L-2-Amino-4-Halobutyric Acid Derivative-L-Tartrate and Preparation Method Thereof
20250333373 ยท 2025-10-30
Assignee
Inventors
Cpc classification
C07C229/20
CHEMISTRY; METALLURGY
International classification
Abstract
The present disclosure describes an L-S2-amino-4-halobutyric acid derivative-L-tartrate salt. The present disclosure also describes a method of preparing L-S-amino-4-halobutyric acid derivative-L-tartrate salt, comprising the following steps: using D, L-S2-amino-4-halobutyric acid derivative enantiomeric mixture as the raw material, using L-tartrate as the resolution agent, and obtaining L-S2-Amino-4-halobutyric acid derivative-L-tartrate by resolution reaction, crystallization and filtration in the same resolution agent system; or the enantiomeric mixture of D, L-S2-amino-4-halobutyric acid derivatives is used as raw material, L-tartrate is used as resolution agent under aromatic aldehyde catalysis or aromatic aldehyde and organic acid co-catalysis, and dynamic resolution reaction is carried out in the same resolution agent system, further comprising crystallization and filtration to obtain L-S2-amino-4-halobutyric acid derivative-L-tartrate.
Claims
1. An L-2-amino-4-halobutyric acid derivative-L-tartrate with a structure of formula I: ##STR00010## wherein z is the molar ratio of L-2-amino-4-halobutyric acid derivative to L-tartaric acid, z is from 1 to 2; X is Cl or Br; and R is OR.sup.1 or NR.sup.2R.sup.3, wherein R.sup.1 is a C.sub.1 to C.sub.4 aliphatic hydrocarbon, R.sup.2 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon, and R.sup.3 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon.
2. A method of preparing a L-2-amino-4-halobutyric acid derivative-L-tartaric acid salt, the method comprising: a) mixing a D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture, L-tartaric acid, and a solvent to facilitate a resolution reaction and produce a resolution reaction mixture comprising L-2-amino-4-halobutyric acid derivative-L-tartrate; b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and c) separating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.
3. The method of claim 2, wherein the molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives in the D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture is from 0.5 to 1.5:1.
4. The method of claim 2, wherein the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to L-tartaric acid is from 1:0.2 to 1.5.
5. The method of claim 2, wherein the solvent is selected from one or more C.sub.1 to C.sub.4 lower alcohols or a mixture of one or more C.sub.1 to C.sub.4 lower alcohols with water; the C.sub.1 to C.sub.4 lower alcohol being one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol; and the mixture of one or more C.sub.1 to C.sub.4 lower alcohols with water having a volume percentage of C.sub.1 to C.sub.4 lower alcohols from 10% to 99.99%.
6. The method of claim 2, wherein the volume of the solvent is from 1 mL/g D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture to 30 mL/g D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture.
7. A method of preparing a L-2-amino-4-halobutyric acid derivative-L-tartaric acid salt, the method comprising: a) mixing a D-2-amino-4-halobutyric acid derivative or a D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture, L-tartaric acid, aromatic aldehydes or aromatic aldehydes and organic acids, and a solvent to facilitate a dynamic resolution reaction and produce a resolution reaction mixture comprising L-2-amino-4-halobutyric acid derivative-L-tartrate; b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and c) separating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.
8. The method of claim 7, wherein the molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives in the D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture is from 0 to 1.5:1.
9. The method of claim 7, wherein the molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to L-tartaric acid is from 1:0.3 to 1.5.
10. The method of claim 7, wherein the aromatic aldehydes are one or more of benzaldehyde, salicylaldehyde, 5-nitrosalicylaldehyde, and 3,5-dinitrosalicylaldehyde.
11. The method of claim 7, wherein the molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to the aromatic aldehyde is from 1:0.01 to 0.5.
12. The method of claim 7, wherein the organic acids are one or more of formic acid, acetic acid, and propionic acid.
13. The method of claim 7, wherein the molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to the organic acid is from 1:0.1 to 5.
14. The method of claim 7, wherein the solvent is selected from one or more C.sub.1 to C.sub.4 lower alcohols or a mixture of one or more C.sub.1 to C.sub.4 lower alcohols and water; the C.sub.1 to C.sub.4 lower alcohol being one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol; and the mixture of one or more C.sub.1 to C.sub.4 lower alcohols and water having a volume percentage of C.sub.1 to C.sub.4 lower alcohols from 80% to 99.99%.
