WO2015161781A1

WO2015161781A1 - Method for preparing nucleoside analogue and intermediate thereof

Info

Publication number: WO2015161781A1
Application number: PCT/CN2015/077078
Authority: WO
Inventors: 魏用刚; 邱关鹏; 卢泳华; 祝国智
Original assignee: 四川海思科制药有限公司
Priority date: 2014-04-21
Filing date: 2015-04-21
Publication date: 2015-10-29
Also published as: HK1217201A1; CN105531281A; CN105518011B; CN105531281B; WO2015161785A1; CN105518011A

Abstract

The present invention relates to a method for preparing a nucleoside analogue and an intermediate thereof, i.e. a method for preparing a compound as shown by formula (I) and an intermediate thereof. The method has the following advantages: a high reaction yield and a high product purity, is convenient to post-process and is suitable for industrial production. Wherein the compound (III) is a key intermediate for making the high-purity compound (I), and the definition of the substituents in the compound (III) is identical to that in the specification.

Description

Preparation method of nucleoside analog and intermediate thereof

Technical field

The invention relates to a method for preparing a nucleoside analog and an intermediate thereof.

Background technique

The compound of formula (I) is a prodrug of tenofovir, first disclosed in WO2002008241, which inhibits viral polymerase by direct competitive binding to natural deoxyribose substrates for the treatment of HIV and HBV. infection.

Compared with tenofovir, Compound (I) increases plasma stability, thereby increasing the cumulative concentration of the active metabolite tenofovir in peripheral blood mononuclear cells (PBMCs) and improving the therapeutic effect.

At present, the methods for synthesizing compound (I) disclosed at home and abroad mainly include the following:

1) CN1443189A discloses the preparation of a mixture of diastereomers GS-7171 starting from 9-(2-(phosphonomethoxy)propyl]adenine (PMPA), GS-7171 by chromatography or The method of recrystallization is purified to obtain the compound (I), wherein the route of preparing GS-7171 is as follows:

2) WO2013052094 discloses a compound represented by 16 in the preparation route, that is, the compound (I) in the present invention, and the route is as follows:

This route employs an alanine isopropyl ester obtained by alkaline relaxation of alanine isopropyl ester salt, and then the isopropyl alanate is stored at a low temperature of -20 ° C. The alanine isopropyl ester hydrochloride is prone to hydrolysis reaction when it is free, and the resulting isopropanol is substituted with the compound 13a to obtain a by-product, and the free alanine isopropyl ester is not stable at room temperature and is easily hydrolyzed. Need to be used now.

The present invention can be reacted with the compound (III) using L-alanine isopropyl ester salt, and the free alanine isopropyl ester disclosed in WO2013052094 has the characteristics of reducing the free neutralization reaction and overcoming the free The disadvantage of the stability of isopropyl alanate.

Gland in the key intermediate [2-(6-aminopurine-9-yl)-1-methyl-ethoxy]methyl-phenoxy-monophosphate (monophenyl PMPA) in the currently disclosed synthetic method The amino group of the oxime group is bare, and the intermediate has large polarity and good water solubility, and is difficult to be separated and purified.

Summary of the invention

The invention relates to a preparation method of a compound represented by the formula (I) and an intermediate thereof, which has high reaction yield, high product purity, simple operation, convenient post-treatment, and is suitable for industrial production. Among them, the compound (III) is a key intermediate for obtaining a compound (I) of high purity, and the definition of the substituent in the compound (III) is the same as defined in the specification.

In particular, the present invention provides a process for the preparation of a compound of formula (III):

In a solvent of 50 ° C to 110 ° C and a toluene solvent, the compound (IV) is halogenated with a halogenating reagent to form a compound (III);

Wherein the compound (III) has a diastereomer purity of at least 90% or more;

R ¹ and R ² are each independently selected from t-butoxycarbonyl or hydrogen, provided that R ¹ and R ^{2 are} not hydrogen at the same time;

The halogenating agent is selected from the group consisting of thionyl chloride.

