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CN114516866B - Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound - Google Patents

Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound Download PDF

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CN114516866B
CN114516866B CN202111478995.9A CN202111478995A CN114516866B CN 114516866 B CN114516866 B CN 114516866B CN 202111478995 A CN202111478995 A CN 202111478995A CN 114516866 B CN114516866 B CN 114516866B
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CN114516866A (en
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李强
刘华权
王春健
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Nanjing Zhuoke Pharmaceutical Technology Co.,Ltd.
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Nanjing Choipharm Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a preparation method of a chiral 4-alkyl-pyrrole-3-formic acid compound, which utilizes the space effect of Evans chiral prosthetic groups to realize asymmetric hydrogenation reduction by metal catalytic hydrogenation so as to obtain a chiral target compound. Compared with the prior art, the invention can use the achiral pyrrolidine-3-formic acid with low price as the starting material, thereby reducing the production cost. Avoiding the use of hazardous reagents such as nitromethane, sodium borohydride and the like and improving the safety of the production process.

Description

Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 4-alkyl-pyrrole-3-formic acid compound.
Background
Wu Pati is a JAK kinase inhibitor and is approved by the FDA in 2019 for the treatment of moderate to severe adult rheumatoid arthritis, and has a structure shown in formula 1.
In the synthetic route of Wu Pati, compound 2 is an important intermediate thereof, both chiral centers of the lapatinib being taken in by it.
In chinese patent application CN108368121a, several methods for the preparation of compound 2 are disclosed.
Route one is as follows:
in the first route, ethyl pent-2-ynoate is used as a starting material, and is partially reduced into ethyl Z-pent-2-enoate under the action of a Lindlar catalyst, then the ethyl Z-pent-2-enoate reacts with N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine, the obtained compound is hydrogenated and debenzylated, an ester bond of the hydrogenated and debenzylated compound is further hydrolyzed, then N- (benzyloxycarbonyloxy) succinimide is used, secondary amine is protected by Cbz, and finally chiral 1- (naphthalene-1-yl) ethylamine is used for resolution, so that chiral compound is obtained.
Route two is shown below:
wherein R is selected from methyl, trifluoromethyl and p-tolyl.
Route two use Cbz protected glycine ethyl ester and ethyl acrylate under strong alkali conditions, such as tertiary butyl alcohol sodium reaction, form unsaturated substituted pyrrole, then with three fluoro methyl sulfonyl anhydride, methyl sulfonyl chloride, p-toluene sulfonyl chloride reaction, hydroxyl group conversion to sulfonate, further with ethyl boric acid, ethyl magnesium bromide, ethyl zinc chloride reaction, ethyl substituted compounds obtained further ester hydrolysis, then the unsaturated pyrrole compounds obtained using chiral phosphine and ruthenium catalyst, such as diacetate [(s) - (-) -5,5 '-two (diphenyl phosphine) -4, 4' -two-1, 3-benzene two oxygen two cyclopentene]Ruthenium (II) ((S) -Segphos Ru (OAc) 2 ) Hydrogenation reaction is carried out to obtain chiral compound 2.
In WO2019016745 another method of preparation of compound 2 is disclosed as follows:
in the path, diethyl malonate is firstly used to react with propionaldehyde to obtain diethyl 2-methylene acrylate, then the diethyl malonate is reacted with nitromethane, the obtained compound is hydrogenated, reduced and closed, the pyrrole ring secondary amine is further protected by using Boc anhydride, the compound is reduced by using sodium borohydride, the reduced compound is hydrogenated and reduced again, then the Boc protecting group and the ester bond are further removed by acid hydrolysis, the secondary amine is further protected by using Cbz protecting group, and the chiral 1- (naphthalene-1-yl) ethylamine is used for resolution to obtain the compound 2.
It is clear that in the prior art, the routes for preparing compound 2 with 2 chiral centers are long, and some routes require the last step of resolution by chiral base, so that the yield loss is large. Some synthesis processes require the use of hazardous reagents such as nitromethane, sodium borohydride, and the like. Some synthetic routes require the use of expensive transition metal catalysts. Thus, there remains a need for an improved process for preparing compound 2 and analogs thereof.
Disclosure of Invention
The invention aims to: in order to solve the technical problems in the prior art, the invention provides a preparation method of a 4-alkyl-pyrrole-3-formic acid compound, which utilizes the steric effect of Evans prosthetic groups to prepare the compound 4-alkyl-pyrrole-3-formic acid or similar alkyl substituted compounds,
in order to achieve the above purpose, the invention provides a preparation method of chiral 4-alkyl-pyrrole-3-carboxylic acid compounds, which is characterized by comprising the following steps:
1) Reacting an organolithium reagent with (R) -4-benzyl-2-oxazolidinone to form a lithium complex, and then reacting with N-benzyloxycarbonyl pyrrolidine-3-carboxylic acid to obtain a compound 5; preferably, the step is carried out by taking tetrahydrofuran or 2-methyltetrahydrofuran as a solvent;
2) Under the action of organic amine, after the compound 5 reacts with tributylboron triflate, N-bromosuccinimide is added to obtain a compound 7, and preferably, dichloromethane is used as a solvent in the step;
3) Reacting the compound 7 with an aldehyde RCHO after the action of n-butyllithium to obtain a compound 8, wherein R in the aldehyde RCHO is a C1-C6 linear alkyl, branched alkyl or cycloalkyl, and preferably tetrahydrofuran or 2-methyltetrahydrofuran is used as a solvent;
4) Hydrogenating the compound 8 under normal pressure under the action of a nickel catalyst to obtain a compound 9;
5) Hydrolyzing the compound 9 to obtain a compound 2;
wherein the organic lithium reagent in the step 1) is n-butyllithium or lithium bis (trimethylsilyl) amide. Preferably, the organolithium reagent is lithium bistrimethylsilylamino.
