1H),3.71(d,J＝9.6Hz,1H),3.69(dd,J＝11.6,6.0Hz,1H),2.12(s,3H)； ¹³ CNMR(100MHz,D ₂ O):δ174.9,168.8,150.2,101.8,75.2,69.8,68.0,62.2,50.1,46.8,22.2；ESI-MS(m/z):291([M+H] ⁺ ),313([M+Na] ⁺ ),329([M+K] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₁ H ₁₈ N ₂ NaO ₇ ([M+Na] ⁺ ) 313.1006, experimental values: 313.1012.

EXAMPLE 25 Synthesis of Zanaamivir

Compound 2 (R is hydrogen) (19 mg,0.056 mmol) is dissolved in water (1.5 mL) and potassium carbonate (4.5 mg,0.056 mmol) and thiourea trioxide (4.1 mg,0.056 mmol) are added sequentially every 0.5h for a total of 12 times. Room temperature The reaction was carried out for 36h. After concentration and filtration, the filtrate was separated by HPLC to give the product (10 mg, yield 50%). ¹ H NMR(D ₂ O,500MHz):δ5.65(d,J＝2.5Hz,1H),4.47(dd,J＝9.5,2.5Hz,1H),4.40(dd,J＝10,1.5Hz,1H),4.25(t,J＝10.0Hz,1H),3.97(ddd,J＝9.5,6.5,3.0Hz,1H),3.91(dd,J＝11.5,2.5Hz,1H),3.70(dd,J＝9.0Hz,1H),3.67(dd,J＝12.0,6.5Hz,1H),2.06(s,3H)；ESI-MS(m/z):333.3([M+H] ⁺ ) Calculated values: c (C) ₁₂ H ₂₁ N ₄ NaO ₇ ([M+Na] ⁺ ) 333.14048, experimental values: 333.14077.

example 26 Compound 8 (R) ¹ Methyl) synthesis

Compound 9 (R) ¹ Is methyl, R ² And R is ⁵ Each independently was methyl) (7.00 g,40.19 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) for further use. Weigh compound 10 (R) ⁴ Boc) (49.20 g,199.79 mmol), copper bromide (2.68 g,12.00 mmol), cesium carbonate (5.86 g,12.00 mmol), catalyst ligand(5.13 g,12.00 mmol) was placed in an egg-shaped bottle, anhydrous tetrahydrofuran (500 mL) was added thereto, and the mixture was stirred at room temperature for 4 hours to give a small amount of a white solid, and then Compound 10 (R) was added at 0 ℃ ⁴ T-butoxycarbonyl) tetrahydrofuran solution, continuing the reaction at 0 ℃ for 36 hours, quenching the saturated ammonium chloride solution, extracting with ethyl acetate, and performing direct column chromatography after the solvent is spun, wherein petroleum ether/ethyl acetate=4:1 to obtain a compound 8 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Is t-butoxycarbonyl) (14.12 g, 78%), the catalyst ligand +.>(4.10 g, 80%) and compound 10 (R) ⁴ T-butoxycarbonyl) (41.50 g, 84% yield). ¹ HNMR(400MHz,CDCl ₃ ):δ4.55～4.80(m,4H),3.94～4.18(m,4H),3.41～3.55(m,3H),3.37(br,1H),2.65～2.80(m,1H),2.17～2.24(m,1H),1.48(m,3H),1.35～1.46(m,12H),1.33(m,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ155.04,108.16,96.03,86.00,80.23,78.29,77.09,70.70,65.14,61.75,48.17,40.33,28.53,28.07,26.36,25.20；ESI-MS(m/z):443.4([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₈ H ₃₂ N ₂ NaO ₉ ([M+Na] ⁺ ) 443.2000, experimental values: 443.19987.

The catalyst type screening in the synthesis of the compound 8 is shown in table 9, and the catalyst equivalent screening is shown in table 10; the equivalent screening of compound 10 is shown in table 11.

TABLE 9 screening of Compound 8 Synthesis catalyst species

(the molar percentage of the catalyst was 20%)

Table 10 screening of compound 8 synthesis catalyst equivalent

Table 11 screening of equivalent of compound 10 in the synthesis of compound 8

Example 27 Compound 7 (R) ¹ Methyl) synthesis

Compound 8 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (11.57 g,27.53 mmol) was dissolved in anhydrous dichloromethane (1.5L), pyridine (110.82 mL,1376.50 mmol) and thionyl chloride (10 mL,137.65 mmol) were added sequentially at 0deg.C, reacted for 2h at 0deg.C, quenched with 15mL of water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=8:1, to give compound 7 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (8.36 g, 76% yield) (d: r=8: 1). [ alpha ]] _D ²⁰ ＝+31.20°(c 0.2,CHCl ₃ )； ¹ H NMR(Pyridine-d ₅ ,400MHz):δ8.52(d,J＝8.4Hz,1H),5.45(dd,J＝9.6,8.0Hz,1H),5.31(t,J＝9.6,1H),4.75(d,J＝10.0Hz,1H),4.70(s,1H),4.48(m,1H),4.20(dd,J＝6.4,2.4Hz,1H),3.74(d,J＝3.6,1H),3.50(s,3H),1.69(s,3H),1.50(s,9H),1.48(s,3H),1.41(s,3H)； ¹³ CNMR(100MHz,Pyridine-d ₅ ):δ156.85,153.24,109.04,98.89,85.74,79.66,79.08,77.23,77.16,66.43,61.79,51.00,28.83,27.18,25.80,19.27；ESI-MS(m/z):425.5([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₈ H ₃₀ N ₂ NaO ₈ ([M+Na]425.1894, experimental values: 425.1900.

compound 8 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (100 mg,0.24 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), triethylamine (100. Mu.L, 0.72 mmol), DMAP (7 mg,0.04 mmol) and methanesulfonyl chloride (53. Mu.L, 0.24 mmol) were added in this order, and the reaction was continued at room temperature for 8 hours, with additional triethylamine (66. Mu.L, 0.48 mmol), DMAP (4 mg,0.03 mmol) and methanesulfonyl chloride (31. Mu.L, 0.14 mmol) and continued for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=8:1, to give compound 7 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (44 mg, 46% yield).