In a preferred embodiment of the invention, the reaction temperature is preferably from 50 ° C to 90 ° C, more preferably from 70 ° C to 90 ° C.

In a preferred embodiment of the present invention, the diastereomer purity of the compound (III) is monitored by HPLC during the reaction. After the diastereomer purity is 90% or more, the reaction is stopped, and the reaction time is preferably 48 hours to 96 hours.

According to a preferred embodiment of the present invention, a method for preparing a compound represented by the formula (III):

In the toluene solvent, compound (IV) is halogenated with thionyl chloride to form compound (III);

Wherein the compound (III) has a diastereomer purity of at least 90% or more;

The reaction temperature is selected from 50 ° C to 110 ° C, preferably from 50 ° C to 90 ° C, further preferably from 70 ° C to 90 ° C;

The amount of the thionyl chloride is 3 to 12 times, preferably 5 to 10 times the molar amount of the compound (IV);

The reaction concentration of the thionyl chloride is 0.5 to 2 mol / L, preferably 0.8 to 1.5 mol / L;

During the reaction, the diastereomer purity of the compound (III) was monitored by HPLC, and after the diastereomer purity was 90% or more, the reaction was stopped, and the reaction time was preferably 48 hours to 96 hours.

The invention also provides a preparation method of the compound represented by the formula (I):

-50 ° C ~ 30 ° C and a mixed solvent of toluene and dichloromethane, compound (III) and compound (II) substitution reaction to form compound (I);

Wherein A is selected from the group consisting of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid, preferably hydrochloric acid.

A preferred embodiment of the invention, a method for preparing a compound of formula (I):

In a mixed solvent of toluene and dichloromethane, the compound (III) is substituted with the compound (II) to form the compound (I);

Wherein, the definition of A is as described above;

The reaction may optionally be added with the alkaline reagent triethylamine;

The reaction temperature is -30 ° C ~ 30 ° C;

The diastereomer purity of the compound (I) is at least 90% or more.

In a preferred embodiment of the present invention, the mixed solvent volume ratio of toluene to dichloromethane may be any ratio, preferably 1:0.6 to 1:2, more preferably 1:0.6 to 1:1.

In a preferred embodiment of the present invention, the amount of the compound (II) is preferably from 1 to 5 times, more preferably from 1 to 3 times, still more preferably from 2 to 3 times the molar amount of the compound (III).

The invention also provides another method for preparing the compound of formula (I):

-40 ° C ~ 30 ° C and a mixed solvent of toluene and dichloromethane, compound (III) and compound (IX) substitution reaction to form compound (I);

Wherein the diastereomer purity of the compound (I) is at least 90% or more.

Preferably, the mixed solvent volume ratio of toluene to dichloromethane may be any ratio, preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5;

Theoretical analysis, the amount of the compound (IX) is 1 times the molar amount of the compound (III). Considering the formation of hydrochloric acid in the reaction, the presence of hydrochloric acid is not conducive to the reaction, and the compound (IX) is an organic The amine can neutralize the hydrochloric acid formed in the reaction to promote the reaction, so the amount of the compound (IX) is more than 1 times the molar amount of the compound (III). In general, the excess compound (IX) is advantageous. Formation of Compound (I), amount of Compound (IX) Preferably, it is 1 to 10 times, more preferably 2 to 7 times, further preferably 3 to 5 times the molar amount of the compound (III);

The diastereomer purity of the compound (I) is at least 90% or more. In this method, the reaction process is simpler without adding an alkaline reagent such as triethylamine to adjust the pH of the reaction solution system.

