CN114478422A - Pregabalin intermediate and preparation method thereof - Google Patents

Pregabalin intermediate and preparation method thereof Download PDF

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CN114478422A
CN114478422A CN202011146809.7A CN202011146809A CN114478422A CN 114478422 A CN114478422 A CN 114478422A CN 202011146809 A CN202011146809 A CN 202011146809A CN 114478422 A CN114478422 A CN 114478422A
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CN114478422B (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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China State Institute of Pharmaceutical Industry
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    • 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
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    • 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
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    • C07D263/18—Oxygen atoms
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Abstract

The invention discloses an intermediate of pregabalin and a preparation method thereof. The invention provides a compound shown as a formula (I) and a preparation method thereof, wherein the preparation method of the compound shown as the formula (I) is any one of the following methods: the method (1) comprises the following steps: reacting a compound shown as a formula (III) with nitromethane in an organic solvent in the presence of alkali, and obtaining the compound shown as the formula (I) through manual resolution; 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 the 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 scale-up production, and can be used for synthesizing pregabalin.

Description

Pregabalin intermediate and preparation method thereof
Technical Field
The invention relates to a pregabalin intermediate and a preparation method thereof.
Background
Pregabalin (pregabalin), chemically named (S) -3-aminomethyl-5-methylhexanoic acid, is a gamma-aminobutyric acid (GABA) receptor antagonist developed by the company pyroxene, acts primarily by modulating pressure-dependent calcium channels in the central nervous system, is clinically used for peripheral neuralgia or for adjuvant treatment of partial seizures, has been approved by the european union in 2004 and first marketed in the uk, and is approved by the FDA in the united states 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 method of pregabalin is mainly divided into two main categories: the conventional chemical method and the enzymatic method generally have higher requirements on process conditions, so that production amplification is difficult to carry out, the conventional chemical method is generally adopted to prepare the pregabalin at present, and the conventional chemical method can be subdivided into the following three types:
the first type is a chemical resolution method, generally, pregabalin racemate is prepared first, and then pregabalin is prepared by resolution of a resolving agent, and the method is also used for production in the industry at present, and the specific route is as follows:
Figure BDA0002739932810000011
the overall yield of this route is low (25-29%) and the other isomer (R) -3-aminomethyl-5-methylhexanoic acid produced is discarded, causing a large waste of raw materials. In addition, potassium cyanide (KCN) is used in the route, belongs to a highly toxic reagent, and has great potential safety hazard.
The second type is chiral source synthesis, in which a chiral compound is used as a starting material to directly introduce chirality to prepare pregabalin, as disclosed in document j. For example: chiral epichlorohydrin 15 and diethyl malonate 16 are used as starting materials, a key intermediate 19 is prepared, ring-opening bromination, azidation and ester group hydrolysis are carried out on trimethyl bromosilane, pregabalin is obtained by reduction, and the total yield is as follows: 57%, ee of azide: 99 percent.
Figure BDA0002739932810000021
The preparation of the azide (21) is related in the route and the synthesis method, and the adopted reagents, namely sodium azide and the azide (21), are extremely unstable and easy to cause explosion, so that the method has hidden troubles in operation and safety and is not suitable for production amplification.
The third type is an asymmetric synthesis method, and the target product is obtained by controlling the chirality of the target product through a chiral catalyst or a chiral auxiliary agent.
The preparation of pregabalin by a cinchona chiral catalyst is reported in Org Process Res Dev 2015,19(9):1274, the synthetic route is as follows:
Figure BDA0002739932810000022
in the route, an olefin intermediate 26 and nitromethane are subjected to addition reaction, an optical selective compound 28 is generated under the catalysis of a quinine catalyst 27, and then the pregabalin is prepared through hydrolysis and reduction. However, the cinchona alkaloid catalyst 27 disclosed in the route is not commercially available, the preparation cost is high, the dosage is relatively large, and the economy for preparing pregabalin is poor.
Can.J. chem.92: 45-48 (2014) reports that Evans reagent IV-3 is used as a chiral auxiliary agent and Et is used as a chiral auxiliary agent2A method for preparing pregabalin by using AlCN as an ammonia source. The synthetic route is as follows:
Figure BDA0002739932810000023
this route has two important drawbacks: first, reagent Et2AlCN is expensive and a highly toxic reagent, which greatly limits the application thereof. Secondly, the key intermediate 33 in the route is oily matter, column chromatography cannot be avoided in the purification process, and the optical purity is only 74%. Therefore, the method has no practical value for producing pregabalin.
In the third asymmetric synthesis, both preparation methods adopt olefin addition technical means and chiral catalysts or chiral auxiliaries for chiral control of target products, but the methods still exist: using expensive catalyst, potassium cyanide and Et2AlCN virulent reagent and the like.
In summary, the currently disclosed methods for preparing pregabalin still have many defects, and therefore, it is urgently needed to develop a production process which is cheap and easily available in raw materials and reagents, suitable for scale-up production and quality control, low in cost and large in scale to prepare pregabalin.
Disclosure of Invention
The invention aims to solve the technical problem of providing a pregabalin intermediate and a preparation method thereof in order to overcome the defects of the prior art that a potassium cyanide virulent reagent, an explosive azide reagent and intermediate, an expensive catalyst and the like are used. The method has the advantages of mild reaction conditions, low toxicity of raw materials, simplicity and easiness in obtaining, simplicity in operation, easiness in scale-up production and capability of being used for preparing pregabalin.
The present invention solves the above technical problems by the following means.
The invention provides a compound shown as a formula (I);
Figure BDA0002739932810000031
wherein R is C1-C6Alkyl, phenyl, RaSubstituted phenyl, benzyl or RbA substituted benzyl group; raAnd RbIs independently one or more, when said R isaWhen the number of (A) is plural, R isaThe same or different; when said R isbWhen the number of (A) is plural, R isbThe same or different;
Raand RbIndependently is C1-C6Alkyl or C1-C6An alkoxy group.
R is preferably methyl, ethyl or isopropyl.
The R isaAnd RbIndependently preferably methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy.
The R isaThe number of (a) is preferably 1 or 2; when said R isaWhen the number of (2) is provided, R isaThe same or different.
The R isbThe number of (a) is preferably 1 or 2; when said R isbWhen the number of (2) is provided, R isbThe same or different.
Preferably, the compound represented by formula (I) includes, but is not limited to, any of the following compounds:
Figure BDA0002739932810000032
Figure BDA0002739932810000041
the invention provides a preparation method of a compound shown as a formula (I), which is any one of the following methods:
the method (1) comprises the following steps: reacting a compound shown as a formula (III) with nitromethane in an organic solvent in the presence of alkali, and obtaining the compound shown as the formula (I) through manual resolution;
Figure BDA0002739932810000042
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);
Figure BDA0002739932810000051
in the method (1) and the method (2), the base is K2CO3And/or Cs2CO3；
In the above-mentioned method (1) and the above-mentioned method (2), R is C1-C6Alkyl, phenyl, RaSubstituted phenyl, benzyl or RbA substituted benzyl group; raAnd RbIs independently one or more, when said R isaWhen there are more than one, RaThe same or different; when said R isbWhen the number of (A) is plural, R isbThe same or different;
in the above method (1) and the above method (2), RaAnd RbIndependently is C1-C6Alkyl or C1-C6An alkoxy group;
in the above process (2), R2Is C6-C14Aryl or benzyl; r3Is hydroxy or amino; x is halogen.
In the method (1) and the method (2), R is preferably a methyl group, an ethyl group or an isopropyl group.
