Preparation method of captopril intermediate D-3-acetylmercapto-2-methylpropionic acid

Abstract

The present application provides a method for preparing a captopril intermediate D-3-acetylmercapto-2-methylpropionic acid, and relates to the pharmaceutical field. The method for preparing the captopril intermediate D-3-acetylmercapto-2-methylpropionic acid comprises: reacting a chiral amine with racemic 3-acetylmercapto-2-methylpropionic acid to obtain a chiral amine salt, wherein the chiral amine salt is subjected to alkaline hydrolysis to obtain sodium D-3-acetylmercapto-2-methylpropionic acid, and then acidified to obtain D-3-acetylmercapto-2-methylpropionic acid; wherein the chiral amine comprises one or more of R(+)-alpha-methylbenzylamine, (R)-(+)-1-amphetamine, and R(+)-alpha-tert-butylbenzylamine. The method for preparing the captopril intermediate D-3-acetylmercapto-2-methylpropionic acid provided in the present application comprises splitting 3-acetylmercapto-2-methylpropionic acid with a chiral amine, and the method is controllable and suitable for large-scale production.

Description

Technical Field

[0001] The present application relates to the pharmaceutical field, and in particular to a method for preparing D-3-acetylmercapto-2-methylpropionic acid, a captopril intermediate. Background Art

[0002] Captopril is an angiotensin-converting enzyme inhibitor used to treat hypertension and certain types of congestive heart failure. Captopril chemical name: 1-((2S)-2-methyl-3-mercapto-1-oxopropyl)-L-proline, chemical structure is as follows:

[0003] ;

[0004] The structure of captopril contains two chiral centers, of which L-proline is natural and the other chiral methyl needs to be artificially synthesized or split.

[0005] The existing technical means include: US4046889 uses L-proline chiral induction to split:

[0006] ;

[0007] This method does not conform to the atom economy of green chemistry because the main structure of captopril has been completely synthesized and assembled before the chiral induced splitting.

[0008] Gao Xiangdong et al. (Journal of China Pharmaceutical University, 2000, 31 (5): 393-396) reported a method for synthesizing the chiral methyl group of captopril. The intermediate can then be easily combined with L-proline to synthesize captopril with two chiral centers. The chemical name of the intermediate is: D-3-acetylmercapto-2-methylpropionic acid, and the chemical structure is as follows:

[0009] ;

[0010] The raw material used is racemic 3-acetylmercapto-2-methylpropionic acid, and the chemical structure is as follows:

[0011] ;

[0012] The method used is to use lipase and pancreatin for enzymatic splitting. This method has strict requirements on enzyme activity and splitting process parameters, is not easy to control, and is not suitable for large-scale production. Summary of the invention

[0013] The purpose of the present application is to provide a method for preparing a captopril intermediate D-3-acetylmercapto-2-methylpropionic acid to solve the above problems.

[0014] To achieve the above objectives, this application adopts the following technical solutions:

[0015] A method for preparing D-3-acetylmercapto-2-methylpropionic acid, an intermediate of captopril, comprises:

[0016] A chiral amine reacts with racemic 3-acetylmercapto-2-methylpropionic acid to obtain a chiral amine salt, the chiral amine salt is subjected to alkaline hydrolysis to obtain sodium D-3-acetylmercapto-2-methylpropionic acid, and then acidified to obtain D-3-acetylmercapto-2-methylpropionic acid;

[0017] The chiral amine includes one or more of R(+)-alpha-methylbenzylamine, (R)-(+)-1-amphetamine, and R(+)-alpha-tert-butylbenzylamine.

[0018] Preferably, the solvent for the reaction is methanol.

[0019] Preferably, the chiral amine is added to the mixed system of the racemic 3-acetylmercapto-2-methylpropionic acid and the methanol at 30-35°C.

[0020] Preferably, the reaction time is 2-4 hours.

[0021] Preferably, after the reaction is completed, the system is cooled to -5°C to 0°C and centrifuged to obtain the chiral amine salt.