The present invention provides a process for the preparation of a compound of formula (I), the process comprising the steps of:

a. The acetonitrile solvent, the compound (VIII) is halogenated with thionyl chloride to form the compound (VII), the halogenating agent is selected from the group consisting of thionyl chloride or oxalyl chloride, and the halogenation reaction is selective. Catalyst added, the catalyst is selected from N,N-dimethylformamide;

b. In a dichloromethane solvent, compound (VII) and phenol are substituted by the action of the alkaline reagent triethylamine to form compound (VI);

c. In the tetrahydrofuran solvent, the compound (VI) is reacted with the amino-protecting reagent di-tert-butyl dicarbonate to form the compound (V), and the catalyst 4-dimethylaminopyridine is added to the reaction;

d. In the solvent, the compound (V) is hydrolyzed with an alkaline reagent to form a compound (IV), the solvent is selected from one or a combination of acetonitrile and water, and the alkaline agent is selected from the group consisting of triethylamine and One or a combination of ammonia water;

e. In the toluene solvent, the compound (IV) is halogenated with the halogenating reagent thionyl chloride to form the compound (III), and the diastereomer purity of the compound (III) is 90% or more;

f. In a mixed solvent of dichloromethane and toluene, the compound (III) is substituted with the compound (II) alanine isopropyl ester to form the compound (I), and the alkaline reagent triethylamine is optionally added. The diastereomer purity of the compound (I) is 90% or more; or

g. In a mixed solvent of dichloromethane and toluene, the compound (III) is substituted with the compound (IX) alanine isopropyl ester to form the compound (I), and the diastereomer purity of the compound (I) is greater than or equal to 90%;

Wherein R ¹ , R ² and A are as defined above.

A preferred embodiment of the invention, a process for the preparation of a compound of formula (I), the process comprising the steps of:

a. halogenation reaction of compound (VIII) with thionyl chloride at 75 ° C to 85 ° C in acetonitrile to form compound (VII), said halogenating agent being selected from the group consisting of thionyl chloride or oxalyl chloride, said The halogenation reaction may be selectively added to the catalyst, the catalyst is selected from N,N-dimethylformamide, and the amount of the thionyl chloride is 4 to 10 times the molar amount of the compound (VIII), and the reaction is carried out for 3 to 4 hours;

b. At -30 ° C ~ room temperature and dichloromethane, the compound (VII) and phenol are substituted under the action of the alkaline reagent triethylamine to form compound (VI), the amount of phenol is the mole of compound (VII) 2 to 3 times the amount, triethylamine is used in an amount of 6 to 10 times the molar amount of the compound (VII), and the reaction is carried out for 10 to 14 hours;

c. Compound (VI) is reacted with aminoprotective reagent di-tert-butyl dicarbonate at 60 ° C to 70 ° C in tetrahydrofuran to form compound (V). The amount of di-tert-butyl dicarbonate added in the reaction is compound (VI). 2 to 4 times the molar amount, the catalyst 4-dimethylaminopyridine is used in an amount of 0.2 to 0.5 times the molar amount of the compound (VI), and the reaction is carried out for 2 to 4 hours;

d. In a mixed solvent of acetonitrile-water at 50 ° C to 60 ° C, the compound (V) is hydrolyzed with the alkaline reagent triethylamine to form the compound (IV), and the amount of the triethylamine is the molar amount of the compound (V). 1 to 5 times the amount, the reaction is 10 to 14 hours;

e. The compound (IV) is halogenated with a halogenating reagent, thionyl chloride, at 70 ° C to 90 ° C in a toluene solvent to form a compound (III). The diastereomer purity of the compound (III) is greater than or equal to 90%, the amount of the thionyl chloride is 5 to 10 times the molar amount of the compound (IV), and the reaction is carried out for 48 to 96 hours;

f. In the mixed solvent of dichloromethane and toluene at -30 ° C to 30 ° C, the compound (III) is substituted with the compound (II) alanine isopropyl ester to form compound (I), and the reaction is selective. Adding the alkaline reagent triethylamine, the compound (II) is used in an amount of 1 to 3 times the molar amount of the compound (III), and the reaction is carried out for 1 to 2 hours, and the diastereomer purity of the compound (I) is 90 or more. %;or

g. In the mixed solvent of dichloromethane and toluene at -40 ° C to 30 ° C, compound (III) and compound (IX) alanine isopropyl ester are substituted to form compound (I), compound (IX) The amount of the compound (III) is 3 to 5 times the molar amount, and the reaction is carried out for 1 to 2 hours, and the diastereomer purity of the compound (I) is 90% or more;

Wherein R ¹ , R ² and A are as defined above.