In the step 1), the molar ratio of (R) -4-benzyl-2-oxazolidone, N-carbobenzoxy pyrrolidine-3-formic acid and organic lithium is 1 (1.0-1.5), preferably the molar ratio of (R) -4-benzyl-2-oxazolidone, N-carbobenzoxy pyrrolidine-3-formic acid and organic lithium is 1:1.1:1.2. In a more preferred method, the molar ratio of (R) -4-benzyl-2-oxazolidinone, N-benzyloxycarbonyl pyrrolidine-3-carboxylic acid to organolithium is 1:1.1:1.2, and the organolithium is lithium bis trimethylsilylamide.
The reaction temperature of the step 1) is-50 to-40 ℃ and the reaction time is 0.8 to 2 hours.
The organic amine in the step 2) is diisopropylethylamine or triethylamine.
In the step 2), the molar ratio of the compound 5 to the dibutyl boron triflate to the organic amine to the N-bromosuccinimide is 1 (1.0-1.5): 1.1-1.6): 1.1-1.4. Preferably, the molar ratio of compound 5, dibutyl boron triflate, organic amine and N-bromosuccinimide is 1:1.1:1.4:1.1. In a more preferred method, the organic amine is triethylamine and the molar ratio of compound 5, dibutyl boron triflate to triethylamine to N-bromosuccinimide is 1:1.1:1.4:1.1.
The reaction temperature of the step 2) is-78 ℃ to-65 ℃ and the reaction time is 0.5 to 2 hours;
in step 3), the molar ratio of the compound 7, n-butyllithium and the aldehyde RCHO is 1 (1.0-1.2): (1.3-2.0), preferably the molar ratio of the compound 7, n-butyllithium and the aldehyde RCHO is 1:1.1:1.5.
In the step 3), the reaction is carried out for 0.5 to 1 hour at the temperature of minus 78 ℃ to minus 65 ℃ and then stirred for 1.5 to 2 hours at the temperature of 0 ℃.
In step 4), the nickel catalyst is used in an amount of 5% to 20% by weight of the compound 7, preferably 10% by weight of the compound 7.
The nickel catalyst can be purchased as a commercial nickel hydrogenation catalyst or can be obtained by treating an aluminum nickel alloy with a NaOH solution.
Both starting materials N-carbobenzoxy pyrrolidine-3-carboxylic acid and (R) -4-benzyl-2-oxazolidinone are conventional commercially available chemicals and do not require pretreatment prior to use.
In the preparation process, the n-butyllithium reagent is 1.6mol/L of n-hexane solution, the lithium bis (trimethylsilyl) amide is 1mol/L of tetrahydrofuran solution, and the dibutyl boron triflate is 1mol/L of dichloromethane solution, which are all conventional commercial chemical reagents.
The lithium hydroxide solution used in the preparation process can be prepared by using anhydrous lithium hydroxide or lithium hydroxide monohydrate.
In the case of Wu Pa as an intermediate, R in the compound 2 is methyl. Other aldehydes RCHO (R is C1-C6 straight chain alkyl, branched alkyl, cycloalkyl) can also be used in the present invention to prepare the corresponding R-substituted compound 2.
In a more preferred method, compound 2 is prepared as follows:
step 1: dissolving the compound 4 in tetrahydrofuran with the volume-mass ratio of 5-times, cooling to below-40 ℃, dropwise adding 1.2 equivalents of lithium bistrimethylsilyl amide tetrahydrofuran solution, controlling the dropwise adding speed, controlling the temperature to be not higher than-40 ℃, stirring for 10 minutes after the dropwise adding is finished, dissolving 1.1 equivalents of the compound 3 in tetrahydrofuran with the volume-mass ratio of 3.2, dropwise adding, controlling the dropwise adding speed, and keeping the temperature to be not higher than-40 ℃. After the dropwise addition, reacting for 1 hour at the temperature of minus 50 ℃ to minus 40 ℃, adding saturated ammonium chloride solution, adding ethyl acetate, standing for layering, washing an upper organic phase with saturated sodium chloride solution for 3 times, concentrating the organic phase under reduced pressure until the organic phase is dried, adding ethyl acetate into the residue, stirring for dissolving, heating to 40+/-5 ℃, dropwise adding n-heptane, cooling to 5+/-5 ℃, stirring for crystallization, filtering out precipitated solid, washing with a mixed solvent of n-heptane and ethyl acetate, and drying in vacuum at 40+/-5 ℃ to obtain the compound 5.