Compound 8 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (100 mg,0.24 mmol) was dissolved in anhydrous toluene (15 mL), and Burgess reagent (Burgess reagent means methyl N- (triethylammonium sulfonyl) carbamate, i.e., N- (triethylammonium sulfonyl) methyl carbamate, CAS: 29684-56-8) (86 mg,0.36 mmol) was added and reacted at room temperature for 8 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=8:1, to give compound 7 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (41 mg, 43% yield).

Example 28 Compound 6 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 7 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (8.36 g,20.773 mmol) was dissolved in ethyl acetate (1L), and after cooling to 0deg.C, zinc powder (135.80 g,2077.30 mmol) and glacial acetic acid (118.80 mL,2077.30 mmol) were added sequentially and reacted at room temperature for 18h. Excess zinc powder was removed by filtration, the filtrate was concentrated and then column chromatographed, petroleum ether/ethyl acetate=2:1 to give compound 6 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (5.91 g, 76% yield). [ alpha ]] _D ²⁰ ＝+29.63°(c 2.0,CHCl ₃ )； ¹ H NMR(CDCl ₃ ,400MHz):δ4.47(d,J＝8.8Hz,1H),4.31(s,1H),4.21～4.26(m,2H),3.95～4.05(m,4H),3.70(d,J＝10.0Hz,1H),2.81(t,J＝9.6Hz,1H),1.67(s,3H),1.42(s,9H),1.41(s,3H),1.33(s,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ156.53,153.15,108.15,97.72,80.17,79.64,77.87,77.23,65.70,61.42,52.75,51.44,28.37,26.52,25.29,19.24；ESI-MS(m/z):373.3([M+H] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₈ H ₃₃ N ₂ O ₆ ([M+H]373.2335, experimental values: 373.2333.

chemical combinationObject 7 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (1 g,2.48 mmol) was dissolved in ethyl acetate (110 mL), and after cooling to 0deg.C iron powder (13.88 g,247.71 mmol) and glacial acetic acid (14.2 mL,248 mmol) were added sequentially and the reaction was continued at this temperature overnight. Excess iron powder was removed by filtration, excess aqueous ammonia was added to the filtrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to give compound 6 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (622 mg, 65% yield).

Compound 7 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1 g,2.48 mmol) was dissolved in ethyl acetate (110 mL), aluminum powder (6.70 g,248 mmol) and glacial acetic acid (14.2 mL,248 mmol) were added sequentially after cooling to 0deg.C, and the reaction was continued at this temperature overnight. Excess aluminum powder was removed by filtration, excess ammonia water was added to the filtrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to give compound 6 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (412 mg, 43% yield).

Example 29 Compound 5 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 6 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (5.91 g,15.87 mmol) was dissolved in dichloromethane (1L), and triethylamine (8.82 mL,62.83 mmol) and acetyl chloride (1.11 mL,15.87 mmol) were added sequentially after cooling to 0deg.C and reacted for 2h at 0deg.C. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, to give compound 5 (R ¹ Is methyl, R ² And R is ⁵ Each independently isMethyl, R ⁴ T-butoxycarbonyl) (5.81 g, 88% yield). [ alpha ]] _D ²⁰ ＝-1.43°(c 1.0,CHCl ₃ )； ¹ H NMR(CD ₃ CN,400MHz):δ6.55(d,J＝7.6Hz,1H),5.32(d,J＝8.4Hz,1H),4.42(s,J＝1.6Hz,1H),4.20(m,2H),4.02～4.07(m,2H),3.93～3.99(m,2H),3.61(d,J＝4.0Hz,1H),3.43(s,3H),1.90(s,3H),1.70(s,3H),1.42(s,9H),1.40(s,3H),1.32(s,3H)； ¹³ C NMR(100MHz,CD ₃ CN):δ171.06,156.88,152.75,108.71,98.75,79.34,78.91,77.98,77.91,66.29,61.63,51.17,49.33,28.56,26.77,25.51,23.39,19.24；ESI-MS(m/z):437.4([M+Na] ⁺ ),453.5([M+K] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₀ H ₃₄ N ₂ NaO ₇ ([M+Na] ⁺ ) 437.2269, experimental values: 437.2264.

compound 6 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1 g,2.67 mmol) was dissolved in pyridine (120 mL), acetic anhydride (5 mL) was added, and the reaction was allowed to proceed at 60℃for 12h. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gives compound 5 (0.88 g, yield 74%).

Compound 6 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (1 g,2.67 mmol) was dissolved in piperidine (120 mL), acetic anhydride (5 mL) was added, and the reaction was allowed to proceed at 60℃for 12h. Direct column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1, gives compound 5 (1.02 g, 86% yield).

Example 30 Compound 4 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 5 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (5.81 g,14.02 mmol) was dissolved in anhydrous 1, 4-dioxane (1L) and selenium dioxide (3.11 g,28.04 mmo) was addedl). Argon is introduced into the solution for 5min to remove oxygen in the solution, and the solution is reacted for 2h at 75 ℃ under the protection of argon. Direct column chromatography after system concentration, petroleum ether/ethyl acetate=1:1, gives compound 4 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (3.12 g, 52% yield). [ alpha ]] _D ²⁰ ＝+48.01°(c 1.0,CHCl ₃ )； ¹ H NMR(400MHz,CDCl ₃ ):δ9.15(s,1H),6.09(d,J＝9.6Hz,1H),5.68(d,J＝2.0Hz,1H),5.15(d,J＝9.2Hz,1H),4.56(td,J＝9.6,2.0Hz,1H),4.27～4.37(m,2H),4.19(dd,J＝8.8,6.0Hz,1H),4.13(d,J＝10.4Hz,1H),4.02(dd,J＝8.8,6.0Hz,1H),3.60(d,J＝4.4Hz,1H),3.49(s,3H),2.01(s,3H),1.43(m,12H),1.34(s,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ185.16,170.66,156.34,151.89,118.76,108.43,80.28,78.12,78.04,65.93,61.47,50.13,48.02,28.32,26.56,25.26,23.31；ESI-MS(m/z):451.4([M+Na] ⁺ ),467.4([M+K] ⁺ ),483.3([M+MeOH+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₀ H ₃₂ N ₂ NaO ₈ ([M+Na] ⁺ ) 451.2051, experimental values: 451.20509.