15. The method of claim 7, wherein the volume of the solvent is from 1 mL/g D-2-amino-4-halobutyric acid derivative or D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture to 30 mL/g D-2-amino-4-halobutyric acid derivative or D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture.
16. The method of claim 2, wherein the temperature of step a) is from 0 C. to the reflux temperature of the system.
17. The method of claim 2, wherein the L-2-amino-4-halobutyric acid derivative-L-tartaric acid salt is an L-2-amino-4-halobutyric acid derivative-L-tartrate with a structure of formula I: ##STR00011## wherein z is the molar ratio of L-2-amino-4-halobutyric acid derivative to L-tartaric acid, z is from 1 to 2; X is Cl or Br; and R is OR.sup.1 or NR.sup.2R.sup.3, wherein R.sup.1 is a C.sub.1 to C.sub.4 aliphatic hydrocarbon, R.sup.2 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon, and R.sup.3 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon.
18. The method of claim 2, wherein the D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture is a mixture of L-2-amino-4-halobutyric acid derivatives and D-2-amino-4-halobutyric acid derivatives with a structure of formula II: ##STR00012## wherein X is Cl or Br; R is OR.sup.1 or NR.sup.2R.sup.3, wherein R.sup.1 is a C.sub.1 to C.sub.4 aliphatic hydrocarbon, R.sup.2 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon, and R.sup.3 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon; and w is the molar percentage of L-2-amino-4-halobutyric acid derivatives in the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives.
Description
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
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DETAILED DESCRIPTION OF THE INVENTION
[0059] One aspect of the disclosure is a L-2-amino-4-halobutyric acid derivative-L-tartrate with a structure of formula I.
##STR00005## [0060] wherein [0061] z is the molar ratio of L-2-amino-4-halobutyric acid derivative to L-tartaric acid, z is from 1 to 2; [0062] X is Cl or Br; and [0063] R is OR.sup.1 or NR.sup.2R.sup.3, wherein R.sup.1 is a C.sub.1 to C.sub.4 aliphatic hydrocarbon, R.sup.2 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon, and R.sup.3 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon.
[0064] Another aspect of the disclosure is a method of preparing a L-2-amino-4-halobutyric acid derivative-L-tartaric acid salt, described as method a) elsewhere in the disclosure, the method comprising: [0065] a) mixing a D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture, L-tartaric acid, and a solvent to facilitate a resolution reaction and produce a resolution reaction mixture comprising L-2-amino-4-halobutyric acid derivative-L-tartrate; [0066] b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and [0067] c) separating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.
[0068] The molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives in the D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture can be from 0.5 to 1.5:1. The molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to L-tartaric acid can be from 1:0.2 to 1.5.
[0069] The solvent can be selected from one or more C.sub.1 to C.sub.4 lower alcohols or a mixture of one or more C.sub.1 to C.sub.4 lower alcohols with water; the C.sub.1 to C.sub.4 lower alcohol being one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol; and the mixture of one or more C.sub.1 to C.sub.4 lower alcohols with water having a volume percentage of C.sub.1 to C.sub.4 lower alcohols from 10% to 99.99%. The volume of the solvent can be from 1 mL/g D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture to 30 mL/g D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture. The temperature of step a) of the method can be from 0 C. to the reflux temperature of the system.
[0070] A further aspect of the disclosure is a method of preparing a L-2-amino-4-halobutyric acid derivative-L-tartaric acid salt, described as method b) elsewhere in the disclosure, the method comprising: [0071] a) mixing a D-2-amino-4-halobutyric acid derivative or a D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture, L-tartaric acid, aromatic aldehydes or aromatic aldehydes and organic acids, and a solvent to facilitate a dynamic resolution reaction and produce a resolution reaction mixture comprising L-2-amino-4-halobutyric acid derivative-L-tartrate; [0072] b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and [0073] c) separating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.
[0074] The molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives in the D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture can be from 0 to 1.5:1. The molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to L-tartaric acid can be from 1:0.3 to 1.5.