[0022] Preferably, the alkaline hydrolysis comprises:

[0023] The chiral amine salt is mixed with dichloromethane and water, and the pH of the system is adjusted to be alkaline using sodium hydroxide. The organic phase is the dissociated chiral amine, and the aqueous phase is extracted with dichloromethane to obtain an aqueous solution of sodium D-3-acetylmercapto-2-methylpropionate.

[0024] Preferably, sodium hydroxide is used to adjust the pH of the system to 7.5-8.5.

[0025] Preferably, the acidification comprises:

[0026] The system is neutralized with hydrochloric acid to be acidic, and then the aqueous phase is extracted with dichloromethane to obtain a dichloromethane organic phase, which is then washed with water, separated, and the organic phase is concentrated at normal pressure to obtain the D-3-acetylmercapto-2-methylpropionic acid.

[0027] Preferably, the acidic pH is 3-5.

[0028] Preferably, the neutralization is carried out at a system temperature of 5-10°C.

[0029] Compared with the prior art, the beneficial effects of this application include:

[0030] The preparation method of the captopril intermediate D-3-acetylmercapto-2-methylpropionic acid provided in the present application uses a chiral amine and a carboxyl group of a racemic raw material 3-acetylmercapto-2-methylpropionic acid to form a salt, the chiral amine salt is subjected to alkaline hydrolysis to obtain sodium D-3-acetylmercapto-2-methylpropionic acid, and then acidified to obtain D-3-acetylmercapto-2-methylpropionic acid. The chemical structure of the chiral amine is determined, and it is easier to control the quality than biological enzymes, and more convenient for large-scale production.

[0031] The method has good controllability, is green and economical, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope of the present application.

[0033] Figure 1 This is the H spectrum of D-3-acetylmercapto-2-methylpropionic acid obtained in Example. DETAILED DESCRIPTION

[0034] As used herein:

[0035] "Prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0036] The conjunction "consisting of excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed-ended so that it does not include materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than immediately following the subject matter, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0037] When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described in this article, unless otherwise stated, the range is intended to include its end values ​​and all integers and fractions within the range.

[0038] In these examples, parts and percentages are by mass unless otherwise indicated.

[0039] "Mass parts" refers to the basic unit of measurement for expressing the mass ratio of multiple components. 1 part can represent any unit mass, such as 1g or 2.689g. If we say that the mass parts of component A are a parts and the mass parts of component B are b parts, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it means that the mass of component A is aK and the mass of component B is bK (K is an arbitrary number, indicating a multiple factor). It should not be misunderstood that, unlike the mass parts, the sum of the mass parts of all components is not limited to 100 parts.

[0040] "And / or" is used to indicate that one or both of the stated situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0041] A method for preparing D-3-acetylmercapto-2-methylpropionic acid, an intermediate of captopril, comprises:

[0042] A chiral amine reacts with racemic 3-acetylmercapto-2-methylpropionic acid to obtain a chiral amine salt, the chiral amine salt is subjected to alkaline hydrolysis to obtain sodium D-3-acetylmercapto-2-methylpropionic acid, and then acidified to obtain D-3-acetylmercapto-2-methylpropionic acid;

[0043] The chiral amine includes one or more of R(+)-alpha-methylbenzylamine, (R)-(+)-1-amphetamine, and R(+)-alpha-tert-butylbenzylamine.

[0044] The reaction equation is as follows:

[0045] .

[0046] The structural formula of chiral amine is as follows:

[0047] .

[0048] In an optional embodiment, the solvent for the reaction is methanol.

[0049] In an optional embodiment, the chiral amine is added to a mixed system of the racemic 3-acetylmercapto-2-methylpropionic acid and the methanol at 30-35°C.

[0050] Optionally, when the chiral amine is added, the temperature of the mixed system can be 30°C, 31°C, 32°C, 33°C, 34°C, 35°C or any value between 30-35°C.

[0051] In an optional embodiment, the reaction time is 2-4 hours.

[0052] Optionally, the reaction time can be 2 h, 3 h, 4 h or any value between 2-4 h.

[0053] In an optional embodiment, after the reaction is completed, the system is cooled to -5°C to 0°C and centrifuged to obtain the chiral amine salt.