Step 2: dissolving the compound 5 in dichloromethane with the volume-mass ratio of 5 times, adding 1.4 equivalent of triethylamine, cooling to-78 ℃, dropwise adding 1.1 equivalent of methylene dichloride solution of dibutyl boron triflate, controlling the dropwise adding speed, keeping the temperature not higher than-65 ℃, stirring for 30 minutes at-78 ℃ after the dropwise adding is finished, dissolving 1.1 equivalent of N-bromosuccinimide in dichloromethane with the volume-mass ratio of 3 times, dropwise adding, controlling the dropwise adding speed, dripping for about 1 hour, stirring for 60 minutes at-78 ℃ after the dropwise adding is finished, dropwise adding potassium hydrogen sulfate solution, adding ethyl acetate, separating out an organic phase, washing 3 times by using sodium thiosulfate solution, drying by using magnesium sulfate, and concentrating an organic phase to dryness to obtain oily matter. Is compound 7.
Step 3: dissolving the compound 7 in toluene with the volume-to-mass ratio of 5 times, concentrating under reduced pressure to dryness, adding tetrahydrofuran with the volume-to-mass ratio of 4 times to dissolve the residue, cooling to-78 ℃, dropwise adding 1.1 equivalent of n-butyllithium solution, keeping the temperature not higher than-65 ℃, dropwise adding 1.5 equivalent of tetrahydrofuran solution with the volume-to-mass ratio of 10 times of corresponding aldehyde, stirring for 30 minutes at-78 ℃, stirring for 2 hours at 0 ℃, adding potassium hydrogen sulfate solution, adding methyl tert-butyl ether, separating out an organic phase, washing 3 times with saturated sodium chloride solution, and directly carrying out the next reaction.
Step 4: to the solution of the above step was added a nickel catalyst in an amount of 10% by weight of compound 7, hydrogenated at normal pressure, and the reaction was monitored by TLC until the reaction was completed, the catalyst was filtered off, and the filtrate was directly subjected to the next reaction.
The reaction was monitored using GF254 silica gel plates with ethyl acetate in n-heptane=1:1 (v/v) and observed using a 254nm UV lamp.
Step 5: cooling the solution in the previous step to below 10 ℃, dissolving 2 equivalents of lithium hydroxide in water, adding the solution in the previous step, removing a cold bath, slowly heating to 20+/-5 ℃ for reaction, monitoring the reaction by TLC until the reaction is complete, adding methyl tertiary butyl ether and water into the reaction solution, standing for liquid separation, washing the water phase with the methyl tertiary butyl ether for 1 time, adjusting the pH value to 2-3 by 0.1mol/L of dilute hydrochloric acid, precipitating white solid, filtering, and vacuum drying at 40+/-5 ℃ to obtain the compound 2.
The reaction was monitored using GF254 silica gel plates with ethyl acetate in n-heptane=1:1 (v/v) and observed using a 254nm UV lamp.
The molecular weight of the obtained compound 2 was determined by mass spectrometry, optical rotation was measured by polarimeter, and the optical rotation value was similar to that of the commercially available compound 2 (Wu Pa tenib intermediate), confirming that the optical purity of the sample obtained by the method was good.
The beneficial effects are that: compared with the prior art, the method uses the induction effect of chiral prosthetic groups and uses a solid hydrogenation catalyst to carry out chiral reduction on the intermediate 8 to obtain the target compound 2. Compared with the prior art, the method can use the achiral pyrrolidine-3-formic acid with low price as the starting material, thereby reducing the production cost. Avoiding the use of hazardous reagents such as nitromethane, sodium borohydride and the like and improving the safety of the production process.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, which will aid in understanding the present invention, but the scope of the present invention is not limited to the following examples.
Example 1 synthesis of compound 5.
Compound 4 (100 g,0.56mol,1.0 eq.) was dissolved in tetrahydrofuran (500 ml), cooled to below-40 ℃, 1mol/L lithium bistrimethylsilylaminide in tetrahydrofuran (677 ml,0.677mol,1.2 eq.) was added dropwise, the dropping rate was controlled so that the reaction system temperature was not higher than-40 ℃, after the addition was completed, stirring was carried out for 10 minutes, compound 3 (154.7 g,0.62mol,1.1 eq.) was dissolved in tetrahydrofuran (500 ml), the addition was carried out dropwise, and the dropping rate was controlled so that the temperature was kept not higher than-40 ℃. After the completion of the dropwise addition, a saturated ammonium chloride solution (550 ml) was added, ethyl acetate (500 ml) was added, the mixture was allowed to stand and separate, the organic phase was washed with a saturated sodium chloride solution (300 ml. Times.3), the organic phase was concentrated to dryness under reduced pressure at 45℃and the residue was added with ethyl acetate (320 ml), stirred and dissolved, heated to 40.+ -. 5 ℃, n-heptane (1280 ml) was added dropwise, cooled to 5.+ -. 5 ℃, stirred and crystallized, the precipitated solid was filtered off, washed with a mixed solvent of n-heptane and ethyl acetate (5:1), and vacuum-dried at 40.+ -. 5 ℃ to give a total of 201.3g of compound 5, the yield of which was 87.3%. ESI-MS (+): 409.2[ M+H ]] +
Example 2 synthesis of compound 5.