[0075] The aromatic aldehydes can be one or more of benzaldehyde, salicylaldehyde, 5-nitrosalicylaldehyde, and 3,5-dinitrosalicylaldehyde. The molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to the aromatic aldehyde can be from 1:0.01 to 0.5.
[0076] The organic acids can be one or more of formic acid, acetic acid, and propionic acid. The molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to the organic acid can be from 1:0.1 to 5.
[0077] The solvent can be selected from one or more C.sub.1 to C.sub.4 lower alcohols or a mixture of one or more C.sub.1 to C.sub.4 lower alcohols and water; the C.sub.1 to C.sub.4 lower alcohol being one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol; and the mixture of one or more C.sub.1 to C.sub.4 lower alcohols and water having a volume percentage of C.sub.1 to C.sub.4 lower alcohols from 80% to 99.99%. The volume of the solvent can be from 1 mL/g D-2-amino-4-halobutyric acid derivative or D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture to 30 mL/g D-2-amino-4-halobutyric acid derivative or D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture. The temperature of step a) of the method can be from 0 C. to the reflux temperature of the system.
[0078] For any of the methods described herein, the L-2-amino-4-halobutyric acid derivative-L-tartaric acid salt can be an L-2-amino-4-halobutyric acid derivative-L-tartrate with a structure of formula I:
##STR00006## [0079] wherein [0080] z is the molar ratio of L-2-amino-4-halobutyric acid derivative to L-tartaric acid, z is from 1 to 2; [0081] X is Cl or Br; and [0082] R is OR.sup.1 or NR.sup.2R.sup.3, wherein R.sup.1 is a C.sub.1 to C.sub.4 aliphatic hydrocarbon, R.sup.2 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon, and R.sup.3 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon.
[0083] For any of the methods described herein, the D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture can be a mixture of L-2-amino-4-halobutyric acid derivatives and D-2-amino-4-halobutyric acid derivatives with a structure of formula II:
##STR00007## [0084] wherein [0085] X is Cl or Br; [0086] R is OR.sup.1 or NR.sup.2R.sup.3, wherein R.sup.1 is a C.sub.1 to C.sub.4 aliphatic hydrocarbon, R.sup.2 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon, and R.sup.3 is H or a C.sub.1 to C.sub.4 aliphatic hydrocarbon; and [0087] w is the molar percentage of L-2-amino-4-halobutyric acid derivatives in the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives.
[0088] In the present disclosure, the inventors found that 4-halo-2-aminobutyric acid and 4-halo-2-aminobutyramide are extremely unstable, and the existing resolution technique of D, L-aminobutyric acid or D, L-aminobutyramide using L-tartaric acid as directed by patent applications WO2006103696A2 and CN102060721A cannot be directly used for the resolution of 4-halo-2-aminobutyric acid and 4-halo-2-aminobutyramide. In the course of their research, the inventors were surprised to find that 4-halo-2-aminobutyrate and 4-halo-2-aminobutyramide tartrates were structurally stable and that the tartrates of stable L-2-amino-4-halo-butyric acid derivatives could be obtained after the resolution reaction. L-2-amino-4-halobutyric acid derivative is an important intermediate for the preparation of L-ammonium glufosinate.
[0089] The present disclosure also provides a simple and workable method for the preparation of L-2-amino-4-halobutyric acid derivative-L-tartrate.
[0090] In the course of studying the resolution of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives, the inventors were surprised to find that the resolution could be done in one step using the same resolution solvent system according to the methods described herein.
[0091] According to method a) described herein, L-2-amino-4-halobutyric acid derivative-L-tartrate can be prepared by a method comprising using D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture as raw material, using L-tartaric acid as the resolution agent, and obtaining L-2-amino-4-halobutyric acid derivative-L-tartrate by resolution reaction, precipitation, and filtration in the same resolution agent system.
[0092] According to method b) described herein, L-2-amino-4-halobutyric acid derivative-L-tartrate can be prepared by a method comprising using D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture as raw material, catalyzing by aromatic aldehydes or aromatic aldehydes and organic acids, with L-tartaric acid as the resolution agent, in the same resolution agent system, by dynamic resolution reaction so that the resolution and racemization proceed simultaneously, further comprising precipitation and filtration to obtain L-2-amino-4-halobutyric acid derivative-L-tartrate.