compound 5 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (5.81 g,14.02 mmol) was dissolved in anhydrous 1, 4-dioxane (1L) and selenium dioxide (3.11 g,28.04 mmol) was added. Argon is introduced into the solution for 5min to remove oxygen in the solution, and the solution is reacted for 2h at 100 ℃ under the protection of argon. Direct column chromatography after system concentration, petroleum ether/ethyl acetate=1:1, gives compound 4 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (1.32 g, 22% yield).

Example 31 Compound 3 (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compounds of formula (I)4(R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (2.33 g,5.44 mmol) was dissolved in t-butanol (180 mL) and water (60 mL), 2-methylbutene (20 mL) and sodium dihydrogen phosphate (5.25 g,43.76 mmol) were added sequentially, and finally sodium chlorite (1.98 g,21.89 mmol) was added. The reaction was carried out at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain compound 3 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (2.13 g, 95% yield). [ alpha ]] _D ²⁰ ＝+42.60°(c 0.25,DMSO)； ¹ H NMR(CD ₃ OD,500MHz):δ5.57(d,J＝2.5Hz,1H),4.35～4.45(m,2H),4.23(dd,J＝9.0,6.0Hz,1H),4.16(d,J＝9.5Hz,1H),4.06(t,J＝9.5Hz,1H),4.04(dd,J＝9.0,7.5Hz,1H),3.67(d,J＝2.5Hz,1H),3.49(s,3H),1.98(s,3H),1.44(s,9H),1.41(s,3H),1.34(s,3H)； ¹³ C NMR(125MHz,DMSO-d ₆ ):δ169.57,163.57,156.11,145.00,111.10,107.72,78.31,77.93,77.65,77.48,65.35,61.26,49.46,47.50,28.63,26.81,25.80,23.29.ESI-MS(m/z):443.7([M-H] ^- ) ESI-HRMS (m/z) calculated: c (C) ₂₀ H ₃₂ N ₂ NaO ₉ ([M+Na] ⁺ ) 467.2000, experimental values: 467.2004.

EXAMPLE 32 Synthesis of Compound 2 (R is methyl)

Compound 3 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (100 mg,0.225 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL) was added thereto for reaction at room temperature for 2h. Water (0.1 mL) was added and the mixture was reacted at room temperature for 1h. After concentration of the system, the trifluoroacetate salt of compound 2 (R is methyl) was obtained (129 mg, yield 100%). [ alpha ] ] _D ²⁰ ＝+0.33°(c 1.3,MeOH)； ¹ H NMR(D ₂ O,500MHz):δ5.85(d,J＝2.5Hz,1H),4.35(d,J＝11.0Hz,1H),4.26(dd,J＝10.5,9.5Hz,1H),4.10(dd,J＝9.5,2.5Hz,1H),3.88(ddd,J＝9.0,5.5,3.0Hz,1H),3.76(dd,J＝12.0,3.0Hz,1H),3.57(dd,J＝12.0,5.5Hz,1H),3.46(dd,J＝9.0,1Hz,1H),3.30(s,1H),1.98(s,3H)； ¹³ C NMR(125MHz,D ₂ O):δ174.55,164.72,146.71,104.12,77.23,75.73,69.52,62.27,60.32,50.44,45.43,22.13；ESI-MS(m/z):305.2([M+H] ⁺ ) ESI-HRMS (m/z) calculated: c (C) ₁₂ H ₂₁ N ₂ O ₇ ([M+H] ⁺ ) 305.1343, experimental values: 305.1342.

example 33 Compound 26 (R ⁴ t-Butoxycarbonyl group)

Nitro compound 11 (R) ⁴ Boc) (165.41 g,879 mmol) was dissolved in chloroform (1500 mL), jacobsen catalyst (11.45 g,29.31 mmol) was added sequentially, and methyl pyruvate (26.9 mL,293 mmol) was added and then reacted at room temperature for 24h. The reaction was washed with saturated sodium bicarbonate solution 2 times, saturated sodium chloride solution once, column chromatography after completion of the solvent, petroleum ether/ethyl acetate=4:1 to give 26 (R) as a pale yellow solid ⁴ T-butoxycarbonyl) (63.25 g, yield 74%,81% ee). The product was recrystallized from tetrahydrofuran/n-hexane=1:2 to give white solid 26 (R ⁴ t-Butoxycarbonyl) (51 g, yield 81%,94% ee)

[α] _D ²⁰ ＝-0.8480°(c 1.0,CHCl ₃ )

¹ H NMR(400MHz,CDCl ₃ )δ5.15(s,1H),4.85～4.68(m,1H),4.68～4.52(m,2H),3.90(s,3H),3.40～3.20(m,2H),1.43(s,9H)；

¹³ CNMR(126MHz,CDCl ₃ ):δ190.92,160.43,154.85,80.86,76.90,53.46,45.12,41.05,28.31(3C)；

ESI-MS(m/z):313.4([M+Na] ⁺ ),345.3([M+MeOH+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₂ H ₂₂ N ₂ NaO ₈ ([M+Na+MeOH] ⁺ ) 345.1268, experimental values: 345.1271.

