CN114478422B - Intermediate of pregabalin and preparation method thereof - Google Patents

Intermediate of pregabalin and preparation method thereof Download PDF

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CN114478422B
CN114478422B CN202011146809.7A CN202011146809A CN114478422B CN 114478422 B CN114478422 B CN 114478422B CN 202011146809 A CN202011146809 A CN 202011146809A CN 114478422 B CN114478422 B CN 114478422B
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formula
compound
organic solvent
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compound shown
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CN114478422A (en
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李建其
王冠
何茶生
翟自然
周阳
杜新丽
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C205/51—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • 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

Abstract

The invention discloses an intermediate of pregabalin and a preparation method thereof. The invention provides a compound shown in a formula (I) and a preparation method thereof, wherein the preparation method of the compound shown in the formula (I) is any one of the following methods: the method (1) comprises the following steps: in an organic solvent, reacting a compound shown as a formula (III) with nitromethane in the presence of alkali, and carrying out chiral resolution to obtain the compound shown as the formula (I); the method (2) comprises the following steps: in an organic solvent in the presence of a baseThe compound shown in the formula (III) reacts with nitromethane under the action of a catalyst shown in the formula (II). The method has the advantages of mild reaction conditions, low toxicity of raw materials, simplicity and easiness in obtaining, simplicity in operation and easiness in large-scale production, and can be used for synthesizing pregabalin.

Description

Intermediate of pregabalin and preparation method thereof
Technical Field
The invention relates to an intermediate of pregabalin and a preparation method thereof.
Background
Pregabalin (pregabalin), chemically known as (S) -3-aminomethyl-5-methylhexanoic acid, is a gamma-aminobutyric acid (GABA) receptor antagonist developed by the company xenobiotics, acting primarily by modulating pressure-dependent calcium channels in the central nervous system, is clinically used for peripheral neuralgia or for the adjuvant treatment of partial seizures, is approved by the european union in 2004 and marketed for the first time in the united kingdom, and is approved by the FDA in the united kingdom in 2005. Compared with gabapentin, pregabalin has the characteristics of low dosage, quick response, high bioavailability and the like, and has great market potential.
The preparation methods of pregabalin are mainly divided into two main classes: the traditional chemical method and the enzymatic method generally have higher requirements on process conditions, so that the production is difficult to amplify, the traditional chemical method is generally adopted to prepare pregabalin at present, and the traditional chemical method can be subdivided into the following three types:
the first type is a chemical resolution method, generally, pregabalin racemate is prepared first, then pregabalin is prepared by resolution of a resolving agent, and the method is also adopted for production in industry at present, and the specific route is as follows:
the overall yield of this route is low (25-29%) and the other isomer (R) -3-aminomethyl-5-methylhexanoic acid produced is discarded, resulting in a large waste of raw material. In addition, potassium cyanide (KCN) is used in the route, belongs to a highly toxic reagent, and has great potential safety hazard.
The second category is chiral source synthesis, where chiral compounds are used as starting materials to directly introduce chirality to prepare pregabalin, as in document j.org.chem.2007,72,7390. For example: chiral epichlorohydrin 15 and diethyl malonate 16 are used as starting materials, and the key intermediate 19 is prepared through trimethyl bromosilane ring-opening bromination, azide, ester group hydrolysis and reduction to obtain pregabalin, and the total yield is: 57%, ee of azide: 99%.
The route and the synthesis method involve the preparation of the azide compound (21), and the adopted reagent sodium azide and the azide compound 21 are extremely unstable and are easy to cause explosion, so that hidden dangers in operation and safety exist, and the method is not suitable for production and amplification.
The third type is an asymmetric synthesis method, wherein the target product is obtained by controlling the chirality of the target product through a chiral catalyst or a chiral auxiliary.
Org Process Res Dev 2015,19 (9): 1274 reports the preparation of pregabalin by means of a cinchona chiral catalyst, the synthetic route being as follows:
in the route, the olefin intermediate 26 and nitromethane are subjected to addition reaction, are catalyzed by a cinchona alkaloid catalyst 27 to generate an optical selective compound 28, and are subjected to hydrolysis and reduction to prepare the pregabalin. However, the cinchona alkaloid catalyst 27 disclosed in this route is not commercially available, is expensive to prepare, is relatively large in dosage, and is not economical to produce and prepare pregabalin.
Can.J.chem.92:45-48 (2014) reported the use of Evans reagent IV-3 as chiral auxiliary, et 2 A method for preparing pregabalin by using AlCN as an ammonia source. The synthetic route is as follows:
this route has two important drawbacks: first, reagent Et 2 AlCN is expensive and is a highly toxic reagent, which greatly limits its application. Secondly, the key intermediate 33 in the route is an oil, column chromatography is unavoidable in the purification process, and the optical purity is only 74%. Therefore, the method has no practical value for producing pregabalin.
In the third type of asymmetric synthesis method, two preparation methods are adopted, the technical means of olefin addition are adopted, chiral catalysts or chiral auxiliary agents are adopted to control the chirality of target products, and the following steps are still existed: using expensive catalysts, potassium cyanide and Et 2 AlCN highly toxic reagent and the like.
In summary, the currently disclosed preparation method of pregabalin still has a plurality of defects, so that development of a low-cost and easily available raw material and reagent suitable for mass production and quality control and low-cost and large-scale production process for preparing pregabalin is needed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art that a potassium cyanide highly toxic reagent, an explosive azide reagent, an intermediate, an expensive catalyst and the like are used, and provides a pregabalin intermediate and a preparation method thereof. The method has the advantages of mild reaction conditions, low toxicity and simple and easily obtained raw materials, simple operation and easy scale-up production, and can also be used for preparing pregabalin.
The invention solves the technical problems by the following scheme.
The invention provides a compound shown as a formula (I);
wherein R is C 1 -C 6 Alkyl, phenyl, R a Substituted phenyl, benzyl or R b A substituted benzyl group; r is R a And R is b Is independently one or more, when R is a When the number of R is plural, R is a The same or different; when said R is b When the number of R is plural, R is b The same or different;
R a and R is b Independently C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group.
R is preferably methyl, ethyl or isopropyl.
The R is a And R is b Independently, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy are preferred.
The R is a Preferably 1 or 2; when said R is a When the number of R is 2, R is a The same or different.
The R is b Preferably 1 or 2; when said R is b When the number of R is 2, R is b The same or different.
Preferably, the compound shown as the formula (I) comprises, but is not limited to, any one of the following compounds:
the invention provides a preparation method of the compound shown as the formula (I), which is any one of the following methods:
the method (1) comprises the following steps: in an organic solvent, reacting a compound shown as a formula (III) with nitromethane in the presence of alkali, and carrying out chiral resolution to obtain the compound shown as the formula (I);
the method (2) comprises the following steps: in an organic solvent, in the presence of alkali, reacting a compound shown as a formula (III) with nitromethane under the action of a catalyst shown as a formula (II);
In the method (1) and the method (2), the alkali is K 2 CO 3 And/or Cs 2 CO 3 ；
In the method (1) and the method (2), R is C 1 -C 6 Alkyl, phenyl, R a Substituted phenyl, benzyl or R b A substituted benzyl group; r is R a And R is b Is independently one or more, when R is a When the number of R is plural, R is a The same or different; when said R is b When the number of R is plural, R is b The same or different;
in the method (1) and the method (2), R a And R is b Independently C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
in the method (2), R 2 Is C 6 -C 14 Aryl or benzyl; r is R 3 Is hydroxyl or amino; x is halogen.
In the method (1) and the method (2), R is preferably methyl, ethyl or isopropyl.
In the method (1) and the method (2), the R a And R is b Independently, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy are preferred.
In the method (1) and the method (2), the R a Preferably 1 or 2; when said R is a When the number of R is 2, R is a The same or different.
In the method (1) and the method (2), the R b Preferably 1 or 2; when said R is b When the number of R is 2, R is b The same or different.
In the method (1), a solution of the compound represented by the formula (III), the nitromethane and an organic solvent is preferably added dropwise to the organic solvent suspension of the base.
In the method (1), the organic solvent may be conventional in the art, preferably one or more of dichloromethane, acetonitrile, toluene, THF, acetone, DMSO and methanol.
In the method (1), the molar ratio of the compound represented by formula (III) and nitromethane may be conventional in the art, preferably 1: (1 to 3), more preferably 1: (1.5-2.5), e.g., 1:2.
In the method (1), the ratio of the molar ratio of the base to the compound represented by the formula (III) may be conventional in the art, preferably 1.0 to 2.8, for example: 2.5 or 2.6.
In the method (1), the temperature of the reaction may be conventional in the art, preferably 10 to 40 ℃, more preferably 20 to 30 ℃.
In the method (1), the reaction time of the reaction is preferably 22 to 36 hours, and the reaction time is related to the selectivity of the base.
In the method (1), the progress of the reaction can be monitored by a conventional monitoring method in the art (for example, TLC, HPLC or NMR), and the end point of the reaction is generally the point when the compound represented by the formula (III) disappears or no longer reacts.
In the method (1), after the reaction is finished and before chiral resolution, the method further comprises the following steps: quenching, separating liquid and concentrating the reaction system in turn.