[0093] In method a), the main reaction formula for the preparation of L-2-amino-4-halobutyric acid derivative-L-tartrate as described is as follows:
##STR00008##
[0094] The following are the preferred technical solutions of method a) of the present disclosure.
[0095] In method a), the molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives is from 0.5 to 1.5:1. When the content of D-2-amino-4-halobutyric acid derivatives in the raw material is too high, the resolution process cannot precipitate solids well, and the products obtained from the resolution system are still mostly of D-configuration, which need to be recrystallized several times to obtain products rich in L-configuration. Therefore, the D, L-2-amino-4-halobutyric acid derivatives of the D-configuration-rich isomers are not suitable for direct disassembly in method a); whereas, when the L-2-amino-4-halobutyric acid derivatives in the feedstock are too high, they can be salified with L-tartaric acid first, and then recrystallized to obtain the L-configuration-rich products. Further preferably, the molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives in the raw material is from 1 to 1.5:1.
[0096] In method a), the resolving agent used is L-tartaric acid. In a suitable solvent system, the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives reacts with L-tartaric acid to form L-2-amino-4-halobutyric acid derivative-L-tartrate (I) and D-2-amino-4-halobutyric acid derivative-L-tartrate, which are enantiomeric to each other, and L-2-amino-4-halobutyric acid derivative-L-tartrate (I) can be further isolated by using their different solubility in the solvent system.
[0097] In method a), the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to L-tartaric acid is from 1:0.2 to 1.5. When the amount of L-tartaric acid is low, the product yield is low; when the amount of L-tartaric acid is large, the resolution effect is not significantly changed, and the resolution agent is wasted, which increases the difficulty of post-processing and causes unnecessary pollution. Further preferably, the molar ratio of D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture to L-tartaric acid is from 1:0.2 to 1.
[0098] In method a), the resolution solvent is a mixture of C.sub.1 to C.sub.4 lower alcohol and water or C.sub.1-C.sub.4 lower alcohol; the C.sub.1-C.sub.4 lower alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol, further preferably methanol or ethanol. The volume percentage of the C.sub.1-C.sub.4 lower alcohol in the mixed solvent composed of the C.sub.1-C.sub.4 lower alcohol and water is from 10% to 99.99%. When the volume percentage of C.sub.1-C.sub.4 lower alcohols is low, the solubility of L-2-amino-4-halobutyric acid derivative-L-tartrate and D-2-amino-4-halobutyric acid derivative-L-tartrate are both very large, and their solubility also varies greatly, so the resolution reaction yield is low. As the alcohol volume percentage increases, the solubility of L-2-amino-4-halobutyric acid derivative-L-tartrate (formula I structure) and D-2-amino-4-halobutyric acid derivative-L-tartrate as well as the solubility difference became smaller, and the product optical purity was poor and the yield was low. Further preferably, the volume percentage of C.sub.1-C.sub.4 lower alcohols in the solvent mixture consisting of C.sub.1-C.sub.4 lower alcohols and water is from 70 to 95%.
[0099] In method a), the volume of the resolution solvent is from 1 mL/g raw material to 30 mL/g raw material, that is, lg of D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture requires 1.5 mL-30 mL of resolution solvent. When 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives uses a resolution solvent less than 1.5 mL, in addition to most of the L-2-amino-4-halobutyric acid derivative-L-tartrate being in the precipitated solid, there is also part of the D-2-amino-4-halobutyric acid derivative-L-tartrate; the obtained products have poor optical purity. When 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives uses a resolution solvent more than 30 mL, only a small amount of L-2-amino-4-halobutyric acid derivative-L-tartrate is precipitated, and the product yield is low. Further preferably, the volume of the resolution solvent is from 3 mL to 8 mL/g raw material, i.e., 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives requires 3 mL to 8 mL of resolution solvent.
[0100] In method a), the temperature of the resolution reaction is 0 C. to the reflux temperature of the system. The solubility of L-2-amino-4-halobutyric acid derivative-L-tartrate (I) and D-2-amino-4-halobutyric acid derivative-L-tartrate and their relative solubility differences vary with temperature. At high temperature, the solubility difference between the two is large, and a product with high optical purity can be obtained, but at high temperature conditions the solubility of the two is large, so the yield is extremely low. At low temperature, the solubility difference between the two is small, and the product obtained has poor optical purity. Further preferably, the temperature of the resolution reaction is from 20 to 65 C.