The present invention provides a compound of the formula (V), characterized in that:

Wherein R ¹ and R ² are as defined above.

Detailed description of the invention:

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The elements carbon, hydrogen, oxygen, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the elements and carbons, hydrogen, oxygen and sulfur involved in the groups and compounds of the present invention. Or the nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, and the hydrogen isotopes include ruthenium (H), ruthenium (D, also known as heavy hydrogen),氚 (T, also known as super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, nitrogen isotopes include ¹⁴ N and ¹⁵ N, fluorine isotope ¹⁹ F, and chlorine isotopes include ³⁵ Cl and ³⁷ Cl.

The "aromatic solvent" means a solvent having an aromatic ring in its molecular structure, and non-limiting examples include benzene, toluene, ethylbenzene, xylene or chlorobenzene.

"Optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "halogenation reaction can be selectively added to the catalyst" means that the catalyst can be added to the reaction without necessarily adding to the reaction.

detailed description

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). ), the internal standard is tetramethylsilane (TMS), and the external standard is 85% phosphoric acid aqueous solution.

The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.

Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The room temperature is an optimum temperature of 20 ° C to 30 ° C.

M is moles per liter.

Boc is a tert-butyloxycarbonyl group.

Example 1:

[(1R)-2-[6-[Di(tert-Butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1)

[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid

First step: 6-amino-9-[(2R)-2-(dichlorophosphorylmethoxy)propyl]indole (1B)

9-[2-(dichlorophosphorylmethoxy)propyl]purin-6-amine

[[(1R)-2-(6-Aminofluoren-9-yl)-1-methylethoxy]methyl]phosphoric acid (PMPA, Tenofovir) (1 kg, 3.48 mol) was dissolved in acetonitrile (5.0 L) Further, thionyl chloride (1.65 kg, 13.92 mol) was added dropwise at room temperature, and the mixture was heated to reflux for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel Kg, directly cast the next reaction.

Second step: 6-amino-9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]pyrene (1C)

9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-amine

6-Amino-9-[(2R)-2-(dichlorophosphorylmethoxy)propyl]indole (1B) (crude weight 1.6 kg) was dissolved in dichloromethane (7.0 L), and phenol was added. 725 g, 7.70 mol), cooled to -30 ° C, added triethylamine to adjust pH > 7, and warmed to room temperature overnight. Water (3.0 L) was added to the reaction mixture, and the mixture was separated, and the aqueous layer was extracted with methylene chloride (1.0 L×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, Add 4M aqueous hydrochloric acid (3.0 L), stir well, then add ethyl acetate (1.0 L × 2) for extraction, the aqueous phase is cooled to 0 ° C, add aqueous ammonia to adjust pH > 7, then add ethyl acetate (2.0 L × 2) The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated Base] 嘌呤 (1C) (850 g, two-step total yield 55.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.34 - 7.26 (m, 4H), 7.21 - 7.13 (m, 4H), 7.10 - 7.05 (m, 2H) ), 5.86 (s, 2H), 4.35 (dd, 1H), 4.19 - 4.10 (m, 2H), 4.08 - 3.98 (m, 1H), 3.90 (dd, 1H), 1.25 (d, 3H).

Third step: N-tert-butoxy-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indol-6-yl]carbamic acid tert-butyl ester ( 1D)

Tert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-yl]carbamate

6-Amino-9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indole (1C) (850 g, 1.93 mol) was dissolved in tetrahydrofuran (4.0 L), and dicarbonic acid was added. Di-tert-butyl ester (1266 g, 5.80 mol) was added to 4-dimethylaminopyridine (47 g, 0.38 mol) in three portions, and the mixture was warmed to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was evaporated to ethyl acetate (3.0L). Drying over sodium sulfate, filtration, and EtOAc (EtOAc) tert-Butylamino-6-ylcarbamate (1D), crude weight 1.4 kg, was used directly in the next reaction.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.83 (s, 1H), 8.17 (s, 1H), 7.37 - 7.28 (m, 4H), 7.25 - 7.13 (m, 6H), 4.48 - 4.39 (m, 1H) ), 4.28 (dd, 1H), 4.15 (dd, 1H), 4.09 - 4.00 (m, 1H), 4.01 - 3.91 (m, 1H), 1.51 - 1.39 (m, 18H), 1.22 (d, 3H).