Compound 4 (100 g,0.56mol,1.0 eq.) was dissolved in 2-methyltetrahydrofuran (500 ml), cooled to below-40 ℃, 1mol/L lithium bistrimethylsilylaminide in tetrahydrofuran (564 ml,0.56 mol,1.0 eq.) was added dropwise, the dropping rate was controlled so that the reaction system temperature was not higher than-40 ℃, after the addition was completed, stirring was carried out for 10 minutes, compound 3 (154.7 g,0.62mol,1.1 eq.) was dissolved in 2-methyltetrahydrofuran (500 ml), the dropping rate was controlled, and the temperature was kept not higher than-40 ℃. After the completion of the dropwise addition, a saturated ammonium chloride solution (450 ml) was added, ethyl acetate (500 ml) was added, the mixture was allowed to stand and separate, the organic phase was washed with a saturated sodium chloride solution (300 ml. Times.3), the organic phase was concentrated to dryness under reduced pressure at 45℃and the residue was added with ethyl acetate (320 ml), stirred and dissolved, heated to 40.+ -. 5 ℃, n-heptane (1280 ml) was added dropwise, cooled to 5.+ -. 5 ℃, stirred and crystallized, the precipitated solid was filtered off, washed with a mixed solvent of n-heptane and ethyl acetate (5:1), and dried under vacuum at 40.+ -. 5 ℃ to give a total of 199.07g of compound 5, the yield of which was 86.4%.
Example 3 synthesis of compound 5.
Compound 4 (100 g,0.56mol,1.0 eq.) was dissolved in tetrahydrofuran (500 ml), cooled to below-40 ℃, 1mol/L lithium bistrimethylsilylaminide in tetrahydrofuran (79ml, 0.79mol, 1.4 eq.) was added dropwise, the dropping rate was controlled so that the reaction system temperature was not higher than-40 ℃, after the addition was completed, stirring was carried out for 10 minutes, compound 3 (140.7 g,0.56mol,1.0 eq.) was dissolved in tetrahydrofuran (500 ml), the addition was carried out dropwise, and the dropping rate was controlled so that the temperature was kept not higher than-40 ℃. After the completion of the dropwise addition, a saturated ammonium chloride solution (640 ml) was added, ethyl acetate (500 ml) was added, the mixture was allowed to stand and separate, the organic phase was washed with a saturated sodium chloride solution (300 ml. Times.3), the organic phase was concentrated to dryness under reduced pressure at 45℃and the residue was added with ethyl acetate (320 ml), stirred and dissolved, heated to 40.+ -. 5 ℃, n-heptane (1280 ml) was added dropwise, cooled to 5.+ -. 5 ℃, stirred and crystallized, the precipitated solid was filtered off, washed with a mixed solvent of n-heptane and ethyl acetate (5:1), and dried under vacuum at 40.+ -. 5 ℃ to give a total of 209.81g of compound 5, the yield of which was 91.0%.
Example 4 synthesis of compound 5.
Compound 4 (100 g,0.56mol,1.0 eq.) was dissolved in tetrahydrofuran (500 ml), cooled to below-40 ℃, 1mol/L lithium bistrimethylsilylaminide in tetrahydrofuran (846 ml,0.846mol,1.5 eq.) was added dropwise, the dropping rate was controlled so that the reaction system temperature was not higher than-40 ℃, after the addition was completed, stirring was carried out for 10 minutes, compound 3 (211 g,0.85mol,1.5 eq.) was dissolved in tetrahydrofuran (700 ml), the dropping rate was controlled, and the temperature was kept not higher than-40 ℃. After the completion of the dropwise addition, a saturated ammonium chloride solution (680 ml) was added, ethyl acetate (500 ml) was added, the mixture was allowed to stand and separate, the organic phase was washed with a saturated sodium chloride solution (300 ml. Times.3), the organic phase was concentrated to dryness under reduced pressure at 45℃and the residue was added with ethyl acetate (320 ml), stirred and dissolved, heated to 40.+ -. 5 ℃, n-heptane (1280 ml) was added dropwise, cooled to 5.+ -. 5 ℃, stirred and crystallized, the precipitated solid was filtered off, washed with a mixed solvent of n-heptane and ethyl acetate (5:1), and dried under vacuum at 40.+ -. 5 ℃ to give a total of 203.67g of compound 5, the yield of which was 88.4%.
Example 5 synthesis of compound 5.
Compound 4 (100 g,0.56mol,1.0 eq.) was dissolved in tetrahydrofuran (500 ml), cooled to below-40 ℃, 1mol/L lithium bistrimethylsilylaminide in tetrahydrofuran (677 ml,0.677mol,1.2 eq.) was added dropwise, the dropping rate was controlled so that the reaction system temperature was not higher than-40 ℃, after the addition was completed, stirring was carried out for 10 minutes, compound 3 (182.9 g,0.73mol,1.3 eq.) was dissolved in tetrahydrofuran (500 ml), the addition was carried out dropwise, and the dropping rate was controlled so that the temperature was kept not higher than-40 ℃. After the completion of the dropwise addition, a saturated ammonium chloride solution (540 ml) was added, ethyl acetate (500 ml) was added, the mixture was allowed to stand and separate, the organic phase was washed with a saturated sodium chloride solution (300 ml. Times.3), the organic phase was concentrated to dryness under reduced pressure at 45℃and the residue was added with ethyl acetate (320 ml), stirred and dissolved, heated to 40.+ -. 5 ℃, n-heptane (1280 ml) was added dropwise, cooled to 5.+ -. 5 ℃, stirred and crystallized, the precipitated solid was filtered off, washed with a mixed solvent of n-heptane and ethyl acetate (5:1), and dried under vacuum at 40.+ -. 5 ℃ to give a total of 203.4g of compound 5, the yield of which was 88.3%.