[0101] In method b), the main reaction formula for the preparation of L-2-amino-4-halobutyric acid derivative-L-tartrate as described is as follows:
##STR00009##
[0102] The following are the preferred technical solutions of method b) of the present disclosure.
[0103] In method b), the molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives is from 0 to 1.5:1. Since the reaction described in b) is a dynamic resolution reaction, when the content of D-2-amino-4-halobutyric acid derivatives in the raw material is too high, using L-tartaric acid as the resolving agent, the resolution and racemization are carried out simultaneously under the catalysis of aromatic aldehydes or the co-catalysis of aromatic aldehydes and organic acids in the same resolution system. This results in the conversion of the D-configuration to the L-configuration in the reaction system and the formation of the corresponding L-2-amino-4-halobutyric acid derivative-L-tartrate, and the difference in solubility between L-configuration tartrate and D-configuration tartrate in the solvent is used to precipitate the product rich in L-configuration. When the content of L-2-amino-4-halobutyric acid derivative in the raw material is too high, it can first form a salt with L-tartrate and then directly refine it by recrystallization to obtain L-2-amino-4-halobutyric acid derivative-L tartaric acid salt. Further preferably, the molar ratio of L-2-amino-4-halobutyric acid derivative to D-2-amino-4-halobutyric acid derivative in the raw material is from 0 to 1:1.
[0104] In method b), the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to L-tartaric acid is from 1:0.3 to 1.5. In the process of dynamic resolution, with the continuous progress of racemization and resolution reactions, the content of L-configuration tartrate in the system is always kept low. Using the solubility difference between L-configuration tartrate and D-configuration tartrate in the solvent system, the L-configuration tartrate is continuously precipitated, and the dissolved tartaric acid in the system is consumed. When the amount of L-tartaric acid is low, the L-configuration salt formation will be insufficient and the yield will be too low. When the amount of L-tartaric acid is large, the resolution effect is not significantly changed, and the resolution agent is wasted, which increases the difficulty of post-processing and causes unnecessary pollution. Further preferably, the molar ratio of D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture to L-tartaric acid is from 1:0.5 to 1.2.
[0105] In method b), the aromatic aldehyde is one or more of benzaldehyde, salicylaldehyde, 5-nitrosalicylaldehyde or 3,5-dinitrosalicylaldehyde. The use of aromatic aldehydes with a hydroxyl group at the 2-position of the aldehyde group in dynamic resolution can better catalyze the racemization reaction. Further preferably, the aromatic aldehyde is salicylic aldehyde.
[0106] In method b), the molar ratio of the D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture to the aromatic aldehyde is from 1:0.01 to 0.5. When the amount of aromatic aldehydes is large, it does not significantly improve the catalytic reaction, wastes raw materials, and is cumbersome for subsequent treatment. When the amount of aromatic aldehydes is small, it does not catalyze the reaction well and the product yield is low. Further preferably, the molar ratio of enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to aromatic aldehydes is from 1:0.01 to 0.4.
[0107] In method b), the catalysis by aromatic aldehydes or aromatic aldehydes and organic acids, with L-tartaric acid as the resolution agent, in the same resolution agent system, by dynamic resolution reaction, so that the resolution and racemization proceed simultaneously. In this case, the reaction catalyzed by aromatic aldehyde alone can achieve the desired effect, but the reaction time is long; when using aromatic aldehyde co-catalyzed with organic acids, the reaction time can be substantially shortened and the reaction efficiency improved.
[0108] In method b), the organic acid is one or more of formic acid, acetic acid, and propionic acid. Further preferred is acetic acid.
[0109] In method b), the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives to organic acid is from 1:0.1 to 5. When the amount of organic acid is large, it does not significantly improve the catalytic reaction, wastes raw materials and has no practical significance; when the amount of organic acid is small, it cannot achieve the expected catalytic efficiency. Further preferably, the molar ratio is from 1:0.3 to 1.5.