Fourth step: [(1R)-2-[6-[bis(tert-butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1)

N-tert-Butoxy-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indol-6-yl]carbamic acid tert-Butyl ester (1D) (crude 1.4 kg) was dissolved in acetonitrile (3.2 L) and water (0.8L, acetonitrile: water (v:v) = 4:1), and triethylamine (979 g, 9.67 mol) was added. The temperature was raised to 50 ° C and allowed to react overnight. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove acetonitrile. <RTI ID=0.0>> 3M hydrochloric acid aqueous solution was added dropwise to adjust the pH = 1 to 3, and then extracted with dichloromethane (3 L × 2). The methylene chloride phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the desired product as a dark red oil. (1R)-2-[6-[bis(tert-butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1) ( 850 g, total yield of 78% in two steps).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ12.53 (s, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 7.29-7.19 (m, 4H), 7.02 (m, 1H), 4.43 ( d, 1H), 4.23 (dd, 1H), 3.91 (m, 2H), 3.66 - 3.61 (m, 1H), 1.42 (s, 18H), 1.09 (d, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 15.05.

Example 2

6-Amino-9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]isopropyl]anthracene (Compound 2)

9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine

[(1R)-2-[6-[Di(tert-Butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1 (200 g, 0.355 mol) dissolved in toluene (2.0 L), added with thionyl chloride (422 g, 3.55 mol), and warmed to 90 ° C for 48 hours. After the reaction, the diastereomer of compound 2 was monitored by HPLC. The purity of the isomer, and the purity of the diastereomer is 90% or more, and the reaction is stopped. The reaction mixture was evaporated under reduced pressure to give the title compound 6-amino-9-[(2.sup. The crude product was 150 g and used directly in the next reaction.

Example 3

9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine

[(1R)-2-[6-[Di(tert-Butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1 (1500 g, 2.66 mol) was dissolved in toluene (15.0 L), thionyl chloride (1582.7 g, 13.3 mol) was added, and the temperature was raised to 90 ° C for 48 hours. During the reaction, the diastereomeric reaction of compound 2 was monitored by HPLC. The purity of the isomer, and the purity of the diastereomer is 90% or more, and the reaction is stopped. The reaction mixture was evaporated under reduced pressure to give the title compound 6-amino-9-[(2.sup. The crude product was 1015 g and used directly for the next reaction.

Example 4

(2S)-2-[[[(1R)-2-(6-aminofluoren-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate Propyl ester (compound 3)

Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

L-alanine isopropyl ester hydrochloride (52.5 g, 0.314 mol) was dissolved in dichloromethane (200 mL), then 6-amino-9-[(2R)-2-[[chloro(phenoxy) A solution of the phosphonyl]methoxy]isopropyl]indole (Compound 2) (crude 60g) in toluene (300 mL) was added to the reaction mixture. After the addition was completed, the mixture was cooled to -25 ° C, and triethylamine (31.8) was added dropwise. g, 0.314 mol), the reaction was stirred for 1 hour after the completion of the dropwise addition, and the reaction was terminated. A 10% aqueous solution of sodium dihydrogen phosphate (400 mL) was added to the reaction mixture, and the mixture was thoroughly stirred and extracted. The organic phase was extracted with a 15% aqueous solution of potassium hydrogencarbonate (170 mL), and the organic phase was applied with deionized water (150 mL). ×1) Washing, drying over anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure to give (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethyl A crude product of oxy]methyl-phenoxy-phosphino]amino]propionic acid isopropyl ester (Compound 3).