preparation of compound 26 the reaction conditions are optimized under different catalysts as shown in table 1; preparation of compound 26 under the catalysis of catalyst 12 (cat.12), the reaction conditions are optimized as shown in table 2 under different organic solvent conditions; preparation of compound 26 under the catalysis of catalyst 12 (cat.12) under different additive conditions, the reaction conditions are optimized as shown in table 3; . Cat.1, cat.2 and Cat.3 are commercially available products. Cat.4 can be referred to: j.am.chem.soc.2012,134,20197; the reported methods were synthesized. Cat.5 may be referred to: angel.chem.int.ed.2012, 51,8838; the reported methods were synthesized. Cat.6 can be referred to: chem.commun.2012,48,5193; the reported methods were synthesized. Cat.7 can be referred to: org.lett.2007,9,599; the reported methods were synthesized. Cat.8 can be referred to: am.chem.soc.2006,128,9624; the reported methods were synthesized. Cat.9 can be referred to: eur.J.org.chem.2010,1849; the reported methods were synthesized. Cat.10 may be referred to: tetrahedron. Lett.2010,51,209; the reported methods were synthesized. Cat.11 can be referred to: org.lett.2010,12,1756; the reported methods were synthesized. Cat.12 can be referred to: am.chem.soc.2006,128,7170; synthesizing the reported method; cat.13 may be referred to: adv.synth.catalyst.2012, 354,740; the reported methods were synthesized.

Table 1 compound 26 synthesis catalyst screening

Table 2 Compound 26 synthetic organic solvent Screen (Cat.12)

Table 3 Compound 26 synthetic additive Screen (Cat.12)

Experiment number

Additive agent

Organic solvents

Temperature (temperature)

Time

Yield (%)

ee(％)

1

Acetic acid

Chloroform (chloroform)

Room temperature

2d

58

75

2

Para-dibenzoic acid

Chloroform (chloroform)

Room temperature

2d

24

73

3

Para-hydroxybenzoic acid

Chloroform (chloroform)

Room temperature

2d

56

79

4

P-nitrobenzoic acid

Chloroform (chloroform)

Room temperature

2d

47

79

5

(+) -camphorsulfonic acid

Chloroform (chloroform)

Room temperature

2d

67

64

6

Para-toluene sulfonic acid

Chloroform (chloroform)

Room temperature

2d

34

68

7

-

Chloroform (chloroform)

Room temperature

2d

74

81

The structure of the catalyst is as follows:

the structure of the Jacobsen catalyst (cat.12) is shown below:

example 34 Compound 27 (R) ⁴ t-Butoxycarbonyl group)

Compound 26 (5 g,17.2 mmol) was dissolved in methanol (200 mL) and NaBH was added ₄ (260 mg,6.87 mmol) at room temperature for 10min, quenching with saturated ammonium chloride, removing methanol by spin-drying, dissolving with water, extracting with ethyl acetate twice, drying with anhydrous sodium sulfate, and performing spin-drying column chromatography to obtain white solid 27 (R) ⁴ T-butoxycarbonyl) (4.95 g, 98% yield).

¹ H NMR(500MHz,CDCl ₃ ) (pair of diastereomers in a ratio of 1:1) δ5.28 (d, j=7.3 hz,1 h)&5.03(d,J＝6.7Hz,1H),4.73～4.51(m,4H),4.48～4.37(m,2H),4.31(dd,J＝13.3,8.0Hz,2H),3.80(s,3H)&3.79(s,3H)3.09(br,2H),2.24～2.04(m,3H),1.91～1.78(m,1H),1.44(s,18H)；

¹³ C NMR(126MHz,CDCl ₃ ) (a pair of diastereomers in a ratio of 1:1) delta 174.59&174.38,155.54&155.05,80.53&80.41,78.09,67.53,52.80&52.73,46.57&45.84,36.05&35.34,28.27(3C)&28.24(3C)；

ESI-MS(m/z):315.2([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₁ H ₂₀ N ₂ NaO ₇ ([M+Na] ⁺ ):315.1163, experimental values: 315.1166.

compound 26 (2.9 g,17.2 mmol) was dissolved in tetrahydrofuran (100 mL) and ZnCl was added ₂ (1.36 g,10 mmol), -stirring at 78deg.C for 0.5h, adding lithium tri-sec-butylborohydride in tetrahydrofuran (1.0 mol/L,11 mL), -continuing the reaction at 78deg.C for 10min, adding saturated NH ₄ Quenching the Cl solution, heating to room temperature, adding a small amount of 1mol/L hydrochloric acid, diluting with water, extracting with ethyl acetate twice, drying with anhydrous sodium sulfate, filtering, concentrating, and performing spin-drying column chromatography to obtain white solid 27 (R) ⁴ T-butoxycarbonyl) (2.9 g, 99% yield, dr=1:2.7).

¹ H NMR(500MHz,CDCl ₃ )δ5.28(d,J＝7.3Hz,1H)&5.03(d,J＝6.7Hz,1H),4.73～4.51(m,4H),4.48～4.37(m,2H),4.31(dd,J＝13.3,8.0Hz,2H),3.80(s,3H)&3.79(s,3H)3.09(br,2H),2.24～2.04(m,3H),1.91～1.78(m,1H),1.44(s,18H)；

¹³ C NMR(126MHz,CDCl ₃ )δ174.59&174.38,155.54&155.05,80.53&80.41,78.09,67.53,52.80&52.73,46.57&45.84,36.05&35.34,28.27&28.24；

ESI-MS(m/z):315.2([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₁ H ₂₀ N ₂ NaO ₇ ([M+Na] ⁺ ) 315.1163, experimental values: 315.1166.

example 35 Compound 28 (R) ⁴ t-Butoxycarbonyl group)

Compound 27 (R) ⁴ Boc) (1.8 g,6.16 mmol) was dissolved in dry tetrahydrofuran (40 mL), 4-dimethylaminopyridine (75 mg,0.62 mmol) was added, acetic anhydride (0.7 mL,7.39 mmol) was added, triethylamine (2.6 mL,18.18 mmol) was added, and the reaction was carried out at room temperature for 10min, and spin-dry column chromatography gave 28 (2.02 g, 99% yield) as a colorless oily liquid.