[0110] In method b), the resolution solvent is a mixture of C.sub.1 to C.sub.4 lower alcohol and water or C.sub.1-C.sub.4 lower alcohol; the C.sub.1-C.sub.4 lower alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, further preferably methanol or ethanol. The volume percentage of the C.sub.1-C.sub.4 lower alcohol in the mixed solvent composed of the C.sub.1-C.sub.4 lower alcohol and water is from 80% to 99.99%. When the water content in the resolution solvent is high, the racemization reaction cannot occur well, and the solubility of L-2-amino-4-halobutyric acid derivative-L-tartrate and D-2-amino-4-halobutyric acid derivative-L-tartrate is very large, the solubility difference is also very large, and the yield is low. Further preferably, the volume percentage of C.sub.1-C.sub.4 lower alcohols in the solvent mixture consisting of C.sub.1-C.sub.4 lower alcohols and water is from 85 to 99.99%.
[0111] In method b), the volume of the resolution solvent is from 1 mL/g raw material to 30 mL/g raw material, that is, lg of D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture requires 1.5 mL-30 mL of resolution solvent. When 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives uses a resolution solvent less than 1.5 mL, in addition to most of the L-2-amino-4-halobutyric acid derivative-L-tartrate being in the precipitated solid, there is also part of the D-2-amino-4-halobutyric acid derivative-L-tartrate; the obtained products have poor optical purity. When 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives uses a resolution solvent more than 30 mL, only a small amount of L-2-amino-4-halobutyric acid derivative-L-tartrate is precipitated, and the product yield is low. Further preferably, the volume of the resolution solvent is from 3 mL to 8 mL/g raw material, i.e., 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives requires 3 mL to 8 mL of resolution solvent.
[0112] In method b), the temperature of the resolution reaction is 0 C. to the reflux temperature of the system. The solubility of L-2-amino-4-halobutyric acid derivative-L-tartrate (I) and D-2-amino-4-halobutyric acid derivative-L-tartrate and their relative solubility differences vary with temperature. At high temperature, the solubility difference between the two is large, and a product with high optical purity can be obtained, but at high temperature conditions the solubility of the two is large, so the yield is extremely low. At low temperature, the solubility difference between the two is small, and the product obtained has poor optical purity. Further preferably, the temperature of the resolution reaction is from 20 to 65 C.
[0113] The present invention has the following advantages:
[0114] The L-2-amino-4-halobutyric acid derivative-L-tartrate of the present disclosure is a type of chiral intermediate with stable properties, convenient transportation and storage, and can be converted into L-2-amino-4-halobutyric acid derivatives through simple steps, further used in the synthesis of L-glufosinate.
[0115] The preparation method of L-2-amino-4-halobutyric acid derivative-L-tartrate of the present disclosure is suitable for raw materials with various chiral contents.
[0116] The preparation method of L-2-amino-4-halobutyric acid derivative-L-tartrate of the present disclosure, which adopts the completion of the resolution reaction in the same resolution solvent system, is simple in preparation and operation, and is a low cost process for the preparation of chiral aminobutyric acid blocks, which is a key intermediate of L-glufosinate.
[0117] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.
EXAMPLES
[0118] The following non-limiting examples are provided to further illustrate the present invention.
[0119] The present invention is further elucidated hereinafter in connection with specific embodiments, it being understood that these embodiments are intended only to illustrate the invention and not to limit the scope of the invention, and that after reading the invention, various modifications of the invention in equivalent form by those skilled in the art fall within the scope defined by the claims of the invention.
Example 1
[0120] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=50:50) 16.56 g (0.1 mol) was added to ethanol 100 mL and water 20 mL, and then L-tartaric acid 7.5 g (0.05 mol) was added. This was stirred at 70 C. for 10 min to dissolve clear, slowly cooled down within 4 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate crude 9.86 g, yield 40.98%, optical purity D:L=6.4:93.6.