In the method (1) and the method (2), the RaAnd RbIndependently preferably methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy.
In the method (1) and the method (2), the RaThe number of (a) is preferably 1 or 2; when said R isaWhen the number of (2) is provided, R isaThe same or different.
In the method (1) and the method (2), the RbThe number of (a) is preferably 1 or 2; when said R isbWhen the number of (2) is provided, R isbThe same or different.
In the method (1), the solution of the compound represented by the formula (III), the nitromethane and the 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, and is 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 the formula (III) to the nitromethane may be conventional in the art, and is preferably 1: (1-3), more preferably 1: (1.5-2.5), for example 1:2.
In the method (1), the ratio of the molar ratio of the base to the compound represented by the formula (III) can be conventional in the art, and is preferably 1.0-2.8, for example: 2.5 or 2.6.
In the method (1), the reaction temperature can be conventional in the art, and is preferably 10-40 ℃, and more preferably 20-30 ℃.
In the method (1), the reaction time of the reaction is related to the selectivity of the alkali, and the reaction time is preferably 22 to 36 hours.
In the method (1), the progress of the reaction can be monitored by a conventional monitoring method in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally determined as the disappearance or no longer reaction of the compound represented by the formula (III).
In the method (1), after the reaction and before the chiral resolution, the method further comprises: and sequentially quenching, separating and concentrating the reaction system.
In the method (1), the quenching is preferably carried out by using water, and the amount of the water used is not limited so as not to affect the reaction.
In the process (1), the concentration may be conventional in the art, and is preferably carried out under reduced pressure and vacuum.
In the method (1), the chiral resolution is preferably performed by recrystallization.
In the method (1), in the solution formed by the compound shown in the formula (III), the nitromethane and the organic solvent, the amount of the organic solvent is not limited, so as not to affect the reaction; the mass-to-volume ratio of the compound represented by the formula (III) to the organic solvent can be conventional in the art, and is preferably 0.1 g/mL-0.25 g/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 0.3 g/mL.
In the method (1), the recrystallization includes the steps of: crystallizing the solution of the organic solvent of the compound shown in the formula (I) at the temperature of preferably 50-80 ℃, preferably at the temperature of 15-30 ℃, for example at the temperature of 25-30 ℃.
In the method (1), the organic solvent used for 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: crystallizing the solution of the organic solvent of the compound shown in the formula (I) at the temperature of preferably 50-80 ℃, preferably at the temperature of 15-25 ℃, filtering, drying to obtain a solid, and crystallizing the solution of the organic solvent of the solid at the temperature of preferably 50-80 ℃, preferably at the temperature of 25-30 ℃.
In the above process (2), R2Preferably 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, and is preferably one or more of dichloromethane, acetonitrile, toluene, THF, acetone, DMSO, and methanol.
In the method (2), the solution of the compound represented by the formula (III), the nitromethane, the catalyst represented by the formula (II) and the organic solvent is preferably added dropwise to the suspension of the base and the organic solvent.
In the method (2), the molar ratio of the compound represented by the formula (III) to the nitromethane may be conventional in the art, and is preferably 1: (1-3), more preferably 1: (1.5-2.5), for example 1:2.
In the method (2), the molar ratio of the compound shown in the formula (III) to the catalyst shown in the formula (II) can be conventional in the field, and is preferably 1 (0.07-0.1).
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, and is preferably 1.0 to 2.8, for example: 2.5 or 2.6.
In the method (2), the reaction temperature can be conventional in the art, and is preferably 10-40 ℃, and more preferably 20-30 ℃.
In the method (2), the reaction time of the reaction is related to the selectivity of the alkali, and the reaction time is preferably 22 to 36 hours.
In the method (2), the progress of the reaction can be monitored by a conventional monitoring method in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally determined as the disappearance or no longer reaction of the compound represented by the formula (III).
The method (2) further comprises a post-treatment, wherein the post-treatment comprises the following steps: and sequentially quenching, separating, concentrating and purifying the reaction system.
In the method (2), in the solution formed by the compound shown in the formula (III), the nitromethane, the catalyst shown in the formula (II) and the organic solvent, the dosage of the organic solvent is not limited so as not to influence the reaction; the mass-to-volume ratio of the compound represented by the formula (III) to the organic solvent can be conventional in the art, and is preferably 0.1 g/mL-0.25 g/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 0.3 g/mL.
In the method (2), in the post-treatment method, the quenching is preferably carried out using water, and the amount of water used may not be 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, and is preferably performed under reduced pressure and 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 a phenyl group or RaIn the case of substituted phenyl groups, the purification is preferably carried out by recrystallization; when R is C1-C6Alkyl, benzyl or RbWhere a substituted benzyl group, for example 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: crystallizing the solution of the organic solvent of the compound shown in the formula (I) at the temperature of preferably 50-80 ℃, preferably at the temperature of 15-30 ℃, for example at the temperature of 25-30 ℃.
In the method (2), in the post-treatment method, the organic solvent used for 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 (2), in the post-treatment method, preferably, the recrystallization employs secondary recrystallization.
In the method (2), in the post-treatment method, the secondary recrystallization includes the steps of: crystallizing the solution of the organic solvent of the compound shown in the formula (I) at the temperature of preferably 50-80 ℃, preferably at the temperature of 15-25 ℃, filtering, drying to obtain a solid, and crystallizing the solution of the organic solvent of the solid at the temperature of preferably 50-80 ℃, preferably at the temperature of 25-30 ℃.
In the method (2), in the post-treatment method, the eluent for the column chromatography is preferably a mixed solution of petroleum ether and ethyl acetate. The volume ratio of the petroleum ether to the ethyl acetate is preferably (8-10): 1.
in the invention, the preparation method of the compound shown in the formula (I) can further comprise 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 alkali to obtain a compound shown as a formula (III);
Figure BDA0002739932810000081
wherein R is C1-C6Alkyl, phenyl, RaSubstituted phenyl, benzyl or RbA substituted benzyl group; raAnd RbIs independently one or more, when said R isaWhen the number of (A) is plural, R isaThe same or different; when said R isbWhen the number of (A) is plural, R isbThe same or different;
Raand RbIndependently is C1-C6Alkyl or C1-C6An alkoxy group;
R4is hydroxyl or halogen. Preferably, R4Chlorine is preferred.
In the preparation method of the compound shown in the formula (III), R is preferably methyl, ethyl or isopropyl.
In the preparation method of the compound shown as the formula (III), R isaAnd RbIndependently preferably methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy.
In the preparation method of the compound shown as the formula (III), R isaThe number of (a) is preferably 1 or 2; when said R isaWhen the number of (2) is provided, R isaThe same or different.
In the preparation method of the compound shown as the formula (III), R isbThe number of (a) is preferably 1 or 2; when said R isbWhen the number of (2) is provided, R isbThe same or different.
In the preparation method of the compound represented by the formula (III), the compound represented by the formula (V) is preferably added dropwise to a solution formed by the compound represented by the formula (IV), the catalyst, the base and the organic solvent.
In the preparation method of the compound shown in the formula (III), the compound shown in the formula (V) at 0-30 ℃ is preferably dripped into the solution formed by the compound shown in the formula (IV), the catalyst, the alkali and the organic solvent at 0-10 ℃.
In the preparation method of the compound shown in the formula (III), the compound shown in the formula (V) at 0-10 ℃ is more preferably dripped into the solution formed by the compound shown in the formula (IV), the catalyst, the alkali and the organic solvent at 0-5 ℃.
