CN115557873A - Synthesis method of methyl esterification impurity of brivaracetam - Google Patents

Synthesis method of methyl esterification impurity of brivaracetam Download PDF

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CN115557873A
CN115557873A CN202211291386.7A CN202211291386A CN115557873A CN 115557873 A CN115557873 A CN 115557873A CN 202211291386 A CN202211291386 A CN 202211291386A CN 115557873 A CN115557873 A CN 115557873A
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黄义
马建雄
阎智勇
周长岳
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Zhejiang Menovo Pharmaceuticals Co ltd
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Abstract

The invention relates to a synthesis method of a (S, R) -configuration bravaracetam methyl esterification impurity, which takes 4-propyl dihydrofuran-2-ketone as a raw material and prepares the (S, R) -configuration bravaracetam methyl esterification impurity through reactions such as ring opening, acyl chlorination, condensation cyclization, hydrolysis, methyl esterification and the like. The invention provides a preparation method for chiral synthesis of (S, R) -configuration brucetin methyl esterification impurities for the first time, and a high-purity target product is prepared and can be used as a standard substance for quality research of brucetin; the invention has the advantages of simple synthetic route, mild reaction condition, simple post-treatment, low price and easy obtaining of starting materials, and process cost, and is suitable for industrial production.

Description

Synthesis method of methyl esterification impurity of brivaracetam
Technical Field
The invention relates to a preparation method of a medicine and a medicine intermediate, in particular to a synthesis method of a bloacetam methyl esterification impurity.
Background
The structure formula of the brivacet is shown as follows, the Briviact is used as an English name, the chemical name is (S) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) butanamide, and the brivacet is a structural derivative of levetiracetam. The product is superior to the third generation antiepileptic drug developed by pharmaceutical company, approved by European medical administration at 1/14 in 2016 and approved by the U.S. food administration at 2/18 in 2016. Brivaracetam is mainly used for treating partial seizures of patients with epilepsy in adolescents and adults over 16 years old, with or without secondary generalized seizures as adjuvant therapy. Compared with other antiepileptic drugs, brivaracetam has the advantages of higher brain penetration rate, lower effective dose, higher therapeutic index and the like, so that the brivaracetam has great development prospect in the market of antiepileptic drugs.
Figure BDA0003897808010000011
The structural formula of the impurity is shown as the following, the chemical name of the impurity is (S) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) methyl butyrate, the impurity is CO impurity in the Buvalsartan project, and the impurity also has a spatial configuration (S, R configuration). The starting raw material of the brivaracetam may contain (2S) -2-aminobutyric acid methyl ester hydrochloride impurities, so that the brivaracetam methyl esterification impurities may be derived in a process route for preparing the brivaracetam, the purity of a brivaracetam raw material drug is influenced, the generation of the impurities needs to be controlled in a synthesis process, and the impurities need to be prepared to be used as a standard substance for carrying out quality research on the brivaracetam.
Figure BDA0003897808010000012
Figure BDA0003897808010000021
At present, the (S, R) steric-configuration Buvaracetam methyl esterification impurity is mainly prepared by a chiral column, the cost is high, and the report of chiral synthesis of the (S, R) configuration is not disclosed in the existing literature. Therefore, it is particularly necessary to develop an efficient and low-cost chiral synthesis method for synthesizing the (S, R) form of the brivaracetam methyl esterification impurity.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for synthesizing a bloacetam methyl esterification impurity, which has the advantages of mild reaction conditions, simple post-treatment, high yield, high purity and low cost, is suitable for industrial production, and can provide a research standard product for the quality research of bloacetam.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a synthetic method of a blovaracetam methyl esterification impurity comprises the following steps:
(1) The compound I is subjected to ring-opening reaction to obtain a compound II,
Figure BDA0003897808010000022
(2) Performing acyl chlorination reaction on the compound II to obtain a compound III,
Figure BDA0003897808010000023
(3) Condensing the compound III and the compound IV to obtain a compound V, closing a ring of the compound V to obtain a compound VI,
Figure BDA0003897808010000024
(4) Hydrolyzing the compound VI to obtain a compound VII,
Figure BDA0003897808010000031
(5) Firstly, acylating and chlorinating the compound VII to obtain a compound VIII, then carrying out methyl esterification on the compound VIII to obtain a compound IX, wherein the compound IX is a target product,
Figure BDA0003897808010000032
preferably, the reaction in the step (1) is carried out in a solvent of dichloromethane, during operation, the compound I is dissolved in dichloromethane, the temperature is reduced to 0-5 ℃ by stirring, and the iodotrimethylsilane is slowly dripped into the reaction liquid; after the dripping is finished, the temperature is raised to room temperature for reaction.