[0054] Optionally, the end temperature of the cooling may be -5°C, -4°C, -3°C, -2°C, -1°C, 0°C or any value between -5°C and 0°C.

[0055] In an optional embodiment, the alkaline hydrolysis comprises:

[0056] The chiral amine salt is mixed with dichloromethane and water, and the pH of the system is adjusted to be alkaline using sodium hydroxide. The organic phase is the dissociated chiral amine, and the aqueous phase is extracted with dichloromethane to obtain an aqueous solution of sodium D-3-acetylmercapto-2-methylpropionate.

[0057] In an optional embodiment, sodium hydroxide is used to adjust the pH of the system to 7.5-8.5.

[0058] Optionally, the end point of adjusting the pH of the system using sodium hydroxide can be 7.5, 8, 8.5 or any value between 7.5 and 8.5.

[0059] In an optional embodiment, the acidification comprises:

[0060] The system is neutralized with hydrochloric acid to be acidic, and then the aqueous phase is extracted with dichloromethane to obtain a dichloromethane organic phase, which is then washed with water, separated, and the organic phase is concentrated at normal pressure to obtain the D-3-acetylmercapto-2-methylpropionic acid.

[0061] In an optional embodiment, the acidic pH is 3-5.

[0062] Optionally, the acidic pH may be 3, 4, 5 or any value between 3-5.

[0063] In an optional embodiment, the neutralization is carried out at a system temperature of 5-10°C.

[0064] Optionally, during the neutralization, the system temperature can be 5°C, 6°C, 7°C, 8°C, 9°C, 10°C or any value between 5-10°C.

[0065] The embodiments of the present application will be described in detail below in conjunction with specific examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. If specific conditions are not specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0066] Example 1

[0067] This embodiment provides a method for preparing a captopril intermediate D-3-acetylmercapto-2-methylpropionic acid, comprising the following steps:

[0068] 3000L methanol and 162.21kg of 3-acetylmercapto-2-methylpropionic acid were added to a 5000L enamel reactor, and the mixture was stirred for 1 hour. 121.18kg of R(+)-alpha-methylbenzylamine was added at 30°C, and stirring was continued for 3 hours at this temperature to allow the two to fully form salts. The mixture was cooled and centrifuged to obtain a chiral amine salt of D-3-acetylmercapto-2-methylpropionic acid. The salt was added to a 2000L stainless steel reactor, and 800L of dichloromethane and 800L of water were added. Solid sodium hydroxide was added in batches under stirring until the pH was equal to 7.5, and the mixture was separated. At this time, the sodium salt of the product was dissolved in water, and the dichloromethane phase was the dissociated chiral amine. The aqueous phase was extracted twice with 100L of dichloromethane, and the chiral amine was completely extracted into the dichloromethane organic phase.

[0069] The sodium salt of the product in the aqueous phase was neutralized with hydrochloric acid at 5°C to pH 3, the aqueous phase was extracted three times with 300 L of dichloromethane, the dichloromethane organic phases were combined, the dichloromethane organic phases were washed once with 300 L of water, the liquids were separated, and the dichloromethane was concentrated to dryness under normal pressure to obtain the product D-3-acetylmercapto-2-methylpropionic acid.

[0070] The one-time yield can reach 46%.

[0071] [α] 20 D =-45.8°(C=1, ethanol).

[0072] The hydrogen spectrum of the obtained product is as follows Figure 1 As shown. 1-H NMR (CDCl 3, 300MHz) δ 1.29 (d, 3H), 2.35(s,3H), 2.73 (m, 1H), 3.05 (dd, 1H), 3.13 (dd,1H, ).

[0073] The product D-3-acetylmercapto-2-methylpropionic acid has a melting point of 5°C and is liquid at room temperature in the south.