In the preparation method of the compound shown as the formula (III), when R4In the case of hydroxyl, the method preferably further comprises the following steps: in an organic solvent, reacting the compound shown in the formula (V) with an acylating reagent to prepare 5-methyl-2-hexenoyl halide, and directly reacting with the compound shown in the formula (IV) without post-treatment to obtain the compound shown in the formula (III).
In the 5-methyl-2-hexenoyl halide preparation process, in certain embodiments, the organic solvent is preferably a halogenated hydrocarbon solvent, such as: dichloromethane.
In the 5-methyl-2-hexenoyl halide preparation process, in certain embodiments, the acylating agent is preferably oxalyl chloride, thionyl chloride.
In the 5-methyl-2-hexenoyl halide preparation process, in certain embodiments, the temperature of the reaction may be conventional in the art, preferably 10 to 40 ℃, more preferably 20 to 30 ℃.
In the 5-methyl-2-hexenoyl halide preparation process, in certain embodiments, the reaction time may be conventional in the art, preferably 4 to 12 hours.
In the preparation method of the compound shown as the formula (III), when R is4When the halogen is contained, the compound shown as the formula (V) is 5-methyl-2-hexenoyl halide, and directly reacts with the compound shown as the formula (IV) to obtain the compound shown as the formula (III).
In the preparation method of the compound represented by the formula (III), in certain embodiments, the organic solvent may be conventional in the art, and is preferably one or more of dichloromethane, acetonitrile, toluene, tetrahydrofuran, acetone, DMSO, and methanol.
In the preparation of the compounds of formula (III), the base may be conventional in the art, and is preferably pyridine, sodium carbonate or triethylamine in certain embodiments.
In the preparation of the compounds of formula (III), the catalyst may be conventional in the art, and is preferably DMAP (4-dimethylaminopyridine), in certain embodiments.
In the preparation method of the compound shown in the formula (III), in some embodiments, the molar ratio of the compound shown in the formula (V) to the compound shown in the formula (IV) may be conventional in the art, and is preferably (1-1.5): 1, and more preferably (1.0-1.3): 1.
In the process for the preparation of the 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: (0.01-0.2), more preferably 1 (0.01-0.1).
In the preparation method of the compound shown in the formula (III), in some embodiments, the molar ratio of the compound shown in the formula (IV) to the base is conventional in the art, and is preferably 1 (1-5), such as 1:2.4, 1:2.8 or 1: 4.7.
In the process for the preparation of the compound of formula (III), in certain embodiments, the progress of the reaction may be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC, or NMR), typically by the disappearance or no longer reaction of the compound of formula (IV) as an end point of the reaction.
In the process for the preparation of the compound of formula (III), in certain embodiments, the reaction further comprises a work-up comprising the steps of: and sequentially filtering, concentrating and purifying the reaction system to obtain the catalyst.
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 method for preparing the compound represented by the formula (III), in some embodiments, the organic solvent used for the recrystallization is preferably one or more of ethyl acetate, petroleum ether, n-heptane and n-hexane in the post-treatment method.
In the preparation method of the compound represented by the formula (III), in some embodiments, in the post-treatment method, the eluent for the column chromatography may be conventional in the art, and is preferably a mixed solution of petroleum ether and ethyl acetate. The volume ratio of the petroleum ether to the ethyl acetate can be conventional in the field, and is preferably (10-15): 1.
the invention provides a preparation method of a compound shown as a formula 1, which comprises the following steps of reacting the compound shown as the formula (I) in an organic solvent in the presence of alkali and an oxidant;
Figure BDA0002739932810000101
wherein R is C1-C6Alkyl, phenyl, RaSubstituted phenyl, benzyl or RbA substituted benzyl group; raAnd RbIs independently one or more, when said R isaWhen the number of (A) is plural, R isaThe same or different; when said R isbWhen the number of (A) is plural, R isbThe same or different;
Raand RbIndependently is C1-C6Alkyl or C1-C6An alkoxy group.
In the preparation method of the compound shown in the formula 1, R is preferably methyl, ethyl or isopropyl.
In the preparation method of the compound shown as the formula 1, R isaAnd RbIndependently preferably methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy.
In the preparation method of the compound shown as the formula 1, R isaThe number of (a) is preferably 1 or 2; when said R isaWhen the number of (2) is provided, R isaThe same or different.
In the preparation method of the compound shown as the formula 1, R isbThe number of (a) is preferably 1 or 2; when said R isbWhen the number of (2) is provided, R isbThe same or different.
In the preparation method of the compound shown in the formula 1, a solution of the organic solvent of the compound shown in the formula (I) is preferably dropwise added into a solution formed by the base, the oxidant and the organic solvent.
In the preparation method of the compound shown in the formula 1, preferably <10 ℃ solution of the organic solvent of the compound shown in the formula (I) is dripped into a solution formed by the alkali, the oxidant and the organic solvent, preferably 0-5 ℃.
In the preparation method of the compound represented by formula 1, in certain embodiments, the organic solvent may be conventional in the art, and is preferably an ether solvent, such as tetrahydrofuran.
In the preparation of the compound of formula 1, in certain embodiments, the base may be conventional in the art, and is preferably lithium hydroxide.
In the preparation method of the compound shown in formula 1, in certain embodiments, the oxidizing agent may be conventional in the art, and is preferably hydrogen peroxide.
In the preparation method of the compound shown in the formula 1, in certain embodiments, the mass-to-volume ratio of the compound shown in the formula (I) to the organic solvent can be conventional in the art, and is preferably 0.1 g/mL-0.5 g/mL, and more preferably 0.2 g/mL.
In the process for the preparation of the 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 the preparation of the 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), for example, 1:3, 1:3.3, 1:3.6 or 1: 3.8.
In the preparation method of the compound shown in the formula 1, in some embodiments, the reaction time of the reaction can be conventional in the art, preferably 4-12 h, and more preferably 6 h.
In certain embodiments, the progress of the reaction may be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), typically by the disappearance or cessation of the reaction of the compound of formula (IV).
In the process for preparing a compound represented by formula 1, in certain embodiments, the reaction further comprises a post-treatment comprising the steps of: adding a reducing agent into a reaction system, and sequentially extracting and concentrating.
In the preparation method of the compound represented by formula 1, in certain embodiments, in the post-treatment method, the reducing agent may be conventional in the art, and is preferably sodium sulfite or sodium thiosulfate, and more preferably sodium sulfite.
In the process for the preparation of the compound of formula 1, in certain embodiments, the molar ratio of the compound of formula (I) to the reducing agent in the work-up process 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 preparing a compound represented by formula 1, in certain embodiments, in the post-treatment process, the aqueous phase obtained by the extraction is preferably neutralized by adding an acid. The acids may be conventional in the art, and are preferably inorganic acids, such as: dilute hydrochloric acid.
In the preparation method of the compound shown in the formula 1, in some embodiments, in the post-treatment method, the pH value of the water phase after acid neutralization is preferably 4 to 5.
The invention provides a preparation method of pregabalin, which has the following reaction route:
Figure BDA0002739932810000121
the invention also provides a compound shown as the formula (III), which is any one of the following compounds:
Figure BDA0002739932810000122
on the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
In the present invention, said C is, unless otherwise specified1-C6Alkyl means unsubstituted C1-C6An alkyl group.
In the present invention, said C is, unless otherwise specified6-C14Aryl means unsubstituted C6-C14And (4) an aryl group.