In the method (1), the quenching is preferably performed by using water, and the amount of water may be not limited so as not to affect the reaction.
In the method (1), the concentration may be conventional in the art, preferably performed under reduced pressure vacuum.
In the method (1), the chiral resolution is preferably performed by recrystallization.
In the method (1), the use amount of the organic solvent in the solution formed by the compound shown in the formula (III), the nitromethane and the organic solvent is not limited, so that the reaction is not affected; the ratio of the mass to volume ratio of the compound represented by the formula (III) to the organic solvent may be conventional in the art, and is preferably 0.1g/mL to 0.25g/mL.
In the method (1), the ratio of the mass-to-volume ratio of the base to the organic solvent in the suspension of the base and the organic solvent may be conventional in the art, and is preferably 0.1g/mL to 0.4g/mL, for example, 0.3g/mL.
In the method (1), the recrystallization includes the steps of: the solution of the compound of formula (I) in an organic solvent, preferably at 50-80 ℃, is preferably subjected to crystallization at 15-30 ℃, for example 25-30 ℃.
In the method (1), the organic solvent used for the recrystallization is preferably one or more of an alcohol solvent and a mixed solvent of an alcohol solvent and water, and more preferably isopropanol.
In the method (1), the chiral resolution is more preferably performed by secondary recrystallization.
In the method (1), the secondary recrystallization includes the steps of: the solution of the organic solvent of the compound shown in the formula (I) with the temperature of preferably 50-80 ℃ is preferably placed at the temperature of 15-25 ℃ for crystallization, filtering and drying to obtain solid, and the solution of the organic solvent of the solid with the temperature of preferably 50-80 ℃ is preferably placed at the temperature of 25-30 ℃ for crystallization.
In the method (2), R 2 Preferably phenyl, anthracyl or naphthyl.
In the method (2), X is preferably Cl or Br.
In the method (2), the organic solvent may be conventional in the art, preferably one or more of dichloromethane, acetonitrile, toluene, THF, acetone, DMSO and methanol.
In the method (2), a solution of the compound represented by the formula (III), the nitromethane, the catalyst represented by the formula (II) and an organic solvent is preferably added dropwise to a suspension of the base and the organic solvent.
In the method (2), the molar ratio of the compound represented by formula (III) and the nitromethane may be conventional in the art, preferably 1: (1 to 3), more preferably 1: (1.5-2.5), e.g., 1:2.
In the method (2), the molar ratio of the compound represented by the formula (III) to the catalyst represented by the formula (II) may be conventional in the art, and preferably is 1 (0.07 to 0.1).
In the method (2), the ratio of the molar ratio of the base to the compound represented by the formula (III) may be conventional in the art, preferably 1.0 to 2.8, for example: 2.5 or 2.6.
In the method (2), the temperature of the reaction may be conventional in the art, preferably 10 to 40 ℃, more preferably 20 to 30 ℃.
In the method (2), the reaction time of the reaction is preferably 22 to 36 hours, and the reaction time is related to the selectivity of the base.
In the method (2), the progress of the reaction can be monitored by a conventional monitoring method in the art (for example, TLC, HPLC or NMR), and the end point of the reaction is generally the point when the compound represented by the formula (III) disappears or no longer reacts.
The method (2) further comprises a post-treatment, wherein the post-treatment comprises the following steps: quenching, separating liquid, concentrating and purifying the reaction system in sequence.
In the method (2), the compound shown in the formula (III), the nitromethane, the catalyst shown in the formula (II) and an organic solvent form a solution, and the dosage of the organic solvent is not limited so as not to influence the reaction; the ratio of the mass to volume ratio of the compound represented by the formula (III) to the organic solvent may be conventional in the art, and is preferably 0.1g/mL to 0.25g/mL.
In the method (2), the ratio of the mass-to-volume ratio of the base to the organic solvent in the suspension of the base and the organic solvent may be conventional in the art, and is preferably 0.1g/mL to 0.4g/mL, for example, 0.3g/mL.
In the method (2), in the post-treatment method, the quenching is preferably performed using water, and the amount of water may be not limited so as not to affect the reaction.
In the method (2), in the post-treatment method, the concentration may be conventional in the art, preferably performed under reduced pressure vacuum.
In the method (2), in the post-treatment method, the purification is preferably performed by recrystallization or column chromatography.
In the method (2), in the post-treatment method, when R is phenyl or R a In the case of substituted phenyl groups, the purification is preferably carried out by recrystallisation; when R is C 1 -C 6 Alkyl, benzyl or R b Where a substituted benzyl group, such as R is isopropyl or benzyl, the purification is preferably by column chromatography.
In the method (2), in the post-treatment method, the recrystallization includes the steps of: the solution of the compound of formula (I) in an organic solvent, preferably at 50-80 ℃, is preferably subjected to crystallization at 15-30 ℃, for example 25-30 ℃.
In the method (2), in the post-treatment method, the organic solvent used for the recrystallization is preferably one or more of an alcohol solvent and a mixed solvent of an alcohol solvent and water, and more preferably isopropyl alcohol.
In the method (2), in the post-treatment method, preferably, the recrystallization is a secondary recrystallization.
In the method (2), in the post-treatment method, the secondary recrystallization includes the steps of: the solution of the organic solvent of the compound shown in the formula (I) with the temperature of preferably 50-80 ℃ is preferably placed at the temperature of 15-25 ℃ for crystallization, filtering and drying to obtain solid, and the solution of the organic solvent of the solid with the temperature of preferably 50-80 ℃ is preferably placed at the temperature of 25-30 ℃ for crystallization.
In the method (2), in the post-treatment method, the eluent for column chromatography is preferably a mixed solution of petroleum ether and ethyl acetate. The volume ratio of petroleum ether to ethyl acetate is preferably (8-10): 1.
in the invention, the preparation method of the compound shown as the formula (I) can further comprise the following steps: in an organic solvent, reacting a compound shown in a formula (IV) with a compound shown in a formula (V) in the presence of a catalyst and alkali to obtain a compound shown in a formula (III);
Wherein R is C 1 -C 6 Alkyl, phenyl, R a Substituted phenyl, benzyl or R b A substituted benzyl group; r is R a And R is b Is independently one or more, when R is a When the number of R is plural, R is a The same or different; when said R is b When the number of R is plural, R is b The same or different;
R a and R is b Independently C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
R 4 is hydroxyl or halogen. Preferably, R 4 Preferably chlorine.
In the process for producing a compound represented by the formula (III), R is preferably methyl, ethyl or isopropyl.
In the preparation method of the compound shown in the formula (III), the R a And R is b Independently, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy are preferred.
In the preparation method of the compound shown in the formula (III), the R a Preferably 1 or 2; when said R is a When the number of R is 2, R is a The same or different.
In the preparation method of the compound shown in the formula (III), the R b Preferably 1 or 2; when said R is b When the number of R is 2, R is b The same or different.
In the method for producing a compound represented by the formula (III), the compound represented by the formula (V) is preferably added dropwise to a solution of the compound represented by the formula (IV), the catalyst, the base and the organic solvent.
In the method for producing a compound represented by the formula (III), the compound represented by the formula (V) is preferably added dropwise to a solution of the compound represented by the formula (IV), the catalyst, the base and the organic solvent at a temperature of preferably 0 to 30 ℃.
In the method for producing a compound represented by the formula (III), the compound represented by the formula (V) is added dropwise to a solution of the compound represented by the formula (IV), the catalyst, the base and the organic solvent at a temperature of more preferably 0 to 10 ℃.
In the preparation method of the compound shown in the formula (III), when R 4 In the case of hydroxyl, the method preferably further comprises the following steps: in an organic solvent, the compound shown in the formula (V) and an acylating reagent are reacted to prepare 5-methyl-2-hexenoyl halide, and then the 5-methyl-2-hexenoyl halide is directly reacted with the compound shown in the formula (IV) without post treatment to obtain the compound shown in the formula (III).
In the process for the preparation of 5-methyl-2-hexenoyl halides, in certain embodiments, the organic solvent is preferably a halogenated hydrocarbon solvent, for example: dichloromethane.
In the process for the preparation of 5-methyl-2-hexenoyl halide, in certain embodiments, the acylating agent is preferably oxalyl chloride, thionyl chloride.
In the process for the preparation of 5-methyl-2-hexenoyl halide, in certain embodiments, the temperature of the reaction may be conventional in the art, preferably from 10 to 40 ℃, more preferably from 20 to 30 ℃.
In the process for the preparation of 5-methyl-2-hexenoyl halide, in certain embodiments, the reaction time may be conventional in the art, preferably from 4 to 12 hours.
In the preparation method of the compound shown in the formula (III), when R 4 In the case of halogen, the compound shown as the formula (V) is 5-methyl-2-hexenoyl halide, and is directly connected with the compoundThe compound shown in the formula (IV) is reacted to obtain the compound shown in the formula (III).
In the process for preparing the compound of formula (III), in certain embodiments, the organic solvent may be one or more of methylene chloride, acetonitrile, toluene, tetrahydrofuran, acetone, DMSO, and methanol as is conventional in the art.
In the process for the preparation of the compound of formula (III), in certain embodiments, the base may be conventional in the art, preferably pyridine, sodium carbonate or triethylamine.