[0074] Example 2

[0075] This embodiment provides a method for preparing a captopril intermediate D-3-acetylmercapto-2-methylpropionic acid, comprising the following steps:

[0076] In a 5000L enamel reactor, 3000L methanol and 162.21kg of 3-acetylmercapto-2-methylpropionic acid were added, stirred for 1 hour, and 135.21kg of (R)-(+)-1-amphetamine was added at 35°C. Stirring was continued for 3 hours at this temperature to fully salt the two, cool, and centrifuge to obtain the chiral amine salt of D-3-acetylmercapto-2-methylpropionic acid. The salt was put into a 2000L stainless steel reactor, 800L of dichloromethane and 800L of water were added, and solid sodium hydroxide was added in batches under stirring until the pH was equal to 8.5. The liquids were separated. At this time, the sodium salt of the product was dissolved in water, and the dichloromethane phase was the dissociated chiral amine. The aqueous phase was extracted twice with 100L of dichloromethane, and the liquids were separated to extract all the chiral amine into the dichloromethane organic phase.

[0077] The sodium salt of the product in the aqueous phase was neutralized with hydrochloric acid to pH 5 at 10°C, the aqueous phase was extracted three times with 300L of dichloromethane, the dichloromethane organic phases were combined, the dichloromethane organic phases were washed once with 300L of water, the liquids were separated, and the dichloromethane was concentrated to dryness under normal pressure to obtain the product D-3-acetylmercapto-2-methylpropionic acid.

[0078] The one-time yield can reach 48%.

[0079] [α] 26 D =-45.3°(C=1, ethanol).

[0080] Example 3

[0081] This embodiment provides a method for preparing a captopril intermediate D-3-acetylmercapto-2-methylpropionic acid, comprising the following steps:

[0082] 3000L methanol and 162.21kg of 3-acetylmercapto-2-methylpropionic acid were added to a 5000L enamel reactor, and the mixture was stirred for 1 hour. 163.26kg of R(+)-alpha-tert-butylbenzylamine was added at 33°C, and stirring was continued for 3 hours at the same temperature to allow the two to fully form salts. The mixture was cooled and centrifuged to obtain the chiral amine salt of D-3-acetylmercapto-2-methylpropionic acid. The salt was added to a 2000L stainless steel reactor, and 800L of dichloromethane and 800L of water were added. Solid sodium hydroxide was added in batches under stirring until the pH was equal to 8.0, and the mixture was separated. At this time, the sodium salt of the product was dissolved in water, and the dichloromethane phase was the dissociated chiral amine. The aqueous phase was extracted twice with 100L of dichloromethane, and the chiral amine was completely extracted into the dichloromethane organic phase.

[0083] The sodium salt of the product in the aqueous phase was neutralized to pH 4 with hydrochloric acid at 8°C, the aqueous phase was extracted three times with 300L of dichloromethane, the dichloromethane organic phases were combined, the dichloromethane organic phases were washed once with 300L of water, the liquids were separated, and the dichloromethane was concentrated to dryness under normal pressure to obtain the product D-3-acetylmercapto-2-methylpropionic acid.

[0084] The one-time yield can reach 51%.

[0085] [α] 26 D =-45.5°(C=1, ethanol).

[0086] Comparative Example 1

[0087] In a 5000L enamel reactor, 3000L methanol and 162.21kg of 3-acetylmercapto-2-methylpropionic acid were added, stirred for 1 hour, and 145kg of L-phenylalanine methyl ester was added at 30°C. Stirring was continued for 3 hours at this temperature to allow the two to fully form salts. The temperature was lowered and centrifuged to obtain the chiral amine salt of D-3-acetylmercapto-2-methylpropionic acid. The salt was put into a 2000L stainless steel reactor, 800L of dichloromethane and 800L of water were added, and solid sodium hydroxide was added in batches under stirring until the pH was equal to 7.5. The liquids were separated. At this time, the sodium salt of the product was dissolved in water, and the dichloromethane phase was the dissociated chiral amine. The aqueous phase was extracted twice with 100L of dichloromethane, and the liquids were separated to extract all the chiral amine into the dichloromethane organic phase.

[0088] The sodium salt of the product in the aqueous phase was neutralized with hydrochloric acid at 5°C to pH 3, the aqueous phase was extracted three times with 300 L of dichloromethane, the dichloromethane organic phases were combined, the dichloromethane organic phases were washed once with 300 L of water, the liquids were separated, and the dichloromethane was concentrated to dryness under normal pressure to obtain the product D-3-acetylmercapto-2-methylpropionic acid.