In the present invention, unless otherwise specified, the above-mentioned C1-C6Alkoxy denotes in each case unsubstituted C1-C6An alkoxy group.
As used herein, unless otherwise indicated, the terms "phenyl", "benzyl", "anthracenyl" and "naphthyl" refer to unsubstituted phenyl, unsubstituted benzyl, unsubstituted anthracenyl and unsubstituted naphthyl.
Unless otherwise specified, the terms "methyl", "ethyl", "isopropyl", "methoxy", "ethoxy" and "isopropoxy" as used herein refer to unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted methoxy, unsubstituted ethoxy and unsubstituted isopropoxy.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the method has the advantages of mild reaction conditions, easily obtained 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, which confirms the absolute optical configuration of compound I-3 by X-single crystal diffraction pattern, and its chemical name is (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
Example 15 preparation of methyl-2-hexenoic acid (V-1)
Figure BDA0002739932810000131
Pyridine (98.8g, 1.24mol) isovaleraldehyde (92.71g, 1.07mol) is sequentially added into a 500mL three-necked bottle, the mixture is fully stirred uniformly, the temperature is raised to 60-70 ℃, malonic acid (100g, 0.96mol) is added in batches, the mixture is heated to 90 ℃, stirred for 4 hours, the temperature is lowered to 0-5 ℃, 5% diluted hydrochloric acid is added to wash the mixture until the pH value is 2-4, liquid separation is carried out, an organic phase is collected, and the mixture is concentrated under reduced pressure until the weight is constant to obtain 110.46g of oily matter, the yield is 90%, and the purity is 99.05% (HPLC).
1H NMR(400MHz,CDCl3):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)。CDCl3Synthesis of (. + -.) -3-aminomethyl-5-methylhexanoic acid from Chenwenhua, Qixiu, Uaco bee-]J.Chinese medicine industry, 2019(7):746-
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)
Figure BDA0002739932810000132
Step one preparation of 5-methyl-2-hexenoyl chloride (V-2)
Figure BDA0002739932810000141
5-methyl-2-hexenoic acid (50g, 0.4mol) and 50mL of dichloromethane are added into a 250mL round-bottom flask and stirred to be dissolved, oxalyl chloride (75.21g, 0.6mol) solution in dichloromethane (30mL) is added dropwise, the mixture is stirred for reaction at room temperature for 6h, and the yellow oily substance is obtained by decompression and concentration and is directly used for the next reaction.
Step preparation of bis (R) -4-isopropyl-3- (5-methylhexyl-2-enyl) oxazolidin-2-one (III-1)
Figure BDA0002739932810000142
Adding (R) -4-isopropyl-2-oxazolidinone IV-1(5g, 0.038mol), DMAP (0.46g, 0.0038mol) and triethylamine (9.4g, 0.09mol) into 20mL of dichloromethane solution in turn in a 500mL three-necked flask, controlling the internal temperature to be 0-5 ℃, then dropwise adding the prepared acyl chloride V-2, controlling the temperature to be 0-10 ℃, stirring for reaction for 5 hours, filtering, collecting filtrate, concentrating to constant weight, and performing column chromatography (petroleum ether: ethyl acetate: 15:1) to obtain a compound III-1, 5g of light yellow oily matter, the yield is 56%, and the purity is 99.1% (HPLC).
1H NMR(400MHz,CDCl3)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)
Figure BDA0002739932810000143
Sequentially adding (R) -4-benzyl-2-oxazolidinone IV-2(30g, 0.17mol), DMAP (2.1g, 0.017mol) and triethylamine (41g, 0.4mol) into 50mL of dichloromethane solution in a 500mL three-necked bottle, controlling the internal temperature to be 0-5 ℃, dropwise adding the prepared acyl chloride V-2, controlling the temperature to be 0-10 ℃, stirring and reacting for 5 hours, filtering, collecting filtrate, concentrating the filtrate to constant weight, recrystallizing with 80mL of n-hexane to obtain a compound III-2, and drying to obtain 34g of light yellow solid with yield of 71% and purity of 98.87% (HPLC).
1H NMR(400MHz,CDCl3)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)
Figure BDA0002739932810000151
Sequentially adding (R) -4-phenyl-2-oxazolidinone IV-3(30g, 0.17mol), DMAP (2.24g, 0.017mol) and triethylamine (41g, 0.4mol) into 50mL of dichloromethane solution in a 500mL three-necked bottle, controlling the internal temperature to be 0-5 ℃, dropwise adding the prepared acyl chloride V-2, controlling the temperature to be 0-10 ℃, stirring and reacting for 5 hours, filtering, collecting filtrate, concentrating to constant weight, recrystallizing with 80mL of n-hexane to obtain a compound III-3, and drying to obtain 38.7g of light yellow solid, wherein the yield is 80%, and the purity is 99.54% (HPLC).
1H NMR(400MHz,CDCl3):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)
Figure BDA0002739932810000161
In a 500mL three-necked bottle, (R) -4- (2, 6-dimethylphenyl) -2-oxazolidinone IV-4(1g, 5mmol), DMAP (0.06g, 0.5mmol) and triethylamine (1.9g, 14mmol) are sequentially added into a 10mL dichloromethane solution, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is dropwise added, the temperature is controlled to be 0-10 ℃, the mixture is stirred and reacted for 5 hours, the mixture is filtered, the filtrate is collected and concentrated to constant weight, and the mixture is subjected to column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain a compound III-4 which is dried to obtain 1.1g of light yellow solid, the yield is 69%, and the purity is 97.6% (HPLC).
1H NMR(400MHz,CDCl3)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)
Figure BDA0002739932810000162
In a 500mL three-necked bottle, (R) -4- (3, 5-dimethylphenyl) -2-oxazolidinone IV-5(1g, 5mmol), DMAP (0.06g, 0.5mmol) and triethylamine (1.9g, 14mmol) are sequentially added into a 10mL dichloromethane solution, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is dropwise added, the temperature is controlled to be 0-10 ℃, the mixture is stirred and reacted for 5 hours, the mixture is filtered, the filtrate is collected and concentrated to constant weight, and the mixture is subjected to column chromatography (petroleum ether: ethyl acetate: 15:1) to obtain a compound III-5 which is dried to obtain a light yellow solid 0.9g, the yield is 57 percent, and the purity is 98.3 percent (HPLC).
1H NMR(500MHz,CDCl3)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)
Figure BDA0002739932810000171
In a 50mL three-necked bottle, (R) -4- (2, 6-dimethoxyphenyl) -2-oxazolidinone IV-6(1g, 3mmol), DMAP (0.04g, 0.3mmol) and triethylamine (1.9g, 14mmol) are sequentially added into a 10mL dichloromethane solution, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is dropwise added, the temperature is controlled to be 0-10 ℃, the mixture is stirred and reacted for 5 hours, the mixture is filtered, the filtrate is collected and concentrated to constant weight, and the mixture is subjected to column chromatography (petroleum ether: ethyl acetate: 15:1) to obtain a compound III-6 which is dried to obtain a light yellow solid of 0.85g, the yield is 56%, and the purity is 97.9% (HPLC).
1H NMR(500MHz,CDCl3)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)
Figure BDA0002739932810000172
In a 50mL three-necked bottle, (R) -4- (3, 5-dimethoxyphenyl) -2-oxazolidinone IV-7(1g, 3mmol), DMAP (0.04g, 0.3mmol) and triethylamine (1.9g, 14mmol) are sequentially added into a 10mL dichloromethane solution, the internal temperature is controlled to be 0-5 ℃, the prepared acyl chloride V-2 is dropwise added, the temperature is controlled to be 0-10 ℃, the mixture is stirred and reacted for 5 hours, the mixture is filtered, the filtrate is collected and concentrated to constant weight, and the mixture is subjected to column chromatography (petroleum ether: ethyl acetate: 15:1) to obtain a compound III-7 which is dried to obtain 1g of light yellow solid, the yield is 66%, and the purity is 96.3% (HPLC).