Preferably, after the reaction in the step (1) is finished, slowly adding a dilute hydrochloric acid solution, standing for liquid separation, retaining a dichloromethane phase, extracting a water phase by using dichloromethane, combining the dichloromethane phase, adding a sodium thiosulfate aqueous solution, stirring until the feed liquid is colorless and transparent, standing for liquid separation, retaining the dichloromethane phase, discarding the water phase, washing the dichloromethane phase by using saturated saline water, and evaporating to dryness to obtain a colorless oil-like substance compound II.
Preferably, the reaction in the step (2) is carried out in a solvent of dichloromethane, in the operation, the compound II is dissolved in dichloromethane, a catalytic amount of N, N-dimethylformamide is added, the mixture is stirred and cooled, thionyl chloride is slowly dripped into the reaction liquid when the temperature is reduced to 0-5 ℃, and the temperature is raised to the room temperature and stirred after the dripping.
More preferably, after the reaction in step (2) is completed, the reaction mixture is evaporated to dryness to obtain a yellow oily compound iii.
Preferably, the reaction in the step (3) is carried out in a solvent of dichloromethane under the protection of nitrogen, during operation, a compound IV is dissolved in dichloromethane, anhydrous sodium sulfate is added, the temperature is reduced and stirred, a compound III is dissolved in dichloromethane for standby, when the temperature is reduced to-25 ℃ to-15 ℃, powdery potassium hydroxide is added to the reaction liquid in batches, meanwhile, a dichloromethane solution of the compound III is slowly added dropwise to the reaction liquid, and when the compound III is completely added, the potassium hydroxide is just added or residual materials are left; the temperature of the reaction liquid is raised to-5 ℃ to-10 ℃ for heat preservation reaction.
Further preferably, after the reaction in the step (3) is finished, adding acetic acid to quench the reaction, then adding water, stirring, filtering, discarding a filter cake, standing and layering the filtrate, discarding a water layer, and retaining an organic phase; washing the organic phase with 50% of salt solution, evaporating to dryness, carrying with isopropyl ether until the material is solid, adding isopropyl ether, heating to dissolve the material, adding active carbon for decoloring, filtering while hot, taking the filtrate, discarding the filter residue, heating the filtrate to dissolve the filtrate, slowly cooling to crystallize, cooling to 0-5 ℃, filtering, collecting the filter cake, drying and drying to obtain the white solid compound VI.
Preferably, the reaction of step (4) is carried out in aqueous solution, in operation, compound VI is dissolved in aqueous solution, stirred, concentrated hydrochloric acid is slowly added, and then the temperature is raised to 55-65 ℃ for reaction.
Further preferably, after the reaction in the step (4) is finished, adding a sodium bicarbonate aqueous solution to adjust the pH value to 0.5-1.5, and then concentrating and spin-drying the reaction solution; adding water and dichloromethane into the concentrate, stirring and dissolving the mixture to be clear, adjusting the pH value to 5-6 by using an aqueous solution of sodium bicarbonate, standing and layering the mixture, retaining an organic phase, extracting a water phase by using dichloromethane, combining the organic phases, concentrating and spin-drying the mixture to obtain a yellow oily crude product, and purifying the yellow oily crude product by using column chromatography to obtain a white solid compound VII.