Example 6 synthesis of compound 5.
Compound 4 (100 g,0.56mol,1.0 eq.) was dissolved in tetrahydrofuran (500 ml), cooled to below-70 ℃,1.6 mol/L n-hexane solution of n-butyllithium (423 ml,0.677mol,1.2 eq.) was added dropwise, the dropping speed was controlled so that the reaction system temperature was not higher than-40 ℃, after the completion of the addition, stirring was carried out for 10 minutes, compound 3 (154.7 g,0.62mol,1.1 eq.) was dissolved in tetrahydrofuran (500 ml), the addition was carried out dropwise, and the dropping speed was controlled so that the temperature was kept not higher than-40 ℃. After the completion of the dropwise addition, a saturated ammonium chloride solution (540 ml) was added, ethyl acetate (500 ml) was added, the mixture was allowed to stand and separate, the organic phase was washed with a saturated sodium chloride solution (300 ml. Times.3), the organic phase was concentrated to dryness under reduced pressure at 45℃and the residue was added with ethyl acetate (320 ml), stirred and dissolved, heated to 40.+ -. 5 ℃, n-heptane (1280 ml) was added dropwise, cooled to 5.+ -. 5 ℃, stirred and crystallized, the precipitated solid was filtered off, washed with a mixed solvent of n-heptane and ethyl acetate (5:1), and dried under vacuum at 40.+ -. 5 ℃ to give a total of 186.0g of compound 5, the yield of which was 80.7%.
Example 7 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), triethylamine (71.4 ml,0.514mol,1.4 eq.) was added, the temperature was reduced to-78 ℃, a 1mol/L solution of dibutyl boron triflate in dichloromethane (404 ml,0.404mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, stirring was continued for another 30 minutes at-78 ℃, N-bromosuccinimide (71.9 g,0.404mol,1.1 eq.) was dissolved in dichloromethane (220 ml), the dropwise acceleration was controlled, the dropwise was completed for about 1 hour, stirring was continued for 60 minutes at-78 ℃, a 10% potassium hydrogen sulfate solution (900 ml) was added dropwise, the organic phase was separated, washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried at 45 ℃ under reduced pressure to give an oily substance. Compound 7, 136.98g total, yield 76.5%. ESI-MS (+): 487.1[ M+H ]] + ,489.1.
Example 8 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), triethylamine (56.2 ml,0.403mol,1.1 eq.) was added, the temperature was reduced to-78 ℃, a 1mol/L solution of dibutyl boron triflate in dichloromethane (404 ml,0.404mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, stirring was continued for another 30 minutes at-78 ℃, N-bromosuccinimide (71.9 g,0.404mol,1.1 eq.) was dissolved in dichloromethane (220 ml), the dropwise acceleration was controlled, the dropwise was completed for about 1 hour, stirring was continued for 60 minutes at-78 ℃, a 10% potassium hydrogen sulfate solution (900 ml) was added dropwise, the organic phase was separated, washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried at 45 ℃ under reduced pressure to give an oily substance. Compound 7, total 140.22g, yield 78.3%.
Example 9 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), triethylamine (81.7 ml,0.588mol,1.6 eq.) was added, the temperature was reduced to-78 ℃, a 1mol/L solution of dibutyl boron triflate in dichloromethane (404 ml,0.404mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, stirring was continued for another 30 minutes at-78 ℃, N-bromosuccinimide (71.9 g,0.404mol,1.1 eq.) was dissolved in dichloromethane (220 ml), the dropwise acceleration was controlled, dripping was completed for about 1 hour, stirring was continued for 60 minutes at-78 ℃, a 10% potassium hydrogen sulfate solution (900 ml) was added dropwise, the organic phase was separated, washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried under 45 ℃ under reduced pressure, to give an oily substance. Compound 7, 138.23g total, yield 77.2%.
Example 10 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), triethylamine (71.5 ml,0.514mol,1.4 eq.) was added, cooled to-78 ℃, a 1mol/L solution of dibutyl boron triflate in dichloromethane (367 ml,0.367mol,1 eq.) was added dropwise, the dropwise addition rate was controlled, the temperature was kept at not higher than-65 ℃, stirring was further carried out at-78 ℃ for 30 minutes, N-bromosuccinimide (71.9 g,0.404mol,1.1 eq.) was dissolved in dichloromethane (220 ml), the dropwise addition was controlled, the dropwise addition rate was controlled, the dropwise addition was completed for about 1 hour, stirring was carried out at-78 ℃ for 60 minutes, a 10% potassium hydrogen sulfate solution (900 ml) was added, an organic phase was separated, washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried at 45 ℃ under reduced pressure to obtain a dry oily substance. Compound 7, total 139.57g, yield 78.0%.