In the process for preparing the compounds of formula (III), in certain embodiments, the catalyst may be conventional in the art, with DMAP (4-dimethylaminopyridine) being preferred.
In certain embodiments, the molar ratio of the compound of formula (V) to the compound of formula (IV) in the process for the preparation of the compound of formula (III) may be conventional in the art, preferably from (1 to 1.5): 1, more preferably from (1.0 to 1.3): 1.
In the process for the preparation of a compound of formula (III), in certain embodiments, the molar ratio of the compound of formula (IV) to the catalyst DMAP may be conventional in the art, preferably 1: (0.01 to 0.2), more preferably (1) (0.01 to 0.1).
In the preparation of the compounds of formula (III), in certain embodiments, the molar ratio of the compound of formula (IV) to the base may be conventional in the art, preferably 1 (1-5), such as 1:2.4, 1:2.8 or 1:4.7.
In the preparation of compounds of formula (III), in certain embodiments, the progress of the reaction may be monitored by methods conventional in the art (e.g., TLC, HPLC or NMR), typically by taking the compound of formula (IV) as an endpoint of the reaction when it disappears or no longer reacts.
In a process for the preparation of a compound of formula (III), in certain embodiments, the reaction further comprises a post-treatment comprising the steps of: and (3) filtering, concentrating and purifying the reaction system in sequence.
In the preparation of the compounds of formula (III), in certain embodiments, in the work-up procedure, the purification may be conventional in the art, preferably by recrystallization or column chromatography.
In the process for preparing the compound of formula (III), in certain embodiments, in the post-treatment process, the organic solvent used for the recrystallization is preferably one or more of ethyl acetate, petroleum ether, n-heptane and n-hexane.
In certain embodiments, in the method of preparing a compound of formula (III), the eluent of the column chromatography in the post-treatment method may be conventional in the art, preferably a mixed solution of petroleum ether and ethyl acetate. The volume ratio of petroleum ether to ethyl acetate may be conventional in the art, preferably (10 to 15): 1.
the invention provides a preparation method of a compound shown as a formula 1, which comprises the steps of reacting the compound shown as a formula (I) in an organic solvent in the presence of alkali and an oxidant;
wherein R is C 1 -C 6 Alkyl, phenyl, R a Substituted phenyl, benzyl or R b A substituted benzyl group; r is R a And R is b Is independently one or more, when R is a When the number of R is plural, R is a The same or different; when said R is b When the number of R is plural, R is b The same or different;
R a and R is b Independently C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group.
In the process for preparing the compound of formula 1, R is preferably methyl, ethyl or isopropyl.
In the preparation method of the compound shown in the formula 1, the R a And R is b Independently, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy are preferred.
In the preparation method of the compound shown in the formula 1, the R a Preferably 1 or 2; when said R is a When the number of R is 2, R is a The same or different.
In the preparation method of the compound shown in the formula 1, the R b Preferably 1 or 2; when said R is b When the number of R is 2, R is b The same or different.
In the method for producing a compound represented by formula 1, the solution of the organic solvent of the compound represented by formula (I) is preferably added dropwise to the solution of the base, the oxidizing agent and the organic solvent.
In the method for producing a compound represented by formula 1, a solution of an organic solvent of the compound represented by formula (I) at preferably <10 ℃ is added dropwise to a solution of the base, the oxidizing agent and the organic solvent at preferably 0 to 5 ℃.
In the preparation method of the compound shown in formula 1, in some embodiments, the organic solvent may be conventional in the art, and is preferably an ether solvent, such as tetrahydrofuran.
In the process for preparing the compound of formula 1, in certain embodiments, the base may be conventional in the art, preferably lithium hydroxide.
In the preparation method of the compound shown in the formula 1, in certain embodiments, the oxidizing agent may be conventional in the art, and preferably hydrogen peroxide.
In certain embodiments, the ratio of the mass to volume ratio of the compound of formula (I) to the organic solvent in the process for preparing the compound of formula 1 may be conventional in the art, preferably from 0.1g/mL to 0.5g/mL, more preferably 0.2g/mL.
In the process for preparing a compound of formula 1, in certain embodiments, the molar ratio of the compound of formula (I) to the base may be conventional in the art, preferably 1: (1 to 1.5), more preferably 1: (1.1 to 1.3), for example: 1:1.2.
In the process for preparing a compound of formula 1, in certain embodiments, the molar ratio of the compound of formula (I) to the oxidizing agent may be conventional in the art, preferably 1: (1-4), e.g., 1:3, 1:3.3, 1:3.6, or 1:3.8.
In the preparation of the compounds of formula 1, in certain embodiments, the reaction time of the reaction may be conventional in the art, preferably from 4 to 12 hours, more preferably 6 hours.
In certain embodiments, the progress of the reaction may be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), typically with the compound of formula (IV) as an endpoint of the reaction when it disappears or no longer reacts.
In the process for the preparation of a compound of formula 1, in certain embodiments, the reaction further comprises a post-treatment comprising the steps of: and adding a reducing agent into the reaction system, and sequentially extracting and concentrating.
In certain embodiments, in the process for preparing a compound of formula 1, the reducing agent may be conventional in the art, preferably sodium sulfite or sodium thiosulfate, more preferably sodium sulfite, in the post-treatment process.
In certain embodiments, in the method of preparing a compound of formula 1, the molar ratio of the compound of formula (I) to the reducing agent in the post-treatment method may be conventional in the art, preferably 1: (1 to 4), more preferably 1: (3-4), for example: 1:3.3, 1:3.6 or 1:3.8.
In the process for the preparation of the compounds of formula 1, in certain embodiments, the aqueous phase obtained by the extraction is preferably neutralized by adding acid in the work-up process. The acid may be conventional in the art, preferably is a mineral acid, for example: dilute hydrochloric acid.
In the process for the preparation of the compounds of formula 1, in certain embodiments, the pH of the aqueous phase after neutralization with an acid is preferably in the range of 4 to 5.
The invention provides a preparation method of pregabalin, the reaction route of which can be shown as follows:
the invention also provides a compound shown as a formula (III), which is any one of the following compounds:
on the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
In the present invention, unless otherwise specified, the C 1 -C 6 Alkyl groups refer to unsubstituted C 1 -C 6 An alkyl group.
In the present invention, unless otherwise specified, the C 6 -C 14 Aryl groups refer to unsubstituted C 6 -C 14 Aryl groups.
In the present invention, unless otherwise specified, the C 1 -C 6 Alkoxy groups refer to unsubstituted C 1 -C 6 An alkoxy group.
Unless otherwise indicated, the terms "phenyl", "benzyl", "anthracenyl" and "naphthyl" as used herein refer to unsubstituted phenyl, unsubstituted benzyl, unsubstituted anthracenyl and unsubstituted naphthyl.
The terms "methyl", "ethyl", "isopropyl", "methoxy", "ethoxy" and "isopropoxy" as used herein refer to, unless otherwise indicated, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted methoxy, unsubstituted ethoxy and unsubstituted isopropoxy.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the method has the advantages of mild reaction conditions, readily available raw materials, low toxicity, simple reaction operation and easy scale-up production. The compound shown in the formula (I) and the preparation method thereof can also be used for preparing pregabalin.
Drawings
FIG. 1 is an X-single crystal diffraction (XPRD) pattern of compound I-3, from which the absolute optical configuration of compound I-3 has been confirmed under the chemical name (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one.
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.
Example 15 preparation of methyl-2-hexenoic acid (V-1)
Pyridine (98.8 g,1.24 mol) and isovaleraldehyde (92.71 g,1.07 mol) are sequentially added into a 500mL three-necked flask, and are fully and uniformly stirred, the temperature is raised to 60-70 ℃, malonic acid (100 g,0.96 mol) is added in batches, the temperature is raised to 90 ℃ and is stirred for 4 hours, the temperature is lowered to 0-5 ℃, 5% dilute hydrochloric acid is added for washing until the pH value is=2-4, the liquid is separated, the organic phase is collected, the concentration is reduced to constant weight to obtain 110.46g of oily substance, the yield is 90%, and the purity is 99.05% (HPLC).
1 H NMR(400MHz,CDCl 3 ):δ7.07(dt,J＝15.3,7.5Hz,1H)，5.82(dt,J＝15.5,1.5Hz,1H)，2.13(ddd,J＝7.4,6.7,1.5Hz,2H)，1.78(dq,J＝13.4,6.7Hz,1H)，0.94(d,J＝6.7Hz,6H)。CDCl 3 Synthesis of (. + -.) -3-aminomethyl-5-methylhexanoic acid [ J ] with no peak of active hydrogen in solvent (ref. Chen Wenhua, qi Xiuxiu, you Haifeng)]Journal of the Chinese medical industry, 2019 (7): 746-748.)
ESI-MS(m/z)＝127.17[M-H] -
Example 2 preparation of (R) -4-isopropyl-3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-1)
Step one preparation of 5-methyl-2-hexenoyl chloride (V-2)
5-methyl-2-hexenoic acid (50 g,0.4 mol) and dichloromethane (50 mL) are added into a 250mL round bottom flask, stirred and dissolved, oxalyl chloride (75.21 g,0.6 mol) and dichloromethane (30 mL) are added dropwise, stirred and reacted for 6h at room temperature, and concentrated under reduced pressure to obtain yellow oily matter which is directly used for the next reaction.