1H NMR(500MHz,CDCl3)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)
Figure BDA0002739932810000181
Adding 20mL of toluene and potassium carbonate (7.22g, 52.3mmol) into a 250mL round-bottom flask, and stirring to obtain a suspension solution; dissolving the compound III-1(5g, 20.89mmol), N-benzyl cinchonine chloride II-1(0.87g, 2.0mmol) and nitromethane (2.55g, 41.79mmol) in 20mL of toluene, dropwise adding the compound III-1 solution into a toluene suspension solution of potassium carbonate, stirring at room temperature for reacting for 36h, adding 80mL of water into the reaction solution, separating, concentrating the organic phase to dryness, and treating by column chromatography (petroleum ether: ethyl acetate: 8:1) to obtain a light yellow oily substance I-1, 2.5g, yield of 40%, purity of 97.61% (HPLC), de value: 6 percent.
1H NMR(400MHz,CDCl3)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-benzyloxazolidine-2-one (I-2)
Figure BDA0002739932810000191
40mL of toluene and potassium carbonate (12.02g, 0.09mol) are added into a 250mL round-bottom flask and stirred to obtain a suspension solution; dissolving the compound III-2(10g, 0.035mol), N-benzyl cinchonine chloride II-1(1.46g, 0.0035mol) and nitromethane (4.25g, 0.07mol) in 40mL of toluene, dropwise adding the compound III-2 solution into a toluene suspension solution of potassium carbonate, stirring for reaction at room temperature for 36h, adding 80mL of water into the reaction solution, separating, concentrating an organic phase to dryness, and treating by column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain a light yellow oily substance I-2, 10.5g, yield 87%, purity 97.61% (HPLC), de value: 71 percent.
1H NMR(400MHz,CDCl3)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)
Figure BDA0002739932810000192
Adding 40mL of toluene and potassium carbonate (12.02g, 90mmol) into a 250mL round-bottom flask, and stirring to obtain a suspension solution; dissolving the compound III-3(10g, 35mmol), N-benzyl cinchonine chloride II-1(1.1g, 2.45mmol, 0.07eq) and nitromethane (4.25g, 70mmol) in 40mL of toluene, dropwise adding the compound III-3 suspension into the toluene suspension of potassium carbonate, stirring at room temperature for reaction for 36h, adding 80mL of water into the reaction liquid, separating, and concentrating the organic phase to be dry 7.1g, de value: 10 percent. Heating the mixture to dissolve in isopropanol (70g, 1.16mol) at 50-80 ℃, crystallizing at 15-25 ℃, filtering and drying to obtain solid I-3, 7.08g, yield 59%, purity 65.8% (HPLC), de value: 88 percent.
Example 12 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one (I-3)
Figure BDA0002739932810000201
Adding 40mL of toluene and potassium carbonate (12.02g, 90mmol) into a 250mL round-bottom flask, and stirring to obtain a suspension solution; dissolving a compound III-3(10g, 35mmol), N-benzyl cinchonine chloride II-1(1.46g, 3.5mmol, 0.1eq) and nitromethane (4.25g, 70mmol) in 40mL of toluene, dropwise adding the compound III-3 suspension into the toluene suspension of potassium carbonate, stirring at room temperature for reaction for 36h, adding 80mL of water into the reaction liquid, separating, and concentrating an organic phase until the organic phase is dried to obtain 13g of a de value: 26 percent. Heating the mixture to be dissolved by isopropanol (70g, 1.16mol) at the temperature of 50-80 ℃, controlling the temperature to be 15-25 ℃ for crystallization, filtering and drying to obtain solid I-3, 9.7g, and the yield is as follows: 76%, purity 94.05% (HPLC), de value: 46 percent. Heating the mixture to dissolve the solid by isopropanol (97g, 1.6mol) at 50-80 ℃, controlling the temperature to be 25-30 ℃ for crystallization, filtering and drying the mixture 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 percent.
1H NMR(400MHz,CDCl3)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)
Figure BDA0002739932810000202
Adding 40mL of toluene and potassium carbonate (12.02g, 90mmol) into a 250mL round-bottom flask, and stirring to obtain a suspension solution; dissolving a compound III-3(10g, 35mmol), N-benzyl octylclonine bromide II-2(1.6g, 3.5mmol) and nitromethane (4.25g, 70mmol) in 40mL of toluene, dropwise adding the compound III-3 suspension into a toluene suspension of potassium carbonate, stirring at room temperature for 36h, heating to dissolve in isopropanol (9g, 0.15mol) at 50-80 ℃, crystallizing at 15-25 ℃, filtering, and drying to obtain a solid 6.8g, wherein the yield is 56%, the purity is 95% (HPLC), and the de value: 90.07%, heating to dissolve in isopropanol at 50-80 deg.C, crystallizing at 25-30 deg.C, filtering, and drying to obtain compound I-3, 5.52g, yield 46%, purity 98.6% (HPLC), de value: 98.4 percent.
Example 14 preparation of (R) -3- ((S) -5-methyl-3- (nitromethyl) hexanoyl) -4-phenyloxazolidin-2-one (I-3)
Figure BDA0002739932810000211
40mL of toluene and potassium carbonate (12.02g, 0.09mol) are added into a 250mL round-bottom flask and stirred to obtain a suspension solution; dissolving the compound III-3(10g, 0.035mol) and nitromethane (4.25g, 0.07mol) in 40mL of toluene, dropwise adding the compound III-3 solution into a toluene suspension of potassium carbonate, stirring at room temperature for reaction for 36h, adding 80mL of water into the reaction solution, separating the solution, and concentrating the organic phase to dryness. Heating the mixture to be dissolved by isopropanol (70g, 1.16mol) at 50-80 ℃, controlling the temperature to be 15-25 ℃ for crystallization, and filtering the mixture to obtain a solid with the yield of 44%, the purity of 96% (HPLC), and the de value: 96.04%, heating to dissolve in isopropanol at 50-80 deg.C, crystallizing at 25-30 deg.C, filtering to obtain solid, drying to obtain compound I-3, 3.6g, yield 30%, purity 98.6% (HPLC), de value: 100 percent.
1H NMR(400MHz,CDCl3)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) oxazolidine-2-one (I-4)
Figure BDA0002739932810000212
10mL of toluene and potassium carbonate (1.12g, 8.3mmol) were added to a 250mL round-bottom flask, and stirred to obtain a suspension, the compound III-4(1g, 3.2mmol), nitromethane (0.45g, 6.64mmol), N-benzylchloroxining II-1(0.13g, 0.32mmol) and the suspension were dissolved in 10mL of toluene, the compound III-4 solution was added dropwise to the toluene suspension of potassium carbonate, the reaction was carried out at room temperature for 36 hours, 40mL of water was added to the reaction solution, liquid separation was carried out, and the organic phase was concentrated to dryness. Heating to dissolve by isopropanol (10g, 0.16mol) at 50-80 ℃, crystallizing at 15-25 ℃, filtering to obtain solid I-4, 0.83g, yield: 70%, de value: 55%, heating to dissolve by isopropanol (8g, 0.13mol) under the condition of 50-80 ℃, controlling to crystallize at 25-30 ℃, filtering and drying to obtain I-4, 0.75g, the total yield is 63%, the purity is 98.4% (HPLC), the de value: 96.3 percent.