Example 11 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), triethylamine (71.5 ml,0.514mol,1.4 eq.) was added, the temperature was reduced to-78 ℃, a 1mol/L solution of dibutyl boron triflate in dichloromethane (551 ml,0.551mol,1.5 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, stirring was continued for another 30 minutes at-78 ℃, N-bromosuccinimide (71.9 g,0.404mol,1.1 eq.) was dissolved in dichloromethane (220 ml), the dropwise acceleration was controlled, the dropwise addition was completed for about 1 hour, stirring was continued for 60 minutes at-78 ℃, a 10% potassium hydrogen sulfate solution (900 ml) was added dropwise, an organic phase was separated, washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried at 45 ℃ under reduced pressure to give an oily substance. Compound 7, 132.86g in total, yield 74.2%.
Example 12 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), triethylamine (71.5 ml,0.514mol,1.4 eq.) was added, the temperature was reduced to-78 ℃, a 1mol/L solution of dibutyl boron triflate in dichloromethane (477 ml,0.477mol,1.3 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, stirring was continued for another 30 minutes at-78 ℃, N-bromosuccinimide (71.9 g,0.404mol,1.1 eq.) was dissolved in dichloromethane (220 ml), the dropwise acceleration was controlled, the dropwise addition was completed for about 1 hour, stirring was continued for 60 minutes at-78 ℃, a 10% potassium hydrogen sulfate solution (900 ml) was added dropwise, the organic phase was separated, washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried at 45 ℃ under reduced pressure to give an oily substance. Compound 7, 129.82g total, yield 72.5%.
Example 13 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), triethylamine (71.5 ml,0.514mol,1.4 eq.) was added, the temperature was lowered to-78 ℃, a 1mol/L solution of dibutyl boron triflate in dichloromethane (404 ml,0.404mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, stirring was carried out for another 30 minutes at-78 ℃, N-bromosuccinimide (65.4 g,0.367mol,1 eq.) was dissolved in dichloromethane (200 ml), the dropwise acceleration was controlled, the dropwise was completed for about 1 hour, stirring was carried out for 60 minutes at-78 ℃, a 10% potassium hydrogen sulfate solution (900 ml) was added dropwise, an organic phase was separated, washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried at 45 ℃ until it was dried under reduced pressure, to obtain an oily substance. Compound 7, 130.92g in total, yield 73.2%.
Example 14 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), triethylamine (71.5 ml,0.514mol,1.4 eq.) was added, the temperature was reduced to-78 ℃, a 1mol/L solution of dibutyl boron triflate in dichloromethane (404 ml,0.404mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, stirring was continued for another 30 minutes at-78 ℃, N-bromosuccinimide (91.5 g,0.514mol,1.4 eq.) was dissolved in dichloromethane (275 ml), the dropwise acceleration was controlled, the dropwise was completed for about 1 hour, stirring was continued for 60 minutes at-78 ℃, a 10% potassium hydrogen sulfate solution (900 ml) was added dropwise, the organic phase was separated, washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried at 45 ℃ under reduced pressure to give an oily substance. Compound 7, 134.86g total, yield 75.35%.
Example 15 synthesis of compound 7.
Compound 5 (150 g,0.367mol,1 eq.) was dissolved in dichloromethane (750 ml), diisopropylethylamine (89.6 ml,0.514mol,1.4 eq.) was added, cooled to-78 ℃, a 1mol/L solution of dibutylboron triflate in dichloromethane (404 ml,0.404mol,1.1 eq.) was added dropwise, the dropwise addition was controlled at a temperature of not higher than-65 ℃, stirring was carried out for another 30 minutes at-78 ℃, N-bromosuccinimide (71.9 g,0.404mol,1.1 eq.) was dissolved in dichloromethane (220 ml), the dropwise addition was controlled at a speed of about 1 hour, stirring was carried out for 60 minutes at-78 ℃, a 10% potassium hydrogen sulfate solution (900 ml) was added dropwise, an ethyl acetate (750 ml) was separated, the organic phase was washed with a sodium thiosulfate solution (250 ml×3), and the organic phase was dried at 45 ℃ under reduced pressure to give a dry oily substance. Compound 7, 128.83g total, yield 71.98%.
Example 16 compound 2 was prepared from compound 7 using acetaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (141 ml,0.226mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, acetaldehyde (17.3 ml,0.308mol,1.5 eq.) was dissolved in tetrahydrofuran (173 ml), the dropwise addition was entered, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, after completion of the dropwise addition, stirring was carried out at-78 ℃ for 30 minutes, stirring was carried out at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl tert-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was directly carried out.
Raney nickel (10 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to 10℃or lower, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the above solution, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum-dried at 40.+ -. 5 ℃ for 37.16g in total, and the yield was 65.3% to give compound 2.
ESI-MS(+)：278.2[M+H] +
Optical rotation [ alpha ] D= + 32.7 ° (0.1 mol/L NaOH solution, C=0.1 g/ml)
Example 17 compound 2 was prepared from compound 7 using acetaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (128 ml,0.205mol,1 eq.) was added dropwise, the dropping rate was controlled, the temperature was kept at not higher than-65 ℃, acetaldehyde (17.3 ml,0.308mol,1.5 eq.) was dissolved in tetrahydrofuran (173 ml), the dropping rate was controlled, the temperature was kept at not higher than-65 ℃, and stirring was carried out at-78 ℃ for 30 minutes and then at 0 ℃ for 2 hours. 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl t-butyl ether (300 ml) was added, and the organic phase was separated, washed with saturated sodium chloride solution (300 ml. Times.3) and directly subjected to the next reaction.