Preparation of step di (R) -4-isopropyl-3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-1)
In a 500mL three-necked flask, (R) -4-isopropyl-2-oxazolidinone IV-1 (5 g,0.038 mol), DMAP (0.46 g,0.0038 mol) and triethylamine (9.4 g,0.09 mol) were added to a solution of 20mL methylene chloride in sequence, the internal temperature was controlled at 0-5℃and the prepared acid chloride V-2 was added dropwise thereto, the reaction was stirred at 0-10℃for 5 hours, filtered, the filtrate was collected and concentrated to constant weight, and column chromatography (petroleum ether: ethyl acetate: 15:1) was carried out to give Compound III-1 as a pale yellow oil, 5g, yield 56% and purity 99.1% (HPLC).
1 H NMR(400MHz,CDCl 3 )δ7.29–7.23(m,1H),7.18–7.09(m,1H),4.49(ddd,J＝8.3,4.0,3.2Hz,1H),4.28(dd,J＝9.1,8.2Hz,1H),4.22(dd,J＝9.1,3.1Hz,1H),2.42(pd,J＝7.0,4.0Hz,1H),2.18(td,J＝7.1,1.2Hz,2H),1.79(dq,J＝13.4,6.7Hz,1H),0.98–0.86(m,12H)。
ESI-MS(m/z)＝240.20[M+H] +
Example 3 preparation of (R) -4-benzyl-3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-2)
In a 500mL three-necked flask, (R) -4-benzyl-2-oxazolidinone IV-2 (30 g,0.17 mol), DMAP (2.1 g,0.017 mol) and triethylamine (41 g,0.4 mol) are added into 50mL dichloromethane solution in sequence, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is added dropwise, the temperature is controlled to be 0-10 ℃ for stirring reaction for 5 hours, filtration is carried out, the filtrate is collected and concentrated to constant weight, 80mL of n-hexane is used for recrystallization, the compound III-2 is obtained, 34g of light yellow solid is obtained after drying, the yield is 71%, and the purity is 98.87% (HPLC).
1 H NMR(400MHz,CDCl 3 )δ7.37–7.27(m,3H),7.25–7.16(m,4H),4.78–4.69(m,1H),4.26–4.15(m,2H),3.35(dd,J＝13.4,3.3Hz,1H),2.80(dd,J＝13.4,9.6Hz,1H),2.21(dd,J＝7.1,5.9Hz,2H),1.82(dq,J＝13.4,6.7Hz,1H),0.96(dd,J＝6.7,2.1Hz,6H)。
ESI-MS(m/z)＝288.08[M+H] +
Example 4 preparation of (R) -4-phenyl-3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-3)
In a 500mL three-necked flask, (R) -4-phenyl-2-oxazolidinone IV-3 (30 g,0.17 mol), DMAP (2.24 g,0.017 mol) and triethylamine (41 g,0.4 mol) are added into a 50mL dichloromethane solution in sequence, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is added dropwise, the temperature is controlled to be 0-10 ℃ for stirring reaction for 5 hours, the filtration and the filtrate collection are carried out, the concentration is carried out until the constant weight is reached, 80mL n-hexane is used for recrystallization, the compound III-3 is obtained, 38.7g of pale yellow solid is obtained after drying, the yield is 80%, and the purity is 99.54% (HPLC).
1 H NMR(400MHz,CDCl 3 ):δ7.42–7.27(m,5H),7.23(t,J＝1.4Hz,1H),7.08(dt,J＝15.1,7.4Hz,1H),5.49(dd,J＝8.7,3.9Hz,1H),4.70(t,J＝8.8Hz,1H),4.28(dd,J＝8.9,3.8Hz,1H),2.15(td,J＝7.1,1.4Hz,2H),1.77(dq,J＝13.4,6.7Hz,1H),0.91(d,J＝6.7Hz,6H)。
ESI-MS(m/z)＝274.20[M+H] +
Example 5 preparation of (R) -4- (2, 6-dimethylphenyl) -3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-4)
(R) -4- (2, 6-dimethylphenyl) -2-oxazolidinone IV-4 (1 g,5 mmol), DMAP (0.06 g,0.5 mmol) and triethylamine (1.9 g,14 mmol) are added into a 10mL dichloromethane solution in a 500mL three-necked bottle in sequence, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is added dropwise, the temperature is controlled to be 0-10 ℃ and the stirring reaction is carried out for 5 hours, the filtration and the collection of the filtrate are carried out, the concentration is carried out until the constant weight is achieved, the compound III-4 is obtained by column chromatography (petroleum ether: ethyl acetate: 10:1), the light yellow solid is obtained by drying, the yield is 69%, and the purity is 97.6% (HPLC).
1 H NMR(400MHz,CDCl 3 )δ7.12(dd,J＝8.6,6.9Hz,1H),7.07–7.02(m,2H),6.58(dtd,J＝15.4,6.8,1.8Hz,1H),6.43(dt,J＝15.6,0.9Hz,1H),5.63(dd,J＝4.3,2.5Hz,1H),4.42(dd,J＝12.4,2.5Hz,1H),4.33(dd,J＝12.5,4.4Hz,1H),2.27(d,J＝0.5Hz,6H),2.09–1.94(m,2H),1.75(dqd,J＝13.9,6.9,1.8Hz,1H),0.92(d,J＝6.8Hz,3H),0.87(d,J＝6.9Hz,3H)。
ESI-MS(m/z)＝302.17[M+H] +
Example 6 preparation of (R) -4- (3, 5-dimethylphenyl) -3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-5)
In a 500mL three-necked flask, (R) -4- (3, 5-dimethylphenyl) -2-oxazolidinone IV-5 (1 g,5 mmol), DMAP (0.06 g,0.5 mmol) and triethylamine (1.9 g,14 mmol) are added into a 10mL dichloromethane solution in sequence, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is added dropwise, the temperature is controlled to be 0-10 ℃ and stirred for reaction for 5h, the filtration is carried out, the filtrate is collected and concentrated to constant weight, the column chromatography (petroleum ether: ethyl acetate: 15:1) is carried out to obtain a compound III-5, the compound III-5 is dried to obtain a pale yellow solid of 0.9g, the yield is 57%, and the purity is 98.3% (HPLC).
1 H NMR(500MHz,CDCl 3 )δ7.02(d,J＝2.0Hz,2H),6.84–6.82(m,1H),6.58(dtd,J＝15.4,6.8,1.8Hz,1H),6.43(dt,J＝15.6,0.9Hz,1H),5.36(dt,J＝4.3,1.7Hz,1H),4.52(dd,J＝12.5,2.6Hz,1H),4.38(dd,J＝12.4,4.5Hz,1H),2.20(s,6H),2.07–1.96(m,2H),1.75(dtd,J＝13.9,6.9,1.8Hz,1H),0.92(d,J＝6.8Hz,3H),0.87(d,J＝6.9Hz,3H)。
ESI-MS(m/z)＝302.17[M+H] +
Example 7 preparation of (R) -4- (2, 6-Dimethoxyphenyl) -3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-6)
In a 50mL three-necked flask, (R) -4- (2, 6-dimethoxyphenyl) -2-oxazolidinone IV-6 (1 g,3 mmol), DMAP (0.04 g,0.3 mmol) and triethylamine (1.9 g,14 mmol) are added into a 10mL dichloromethane solution in sequence, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is added dropwise, the temperature is controlled to be 0-10 ℃ and the stirring reaction is carried out for 5 hours, the filtration and the filtrate collection are carried out, the concentration is carried out until the constant weight, the column chromatography (petroleum ether: ethyl acetate: 15:1) is carried out, the compound III-6 is obtained, the light yellow solid is obtained by drying, the yield is 0.85g, and the purity is 97.9% (HPLC).
1 H NMR(500MHz,CDCl 3 )δ7.15(t,J＝8.4Hz,1H),6.66(d,J＝8.4Hz,2H),6.58(dtd,J＝15.4,6.8,1.8Hz,1H),6.43(dt,J＝15.6,0.9Hz,1H),5.69(dd,J＝4.7,3.0Hz,1H),4.47–4.38(m,2H),3.84(s,6H),2.07–1.96(m,2H),1.75(dtd,J＝13.8,6.9,1.8Hz,1H),0.92(d,J＝6.8Hz,3H),0.87(d,J＝6.9Hz,3H)。
ESI-MS(m/z)＝334.18[M+H] +
Example 8 preparation of (R) -4- (3, 5-Dimethoxyphenyl) -3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-7)
In a 50mL three-necked flask, (R) -4- (3, 5-dimethoxyphenyl) -2-oxazolidinone IV-7 (1 g,3 mmol), DMAP (0.04 g,0.3 mmol) and triethylamine (1.9 g,14 mmol) are added into a 10mL dichloromethane solution in sequence, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is added dropwise, the temperature is controlled to be 0-10 ℃ and the stirring reaction is carried out for 5 hours, the filtration and the filtrate collection are carried out, the concentration is carried out until the constant weight, the column chromatography (petroleum ether: ethyl acetate: 15:1) is carried out, the compound III-7 is obtained, 1g of pale yellow solid is obtained after drying, the yield is 66%, and the purity is 96.3% (HPLC).