¹ H NMR(400MHz,CDCl ₃ ) (pair of diastereomers, ratio 1:1) δ5.17 (t, j=5.5 hz,1 h), 5.08 (dd, j=10.7, 2.7hz,1 h), 5.064.96(m,2H),4.68(dd,J＝13.1,5.1Hz,1H),4.61～4.50(m,3H),4.39～4.19(m,2H),3.76(s,3H)&3.74(s,3H)2.29(m,1H),2.15(s,3H)&2.14(s,3H),2.05(m,1H),1.42(s,9H)&1.41(s,9H)；

¹³ C NMR(126MHz,CDCl ₃ ) (a pair of diastereomers in a ratio of 1:1) delta 170.26&170.15,170.10&169.71,154.96&154.74,80.78&80.68,78.29&77.59,69.17&68.66,52.84&52.78,46.26&45.69,33.22&32.84,28.36(3C)&28.30(3C),20.70&20.63；

ESI-MS(m/z):357.3([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₃ H ₂₂ N ₂ NaO ₈ ([M+Na] ⁺ ) 357.1268, experimental values: 357.1273.

compound 27 (R) ⁴ Boc) (117 mg,0.4 mmol) was dissolved in dry dichloromethane (5 mL), triethylamine (0.223 mL,1.6 mmol) was added, acetyl chloride (0.057 mL,0.8 mmol) was added, and the reaction was carried out at room temperature for 24h, and the column chromatography was carried out on a spin-dry column to give 28 (54 mg, yield 40%) as colorless oily liquid.

Example 36 Compound 29 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Copper bromide (254 mg,1.14 mmol), cesium carbonate (555 mg,1.70 mmol), catalyst ligand were weighed out(481 mg,1.14 mmol) was placed in an egg-type bottle, anhydrous tetrahydrofuran (50 mL) was added and stirred at room temperature for 2 hours to give a small amount of white solid, which was then placed in a 0℃circulating cold bath, 28 (1.9 g,5.68 mmol) of anhydrous tetrahydrofuran (25 mL) was added, and 9 (1.19 g,6.83 mmol) of anhydrous tetrahydrofuran solution was added and the reaction was continued at 0℃for 48 hours. Extraction with ethyl acetate after quenching reaction with saturated ammonium chloride solution, and direct column chromatography after spinning the solvent to obtain compound 29 (R) ¹ Is methyl, R ² And R is ⁵ Each of which is a single pieceIndependently methyl, R ⁴ T-butoxycarbonyl) (1.92 g, 66% yield).

¹ H NMR(500MHz,CDCl ₃ )δ5.20(t,J＝5.3Hz,1H),5.12(dd,J＝11.3,2.8Hz,1H),4.99(d,J＝10.3Hz,1H),4.87～4.81(m,4H),4.57(d,J＝5.4Hz,1H),4.54～4.47(m,1H),4.47～4.40(m,1H),4.25～4.19(m,2H),4.13～4.05(m,4H),4.01～3.95(m,2H),3.75(s,3H)&3.74(s,3H),3.53(s,3H)&3.52(s,3H),3.29(m,2H),2.21～2.15(m,1H),2.14(s,3H)&2.12(s,3H),2.07～1.99(m,2H),1.90(m,1H),1.47(s,9H)&1.46(s,9H),1.40(s,3H)&1.39(s,3H),1.33(s,3H)&1.32(s,3H)；

¹³ C NMR(126MHz,CDCl ₃ )δ170.14,170.04,169.79,169.44,157.35&157.14,108.49&108.36,90.07&89.99,82.06,82.04,79.44&79.40,77.02,69.92,69.64,68.71,68.35,66.09&66.06,61.50&61.42,52.81&52.77,46.04&46.03,33.36,28.37,28.27,28.21,26.62,25.38&25.36,20.70&20.51；

ESI-MS(m/z):531.6([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₂₁ H ₃₆ N ₂ NaO ₁₂ ([M+Na] ⁺ ) 531.2160, experimental values: 531.2162.

example 37 Compound 30 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 29 (155 mg,0.305 mmol) was dissolved in anhydrous methanol (5 mL), sodium methoxide (16 mg,0.305 mmol) was added, the reaction was carried out at room temperature for 4h, saturated ammonium chloride solution was added to quench the reaction, extraction was carried out with ethyl acetate, drying over anhydrous sodium sulfate, and column chromatography was concentrated to give compound 30 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ As t-butoxycarbonyl) (70 mg, yield 50%) was recovered compound 29 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) 35mg.

¹ H NMR(500MHz,CDCl ₃ )δ4.85(dd,J＝9.8,2.6Hz,1H),4.79(d,J＝10.2Hz,1H),4.71(d,J＝4.9Hz,1H),4.65–4.57(m,1H),4.33(dd,J＝9.2,4.5Hz,1H),4.22(td,J＝6.4,4.7Hz,1H),4.11–4.05(m,2H),3.99(dd,J＝8.5,6.8Hz,1H),3.80(s,3H),3.51(s,3H),3.29(d,J＝4.5Hz,1H),3.13(d,J＝4.0Hz,1H),2.19–2.14(m,1H),1.89(ddd,J＝14.7,10.5,4.5Hz,1H),1.47(d,J＝4.7Hz,9H),1.39(s,3H),1.33(s,3H)；

¹³ C NMR(126MHz,CDCl ₃ )δ174.59&174.41,157.13&155.08,109.17&109.05,108.42&108.28,90.39&89.81,81.65,80.55&80.44,79.51&79.43,78.09,69.67,69.60,67.54,52.79&52.73,45.82,45.36,36.04,35.34,28.26&28.18,26.48&26.38,25.21&25.14.

ESI-MS(m/z):489.5([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₄ N ₂ NaO ₁₁ ([M+Na] ⁺ ) 489.2055, experimental values: 489.2058.

compound 29 (1.2 g,2.36 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL), cesium carbonate (7.69 g,23.6 mmol) was added, followed by 30% hydrogen peroxide (12 mL), stirring was performed at room temperature for 6 hours, the reaction was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound 30 (824 mg, yield 75%) (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Is tert-butyloxycarbonyl group

Example 38 Compound 31 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 30 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (500 mg,1.07 mmol) was dissolved in dry dichloromethane (25 mL) and dess-Martin oxidant (500 mg) was added at-20 ℃1.18 mmol), reaction at 20℃for 4h, addition of saturated NaHCO ₃ Quenching the solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and performing column chromatography to obtain compound 31 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (433 mg, 86% yield).