Preferably, the reaction in the step (5) is carried out in dichloromethane, in operation, the compound VII is dissolved in dichloromethane, a catalytic amount of N, N-dimethylformamide is added, stirring is carried out, the temperature is reduced to 0-5 ℃, thionyl chloride is slowly dripped, after dripping is finished, the reaction solution is heated to room temperature, stirring is carried out, after the reaction is finished, methanol is slowly dripped into the reaction solution, stirring is carried out for a period of time, concentration and evaporation are carried out to obtain a crude product of yellow oily matter, and the crude product is purified by column chromatography to obtain the target product compound IX.
Compared with the prior art, the invention has the advantages that: the invention provides a preparation method for asymmetric synthesis of (S, R) configuration Buvaracetam methyl esterification impurities (compound IX) for the first time, and a high-yield and high-purity target product is prepared and can be used as a standard substance for Buvaracetam quality research; the synthetic route of the invention has mild reaction conditions, simple post-treatment, low price of starting materials, easy obtainment and process cost, and is suitable for industrial production.
Drawings
FIG. 1 is an HPLC chromatogram of a target product;
FIG. 2 is a mass spectrum of a target product;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of a target product;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of the target product.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
The synthesis method of the impurities of the brivaracetam stereoisomer in the embodiment comprises the following steps:
(1) 500g of compound I is dissolved in 5L of dichloromethane, stirred and cooled to 0-5 ℃, and 858.6g of trimethyl iodosilane is slowly dripped into the reaction solution. After the dripping is finished, the temperature is raised to room temperature for reaction. After the reaction is finished, 4.2L of 1 mol/L diluted hydrochloric acid solution is slowly added, the mixture is kept stand for liquid separation, and a dichloromethane phase is reserved. Extracting the water phase with 1L dichloromethane, mixing dichloromethane phases, adding 148g 10% sodium thiosulfate water solution, stirring until the material liquid is colorless and transparent, standing for liquid separation, retaining dichloromethane phase, and discarding water phase. The dichloromethane phase was washed with 2.5L of saturated brine and evaporated to dryness to obtain a colorless oil compound II.
(2) 1Kg of compound II was dissolved in (10L) dichloromethane, and 14g N, N-dimethylformamide was added thereto, followed by stirring and cooling. When the temperature is reduced to 0-5 ℃, 603g of thionyl chloride is slowly dripped into the reaction solution, and the temperature is raised to room temperature and stirred after the dripping is finished. Sampling and detecting, and when the reaction is finished (the compound II is less than or equal to 1.0%), evaporating the reaction solution to dryness to obtain a yellow oily compound III.
(3) 440g of compound IV is dissolved in 15L of dichloromethane under the protection of nitrogen, 554g of anhydrous sodium sulfate is added, the temperature is reduced, the mixture is stirred, and 1.07kg of compound III is dissolved in 1L of dichloromethane for standby. When the temperature is reduced to-25 ℃ to-15 ℃, 613g of powdered potassium hydroxide is added into the reaction liquid in batches, meanwhile, dichloromethane solution of the compound III is slowly dripped into the reaction liquid, and the potassium hydroxide is just added after the dripping of the compound III is finished. The temperature of the reaction liquid is raised to-5 ℃ to-10 ℃ for heat preservation reaction. After the reaction is finished, 234g of acetic acid is added to quench the reaction, then 3.5L of water is added to stir, then the reaction solution is filtered, a filter cake is discarded, the filtrate is kept stand for layering, a water layer is discarded, and an organic phase is remained. The organic phase was washed three times with 5L of 50% saturated brine, evaporated to dryness, added with isopropyl ether and distilled under reduced pressure until solid was precipitated from the material. Adding 2.5L isopropyl ether, heating to dissolve the materials, adding active carbon for decolorization, filtering while hot, taking the filtrate, and discarding the filter residue. Heating the filtrate to dissolve and clear, and then slowly cooling and crystallizing. When the temperature is reduced to 0-5 ℃, filtering, collecting a filter cake, and drying in vacuum to obtain a white solid compound VI.