1 H NMR(500MHz,CDCl 3 )δ6.61(dd,J＝2.2,0.7Hz,2H),6.60–6.54(m,1H),6.47–6.41(m,2H),5.39(ddd,J＝4.3,2.6,0.9Hz,1H),4.48(dd,J＝12.4,2.6Hz,1H),4.38(dd,J＝12.5,4.4Hz,1H),3.80(s,6H),2.08–1.96(m,2H),1.75(dtd,J＝13.8,7.0,1.8Hz,1H),0.92(d,J＝6.8Hz,3H),0.87(d,J＝6.9Hz,3H)。
ESI-MS(m/z)＝334.12[M+H] +
Example 9 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-isopropyloxazolidin-2-one (I-1)
Toluene 20mL and potassium carbonate (7.22 g,52.3 mmol) were added to a 250mL round bottom flask and stirred to give a suspension; compound III-1 (5 g,20.89 mmol), N-benzyl octyining II-1 (0.87 g,2.0 mmol) and nitromethane (2.55 g,41.79 mmol) were dissolved in 20mL of toluene, the compound III-1 solution was added dropwise to a toluene suspension of potassium carbonate, the reaction was stirred at room temperature for 36h, 80mL of water was added to the reaction solution, the solution was separated, the organic phase was concentrated to dryness, and the pale yellow oily substance I-1,2.5g was obtained by column chromatography (petroleum ether: ethyl acetate: 8:1), yield 40%, purity 97.61% (HPLC), de value: 6%.
1 H NMR(400MHz,CDCl 3 )δ4.51–4.48(m,1H),4.48–4.41(m,2H),4.30(td,J＝8.7,3.6Hz,1H),4.23(ddd,J＝9.2,3.0,1.8Hz,1H),3.16–2.98(m,2H),2.81(qd,J＝10.9,8.8,3.5Hz,1H),2.42–2.32(m,1H),1.67(dqd,J＝13.5,6.8,2.1Hz,1H),1.31(dtd,J＝7.4,4.7,2.4Hz,2H),0.97–0.86(m,12H)。
MS(m/z)＝301.20[M+H] +
Example 10 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-benzyloxazolidin-2-one (I-2)
40mL of toluene and potassium carbonate (12.02 g,0.09 mol) were added to a 250mL round bottom flask and stirred to obtain a suspension; compound III-2 (10 g,0.035 mol), N-benzyl cinchonine II-1 (1.46 g,0.0035 mol) and nitromethane (4.25 g,0.07 mol) were dissolved in 40mL of toluene, the compound III-2 solution was added dropwise to a toluene suspension of potassium carbonate, the reaction was stirred at room temperature for 36 hours, 80mL of water was added to the reaction solution, the solution was separated, the organic phase was concentrated to dryness, and the pale yellow oily substance I-2 was obtained by column chromatography (petroleum ether: ethyl acetate: 10:1), 10.5g, yield 87%, purity 97.61% (HPLC), de value: 71%.
1 H NMR(400MHz,CDCl 3 )δ7.43–7.13(m,5H),4.69(ddd,J＝9.5,7.3,3.7Hz,1H),4.50(t,J＝4.8Hz,2H),4.27–4.14(m,2H),3.29(dt,J＝13.4,4.2Hz,1H),3.15–2.99(m,2H),2.89–2.74(m,2H),1.69(ddd,J＝17.1,8.5,4.9Hz,1H),1.40–1.23(m,2H),1.00–0.88(m,6H)。
ESI-MS(m/z)＝349.17[M+H] +
Example 11 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one (I-3)
In a 250mL round bottom flask, 40mL of toluene and potassium carbonate (12.02 g,90 mmol) were added and stirred to give a suspension; compound III-3 (10 g,35 mmol), N-benzyl octyining II-1 (1.1 g,2.45mmol,0.07 eq) and nitromethane (4.25 g,70 mmol) were dissolved in 40mL toluene, a suspension of compound III-3 was added dropwise to a toluene suspension of potassium carbonate, the reaction was stirred at room temperature for 36h, 80mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to a dry 7.1g, de value: 10%. Heating isopropanol (70 g,1.16 mol) to dissolve at 50-80 ℃, controlling the temperature to 15-25 ℃ for crystallization, filtering and drying to obtain solid I-3,7.08g, yield 59%, purity 65.8% (HPLC), de value: 88%.
Example 12 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one (I-3)
In a 250mL round bottom flask, 40mL of toluene and potassium carbonate (12.02 g,90 mmol) were added and stirred to give a suspension; compound III-3 (10 g,35 mmol), N-benzyl octyining II-1 (1.46 g,3.5mmol,0.1 eq) and nitromethane (4.25 g,70 mmol) were dissolved in 40mL toluene, a suspension of compound III-3 was added dropwise to a toluene suspension of potassium carbonate, stirred at room temperature for reaction for 36h, 80mL water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness to give 13g of de value: 26%. Heating isopropanol (70 g,1.16 mol) to dissolve at 50-80 ℃, crystallizing at 15-25 ℃, filtering, and drying to obtain solid I-3,9.7g, yield: 76%, purity 94.05% (HPLC), de value: 46%. Heating to dissolve through isopropanol (97 g,1.6 mol) at 50-80 ℃, crystallizing at 25-30 ℃, filtering, and drying to obtain 6.4g of solid, wherein the total yield is 53%, the purity is 97.61% (HPLC), and the de value is: 99.92%.
1 H NMR(400MHz,CDCl 3 )δ7.43–7.27(m,5H),5.43(dd,J＝8.8,4.0Hz,1H),4.72(t,J＝8.9Hz,1H),4.42(dd,J＝12.1,6.2Hz,1H),4.36–4.26(m,2H),3.15–3.01(m,2H),2.72(dddd,J＝13.2,7.6,5.8,1.8Hz,1H),1.65–1.59(m,1H),1.24(t,J＝7.2Hz,2H),0.88(d,J＝6.6Hz,6H)。
ESI-MS(m/z)＝335.28[M+H] +
Example 13 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one (I-3)
In a 250mL round bottom flask, 40mL of toluene and potassium carbonate (12.02 g,90 mmol) were added and stirred to give a suspension; dissolving a compound III-3 (10 g,35 mmol), N-benzyl octyl bromide II-2 (1.6 g,3.5 mmol) and nitromethane (4.25 g,70 mmol) in 40mL of toluene, dropwise adding the suspension of the compound III-3 into a toluene suspension of potassium carbonate, stirring at room temperature for reaction for 36h, heating to dissolve through isopropanol (9 g,0.15 mol) at 50-80 ℃, controlling the temperature to be 15-25 ℃ for crystallization, filtering and drying to obtain 6.8g of solid, wherein the yield is 56%, the purity is 95% (HPLC), and the de value is as follows: 90.07%, heating to dissolve by isopropanol at 50-80deg.C, crystallizing at 25-30deg.C, filtering, and drying to obtain compound I-3,5.52g, yield 46%, purity 98.6% (HPLC), de value: 98.4%.
Example 14 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one (I-3)
40mL of toluene and potassium carbonate (12.02 g,0.09 mol) were added to a 250mL round bottom flask and stirred to obtain a suspension; compound III-3 (10 g,0.035 mol) and nitromethane (4.25 g,0.07 mol) were dissolved in 40mL of toluene, the compound III-3 solution was added dropwise to a toluene suspension of potassium carbonate, the reaction was stirred at room temperature for 36 hours, 80mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness. Heating to dissolve through isopropanol (70 g,1.16 mol) at 50-80 ℃, controlling the temperature to be 15-25 ℃ for crystallization, filtering to obtain solid, the yield is 44%, the purity is 96% (HPLC), and the de value is: 96.04%, heating to dissolve by isopropanol at 50-80 ℃, crystallizing at 25-30 ℃, filtering to obtain solid, drying to obtain compound I-3,3.6g, yield 30%, purity 98.6% (HPLC), de value: 100%.
1 H NMR(400MHz,CDCl 3 )δ7.43–7.27(m,5H),5.43(dd,J＝8.8,4.0Hz,1H),4.72(t,J＝8.9Hz,1H),4.42(dd,J＝12.1,6.2Hz,1H),4.36–4.26(m,2H),3.15–3.01(m,2H),2.72(dddd,J＝13.2,7.6,5.8,1.8Hz,1H),1.65–1.59(m,1H),1.24(t,J＝7.2Hz,2H),0.88(d,J＝6.6Hz,6H)。
ESI-MS(m/z)＝335.28[M+H] +
Example 15 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4- (2, 6-dimethylphenyl) oxazolidin-2-one (I-4)
In a 250mL round bottom flask, 10mL of toluene and potassium carbonate (1.12 g,8.3 mmol) were added and stirred to obtain a suspension, compound III-4 (1 g,3.2 mmol), nitromethane (0.45 g,6.64 mmol), N-benzyl octreotide II-1 (0.13 g,0.32 mmol) were dissolved in 10mL of toluene, the compound III-4 solution was added dropwise to the toluene suspension of potassium carbonate, reacted at room temperature for 36h, 40mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness. Heating isopropanol (10 g,0.16 mol) to dissolve at 50-80 ℃, controlling the temperature to 15-25 ℃ for crystallization, and filtering to obtain solid I-4,0.83g, yield: 70%, de value: 55%, heating to dissolve by isopropanol (8 g,0.13 mol) at 50-80 ℃, crystallizing at 25-30 ℃, filtering, and drying to obtain I-4,0.75g, total yield 63%, purity 98.4% (HPLC), de value: 96.3%.