[0121] IR (KBr) (cm.sup.1) 3493, 3379, 2973, 1750, 1614, 1564, 1404, 1347, 1231, 1115, 1067, 1016, 915, 864, 617, as shown in
[0122] .sup.1H NMR (500 MHz, D.sub.2O) 4.33-4.16 (m, J=5.1 Hz, 4H), 3.81-3.53 (m, 2H), 2.48-2.36 (m, 1H), 2.32-2.19 (m, 1H), 1.21 (t, J=7.2 Hz, 3H), as shown in
[0123] .sup.13C NMR (126 MHz, D.sub.2O) 178.24, 169.62, 73.68, 63.61, 50.34, 39.90, 32.36, 13.01, as shown in
Example 2
[0124] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=50:50) 24.84 g (0.15 mol) was added to ethanol 150 mL and water 10 mL, and then L-tartaric acid 6.75 g (0.045 mol) was added. This was stirred at 60 C. for 10 min to dissolve clear, slowly cooled down within 4 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate crude 13.12 g, yield 36.35%, optical purity D:L=3.2:96.8.
Example 3
[0125] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=50:50) 20 g (0.12 mol) was added to ethanol 100 mL and salicylaldehyde 4 g, and then L-tartaric acid 9.96 g (0.066 mol) and acetic acid 10 g were added. This was stirred at 60 C. for 3 hours, slowly cooled down within 5 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate crude 20.39 g, yield 70.17%, optical purity D:L=6.2:93.8.
Example 4
[0126] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=80:20) 20 g (0.12 mol) was added to ethanol 100 mL and salicylaldehyde 4 g, and then L-tartaric acid 9.96 g (0.066 mol) and acetic acid 10 g were added. This was stirred at 60 C. for 3 hours, slowly cooled down within 5 hours to 20 C., and filtered. The filter cake is dried to obtain L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate crude 18.25 g, yield 62.8%, optical purity D:L=4.8:95.2.
Example 5
[0127] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=50:50) 20 g (0.12 mol), was added to ethanol 100 mL and salicylaldehyde 4 g, and then L-tartaric acid 9.96 g (0.066 mol) and acetic acid 10 g were added. This was stirred at 60 C. for 10 hours, slowly cooled down within 5 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate crude 14.38 g, yield 49.48%, optical purity D:L=5.3:94.7.
Example 6
[0128] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-bromobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=50:50) 21 g (0.1 mol) was added to ethanol 100 mL and water 10 mL, and then L-tartaric acid 7.5 g (0.05 mol) was added. This was stirred at 60 C. for 10 min to dissolve clear, slowly cooled down within 4 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-bromobutyric acid ethyl ester-L-tartrate crude 10.55 g, yield 37%, optical purity D:L=6.1:93.9.
[0129] IR (KBr) (cm.sup.1) 3497, 3384, 2988, 2936, 1749, 1614, 1560, 1348, 1279, 1231, 1114, 1067, 865, 694, 619, 524, as shown in
[0130] .sup.1H NMR (500 MHz, D.sub.2O) 4.39-4.14 (m, 4H), 3.83-3.39 (m, 2H), 2.61-2.47 (m, 1H), 2.45-2.29 (m, 1H), 1.26 (t, J=7.2 Hz, 3H), as shown in
[0131] .sup.13C NMR (126 MHz, D.sub.2O) 178.22, 169.59, 73.76, 63.74, 51.41, 32.69, 27.91, 13.18, as shown in
Example 7
[0132] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-bromobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=50:50) 3.15 g (0.15 mol) was added to ethanol 150 mL and salicylaldehyde 5 g, and then L-tartaric acid 11.25 g (0.075 mol) and acetic acid 15 g were added. This was stirred at 60 C. for 18 hours, slowly cooled down within 3 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-bromobutyric acid ethyl ester-L-tartrate crude 27.8 g, yield 65%, optical purity D:L=2.7:97.3.
Example 8
[0133] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid methyl ester enantiomeric mixture (optical purity D:L=50:50) 15.2 g (0.1 mol) was added to methanol 100 mL, and then L-tartaric acid 7.5 g (0.05 mol) was added. This was stirred at 60 C. for 10 min to dissolve clear, slowly cooled down within 5 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyric acid methyl ester-L-tartrate crude 6.93 g, yield 30.5%, optical purity D:L=4.3:95.7.