1H NMR(400MHz,CDCl3)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) oxazolidine-2-one (I-5)
Figure BDA0002739932810000221
A250 mL round-bottom flask was charged with 10mL of toluene and potassium carbonate (1.12g, 8.3mmol) and stirred to obtain a suspension, compound III-5(1g, 3.2mmol), nitromethane (0.45g, 6.64mmol) and N-benzylcinchonine chloride II-1(0.13g, 0.32mmol) were dissolved in 10mL of toluene, the compound III-5 solution was added dropwise to the suspension of potassium carbonate and reacted at room temperature for 36 hours, 40mL of water was added to the reaction solution, followed by liquid separation and the organic phase was concentrated to dryness. Heating the mixture to dissolve in isopropanol (10g, 0.16mol) at 50-80 ℃, controlling the temperature to 15-25 ℃ for crystallization, and filtering to obtain solid I-5, 0.88g, wherein the yield is as follows: 75%, de value: 52 percent, heating the mixture to be dissolved by isopropanol (8g, 0.13mol) under the condition of 50-80 ℃, controlling the temperature to be 25-30 ℃ for crystallization, filtering and drying to obtain I-5, 0.8g, the total yield is 67 percent, the purity is 98.6 percent, and de: 98.7 percent.
1H NMR(400MHz,CDCl3)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)
Figure BDA0002739932810000231
10mL of toluene and potassium carbonate (1.12g, 8.3mmol) are added to a 250mL round-bottom flask, a suspension is obtained by stirring, the compound III-6(1g, 3mmol), nitromethane (0.37g, 6mmol) and N-benzyl cinchonine chloride II-1(0.13g, 0.3mmol) are dissolved in 10mL of toluene, the compound III-6 solution is dropwise added to the potassium carbonate suspension, the reaction is carried out at room temperature for 36h, 40mL of water is added to the reaction solution, the solution is separated, and the organic phase is concentrated to dryness. Heating the mixture to dissolve in isopropanol (10g, 0.16mol) at 50-80 ℃, controlling the temperature to 15-25 ℃ for crystallization, and filtering to obtain solid I-6, 0.82g, wherein the yield is as follows: 70%, de value: 49 percent, heating the mixture to be dissolved by isopropanol (8g, 0.13mol) under the condition of 50-80 ℃, controlling the temperature to be 25-30 ℃ for crystallization, filtering and drying the mixture to obtain I-6, 0.71g, the total yield of 61 percent, the purity of 98.6 percent (HPLC), de: 99.7 percent.
1H NMR(500MHz,CDCl3)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)
Figure BDA0002739932810000232
10mL of toluene and potassium carbonate (1.12g, 8.3mmol) are added to a 250mL round-bottom flask, a suspension is obtained by stirring, the compound III-7(1g, 3mmol), nitromethane (0.37g, 6mmol) and N-benzyl cinchonine chloride II-1(0.13g, 0.3mmol) are dissolved in 10mL of toluene, the compound III-7 solution is dropwise added to the potassium carbonate suspension, the reaction is carried out at room temperature for 36h, 40mL of water is added to the reaction solution, the solution is separated, and the organic phase is concentrated to dryness. Heating the mixture to dissolve in isopropanol (10g, 0.16mol) at 50-80 ℃, controlling the temperature to 15-25 ℃ for crystallization, and filtering to obtain solid I-7, 0.9g, yield: 76%, de value: 68% and heating to dissolve in isopropanol (9g, 0.14mol) at 50-80 ℃, controlling crystallization at 25-30 ℃, filtering and drying to obtain I-7, 0.81g, the total yield is 68%, the purity is 98% (HPLC), de: 99.4 percent.
1H NMR(500MHz,CDCl3)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)
Figure BDA0002739932810000241
A1000 mL round-bottom flask was added with 200mL of toluene and cesium carbonate (59.6g, 0.18mol) and stirred to obtain a suspension solution; compound III-3(50g, 0.18mol) and nitromethane (27.91g, 0.45mol) 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 mixture, the mixture was separated, and the organic phase was concentrated to dryness. Heating the mixture to be dissolved by isopropanol (212.1g, 3.5mol) at the temperature of 50-80 ℃, controlling the temperature to be 15-25 ℃ for crystallization, filtering the mixture to obtain a solid, and drying the solid to a constant weight to obtain 31.2g of a compound I-3 with the yield of 52 percent and the purity of 95.1 percent (HPLC), the de value: 99.5 percent, heating the mixture to be dissolved by isopropanol (310g, 5.2mol) under the condition of 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), the de value: 99.8 percent.
EXAMPLE 20 preparation of (R) -5-methyl-3- (nitromethyl) hexanoic acid (1)
Figure BDA0002739932810000242
In a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.68g, 20mmol) and lithium hydroxide monohydrate (0.17g, 7mmol) were added, and the mixture was stirred at 0-5 ℃ to obtain a mixed solution. Dissolving a compound I-1(2g, 6.6mmol) in 10mL tetrahydrofuran solution, dropwise adding the compound I-1 solution into hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, controlling the reaction temperature to be less than 10 ℃, stirring for reaction for 6h, then adding sodium sulfite (2.82g, 0.02mol) into the reaction liquid in batches, and carrying out ice bath reaction for 0.5 h. To the reaction mixture was added 20mL of water, and 30mL of dichloromethane was extracted, the aqueous phase was placed in an ice bath and diluted hydrochloric acid was added dropwise to adjust the pH to 4-5, 40mL of dichloromethane (20mL × 2) was added for extraction, and the organic phase was concentrated to constant weight to obtain 0.77g of oil, yield: 64%, purity: 91.3% (HPLC).