1 H NMR(400MHz,CDCl 3 )δ7.12(dd,J＝8.6,6.9Hz,1H),7.07–7.02(m,2H),5.50(dd,J＝5.3,3.3Hz,1H),5.07(q,J＝1.2Hz,1H),4.82(q,J＝1.0Hz,1H),4.53(dd,J＝12.5,J＝3.3Hz,1H),4.38(dd,J＝12.4,5.2Hz,1H),4.34–4.28(m,2H),2.73(pt,J＝9.1,6.9Hz,1H),2.45(qdt,J＝13.2,7.0,1.0Hz,2H),2.27(d,J＝0.6Hz,5H),1.63(dq,J＝14.0,7.0Hz,1H),1.50–1.36(m,2H),0.92(d,J＝7.1Hz,5H)。
ESI-MS(m/z)＝361.21[M+H] +
Example 16 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4- (3, 5-dimethylphenyl) oxazolidin-2-one (I-5)
In a 250mL round bottom flask, 10mL of toluene and potassium carbonate (1.12 g,8.3 mmol) were added and stirred to obtain a suspension, compound III-5 (1 g,3.2 mmol), nitromethane (0.45 g,6.64 mmol) and N-benzyl octreotide II-1 (0.13 g,0.32 mmol) were dissolved in 10mL of toluene, the compound III-5 solution was added dropwise to the potassium carbonate suspension, reacted at room temperature for 36h, 40mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness. Heating isopropanol (10 g,0.16 mol) to dissolve at 50-80 ℃, controlling the temperature to 15-25 ℃ for crystallization, and filtering to obtain solid I-5,0.88g, yield: 75%, de value: 52 percent, heating to dissolve through isopropyl alcohol (8 g,0.13 mol) at 50 to 80 ℃, controlling the temperature to be 25 to 30 ℃ for crystallization, filtering and drying to obtain I-5,0.8g, the total yield is 67 percent, the purity is 98.6 percent, de:98.7%.
1 H NMR(400MHz,CDCl 3 )δ7.03–6.99(m,2H),6.85–6.80(m,1H),5.20–5.15(m,1H),5.07(q,J＝1.2Hz,1H),4.82(q,J＝1.0Hz,1H),4.46(dd,J＝12.4,5.2Hz,1H),4.40(dd,J＝12.5,3.7Hz,1H),4.35–4.28(m,2H),2.83–2.70(m,1H),2.45(qdt,J＝13.2,7.0,1.0Hz,2H),2.20(s,6H),1.63(dq,J＝14.1,7.0Hz,1H),1.41–1.28(m,2H),0.92(d,J＝7.0Hz,6H)。
ESI-MS(m/z)＝361.21[M+H] +
EXAMPLE 17 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4- (2, 6-dimethoxyphenyl) oxazolidin-2-one (I-6)
In a 250mL round bottom flask, 10mL of toluene and potassium carbonate (1.12 g,8.3 mmol) were added and stirred to obtain a suspension, compound III-6 (1 g,3 mmol), nitromethane (0.37 g,6 mmol), N-benzyl octreotide II-1 (0.13 g,0.3 mmol) were dissolved in 10mL of toluene, the compound III-6 solution was added dropwise to the potassium carbonate suspension, reacted at room temperature for 36h, 40mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness. Heating isopropanol (10 g,0.16 mol) to dissolve at 50-80 ℃, controlling the temperature to 15-25 ℃ for crystallization, and filtering to obtain solid I-6,0.82g, yield: 70%, de value: 49%, heating to dissolve by isopropanol (8 g,0.13 mol) at 50-80 ℃, crystallizing at 25-30 ℃, filtering, and drying to obtain I-6,0.71g, total yield 61%, purity 98.6% (HPLC), de:99.7%.
1 H NMR(500MHz,CDCl 3 )δ7.15(t,J＝8.4Hz,1H),6.66(d,J＝8.4Hz,2H),5.65(dd,J＝5.3,3.5Hz,1H),4.47–4.40(m,2H),4.39–4.35(m,2H),3.84(s,6H),2.91(tt,J＝8.8,7.8Hz,1H),2.69(dd,J＝15.1,7.8Hz,1H),2.42(dd,J＝15.1,7.8Hz,1H),1.63(dt,J＝13.9,7.0Hz,1H),1.55–1.44(m,2H),0.92(d,J＝7.0Hz,6H).
ESI-MS(m/z)＝395.20[M+H] +
Example 18 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4- (3, 5-dimethoxyphenyl) oxazolidin-2-one (I-7)
In a 250mL round bottom flask, 10mL of toluene and potassium carbonate (1.12 g,8.3 mmol) were added and stirred to obtain a suspension, compound III-7 (1 g,3 mmol), nitromethane (0.37 g,6 mmol), N-benzyl octreotide II-1 (0.13 g,0.3 mmol) were dissolved in 10mL of toluene, the compound III-7 solution was added dropwise to the potassium carbonate suspension, reacted at room temperature for 36h, 40mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness. Heating isopropanol (10 g,0.16 mol) to dissolve at 50-80 ℃, controlling the temperature to 15-25 ℃ for crystallization, filtering to obtain solid I-7,0.9g, yield: 76%, de value: 68%, heating to dissolve by isopropanol (9 g,0.14 mol) at 50-80 ℃, crystallizing at 25-30 ℃, filtering, and drying to obtain I-7,0.81g, total yield 68%, purity 98% (HPLC), de:99.4%.
1 H NMR(500MHz,CDCl 3 )δ6.61(dd,J＝2.2,0.7Hz,2H),6.46(t,J＝2.2Hz,1H),5.40–5.31(m,1H),4.54–4.39(m,2H),4.39–4.34(m,2H),3.80(s,6H),2.91(tt,J＝8.8,7.8Hz,1H),2.69(dd,J＝15.1,7.8Hz,1H),2.42(dd,J＝15.1,7.8Hz,1H),1.63(dt,J＝13.9,7.0Hz,1H),1.53–1.44(m,2H),0.92(d,J＝7.0Hz,6H)。
ESI-MS(m/z)＝395.20[M+H] +
Example 19 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one (I-3)
200mL of toluene and cesium carbonate (59.6 g,0.18 mol) were added to a 1000mL round bottom flask and stirred to obtain a suspension; compound III-3 (50 g,0.18 mol) and nitromethane (27.91 g,0.45 mol) were dissolved in 200mL of toluene, the compound III-3 solution was added dropwise to the cesium carbonate toluene suspension, the reaction was stirred at room temperature for 22 hours, 400mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness. Heating to dissolve through isopropanol (212.1 g,3.5 mol) at 50-80 ℃, crystallizing at 15-25 ℃, filtering to obtain solid, and baking to constant weight to obtain 31.2g of compound I-3, with the yield of 52%, the purity of 95.1% (HPLC), and the de value: 99.5 percent, heating to dissolve by isopropanol (310 g,5.2 mol) at 50-80 ℃, controlling the temperature to be 25-30 ℃ for crystallization, filtering and drying to obtain I-3, 20.4g, the yield is 34 percent, the purity is 98.9 percent (HPLC), and the de value is: 99.8%.
EXAMPLE 20 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Into a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.68 g,20 mmol) and lithium hydroxide monohydrate (0.17 g,7 mmol) were added, and the mixture was stirred at 0-5 ℃. Compound I-1 (2 g,6.6 mmol) was dissolved in 10mL of tetrahydrofuran solution, the compound I-1 solution was added dropwise to the hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, the reaction temperature was controlled to be less than 10 ℃, stirring was carried out for 6 hours, sodium sulfite (2.82 g,0.02 mol) was added to the reaction solution in portions, and the reaction was carried out in an ice bath for 0.5 hour. To the reaction solution was added 20mL of water, 30mL of dichloromethane was used for extraction, the aqueous phase was placed in ice bath conditions and diluted hydrochloric acid was added dropwise to give ph=4-5, 40mL of dichloromethane (20 mL x 2) was added for extraction, the organic phase was concentrated to constant weight to give oil, 0.77g, yield: 64%, purity: 91.3% (HPLC).
1 H NMR(400MHz,CDCl 3 )δ4.49(qd,J＝12.3,6.1Hz,2H),2.74–2.63(m,1H),2.52(d,J＝6.3Hz,2H),1.73–1.60(m,1H),1.36–1.23(m,2H),0.94(q,J＝6.9Hz,6H)。
ESI-MS(m/z)＝190[M+H] +
Example 21 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Into a 100mL three-necked flask, 10mL tetrahydrofuran, hydrogen peroxide (0.7 g,20 mmol) and lithium hydroxide monohydrate (0.3 g,7 mmol) were added, and the mixture was stirred at 0-5 ℃. Dissolving a compound I-2 (2 g,5.2 mmol) in 10mL of tetrahydrofuran solution, dropwise adding the compound I-2 solution into a hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, controlling the reaction temperature to be less than 10 ℃, stirring for reaction for 6h, adding sodium sulfite (2.82 g,0.02 mol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL of water into the reaction solution, extracting 30mL of dichloromethane, dropwise adding diluted hydrochloric acid into the water phase under the ice bath condition to ensure that the pH=4-5, adding 40mL of dichloromethane (20 mL of x 2) for extraction, concentrating an organic phase to constant weight, and obtaining oily matter of 0.72g, wherein the yield: 66%, purity: 92.5% (HPLC).