¹ H NMR(500MHz,CDCl ₃ )δ4.87-4.83(m,1H),4.74-4.72(m,1H),4.65-4.63(m,2H),4.43(br,1H),4.14-4.11(m,1H),3.96-3.88(m,2H),3.82(s,3H),3.53(s,3H),3.47(s,1H),2.22-2.21(m,2H),1.42(s,9H),1.39(s,3H),1.32(s,3H)；

¹³ C NMR(126MHz,CHCl ₃ )δ169.11,154.65,125.64,108.60,94.43,85.49,80.79,78.34,76.61,71.47,62.05,53.93,30.46,28.29(3C),26.65,25.40.

ESI-MS(m/z):487.5([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₂ N ₂ NaO ₁₁ ([M+Na] ⁺ ) 487.1898, experimental values: 487.1896.

example 39 Compound 32 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 31 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Is tert-Butoxycarbonyl) (390 mg,0.84 mmol) is dissolved in anhydrous dichloromethane (8 mL), pyridine (0.55 mL,6.85 mmol) is added at-10deg.C, thionyl chloride (1.4 mL,1.96 mmol) is added, the reaction is continued for 2h at-10deg.C, water is added to quench the reaction, 1mol/L hydrochloric acid is used for one time, dichloromethane extraction, anhydrous sodium sulfate is dried, filtered, and the filtrate is concentrated and then column chromatographed to give compound 32 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (200 mg, 53% yield).

[α] _D ²⁰ ＝+39.6880°(c 1.0,CHCl ₃ )

¹ H NMR(500MHz,CD ₃ CN)δ5.88(d,J＝2.2Hz,1H),5.74(s,1H),5.05–4.96(m,1H),4.93(t,J＝9.7Hz,1H),4.56(d,J＝9.6Hz,1H),4.29–4.23(m,1H),4.14(dd,J＝8.8,6.3Hz,1H),3.96(dd,J＝8.8,6.5Hz,1H),3.76(d,J＝2.8Hz,3H),3.47(s,3H),3.43(dd,J＝4.8,1.6Hz,1H),1.39(s,9H),1.36(s,3H),1.30(s,3H).

¹³ C NMR(126MHz,CD3CN)δ162.20,156.02,145.04,111.60,109.15,83.66,80.78,78.78,77.85,76.89,66.33,61.99,53.11,50.47,28.34(3C),26.74,25.45；

ESI-MS(m/z):469.5([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₀ N ₂ NaO ₁₀ ([M+Na] ⁺ ) 469.1793, experimental values: 469.1797.

compound 31 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (20 mg,0.043 mmol) was dissolved in anhydrous dichloromethane (1 mL), triethylamine (30. Mu.L, 0.21 mmol) was added, methanesulfonyl chloride (12. Mu.L, 0.17 mmol) was added, the reaction was continued at-10℃for 2h, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then chromatographed to give Compound 32 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (5 mg, 26% yield).

Example 40 Compound 33 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 32 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Boc) (38 mg,0.085 mmol) was dissolved in 2mL anhydrous ethyl acetate, zinc powder (552 mg,8.5 mmol) was added, glacial acetic acid (487. Mu.L, 8.5 mmol) was added, and the mixture was reacted overnight at room temperature,filtration over celite, washing with ethyl acetate, and column chromatography concentration gave compound 33 (28 mg, 81% yield) (R ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl).

[α] _D ²⁰ ＝+32.8100°(c 1.0,CHCl ₃ )

¹ H NMR(500MHz,CDCl ₃ )δ5.82(d,J＝2.5Hz,1H),4.53(d,J＝8.6Hz,1H),4.33–4.25(m,2H),4.21(dd,J＝8.8,6.3Hz,1H),4.07(dd,J＝8.7,7.2Hz,2H),3.83(dd,J＝10.1,1.3Hz,1H),3.75(s,3H),3.63(s,3H),2.96(t,J＝9.7Hz,1H),1.55(br,2H),1.46(s,9H),1.45(s,3H),1.37(s,3H).

¹³ C NMR(126MHz,CDCl ₃ )δ162.44,156.41,145.16,110.82,108.27,81.48,77.69,77.56,65.69,61.60,52.35,52.23,50.53,29.82,28.47(3C),26.61,25.44.

ESI-MS(m/z):417.5([M+H] ⁺ )；439.5([M+Na] ⁺ ) The method comprises the steps of carrying out a first treatment on the surface of the ESI-HRMS (m/z): calculated: c (C) ₁₉ H ₃₃ N ₂ O ₈ ([M+H] ⁺ ) 417.2235, experimental values: 417.2231.

example 41 Compound 34 (R) ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl group)

Compound 33 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ t-Butoxycarbonyl) (27 mg,0.064 mmol) was dissolved in anhydrous dichloromethane (3 mL), placed in an ice-water bath, triethylamine (38. Mu.L, 0.26 mmol) was added, acetyl chloride (5. Mu.L, 0.077 mmol) was added, and reacted in an ice-water bath for 30min, and spin-dry column chromatography gave compound 34 (R) ¹ Is methoxymethyl, R ² And R is ⁵ Each independently is methyl, R ⁴ T-butoxycarbonyl) (27 mg, 91% yield);

[α] _D ²⁰ ＝+17.5969°(c0.65,CHCl ₃ )

¹ H NMR(500MHz,CDCl ₃ )δ5.99(br,1H),5.84(d,J＝1.8Hz,1H),4.99(br,1H),4.47–4.45(m,1H),4.31-4.24(m,2H),4.18(dd,J＝8.7,6.2Hz,1H),4.08-4.04(m,2H),3.75(s,3H),3.66(d,J＝3.3Hz,1H),3.52(s,3H),1.99(s,3H),1.43(s,3H),1.42(s,9H),1.35(s,3H).