The crude compound 3 was added to a mixed solvent of acetonitrile (12 mL) and toluene (108 mL) (acetonitrile / toluene (v / v) = 1:9), and the mixture was stirred at room temperature for 6 hours, and then the solid was analyzed and filtered, and the cake was filtered. (200 mL) was washed and the filter cake was dried to give purified product Compound 3 (30 g, yield 35%, HPLC purity 95.10%, chiral HPLC diastereomer purity 96.04%).

If desired, to obtain a higher diastereomeric purity of Compound 3, the following operation can be continued: Compound 3 (30 g) is added to acetonitrile (120 mL), warmed to reflux for 1 hour, and then naturally cooled to ambient temperature. After stirring for 6 hours, the solid was analyzed and filtered, and the filter cake was washed with acetonitrile (40 mL). Compound 3 (15 g, HPLC purity 99.40%, chiral HPLC diastereomer purity 99.79%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.33 (s, 1H), 7.99 (s, 1H), 7.19 (m, 2H), 7.10 (m, 1H), 7.00 (m, 2H), 6.18 (bs, 2H), 5.01 (m, 1H), 4.33 (dd, 1H), 4.12 (m, 3H), 3.88 (m, 2H), 3.67 (m, 1H), 1.28 (d, 3H), 1.22 (m, 9H) ).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.5.

Example 5

L-alanine isopropyl ester (232.5 g, 1.78 mol) was dissolved in dichloromethane (1000 mL), cooled to -25 ° C, then 6-amino-9-[(2R)-2-[[chlorine A solution of (phenoxy)phosphono]methoxy]isopropyl]indole (Compound 2) (crude 149 g) in toluene (600 mL) was added to the reaction mixture, and after the addition was completed, the reaction was further stirred for 1 hour, and then the reaction was completed. 10% aqueous sodium dihydrogen phosphate solution (1.2 L) was added to the reaction solution, and the mixture was thoroughly stirred and extracted. The organic phase was extracted with 15% aqueous potassium hydrogencarbonate solution (0.5 L), and the organic phase was sequentially treated with deionized water. (0.5L × 1) washing, drying with anhydrous sodium sulfate, filtration, and the filtrate was concentrated under reduced pressure to give (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-yl A crude product of isopropyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate (Compound 3).

The crude compound 3 was added to a mixed solvent of acetonitrile (40 mL) and toluene (360 mL) (acetonitrile / toluene (v / v) = 1:9), and the mixture was stirred at room temperature for 6 hours, and then the solid was analyzed and filtered. (400 mL) was washed and the filter cake was dried to give purified product Compound 3 (120 g, yield 71%, HPLC purity: 99.39%, chiral HPLC diastereomer purity 96.05%).

If desired, to obtain a higher diastereomeric purity of Compound 3, the following operation can be continued: Compound 3 is added to acetonitrile (600 mL), warmed to reflux for 1 hour, and then naturally cooled to room temperature for 6 hours. After that, the solid was taken up and filtered, filtered, washed with acetonitrile (200 mL), and filtered to give purified product compound 3 (102 g, HPLC purity: 99.86%, chiral HPLC diastereomer purity: 98.98%).

Example 6

L-Alanine isopropyl ester (1742 g, 13.3 mol) was dissolved in dichloromethane (7.0 L), cooled to -25 ° C, then 6-amino-9-[(2R)-2-[[chlorine A solution of (phenoxy)phosphono]methoxy]isopropyl]indole (Compound 2) (crude 1015 g) in toluene (6.0 L) was added to the reaction mixture, and the mixture was stirred. 10% aqueous sodium dihydrogen phosphate solution (9.0 L) was added to the reaction solution, and the mixture was thoroughly stirred and extracted. The organic phase was extracted with 15% aqueous potassium hydrogencarbonate solution (3.75 L), and the organic phase was sequentially treated with deionized water. (3.75 L × 1) Wash, dry over anhydrous sodium sulfate, filtered, and then filtrated to give (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl A crude product of isopropyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate (Compound 3).