ESI-MS(m/z)＝190[M+H] +
EXAMPLE 22 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Into a 100mL three-necked flask, 10mL tetrahydrofuran, hydrogen peroxide (0.7 g,20 mmol) and lithium hydroxide monohydrate (0.3 g,7 mmol) were added, and the mixture was stirred at 0-5 ℃. The compound I-3 (2 g,6mmol, de value: 99.8%) prepared in example 19 was dissolved in 10mL of tetrahydrofuran solution, the compound I-3 solution was added dropwise to a hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, the reaction temperature was controlled to be less than 10 ℃, stirring was performed for 6 hours, sodium sulfite (2.82 g,0.02 mol) was added to the reaction solution in portions, ice-bath was performed for 0.5 hours, 20mL of water was added to the reaction solution, 30mL of dichloromethane was extracted, the aqueous phase was placed under ice-bath conditions and diluted hydrochloric acid was added dropwise to make ph=4-5, 40mL of dichloromethane (20 mL of 2) was added for extraction, and the organic phase was concentrated to constant weight to obtain oil 0.94g, yield: 87%, purity: 93.5% (HPLC).
ESI-MS(m/z)＝190[M+H] +
EXAMPLE 23 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Into a 100mL three-necked flask, 10mL tetrahydrofuran, hydrogen peroxide (0.7 g,20 mmol) and lithium hydroxide monohydrate (0.3 g,7 mmol) were added, and the mixture was stirred at 0-5 ℃. The compound I-3 (2 g,6mmol, de: 100%) prepared in example 14 was dissolved in 10mL of tetrahydrofuran solution, added dropwise to a hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, the reaction temperature was controlled to be less than 10 ℃, stirred and reacted for 6 hours, sodium sulfite (2.82 g,0.02 mol) was added to the reaction solution in portions, and reacted for 0.5 hours in an ice bath, 20mL of water was added to the reaction solution, 30mL of dichloromethane was extracted, the aqueous phase was placed in ice bath to be extracted with dilute hydrochloric acid dropwise to ph=4-5, 40mL of dichloromethane (20 mL x 2) was added, and the organic phase was concentrated to constant weight to give an oil of 0.9g, yield: 83%, purity: 94.5% (HPLC).
ESI-MS(m/z)＝190[M+H] +
EXAMPLE 24 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Into a 100mL three-necked flask, 10mL tetrahydrofuran, hydrogen peroxide (0.7 g,20 mmol) and lithium hydroxide monohydrate (0.3 g,7 mmol) were added, and the mixture was stirred at 0-5 ℃. Dissolving a compound I-4 (2 g,5.5 mmol) in 10mL of THF solution, dropwise adding the compound I-4 solution into a hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, controlling the reaction temperature to be less than 10 ℃, stirring for reaction for 6h, adding sodium sulfite (2.82 g,0.02 mol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL of water into the reaction solution, extracting 30mL of dichloromethane, dropwise adding diluted hydrochloric acid into the water phase under the ice bath condition to ensure that PH=4-5, adding 40mL of dichloromethane (20 mL of x 2) for extraction, concentrating an organic phase to constant weight, and obtaining oily matter of 0.7g, wherein the yield: 67%, purity: 91.5% (HPLC).
ESI-MS(m/z)＝190[M+H] +
EXAMPLE 25 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Into a 100mL three-necked flask, 10mL tetrahydrofuran, hydrogen peroxide (0.7 g,20 mmol) and lithium hydroxide monohydrate (0.3 g,7 mmol) were added, and the mixture was stirred at 0-5 ℃. Dissolving a compound I-5 (2 g,5.2 mmol) in 10mL of THF solution, dropwise adding the compound I-5 solution into a hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, controlling the reaction temperature to be less than 10 ℃, stirring for reaction for 6h, adding sodium sulfite (2.82 g,0.02 mol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL of water into the reaction solution, extracting 30mL of dichloromethane, dropwise adding diluted hydrochloric acid into the water phase under the ice bath condition to ensure that the pH=4-5, adding 40mL of dichloromethane (20 mL of x 2) for extraction, concentrating an organic phase to constant weight, and obtaining oily matter of 0.8g, wherein the yield: 77%, purity: 94.5% (HPLC).
ESI-MS(m/z)＝190[M+H] +
EXAMPLE 26 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Into a 100mL three-necked flask, 10mL tetrahydrofuran, hydrogen peroxide (0.43 g,12.68 mmol) and lithium hydroxide monohydrate (0.12 g,2.94 mmol) were added, and the mixture was stirred at 0-5 ℃. Dissolving a compound I-6 (1 g,2.5 mmol) in 10mL of THF solution, dropwise adding the compound I-6 solution into a hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, controlling the reaction temperature to be less than 10 ℃, stirring for reaction for 6h, adding sodium sulfite (0.98 g,9.5 mmol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL of water into the reaction solution, extracting 30mL of dichloromethane, dropwise adding diluted hydrochloric acid into the water phase under the ice bath condition to ensure that the pH=4-5, adding 40mL of dichloromethane (20 mL of x 2) for extraction, concentrating an organic phase to constant weight, and obtaining oily matter of 0.28g, wherein the yield: 60%, purity: 91.3% (HPLC).
ESI-MS(m/z)＝190[M+H] +
EXAMPLE 27 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Into a 100mL three-necked flask, 10mL tetrahydrofuran, hydrogen peroxide (0.43 g,12.68 mmol) and lithium hydroxide monohydrate (0.12 g,2.94 mmol) were added, and the mixture was stirred at 0-5 ℃. Dissolving a compound I-7 (1 g,2.5 mmol) in 10mL of THF solution, dropwise adding the compound I-7 solution into a hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, controlling the reaction temperature to be less than 10 ℃, stirring for reaction for 6h, adding sodium sulfite (0.98 g,9.5 mmol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL of water into the reaction solution, extracting 30mL of dichloromethane, dropwise adding diluted hydrochloric acid into the water phase under the ice bath condition to ensure that the pH=4-5, adding 40mL of dichloromethane (20 mL of x 2) for extraction, concentrating an organic phase to constant weight, and obtaining oily matter of 0.28g, wherein the yield: 60%, purity: 92.1% (HPLC).
ESI-MS(m/z)＝190[M+H] +
EXAMPLE 28 preparation of (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)
A suspension of the compound 1 produced in example 22 (0.9 g,4.7 mmol), 10mL of methanol and 0.01g of palladium on carbon was successively added to a round-bottomed flask, and hydrogen was introduced under normal pressure, followed by filtration and concentration, and 5g of isopropyl alcohol-water (mass ratio: 1) was recrystallized to give 0.68g of a white solid, yield 90%, ee:100%.
1 H NMR(400MHz,D 2 O)δ2.84(qd,J＝12.9,6.1Hz,2H),2.18(dd,J＝14.6,6.0Hz,1H),2.13–1.98(m,2H),1.59–1.44(m,J＝6.7Hz,1H),1.08(t,J＝7.1Hz,2H),0.75(dd,J＝6.6,4.7Hz,6H)。D 2 O-exchanged active hydrogen did not peak (see OPRD 1997,1,26-38).
ESI-MS(m/z)＝160[M+H] +
EXAMPLE 29 preparation of (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)
A suspension of the compound 1 produced in example 23 (0.9 g,4.7 mmol), 10mL of methanol and 0.01g of palladium on carbon was successively added to a round-bottomed flask, and hydrogen was introduced under normal pressure, followed by filtration and concentration, and 5g of isopropanol-water (mass ratio 1:1) was recrystallized to give 0.66g of a white solid, yield 88% and ee 100%.
EXAMPLE 30 preparation of (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)
In a round bottom flask, compound 1 (45 g,0.24 mol), methanol 100mL and palladium on carbon 0.45g were suspended in this order
The solution was purged with hydrogen under normal pressure for 10 hours, then filtered and concentrated, and 150g of isopropyl alcohol-water (mass ratio: 1) was recrystallized to obtain 32.56g of a white solid, yield 86%, ee:99.91%.
Comparative example 1
Toluene 20mL and TMG (0.84 g,7.3 mmol) were added to a 100mL round bottom flask and stirred to give a suspension; compound III-3 (2 g,7 mmol) and nitromethane (1.11 g,17.5 mol) were dissolved in 20mL of toluene, the compound III-3 solution was added dropwise to the TMG toluene suspension, the reaction was stirred at room temperature for 36h, 40mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness. Heating isopropanol (15 g,0.25 mol) to dissolve at 50-80 ℃, crystallizing at 15-25 ℃, filtering to obtain solid I-3,0.18g, yield 7.5%, heating isopropanol (1.8 g,0.03 mol) to dissolve at 50-80 ℃, crystallizing at 25-30 ℃, filtering to obtain white solid I-3,0.11g, yield 4.5%, purity 99% (HPLC), de value: 99.22%.