Raney nickel (10 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to 10℃or lower, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the above solution, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum-dried at 40.+ -. 5 ℃ for 30.90g in total, and the yield was 54.3% as compound 2.
Example 18 compound 2 was prepared from compound 7 using acetaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (154 ml,0.246mol,1.2 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, acetaldehyde (17.3 ml,0.308mol,1.5 eq.) was dissolved in tetrahydrofuran (173 ml), the dropwise addition was entered, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, after completion of the dropwise addition, stirring was carried out at-78 ℃ for 30 minutes, stirring was carried out at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl tert-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was directly carried out.
Raney nickel (10 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to 10℃or lower, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the above solution, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum-dried at 40.+ -. 5 ℃ for 37.67g in total, and the yield was 66.2% as compound 2.
Example 19 compound 2 was prepared from compound 7 using acetaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (141 ml,0.226mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, acetaldehyde (15.0 ml,0.267mol,1.3 eq.) was dissolved in tetrahydrofuran (150 ml), the dropwise addition was entered, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, after completion of the dropwise addition, stirring was carried out at-78 ℃ for 30 minutes, stirring was carried out at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl tert-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was directly carried out.
Raney nickel (10 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to 10℃or lower, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the above solution, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum-dried at 40.+ -. 5 ℃ for 35.96g in total, and the yield was 63.2% as compound 2.
Example 20 compound 2 was prepared from compound 7 using acetaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (141 ml,0.226mol,1.1 eq.) was added dropwise, the dropping speed was controlled, the temperature was kept at not higher than-65 ℃, acetaldehyde (23.1 ml,0.410mol,2 eq.) was dissolved in tetrahydrofuran (231 ml), the dropping speed was controlled, the temperature was kept at not higher than-65 ℃, after the completion of the dropping, stirred at-78 ℃ for 30 minutes, stirred at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl t-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was directly carried out.
Raney nickel (10 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to 10℃or lower, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the above solution, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum-dried at 40.+ -. 5 ℃ for 40.02g in total, and the yield was 70.3% as compound 2.
Example 21 compound 2 was prepared from compound 7 using acetaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (141 ml,0.226mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, acetaldehyde (17.3 ml,0.308mol,1.5 eq.) was dissolved in tetrahydrofuran (173 ml), the dropwise addition was entered, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, after completion of the dropwise addition, stirring was carried out at-78 ℃ for 30 minutes, stirring was carried out at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl tert-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was directly carried out.
Raney nickel (5 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to 10℃or lower, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the above solution, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum-dried at 40.+ -. 5 ℃ for 33.69g in total, and the yield was 59.2% as compound 2.
Example 22 compound 2 was prepared from compound 7 using acetaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (141 ml,0.226mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, acetaldehyde (17.3 ml,0.308mol,1.5 eq.) was dissolved in tetrahydrofuran (173 ml), the dropwise addition was entered, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, after completion of the dropwise addition, stirring was carried out at-78 ℃ for 30 minutes, stirring was carried out at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl tert-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was directly carried out.
Raney nickel (20 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to 10℃or lower, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the above solution, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum-dried at 40.+ -. 5 ℃ for 36.82g in total, and the yield was 64.7% as compound 2.
Example 23 compound 2b was prepared from compound 7 using isobutyraldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (141 ml,0.226mol,1.1 eq.) was added dropwise, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, isobutyraldehyde (28.1 ml,0.308mol,1.5 eq.) was dissolved in tetrahydrofuran (230 ml), the dropwise addition was entered, the dropwise acceleration was controlled, the temperature was kept at not higher than-65 ℃, after completion of the dropwise addition, stirring was carried out at-78 ℃ for 30 minutes, stirring was carried out at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl tert-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was carried out directly.
Raney nickel (10 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to below 10 ℃, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the solution of the above step, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum dried at 40.+ -. 5 ℃ for 28.29g in total, and the yield was 45.2% as compound 2b.
ESI-MS(+)：306.2[M+H] +
Example 24 compound 2c was prepared from compound 7 using cyclohexane-based formaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (141 ml,0.226mol,1.1 eq.) was added dropwise, the dropping speed was controlled, the temperature was kept at not higher than-65 ℃, cyclohexane-based formaldehyde (37.3 ml,0.308mol,1.5 eq.) was dissolved in tetrahydrofuran (373 ml), dropwise addition was carried out, the dropping speed was controlled, the temperature was kept at not higher than-65 ℃, after completion of the dropwise addition, stirring was carried out at-78 ℃ for 30 minutes, stirring was carried out at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl tert-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was directly carried out.
Raney nickel (10 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to 10℃or lower, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the above solution, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum-dried at 40.+ -. 5 ℃ for 26.48g in total, and the yield was 37.4% as compound 2c.
ESI-MS(+)：346.2[M+H] + ，368.3[M+Na] +
Example 25 compound 2d was prepared from compound 7 using cyclopropylaldehyde.