The crude compound 3 was added to a mixed solvent of acetonitrile (0.24 L) and toluene (2.16 L) (acetonitrile/toluene (v/v) = 1:9), and the mixture was stirred at room temperature for 6 hours, and the solid was analyzed, filtered, and filtered. After washing with toluene (3.0 L), the cake was dried to give purified product compound 3 (700 g, yield 55%, HPLC purity 97.97%, chiral HPLC diastereomer purity 94.28%).

If desired, to obtain a higher diastereomeric purity of Compound 3, the following operation can be continued: Compound 3 is added to acetonitrile (3.5 L), heated to reflux for 1 hour, and then naturally cooled to room temperature with stirring 6 After an hour, the solid was taken up and filtered, filtered, washed with acetonitrile (500 mL).

Claims

A method for preparing a compound represented by formula (III):

It is characterized in that the compound (IV) is halogenated with a halogenated reagent to form a compound (III) in a solvent of 50 ° C to 110 ° C and a toluene solvent;

Wherein the compound (III) has a diastereomer purity of at least 90% or more;

R 1 and R 2 are each independently selected from t-butoxycarbonyl or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time;

The halogenating agent is selected from the group consisting of thionyl chloride.
The method of claim 1 wherein:

The reaction temperature is from 70 ° C to 90 ° C.
The method of claim 1 wherein:

The reaction time is from 48 hours to 96 hours.
A method for preparing a compound represented by the formula (I):

The compound (III) is substituted with the compound (II) to form the compound (I) in a mixed solvent of -50 ° C to 30 ° C and toluene and dichloromethane;

Wherein A is selected from the group consisting of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid.
The method of claim 4 wherein:

The reaction may optionally be added with the alkaline reagent triethylamine;

The reaction temperature is -30 ° C ~ 30 ° C;

The diastereomer purity of the compound (I) is at least 90% or more.
A method for preparing a compound represented by the formula (I):

The compound (III) is substituted with the compound (IX) to form the compound (I) in a mixed solvent of -40 ° C to 30 ° C and toluene and dichloromethane;

The diastereomer purity of the compound (I) is at least 90% or more.
A method for preparing a compound represented by the formula (I), characterized in that the method comprises the steps of:

a. The acetonitrile solvent, the compound (VIII) is halogenated with thionyl chloride to form the compound (VII), the halogenating agent is selected from the group consisting of thionyl chloride or oxalyl chloride, and the halogenation reaction is selective. Catalyst added, the catalyst is selected from N,N-dimethylformamide;

b. In a dichloromethane solvent, compound (VII) and phenol are substituted by the action of the alkaline reagent triethylamine to form compound (VI);

c. In the tetrahydrofuran solvent, the compound (VI) is reacted with the amino-protecting reagent di-tert-butyl dicarbonate to form the compound (V), and the catalyst 4-dimethylaminopyridine is added to the reaction;

d. In the solvent, the compound (V) is hydrolyzed with an alkaline reagent to form a compound (IV), the solvent is selected from one or a combination of acetonitrile and water, and the alkaline agent is selected from the group consisting of triethylamine and One or a combination of ammonia water;

e. In the toluene solvent, the compound (IV) is halogenated with the halogenating reagent thionyl chloride to form the compound (III), and the diastereomer purity of the compound (III) is 90% or more;

f. In a mixed solvent of dichloromethane and toluene, the compound (III) is substituted with the compound (II) alanine isopropyl ester to form the compound (I), and the alkaline reagent triethylamine is optionally added. The diastereomer purity of the compound (I) is 90% or more; or

g. In a mixed solvent of dichloromethane and toluene, the compound (III) is substituted with the compound (IX) alanine isopropyl ester to form the compound (I), and the diastereomer purity of the compound (I) is greater than or equal to 90%;

Wherein R 1 and R 2 are as defined in claim 1;

The definition of A is as set forth in claim 4.
A compound of the formula (V) characterized by:

Wherein R 1 and R 2 are as defined in claim 1.