Comparative example 2
Into a 100mL round bottom flask was charged toluene 20mL and TBAF H 2 O (2.3 g,7 mmol) was stirred to give a suspension; compound III-3 (2 g,7 mmol) and nitromethane (1.11 g,17.5 mmol) were dissolved in 20mL toluene and the compound III-3 solution was added dropwise to TBAF. H 2 To the O toluene suspension, the reaction was stirred at room temperature for 36 hours, 40mL of water was added to the reaction solution, the solution was separated, and the organic phase was concentrated to dryness. Heating isopropanol (15 g,0.25 mol) to dissolve at 50-80 ℃, crystallizing at 15-25 ℃, filtering to obtain solid I-3,0.42g, yield of 17.5%, heating isopropanol (4.2 g,0.07 mol) to dissolve at 50-80 ℃, crystallizing at 25-30 ℃, filtering to obtain white solid I-3,0.38g, yield of 15.8%, purity of 99.4% (HPLC), de value: 99.92%.

Claims (15)

1. A preparation method of a compound shown as a formula (I),
the compound shown in the formula (I) is any one of the following compounds:
the preparation method comprises any one of the following steps:
the method (1) comprises the following steps: in an organic solvent, reacting a compound shown as a formula (III) with nitromethane in the presence of alkali, and carrying out chiral resolution to obtain the compound shown as the formula (I);
the method (2) comprises the following steps: in an organic solvent, in the presence of alkali, reacting a compound shown as a formula (III) with nitromethane under the action of a catalyst shown as a formula (II);
In the method (1) and the method (2), the alkali is K 2 CO 3 And/or Cs 2 CO 3 ；
In the method (2), R 2 Is C 6 -C 14 Aryl or benzyl; r is R 3 Is hydroxyl or amino; x is halogen.
2. The process for preparing a compound of formula (I) as claimed in claim 1,
in the method (1), the solution formed by the compound shown as the formula (III), the nitromethane and the organic solvent is dripped into the organic solvent suspension of the alkali;
and/or, in the method (1), the organic solvent is one or more of dichloromethane, acetonitrile, toluene, THF, acetone, DMSO and methanol;
and/or, in the method (1), the molar ratio of the compound represented by the formula (III) to the nitromethane is 1: (1-3);
and/or in the method (1), the ratio of the molar ratio of the alkali to the compound shown as the formula (III) is 1.0-2.8;
and/or, in the method (1), the temperature of the reaction is 10-40 ℃;
and/or, in the method (1), the reaction time of the reaction is 22-36 h;
and/or, in the method (1), after the reaction is finished and before chiral resolution, the method further comprises: quenching, separating liquid and concentrating the reaction system in sequence;
and/or, in method (1), the chiral resolution employs recrystallization.
3. The process for preparing a compound of formula (I) according to claim 2, wherein in process (1), the molar ratio of the compound of formula (III) to nitromethane is 1: (1.5-2.5);
and/or in the method (1), the ratio of the molar ratio of the base to the compound represented by formula (III) is 2.5 or 2.6;
and/or, in the method (1), the temperature of the reaction is 20-30 ℃.
4. The process for producing a compound of the formula (I) according to claim 2,
in the method (1), in a solution formed by the compound shown in the formula (III), the nitromethane and the organic solvent, the mass-volume ratio of the compound shown in the formula (III) to the organic solvent is 0.1 g/mL-0.25 g/mL;
and/or, in the method (1), the ratio of the mass volume ratio of the alkali to the organic solvent in the organic solvent suspension of the alkali is 0.1g/mL to 0.4g/mL;
and/or, in the method (1), the recrystallization includes the steps of: placing a solution of an organic solvent of a compound shown as a formula (I) at 50-80 ℃ at 15-30 ℃ for crystallization;
and/or, in the method (1), the organic solvent used for recrystallization is one or more of alcohol solvents and mixed solvents formed by the alcohol solvents and water;
And/or, in method (1), the chiral resolution employs secondary recrystallization.
5. The method for producing a compound represented by the formula (I) according to claim 4, wherein in the method (1), the ratio of the mass/volume ratio of the base to the organic solvent in the organic solvent suspension of the base is 0.3g/mL;
and/or, in the method (1), the recrystallization includes the steps of: placing a solution of an organic solvent of a compound shown as a formula (I) at 50-80 ℃ at 25-30 ℃ for crystallization;
and/or, in the method (1), the organic solvent used for recrystallization is isopropanol.
6. The process for producing a compound of the formula (I) according to claim 4,
in the method (1), the secondary recrystallization includes the steps of: placing a solution of an organic solvent of a compound shown as a formula (I) at 50-80 ℃ in a temperature of 15-25 ℃ for crystallization, filtering, drying to obtain a solid, and placing the solution of the organic solvent of the solid at 50-80 ℃ in a temperature of 25-30 ℃ for crystallization.
7. The process for preparing a compound of formula (I) as claimed in claim 1,
in the method (2), R 2 Phenyl, benzyl, anthracenyl or naphthyl;
and/or, in the method (2), X is Cl or Br;
And/or, in the method (2), the organic solvent is one or more of dichloromethane, acetonitrile, toluene, THF, acetone, DMSO and methanol;
and/or, in the method (2), a solution formed by the compound shown as a formula (III), the nitromethane, the catalyst shown as a formula (II) and an organic solvent is dropwise added to the organic solvent suspension of the alkali;
and/or, in the method (2), the molar ratio of the compound represented by the formula (III) to nitromethane is 1: (1-3);
and/or, in the method (2), the molar ratio of the compound shown in the formula (III) to the catalyst shown in the formula (II) is 1 (0.07-0.1);
and/or, in the method (2), the ratio of the molar ratio of the alkali to the compound shown as the formula (III) is 1.0-2.8;
and/or, in the method (2), the temperature of the reaction is 10-40 ℃;
and/or, in the method (2), the reaction time of the reaction is 22-36 h;
and/or, in the method (2), further comprising a post-treatment comprising the steps of: quenching, separating liquid, concentrating and purifying the reaction system in sequence.
8. The process for preparing a compound of formula (I) according to claim 7, wherein in the process (2), the molar ratio of the compound of formula (III) to nitromethane is 1: (1.5-2.5);
And/or, in the method (2), the ratio of the molar ratio of the base to the compound represented by formula (III) is 2.5 or 2.6;
and/or, in the method (2), the temperature of the reaction is 20-30 ℃.
9. The process for producing a compound of the formula (I) according to claim 7,
in the method (2), the ratio of the mass volume ratio of the compound shown in the formula (III) to the organic solvent in a solution formed by the compound shown in the formula (III), the nitromethane and the catalyst shown in the formula (II) to the organic solvent is 0.1-0.25 g/mL;
and/or, in the method (2), the ratio of the mass volume ratio of the alkali to the organic solvent in the organic solvent suspension of the alkali is 0.1g/mL to 0.4g/mL;
and/or, in the method (2), the purification employs recrystallization or column chromatography;
and/or, in the method (2), when the compound of formula I is compound I-3, I-4, I-5, I-6 or I-7, the purification employs recrystallization; when the compound of formula I is compound I-2, the purification employs column chromatography.
10. The method for producing a compound of formula (I) according to claim 9, wherein in the method (2), the ratio of the mass/volume ratio of the base to the organic solvent in the organic solvent suspension of the base is 0.3g/mL.
11. The process for preparing a compound of formula (I) as claimed in claim 9,
in the method (2), the recrystallization includes the steps of: placing a solution of an organic solvent of a compound shown as a formula (I) at 50-80 ℃ at 15-30 ℃ for crystallization;
and/or, in the method (2), the organic solvent used for recrystallization is one or more of an alcohol solvent and a mixed solvent formed by the alcohol solvent and water;
and/or, in the method (2), the recrystallization employs secondary recrystallization;
and/or, in the method (2), the eluent of the column chromatography is a mixed solution of petroleum ether and ethyl acetate;
and/or, in the method (2), the volume ratio of the petroleum ether to the ethyl acetate is (8-10): 1.
12. the method for producing a compound of formula (I) according to claim 11, wherein in the method (2), the recrystallization comprises the steps of: placing a solution of an organic solvent of a compound shown as a formula (I) at 50-80 ℃ at 25-30 ℃ for crystallization;
and/or, in the method (2), the organic solvent used for the recrystallization is isopropanol.
13. The process for preparing a compound of formula (I) as claimed in claim 11,
In the method (2), the secondary recrystallization includes the steps of: placing a solution of an organic solvent of a compound shown as a formula (I) at 50-80 ℃ in a temperature of 15-25 ℃ for crystallization, filtering, drying to obtain a solid, and placing the solution of the organic solvent of the solid at 50-80 ℃ in a temperature of 25-30 ℃ for crystallization.
14. The process for preparing a compound of formula (I) as claimed in claim 1,
the preparation method of the compound shown in the formula (I) further comprises the following steps: reacting a compound shown as a formula (IV) with a compound shown as a formula (V) in an organic solvent in the presence of a catalyst and a base;
wherein R is 4 Is hydroxyl or halogen.
15. The process for preparing a compound of the formula (I) as claimed in claim 14, wherein R 4 Is chlorine.
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