[0134] IR (KBr) (cm.sup.1) 3479, 3372, 3325, 2959, 2676, 1754, 1615, 1569, 1347, 1306, 1230, 1116, 1067, 806, 688, 618, as shown in
[0135] .sup.1H NMR (500 MHz, D.sub.2O) 4.35 (t, J=6.6 Hz, 1H), 4.31 (s, 1H), 3.85 (s, 3H), 3.82-3.73 (m, 2H), 2.56-2.45 (m, 1H), 2.42-2.28 (m, 1H), as shown in
[0136] .sup.13C NMR (126 MHz, D.sub.2O) 178.32, 170.26, 73.78, 53.69, 50.44, 40.01, 32.48, as shown in
Example 9
[0137] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid methyl ester enantiomeric mixture (optical purity D:L=50:50) 20 g (0.132 mol) was added to methanol 80 mL and salicylaldehyde 4 g, and then L-tartaric acid 9.9 g (0.066 mol) and acetic acid 10 g were added. This was stirred at 50 C. for 3 hours, slowly cooled down within 3 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyric acid methyl ester-L-tartrate crude 16.3 g, yield 54.5%, optical purity D:L=4.8:95.2.
Example 10
[0138] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid isopropyl ester enantiomeric mixture (optical purity D:L=50:50) 17.96 g (0.1 mol) was added to isopropyl alcohol 80 mL and water 16 g, and then L-tartaric acid 15 g (0.1 mol) was added. This was stirred at 50 C. for 10 min to dissolve clear, slowly cooled down within 3 hours to 30 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyric acid isopropyl ester-L-tartrate crude 12.53 g, yield 38%, optical purity D:L=1.3:98.7.
[0139] IR (KBr) (cm.sup.1) 3321, 3277, 2982, 2869, 2592, 1871, 1736, 1577, 1503, 1411, 1305, 1263, 1215, 1103, 1067, 904, 790, 680, 485, as shown in
[0140] .sup.1H NMR (500 MHz, D.sub.2O) 5.25-5.02 (m, 1H), 4.52 (s, 2H), 4.31 (t, J=6.6 Hz, 1H), 3.97-3.68 (m, 2H), 2.59-2.45 (m, 1H), 2.44-2.27 (m, 1H), 1.31 (d, 6H), as shown in
[0141] .sup.13C NMR (126 MHz, D.sub.2O) 176.32, 169.11, 72.80, 72.52, 50.61, 40.06, 32.46, 20.65, as shown in
Example 11
[0142] In a 250 mL three-necked flask under stirring, D, L-2-amino-4-chlorobutyric acid isopropyl ester enantiomeric mixture (optical purity D:L=50:50) 25.15 g (0.14 mol) was added to isopropyl alcohol 120 mL and salicylaldehyde 5 g, and then L-tartaric acid 21 g (0.14 mol) and acetic acid 10 g were added. This was stirred at 55 C. for 3 hours, slowly cooled down within 3 hours to 30 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyric acid isopropyl ester-L-tartrate crude 30.2 g, yield 65.4%, optical purity D:L=2.9:97.1.
Example 12
[0143] In a 250 mL three-necked flask under stirring at 5 C. or less, in sequence D, L-2-amino-4-chlorobutyramide enantiomeric mixture (optical purity D:L=50:50) 13.66 g (0.1 mol), methanol 50 mL, and water 10 g were combined, and then L-tartaric acid 7.5 g (0.05 mol) was added. After stirring below 5 C. for 2 hours, the temperature was slowly increased to 60 C. and stirred to dissolve clear, slowly cooled down within 4 hours to 20 C., and filtered. The filter cake was dried to obtain L-2-amino-4-chlorobutyramide-L-tartrate crude 8.8 g, yield 41.6%, optical purity D:L=5.6:94.4.
[0144] IR (KBr) (cm.sup.1) 3459, 3414, 3376, 3221, 2975, 2699, 1678, 1562, 1403, 1286, 1215, 1128, 1086, 784, 673, 575, as shown in
[0145] .sup.1H NMR (500 MHz, D.sub.2O) 4.51 (s, 2H), 4.23 (t, J=6.8 Hz, 1H), 3.74 (t, J=6.3 Hz, 2H), 2.45-2.28 (m, 2H), as shown in
[0146] .sup.13C NMR (126 MHz, D.sub.2O) 176.36, 171.33, 72.80, 50.88, 39.77, 33.32, as shown in
[0147] When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles a, an, the and said are intended to mean that there are one or more of the elements. The terms comprising, including and having are intended to be inclusive and mean that there may be additional elements other than the listed elements.
[0148] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
[0149] As various changes could be made in the above products and methods without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.