[0089] [α] 26 D =-33.4°(C=1, ethanol).

[0090] By comparing Example 1 with Comparative Example 1, it can be seen that the chiral amine selected in the present application has obvious advantages.

[0091] Comparative Example 2

[0092] 3000L of ethanol and 162.21kg of 3-acetylmercapto-2-methylpropionic acid were added to a 5000L enamel reactor, and the mixture was stirred for 1 hour. 163.26kg of R(+)-alpha-tert-butylbenzylamine was added at 30°C, and stirring was continued for 3 hours at the same temperature to allow the two to fully form salts. The mixture was cooled and centrifuged to obtain a chiral amine salt of D-3-acetylmercapto-2-methylpropionic acid. The salt was added to a 2000L stainless steel reactor, and 800L of dichloromethane and 800L of water were added. Solid sodium hydroxide was added in batches under stirring until the pH was equal to 7.5, and the mixture was separated. At this time, the sodium salt of the product was dissolved in water, and the dichloromethane phase was the dissociated chiral amine. The aqueous phase was extracted twice with 100L of dichloromethane, and the chiral amine was completely extracted into the dichloromethane organic phase.

[0093] The sodium salt of the product in the aqueous phase was neutralized with hydrochloric acid at 5°C to pH 3, the aqueous phase was extracted three times with 300 L of dichloromethane, the dichloromethane organic phases were combined, the dichloromethane organic phases were washed once with 300 L of water, the liquids were separated, and the dichloromethane was concentrated to dryness under normal pressure to obtain the product D-3-acetylmercapto-2-methylpropionic acid.

[0094] The one-time yield can reach 42%.

[0095] [α] 26 D =-45.6°(C=1, ethanol).

[0096] By comparing Example 1 and Comparative Example 2, it can be seen that the methanol selected in the present application as the solvent of the reaction system can significantly improve the yield.

[0097] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

[0098] In addition, those skilled in the art will appreciate that, although some embodiments herein include certain features included in other embodiments but not other features, the combination of features of different embodiments is meant to be within the scope of the present application and form different embodiments. For example, in the above claims, any one of the claimed embodiments may be used in any combination. The information disclosed in this background technology section is intended only to deepen the understanding of the overall background technology of the present application and should not be regarded as an admission or in any form of implication that the information constitutes prior art known to those skilled in the art.

Claims

1. A method for preparing a captopril intermediate D-3-acetylmercapto-2-methylpropionic acid, characterized in that: include: A chiral amine reacts with racemic 3-acetylmercapto-2-methylpropionic acid to obtain a chiral amine salt, the chiral amine salt is subjected to alkaline hydrolysis to obtain sodium D-3-acetylmercapto-2-methylpropionic acid, and then acidified to obtain D-3-acetylmercapto-2-methylpropionic acid; The chiral amine is selected from one or more of R(+)-alpha-methylbenzylamine, (R)-(+)-1-amphetamine, and R(+)-alpha-tert-butylbenzylamine; The solvent of the reaction is methanol; The chiral amine is added to a mixed system of the racemic 3-acetylmercapto-2-methylpropionic acid and the methanol at 30-35° C.; The reaction time is 2-4h; After the reaction is completed, the system is cooled to -5°C to 0°C and centrifuged to obtain the chiral amine salt; The alkaline hydrolysis comprises: The chiral amine salt is mixed with dichloromethane and water, and the pH of the system is adjusted to 7.5-8.5 using sodium hydroxide, and the liquids are separated, the organic phase is the dissociated chiral amine, and the aqueous phase is extracted with dichloromethane to obtain an aqueous solution of sodium D-3-acetylmercapto-2-methylpropionate; The acidification comprises: Neutralize the system with hydrochloric acid to a pH of 3-5, then extract the aqueous phase with dichloromethane to obtain a dichloromethane organic phase, wash the dichloromethane organic phase with water, separate the phases, and concentrate the organic phase at normal pressure to obtain the D-3-acetylmercapto-2-methylpropionic acid; The neutralization is carried out at a system temperature of 5-10°C.

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