¹³ C NMR(126MHz,CDCl ₃ )δ170.63,162.14,156.44,144.81,110.18,108.44,80.34,78.61,77.83,65.87,61.81,52.45,49.99,48.38,29.83,28.43(3C),26.65,25.51,23.50.

ESI-MS(m/z):481.6([M+Na] ⁺ ) ESI-HRMS (m/z) calculated: c (C) ₂₁ H ₃₄ N ₂ NaO ₉ ([M+Na] ⁺ ) 481.2157, experimental values: 481.2157

Example 42 Compound 2 (R ¹ Methyl) synthesis

Compound 34 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Is tert-butyloxycarbonyl) (20 mg,0.044 mmol) was dissolved in 1mL of tetrahydrofuran, sodium hydroxide solution (3 mol/L,0.44 mL) was added, and the mixture was reacted overnight at room temperature to give intermediate compound 3, followed by further addition of hydrochloric acid (3 mol/L,0.9 mL) to the system without post-treatment, followed by further reaction for 0.5h, and concentration of the system to give compound 2 (R) ¹ Methyl) (13 mg, 97.2% yield).

[α] _D ²⁰ ＝+0.33°(c 1.3,MeOH)

¹ H NMR(500MHz,D ₂ O)δ6.09(d,J＝2.2Hz,1H),4.61(d,J＝10.7Hz,1H),4.49(t,J＝10.0Hz,1H),4.39(dd,J＝9.5,2.2Hz,1H),4.14-4.11(m,1H),4.00(dd,J＝12.0,2.8Hz,1H),3.81(dd,J＝12.0,5.7Hz,1H),3.71(d,J＝8.3Hz,1H),3.54(s,3H),2.23(s,3H).

¹³ C NMR(126MHz,D ₂ O)δ174.46,163.98,145.90,104.75,77.16,75.72,69.52,62.21,60.22,50.26,45.35,22.03.

ESI-MS(m/z):305.2([M+H] ⁺ ) ESI-HRMS (m/z) calculated: c (C) ₁₂ H ₂₀ N ₂ NaO ₇ ([M+Na] ⁺ ) 327.1163, experimental values: 327.1160.

compound 34 (R ¹ Is methyl, R ² And R is ⁵ Each independently is methyl, R ⁴ Is tert-butyloxycarbonyl) (20 mg,0.044 mmol) is dissolved in 1mL tetrahydrofuran, hydrochloric acid (3 mol/L,0.44 mL) is added, the reaction is carried out for 1h at room temperature to obtain an intermediate 35, no post-treatment is carried out, sodium hydroxide solution (3 mol/L,0.9 mL) is added into the system, the reaction is continued for 8h, 3mol/L hydrochloric acid is added to adjust the pH to 2-3, and the system is concentrated to obtain a compound 2 (R) ¹ Methyl) (13.2 mg, 98.7% yield).

Compound 35 data

[α] _D ²⁰ ＝+1.3240°(c 0.5,MeOH)

¹ H NMR(500MHz,D ₂ O)δ6.01(d,J＝2.3Hz,1H),4.48(d,J＝10.7Hz,1H),4.38(t,J＝10.1Hz,1H),4.23(dd,J＝9.4,2.4Hz,1H),3.98(m,1H),3.88(dd,J＝12.0,2.5Hz,1H),3.82(s,3H),3.69(dd,J＝12.0,5.4Hz,1H),3.58(d,J＝8.5Hz,1H),3.41(s,3H),2.09(s,3H).

¹³ C NMR(126MHz,D ₂ O)δ174.53,163.07,145.81,104.71,77.17,75.88,69.57,62.22,60.34,53.10,50.33,45.35,22.14.

ESI-MS(m/z):319.4([M+H] ⁺ )；341.3([M+Na] ⁺ ).

EXAMPLE 43 Synthesis of Laninavir

Compound 2 (R is methyl) (19 mg,0.056 mmol) is dissolved in water (1.5 mL) and potassium carbonate (4.5 mg,0.056 mmol) and thiourea trioxide (4.1 mg,0.056 mmol) are added sequentially every 0.5h for a total of 12 times. The reaction was carried out at room temperature for 36 hours. Concentrating and filtering, separating filtrate by HPLC to obtainThe product (10 mg, yield 50%). [ alpha ]] _D ²⁰ ＝+8.44°(c0.5,H ₂ O)； ¹ H NMR(D ₂ O,500MHz):δ5.52(d,J＝2.5Hz,1H),4.30(dd,J＝10.0,2.0Hz,2H),4.10(t,J＝9.5Hz,1H),3.88(ddd,J＝8.5,5.5,3.0Hz,1H),3.78(dd,J＝12.0,3.0Hz,1H),3.57(dd,J＝12.0,5.5Hz,1H),3.45(dd,J＝8.5,1.5Hz,1H),3.31(s,3H),1.94(s,3H)； ¹³ C NMR(125MHz,D ₂ O):δ174.20,168.97,157.03,149.22,104.13,77.72,75.76,69.61,62.42,60.37,51.65,48.97,47.76,22.13；ESI-MS(m/z):347.8([M+H] ⁺ ) ESI-HRMS (m/z) calculated: c (C) ₁₃ H ₂₃ N ₄ O ₇ ([M+H] ⁺ ) 347.15613, experimental values: 347.1565.

the trifluoroacetate salt (R is methyl) (1.35 g,3.23 mmol) of Compound 2 was dissolved in N, N-dimethylformamide (DMF, CAS: 68-12-2) (40 mL), and N, N-Diisopropylethylamine DIPEA (CAS: 7087-68-5, english name N, N-Diisopropyllethylamine) (1.7 mL,9.70 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (1.42 g,9.70 mmol) were added sequentially every 1d for a total of 3 times. The reaction was carried out at room temperature for 5d. After addition of water, each was washed 3 times with ethyl acetate, three times with dichloromethane and recrystallized 3 times with methanol/ethyl acetate=1:8. The product (1.12 g, 100% yield) was obtained.