1H NMR(400MHz,CDCl3)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)
Figure BDA0002739932810000251
In a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.7g, 20mmol) and lithium hydroxide monohydrate (0.3g, 7mmol) were added, and the mixture was stirred at 0-5 ℃ to obtain a mixed solution. Dissolving a compound I-2(2g, 5.2mmol) 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 and reacting for 6h, then adding sodium sulfite (2.82g, 0.02mol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL of water into the reaction solution, extracting with dichloromethane by 30mL, dropwise adding dilute hydrochloric acid into an aqueous phase under the ice bath condition to enable the pH to be 4-5, adding 40mL of dichloromethane (20mL of 2) for extraction, concentrating an organic phase to constant weight to obtain 0.72g of oily matter, and obtaining 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)
Figure BDA0002739932810000252
In a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.7g, 20mmol) and lithium hydroxide monohydrate (0.3g, 7mmol) were added, and the mixture was stirred at 0-5 ℃ to obtain a mixed solution. The compound I-3(2g, 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 hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution with the reaction temperature controlled at <10 ℃, stirred and reacted for 6h, sodium sulfite (2.82g, 0.02mol) was added to the reaction solution in portions, ice-cooled and reacted for 0.5h, 20mL of water was added to the reaction solution, 30mL of dichloromethane was extracted, the aqueous phase was put into ice-cooled and diluted hydrochloric acid was added dropwise to make pH 4-5, 40mL of dichloromethane (20mL × 2) was added to extract, the organic phase was concentrated to constant weight to obtain 0.94g of oil, 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)
Figure BDA0002739932810000261
In a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.7g, 20mmol) and lithium hydroxide monohydrate (0.3g, 7mmol) were added, and the mixture was stirred at 0-5 ℃ to obtain a mixed solution. Dissolving the compound I-3(2g, 6mmol, de value: 100%) prepared in example 14 in 10mL of tetrahydrofuran solution, dropwise adding the solution into hydrogen peroxide-lithium hydroxide monohydrate-tetrahydrofuran solution, controlling the reaction temperature to be less than 10 ℃, stirring and reacting for 6h, adding sodium sulfite (2.82g, 0.02mol) into the reaction solution in batches, reacting for 0.5h in an ice bath, adding 20mL of water into the reaction solution, extracting dichloromethane by 30mL, dropwise adding dilute hydrochloric acid into the aqueous phase under the ice bath condition to ensure that the pH is 4-5, adding 40mL of dichloromethane (20mL × 2) for extraction, concentrating the organic phase to constant weight to obtain 0.9g of oily matter, and obtaining the 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)
Figure BDA0002739932810000262
In a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.7g, 20mmol) and lithium hydroxide monohydrate (0.3g, 7mmol) were added, and the mixture was stirred at 0-5 ℃ to obtain a mixed solution. Dissolving a compound I-4(2g, 5.5mmol) in a 10mL 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 and reacting for 6h, then adding sodium sulfite (2.82g, 0.02mol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL water into the reaction solution, extracting dichloromethane (30mL), dropwise adding dilute hydrochloric acid into an aqueous phase under the ice bath condition to enable the pH to be 4-5, adding 40mL dichloromethane (20mL 2) for extraction, concentrating an organic phase to constant weight, and obtaining 0.7g of oily matter with 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)
Figure BDA0002739932810000271
In a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.7g, 20mmol) and lithium hydroxide monohydrate (0.3g, 7mmol) were added, and the mixture was stirred at 0-5 ℃ to obtain a mixed solution. Dissolving a compound I-5(2g, 5.2mmol) 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 and reacting for 6h, then adding sodium sulfite (2.82g, 0.02mol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL of water into the reaction solution, extracting dichloromethane by 30mL, dropwise adding dilute hydrochloric acid into an aqueous phase under the ice bath condition to enable the pH to be 4-5, adding 40mL of dichloromethane (20mL of 2) for extraction, concentrating an organic phase to constant weight, and obtaining 0.8g of oily matter with 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)
Figure BDA0002739932810000272
In a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.43g, 12.68mmol) and lithium hydroxide monohydrate (0.12g, 2.94mmol) were added, and the mixture was stirred at 0-5 ℃ to obtain a mixed solution. Dissolving a compound I-6(1g, 2.5mmol) in a 10mL 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 and reacting for 6h, then adding sodium sulfite (0.98g, 9.5mmol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL water into the reaction solution, extracting dichloromethane (30mL), dropwise adding dilute hydrochloric acid into an aqueous phase under the ice bath condition to enable the pH to be 4-5, adding 40mL dichloromethane (20mL 2) for extraction, concentrating an organic phase to constant weight, and obtaining 0.28g of oily matter with 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)
Figure BDA0002739932810000281
In a 100mL three-necked flask, 10mL of tetrahydrofuran, hydrogen peroxide (0.43g, 12.68mmol) and lithium hydroxide monohydrate (0.12g, 2.94mmol) were added, and the mixture was stirred at 0-5 ℃ to obtain a mixed solution. Dissolving a compound I-7(1g, 2.5mmol) in a 10mL 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 and reacting for 6h, then adding sodium sulfite (0.98g, 9.5mmol) into the reaction solution in batches, carrying out ice bath reaction for 0.5h, adding 20mL water into the reaction solution, extracting dichloromethane (30mL), dropwise adding dilute hydrochloric acid into an aqueous phase under the ice bath condition to enable the pH to be 4-5, adding 40mL dichloromethane (20mL 2) for extraction, concentrating an organic phase to constant weight, and obtaining 0.28g of oily matter with yield: 60%, purity: 92.1% (HPLC).
ESI-MS(m/z)＝190[M+H]+
Example 28 preparation of (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)
Figure BDA0002739932810000282
A round-bottomed flask was charged with the compound 1(0.9g, 4.7mmol) obtained in example 22, 10mL of methanol and 0.01g of palladium on carbon in this order to prepare a suspension, and hydrogen gas was introduced under normal pressure for 10 hours, followed by filtration, concentration and recrystallization from 5g of isopropanol-water (mass ratio 1:1) to obtain 0.68g of a white solid, yield 90% and ee: 100%.
1H NMR(400MHz,D2O)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)。D2No peak is generated by O exchange of active hydrogen (refer to OPRD 1997,1, 26-38).
ESI-MS(m/z)＝160[M+H]+
Example 29 preparation of (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)
Figure BDA0002739932810000283
A round-bottomed flask was charged with the compound 1(0.9g, 4.7mmol) obtained in example 23, 10mL of methanol and 0.01g of palladium on carbon in this order to prepare a suspension, and hydrogen gas was introduced under normal pressure for 10 hours, followed by filtration and concentration, and 5g of isopropyl alcohol-water (mass ratio 1:1) was recrystallized to obtain 0.66g of a white solid, yield 88%, ee: 100%.
Example 30 preparation of (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)
In a round-bottomed flask, Compound 1(45g, 0.24mol), methanol (100 mL), and palladium on carbon (0.45 g) were placed in this order to prepare a suspension
Figure BDA0002739932810000291
The solution was purified by introducing hydrogen gas under normal pressure for 10 hours, followed by filtration and concentration, and 150g of isopropanol-water (1: 1 by mass) was recrystallized to give 32.56g of a white solid, yield 86%, ee: 99.91%.
Comparative example 1
Figure BDA0002739932810000292
A100 mL round-bottom flask was charged with 20mL of toluene and TMG (0.84g, 7.3mmol) and stirred to obtain a suspension; compound III-3(2g, 7mmol) and nitromethane (1.11g, 17.5mol) are dissolved in 20mL of toluene, the compound III-3 solution is added dropwise to the TMG toluene suspension, the reaction is stirred at room temperature for 36h, 40mL of water is added to the reaction solution, the solution is separated, and the organic phase is concentrated to dryness. Heating to dissolve by isopropanol (15g, 0.25mol) at 50-80 ℃, crystallizing at 15-25 ℃, filtering to obtain solid I-3, 0.18g and yield of 7.5%, heating to dissolve by isopropanol (1.8g, 0.03mol) at 50-80 ℃, crystallizing at 25-30 ℃, filtering to obtain white solid I-3, 0.11g and yield of 4.5%, purity of 99% (HPLC), de value: 99.22 percent.
Comparative example 2
Figure BDA0002739932810000293
In a 100mL round-bottom flask, 20mL of toluene and TBAF & H were added2O (2.3g, 7mmol) was stirred to obtain a suspension; compound III-3(2g, 7mmol) and nitromethane (1.11g, 17.5mmol) were dissolved in 20mL of toluene, and the compound III-3 solution was added dropwise to TBAF. H2And stirring the O toluene suspension for reaction for 36 hours at room temperature, adding 40mL of water into the reaction solution, separating the solution, and concentrating the organic phase until the organic phase is dry. Heating to dissolve by isopropanol (15g, 0.25mol) at 50-80 ℃, crystallizing at 15-25 ℃, filtering to obtain solid I-3, 0.42g and yield of 17.5%, heating to dissolve by isopropanol (4.2g, 0.07mol) at 50-80 ℃, crystallizing at 25-30 ℃, filtering to obtain white solid I-3, 0.38g and yield of 15.8%, purity of 99.4% (HPLC), de value: 99.92 percent.