Compound 7 (100 g,0.205 mol) was dissolved in toluene (500 ml), concentrated to dryness under reduced pressure, the residue was dissolved by adding tetrahydrofuran (400 ml), cooled to-78 ℃, n-butyllithium solution (141 ml,0.226mol,1.1 eq.) was added dropwise, the dropping speed was controlled, the temperature was kept at not higher than-65 ℃, cyclopropylaldehyde (23.0 ml,0.308mol,1.5 eq.) was dissolved in tetrahydrofuran (230 ml), the dropping speed was controlled, the temperature was kept at not higher than-65 ℃, after completion of the dropping, stirring was carried out at-78 ℃ for 30 minutes, stirring was carried out at 0 ℃ for 2 hours, 1mol/L potassium hydrogen sulfate solution (500 ml) was added, methyl tert-butyl ether (300 ml) was added, the organic phase was separated, washed with saturated sodium chloride solution (300 ml×3), and the next reaction was directly carried out.
Raney nickel (10 g) was added to the solution from the previous step, hydrogenated at normal pressure, the reaction monitored by TLC until the reaction was complete, the catalyst Raney nickel was filtered off and the filtrate was directly subjected to the next step.
The above solution was cooled to below 10 ℃, lithium hydroxide monohydrate (17.22 g,0.410mol,2 eq.) was dissolved in water (155 ml), added to the solution of the above step, the cold bath was removed, the reaction was slowly warmed to 20.+ -. 5 ℃ and monitored by TLC until the reaction was complete, methyl tert-butyl ether (300 ml) and water (600 ml) were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous phase was washed 1 time with methyl tert-butyl ether (150 ml), the pH was adjusted to 2 to 3 with 0.1mol/L of dilute hydrochloric acid, a white solid was precipitated, filtered, and vacuum dried at 40.+ -. 5 ℃ for 20.46g in total, and the yield was 32.9% as compound 2d.
ESI-MS(+)：326.2[M+Na] +
Example 26 determination of compound 2 optical rotation number.
Commercially available compound 2 was purchased as a reference, and the optical rotation values of the samples obtained in each example were measured using a WZZ-2B automatic polarimeter.
As a solvent, a 0.1mol/L NaOH solution was used, and the sample concentration was 0.1g/ml
Examples Optical rotation value
Commercial sample 32.6°
16 32.7°
17 32.3°
18 32.4°
19 32.5°
20 32.1°
21 32.3°
22 32.5°
The invention provides a preparation idea and a preparation method of chiral 4-alkyl-pyrrole-3-carboxylic acid compounds, and the method and the way for realizing the technical scheme are numerous, the above description is only a preferred embodiment of the invention, and it should be pointed out that a plurality of improvements and modifications can be made by those skilled in the art without departing from the principle of the invention, and the improvements and the modifications are also regarded as the protection scope of the invention. The components not explicitly described in this embodiment can be implemented by using the prior art.

Claims (8)

1. The preparation method of the chiral 4-alkyl-pyrrole-3-carboxylic acid compound is characterized in that the compound has a structure shown as a compound 2 and comprises the following steps:
1) Reacting an organolithium reagent with (R) -4-benzyl-2-oxazolidinone to form a lithium complex, and then reacting with N-benzyloxycarbonyl pyrrolidine-3-carboxylic acid to obtain compound 5
2) Under the action of organic amine, reacting the compound 5 with tributylboron triflate, and adding N-bromosuccinimide to obtain a compound 7;
3) Reacting the compound 7 with aldehyde RCHO after the action of n-butyllithium to obtain a compound 8, wherein R in the aldehyde RCHO is C1-C6 linear alkyl, branched alkyl or cycloalkyl;
4) Hydrogenating the compound 8 under normal pressure under the action of a nickel catalyst to obtain a compound 9;
5) Hydrolyzing the compound 9 to obtain a compound 2;
。
2. the method according to claim 1, wherein the organolithium reagent in step 1) is n-butyllithium or lithium bis (trimethylsilyl) amide.
3. The preparation method according to claim 1, wherein in the step 1), the molar ratio of (R) -4-benzyl-2-oxazolidone, N-benzyloxycarbonyl pyrrolidine-3-carboxylic acid to organolithium is 1 (1.0-1.5): 1.0-1.5.
4. The preparation method according to claim 1, wherein the reaction temperature in the step 1) is-50 to-40 ℃ and the reaction time is 0.8 to 2 hours; the reaction temperature of the step 2) is minus 78 ℃ to minus 65 ℃ and the reaction time is 0.5 to 2 hours; in the step 3), the reaction is carried out for 0.5 to 1 hour at the temperature of minus 78 ℃ to minus 65 ℃ and then the stirring is carried out for 1.5 to 2 hours at the temperature of 0 ℃.
5. The process according to claim 1, wherein the organic amine in step 2) is diisopropylethylamine or triethylamine.
6. The preparation method according to claim 1, wherein in the step 2), the molar ratio of the compound 5, dibutyl boron triflate, the organic amine and the N-bromosuccinimide is 1 (1.0-1.5): 1.1-1.6): 1.1-1.4.
7. The preparation method according to claim 1, wherein in the step 3), the molar ratio of the compound 7, n-butyllithium and the aldehyde RCHO is 1 (1.0-1.2): 1.3-2.0.
8. The method according to claim 1, wherein in step 4), the nickel catalyst is used in an amount of 5 to 20% by weight of the compound 7.
CN202111478995.9A 2021-12-06 2021-12-06 Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound Active CN114516866B (en)

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