(4) 60g of compound VI is dissolved in 210mL of aqueous solution, stirred, and 99mL of 12mol/L concentrated hydrochloric acid is slowly added, and then the temperature is raised to 60 ℃ for reaction for 16h. After the reaction, 10% sodium bicarbonate aqueous solution was added to adjust the pH to about 1, and then the reaction solution was concentrated and spin-dried. Adding water and dichloromethane into the concentrate, stirring and dissolving, adjusting the pH value to 5-6 by using 15g of sodium bicarbonate solid, standing and demixing, retaining an organic phase, extracting a water phase by using dichloromethane, combining the organic phases, concentrating and spin-drying to obtain a yellow oily crude product, and purifying by using column chromatography to obtain a white solid compound VII.
(5) Dissolving 12g of compound VII in 120mL of dichloromethane, adding 4 drops of catalytic amount of N, N-dimethylformamide, stirring, cooling to 0-5 ℃, and slowly dropping 8.7g of thionyl chloride. After the dripping is finished, the temperature is raised to the room temperature and stirred, after the reaction is finished, 50mL of methanol is slowly dripped into the reaction solution, the mixture is stirred for a period of time, and the mixture is concentrated and evaporated to dryness to obtain a crude yellow oily substance. And (5) purifying the crude product by a column to obtain a target product compound IX with the yield of 78%. As shown in fig. 1, the product purity was 99.46%; as shown in fig. 2 to 4, the prepared product is a target product (S, R) configuration of the buffacetam methyl esterification impurity.

Claims (10)

1. A synthetic method of a blovaracetam methyl esterification impurity is characterized by comprising the following steps:
(1) The compound I is subjected to ring-opening reaction to obtain a compound II,
Figure FDA0003897808000000011
(2) Performing acyl chlorination reaction on the compound II to obtain a compound III,
Figure FDA0003897808000000012
(3) The compound III and the compound IV are condensed to obtain a compound V, the compound V is subjected to ring closing to obtain a compound VI,
Figure FDA0003897808000000013
(4) Hydrolyzing the compound VI to obtain a compound VII,
Figure FDA0003897808000000014
(5) Firstly, acylating and chlorinating the compound VII to obtain a compound VIII, then carrying out methyl esterification on the compound VIII to obtain a compound IX, wherein the compound IX is a target product,
Figure FDA0003897808000000021
2. the method of synthesizing bravaracetam methyl esterification impurity according to claim 1, characterized in that: the reaction in the step (1) is carried out in a solvent dichloromethane, during operation, a compound I is dissolved in dichloromethane, the temperature is reduced to 0-5 ℃ by stirring, and the iodotrimethylsilane is slowly dripped into the reaction liquid; after dropping, the temperature is raised to room temperature for reaction.
3. The method of synthesizing bravaracetam methyl esterification impurity according to claim 2, characterized in that: and (2) after the reaction in the step (1) is finished, slowly adding a dilute hydrochloric acid solution, standing for liquid separation, keeping a dichloromethane phase, extracting a water phase by using dichloromethane, combining the dichloromethane phase, adding a sodium thiosulfate water solution, stirring until the material liquid is colorless and transparent, standing for liquid separation, keeping the dichloromethane phase, removing the water phase, washing the dichloromethane phase by using saturated saline solution, and evaporating to dryness to obtain a colorless oil liquid substance compound II.