Laninavir octanoate CS-8958 can be synthesized by esterification of Laninavir with reference to patent (WO 2008/126943).

Claims

1. A method for synthesizing compound 8, comprising the steps of: in an aprotic solvent, reacting a compound 10 with a compound 9 in the presence of a base, a catalyst and a catalyst ligand to obtain a compound 8;

wherein R is ¹ Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen; r is R ² And R is ⁵ Each independently is methyl, ethyl or propylA base; r is R ⁴ Is amino protecting group, which is tert-butyloxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl.

2. The method for synthesizing compound 8 according to claim 1, wherein in the method for producing compound 8, the aprotic solvent is an ether solvent;

and/or in the method for preparing the compound 8, the volume-mass ratio of the aprotic solvent to the compound 9 is 1-50 mL/g;

and/or, in the process for preparing compound 8, the base is an inorganic base;

and/or in the process for preparing compound 8, the molar ratio of said compound 9 to said base is from 1:1 to 10:1;

And/or in the process for preparing compound 8, the catalyst is an inorganic copper salt and/or an organic copper salt;

and/or in the process for preparing compound 8, the molar ratio of compound 9 to the catalyst is from 1:1 to 10:1;

and/or in the process for preparing compound 8, the molar ratio of said compound 10 to said compound 9 is from 1:1 to 5:1;

and/or, in the process for preparing compound 8, the catalyst ligand is

And/or in the process for preparing compound 8, the molar ratio of the catalyst ligand to the compound 9 is 1:10 to 3:10;

and/or in the process for preparing compound 8, the temperature of the reaction is-20 ℃ to 40 ℃.

3. The method for synthesizing compound 8 according to claim 2, wherein in the method for producing compound 8, the ether solvent is tetrahydrofuran;

and/or in the method for preparing the compound 8, the volume-mass ratio of the aprotic solvent to the compound 9 is 1-10 mL/g;

and/or in the method for preparing compound 8, the inorganic base is one or more of cesium carbonate, sodium carbonate, potassium carbonate and potassium tert-butoxide;

And/or in the process for preparing compound 8, the molar ratio of said compound 9 to said base is from 1:1 to 3:1;

and/or, in the method for preparing compound 8, when the catalyst is an inorganic copper salt, the inorganic copper salt is one or more of copper chloride, cuprous bromide, cupric bromide and cuprous iodide;

and/or in the process for preparing compound 8, the molar ratio of compound 9 to the catalyst is from 3:1 to 10:1;

and/or in the process for preparing compound 8, the molar ratio of said compound 10 to said compound 9 is from 2:1 to 5:1;

and/or in the process for preparing compound 8, the molar ratio of the catalyst ligand to the compound 9 is from 2:10 to 3:10;

and/or in the process for preparing compound 8, the temperature of the reaction is-20 ℃ to 30 ℃.

4. A method for synthesizing compound 19, comprising the steps of: reacting compound 10 with compound 20 in the presence of an alkaline substance in an aprotic solvent to give compound 19;

wherein R is ² And R is ⁵ Each independently is methyl, ethyl or propyl; r is R ³ The hydroxyl protecting group is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or methoxymethyl; r is R ⁴ Is amino protecting group, the amino protecting group is tert-butyloxycarbonyl or benzylAn oxycarbonyl group or a p-toluenesulfonyl group.

5. The method for synthesizing compound 19 according to claim 4, wherein in the method for producing compound 19, the aprotic solvent is an ether solvent;

and/or in the process for preparing compound 19, the volume to mass ratio of the aprotic solvent to the compound 10 is 1mL/g to 50mL/g;

and/or in the method for preparing compound 19, the basic substance is one or more of inorganic base, organic base, basic oxide, strong base weak acid salt and ion exchange resin;

and/or in the process for preparing compound 19, the molar ratio of the basic substance to the compound 10 is 1:1 to 1:10;

and/or in the process for preparing compound 19, the temperature of the reaction is from 0 ℃ to 40 ℃.

6. The method for synthesizing compound 19 according to claim 5, wherein in the method for producing compound 19, the ether solvent is tetrahydrofuran;

and/or in the process for preparing compound 19, the volume to mass ratio of the aprotic solvent to the compound 10 is 30mL/g to 50mL/g;

And/or, in the method for preparing compound 19, when the basic substance is an organic base, the organic base is one or more of tetrabutylammonium hydroxide, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tetramethylguanidine, and lithium diisopropylamide;

and/or, in the method for producing compound 19, when the basic substance is a basic oxide, the basic oxide is basic aluminum oxide;

and/or, in the method for producing compound 19, when the basic substance is a strong alkali weak acid salt, the strong alkali weak acid salt is potassium acetate;

and/or, in the preparation of compound 19, when the alkaline material is an ion exchange resin, the ion exchange resin is Amberlite A-21;

and/or in the process for preparing compound 19, the molar ratio of the basic substance to the compound 10 is 1:1 to 1:5;

and/or in the process for preparing compound 19, the temperature of the reaction is from 10 ℃ to 30 ℃.

7. The method for synthesizing compound 19 according to claim 5, wherein in the method for producing compound 19, when the basic substance is an organic base, the organic base is sodium methoxide and/or potassium tert-butoxide.

8. A compound 8, 19, 5, 6, 7, 13, 14, 16, 17, 18, 31, 32 or 33 having the structural formula:

9. The compound 8, 19, 5, 6, 7, 13, 14, 16, 17, 18, 31, 32, or 33 of claim 8, wherein R ¹ Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylA silyl group, a triisopropylsilyl group, a methoxymethyl group, a methyl group or a hydrogen group, R ² And R is ⁵ Each independently is methyl, R ⁴ Is tert-butyloxycarbonyl.

10. A compound 15 having the structural formula:

wherein R is ² And R is ⁵ Each independently is methyl, ethyl or propyl; r is R ⁴ Is an amino protecting group; the amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl.

11. The compound 15 of claim 10, wherein R ² And R is ⁵ Each independently is methyl, R ⁴ Is tert-butyloxycarbonyl.