Claims (16)

1. A compound of formula (I);
Figure FDA0002739932800000011
wherein the content of the first and second substances,
r is C1-C6Alkyl, phenyl, RaSubstituted phenyl, benzyl or RbA substituted benzyl group; raAnd RbIs independently one or more, when said R isaWhen the number of (A) is plural, R isaThe same or different; when said R isbWhen the number of (A) is plural, R isbThe same or different;
Raand RbIndependently is C1-C6Alkyl or C1-C6An alkoxy group.
2. The compound of formula (I) according to claim 1, wherein R is methyl, ethyl or isopropyl;
and/or, said RaAnd RbIndependently methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy;
and/or, said RaThe number of (2) is 1 or 2; when said R isaWhen the number of (2) is provided, R isaThe same or different;
and/or, said RbThe number of (2) is 1 or 2; when said R isbWhen the number of (2) is provided, R isbThe same or different.
3. The compound of formula (I) according to claim 1, which is any one of the following compounds:
Figure FDA0002739932800000012
Figure FDA0002739932800000021
4. a process for the preparation of a compound of formula (I) as claimed in any one of claims 1 to 3, which is any one of the following processes:
the method (1) comprises the following steps: reacting a compound shown as a formula (III) with nitromethane in an organic solvent in the presence of alkali, and obtaining the compound shown as the formula (I) through manual resolution;
Figure FDA0002739932800000022
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);
Figure FDA0002739932800000023
in the method (1) and the method (2), the base is K2CO3And/or Cs2CO3；
In the above process (2), R2Is C6-C14Aryl or benzyl; r is3Is hydroxy or amino; x is halogen.
5. The process according to claim 4 for the preparation of the compound of formula (I),
in the method (1), the compound shown in the formula (III), the nitromethane and the organic solvent form a solution, and the solution 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 shown as the formula (III) to the nitromethane is 1: (1 to 3), preferably 1: (1.5-2.5), for example 1: 2;
and/or, in the method (1), the ratio of the molar ratio of the base to the compound represented by the formula (III) is 1.0-2.8, for example: 2.5 or 2.6;
and/or in the method (1), the reaction temperature is 10-40 ℃, and preferably 20-30 ℃;
and/or in the method (1), the reaction time is 22-36 h;
and/or, in the method (1), after the reaction is finished and before the chiral resolution, further comprising: quenching, separating and concentrating the reaction system in sequence;
and/or, in the method (1), the chiral resolution adopts recrystallization.
6. A process according to claim 5 for the preparation of a compound of formula (I),
in the method (1), in the solution formed by the compound shown in the formula (III), the nitromethane and the organic solvent, the mass-to-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), in the organic solvent suspension of the base, the ratio of the mass-to-volume ratio of the base to the organic solvent is 0.1 g/mL-0.4 g/mL, for example, 0.3 g/mL;
and/or, in the method (1), the recrystallization comprises the steps of: crystallizing the solution of the organic solvent of the compound shown in the formula (I) at the temperature of between 50 and 80 ℃ at the temperature of between 15 and 30 ℃, for example, between 25 and 30 ℃;
and/or, in the method (1), 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 is preferably isopropanol;
and/or, in the method (1), the chiral resolution adopts secondary recrystallization.
7. The process according to claim 6 for the preparation of the compound of formula (I),
in the method (1), the secondary recrystallization includes the steps of: putting the solution of the organic solvent of the compound shown in the formula (I) at 50-80 ℃ into 15-25 ℃ for crystallization, filtering and drying to obtain a solid, and putting the solution of the organic solvent of the solid at 50-80 ℃ into 25-30 ℃ for crystallization.
8. The process according to claim 4 for the preparation of the compound of formula (I),
in the above process (2), R2Is 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), the compound shown in the formula (III), the nitromethane, the catalyst shown in the formula (II) and an organic solvent are formed into a solution, and the solution is dripped into the organic solvent suspension of the alkali;
and/or, in the method (2), the molar ratio of the compound shown in the formula (III) to the nitromethane is 1: (1 to 3), preferably 1: (1.5-2.5), for example 1: 2;
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 base to the compound shown in the formula (III) is 1.0-2.8, such as: 2.5 or 2.6;
and/or in the method (2), the reaction temperature is 10-40 ℃, and preferably 20-30 ℃;
and/or in the method (2), the reaction time of the reaction is 22-36 h;
and/or, in the method (2), the method further comprises a post-treatment, wherein the post-treatment comprises the following steps: and sequentially quenching, separating, concentrating and purifying the reaction system.
9. The process according to claim 8 for the preparation of a compound of formula (I),
in the method (2), in the solution formed by the compound shown in the formula (III), the nitromethane, the catalyst shown in the formula (II) and the organic solvent, the mass-to-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 (2), in the organic solvent suspension of the base, the ratio of the mass-to-volume ratio of the base to the organic solvent is 0.1 g/mL-0.4 g/mL, for example 0.3 g/mL;
and/or, in the method (2), recrystallization or column chromatography is adopted for purification;
and/or, in the method (2), when R is phenyl or RaWhen the phenyl is substituted, recrystallization is adopted for purification; when R is C1-C6Alkyl, benzyl or RbWhere a substituted benzyl group, for example R is isopropyl or benzyl, the purification is by column chromatography.
10. The process according to claim 9 for the preparation of a compound of formula (I),
in the method (2), the recrystallization includes the steps of: placing the solution of the organic solvent of the compound shown in the formula (I) at the temperature of 50-80 ℃ at the temperature of 15-30 ℃, for example, at the temperature of 25-30 ℃ 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 is preferably isopropanol;
and/or, in the method (2), the recrystallization adopts secondary recrystallization;
and/or, in the method (2), the eluent for 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.
11. the process according to claim 10 for the preparation of a compound of formula (I),
in the method (2), the secondary recrystallization includes the steps of: crystallizing the solution of the organic solvent of the compound shown in the formula (I) at 50-80 ℃ at 15-25 ℃, filtering, drying to obtain a solid, and crystallizing the solution of the organic solvent of the solid at 50-80 ℃ at 25-30 ℃.
12. The process according to claim 4 for the preparation of the compound of formula (I),
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 alkali;
Figure FDA0002739932800000051
wherein R is4Is hydroxy or halogen, preferably chlorine.
13. A method for preparing a compound shown as a formula 1, which is characterized in that the compound shown as the formula (I) in claim 1 is reacted in an organic solvent in the presence of alkali and an oxidant;
Figure FDA0002739932800000052
14. a recrystallization method, comprising the steps of: putting a solution of an organic solvent of a compound shown as a formula (I) at 50-80 ℃ into a temperature of 15-30 ℃ for crystallization;
Figure FDA0002739932800000053
15. the recrystallization method as claimed in claim 14,
the organic solvent is one or more of an alcohol solvent and a mixed solvent formed by the alcohol solvent and water, and is preferably isopropanol;
and/or the recrystallization temperature is 25-30 ℃;
preferably, the recrystallization adopts secondary recrystallization, and the secondary recrystallization comprises the following steps: putting the solution of the organic solvent of the compound shown in the formula (I) at 50-80 ℃ into 15-25 ℃ for crystallization, filtering and drying to obtain a solid, and putting the solution of the organic solvent of the solid at 50-80 ℃ into 25-30 ℃ for crystallization.
16. A compound of formula (III), which is any one of the following compounds:
Figure FDA0002739932800000061
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