4. The method of synthesizing bravaracetam methyl esterification impurity according to claim 1, characterized in that: and (3) carrying out the reaction in the step (2) in a solvent dichloromethane, dissolving the compound II in dichloromethane during operation, adding a catalytic amount of N, N-dimethylformamide, stirring, cooling, slowly dropwise adding thionyl chloride into the reaction solution when the temperature is reduced to 0-5 ℃, and heating to room temperature for stirring after the dropwise adding is finished.
5. The method of synthesizing bravaracetam methyl esterification impurity according to claim 4, characterized in that: and (3) when the reaction in the step (2) is finished, evaporating the reaction solution to dryness to obtain a yellow oily compound III.
6. The method of synthesizing bravaracetam methyl esterification impurity according to claim 1, characterized in that: the reaction in the step (3) is carried out in a solvent dichloromethane under the protection of nitrogen, during operation, a compound IV is dissolved in dichloromethane, anhydrous sodium sulfate is added, the temperature is reduced and stirred, a compound III is dissolved in dichloromethane for standby, when the temperature is reduced to-25 to-15 ℃, powdery potassium hydroxide is added to the reaction liquid in batches, meanwhile, a dichloromethane solution of the compound III is slowly dripped into the reaction liquid, and when the dripping of the compound III is finished, the potassium hydroxide is just added or residual materials are left; the temperature of the reaction liquid is increased to-5 ℃ to-10 ℃ for heat preservation reaction.
7. The method of synthesizing bravaracetam methyl esterification impurity according to claim 6, characterized in that: after the reaction in the step (3) is finished, adding acetic acid to quench the reaction, then adding water, stirring, filtering, removing a filter cake, standing and layering the filtrate, removing a water layer, and keeping an organic phase; washing the organic phase with 50% of salt solution, evaporating to dryness, carrying with isopropyl ether until the material is solid, adding isopropyl ether, heating to dissolve the material, adding active carbon for decoloring, filtering while hot, taking the filtrate, discarding the filter residue, heating the filtrate to dissolve the filtrate, slowly cooling to crystallize, cooling to 0-5 ℃, filtering, collecting the filter cake, drying and drying to obtain the white solid compound VI.
8. The method of synthesizing bravaracetam methyl esterification impurity according to claim 1, characterized in that: and (3) carrying out the reaction in the step (4) in an aqueous solution, dissolving the compound VI in the aqueous solution during operation, stirring, slowly adding concentrated hydrochloric acid, and then heating to 55-65 ℃ for reaction.
9. The method of synthesizing bravaracetam methyl esterification impurity according to claim 8, characterized in that: after the reaction in the step (4) is finished, adding a sodium bicarbonate aqueous solution to adjust the pH value to 0.5-1.5, and then concentrating and spin-drying the reaction solution; adding water and dichloromethane into the concentrate, stirring and dissolving the mixture to be clear, adjusting the pH value to 5-6 by using an aqueous solution of sodium bicarbonate, standing and layering the mixture, retaining an organic phase, extracting a water phase by using dichloromethane, combining the organic phases, concentrating and spin-drying the mixture to obtain a yellow oily crude product, and purifying the yellow oily crude product by using column chromatography to obtain a white solid compound VII.
10. The method of synthesizing bravaracetam methyl esterification impurity according to claim 1, characterized in that: and (3) carrying out the reaction in the step (5) in dichloromethane, dissolving a compound VII in dichloromethane, adding a catalytic amount of N, N-dimethylformamide, stirring, cooling to 0-5 ℃, slowly dropwise adding thionyl chloride, after dropwise adding, heating to room temperature, stirring for reaction, after the reaction is finished, slowly dropwise adding methanol into the reaction solution, stirring for a period of time, concentrating and evaporating to dryness to obtain a crude yellow oily substance, and purifying the crude yellow oily substance by passing through a column to obtain a target product compound IX.
CN202211291386.7A 2022-10-19 2022-10-19 Synthesis method of methyl esterification impurity of brivaracetam Pending CN115557873A (en)

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