CN101838195B - Chemical resolution preparation method for optical pure Beta-3, 4-dyhydroxyophenyl lactic acid - Google Patents

Chemical resolution preparation method for optical pure Beta-3, 4-dyhydroxyophenyl lactic acid Download PDF

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CN101838195B
CN101838195B CN200910068146.9A CN200910068146A CN101838195B CN 101838195 B CN101838195 B CN 101838195B CN 200910068146 A CN200910068146 A CN 200910068146A CN 101838195 B CN101838195 B CN 101838195B
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lactic acid
benzyloxy phenenyl
ethyl acetate
phenenyl
benzyloxy
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CN101838195A (en
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秦丽
周微
王国成
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Tasly Pharmaceutical Group Co Ltd
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Abstract

The invention relates to a preparation method for optical pure Beta-3, 4-dyhydroxyophenyl lactic acid. The preparation method comprises the following steps of: carrying out the chemical resolution on the racemic Beta-(3, 4-dyhydroxyophenyl) lactic acid, hydrolyzing and hydrogenating the decomposed product to prepare the optical pure Beta-3, 4-dyhydroxyophenyl lactic acid. The Beta-(3, 4-dyhydroxyophenyl) lactic acid has the structural formula shown in the specification; and the Beta-3, 4-dyhydroxyophenyl lactic acid has the structural formula in the specification. By adopting the preparation method of the invention, the optical pure Beta-3, 4-dyhydroxyophenyl lactic acid can be obtained. The invention can be applied to the development of the cardio cerebrovascular drugs, and the preparation method is simple to operate and is a method suitable for industrialized production.

Description

Optically pure β-3, the chemistry of 4-DLA splits preparation method
Technical field
The present invention relates to optical purity Salvianic acidA R-(+)-3,4-DLA and S-(-)-3, the preparation method of 4-DLA, belongs to pharmacy field.
Background technology
Salvianic acidA (danshensu) is isolated a kind of phenol aromatic acid compound from the red sage root in 1980, has another name called R (+)-β-(3,4-dihydroxy phenyl) lactic acid.The long needle crystal of white, molecular formula is C 9h 10o 5, 84 ℃~86 ℃ of fusing points.Through research, Salvianic acidA has many-sided pharmacological action, as the protection to myocardial ischemia; anticoagulant and anti-freezing, to atherosclerotic antagonism and reducing blood-fat, antisepsis and anti-inflammation and enhancing body immunity; on microcirculatory impact, to the protection of liver and antitumor etc.
In 3,4-DLA molecule, contain chiral centre, the asymmetric synthesis of its optically pure individual isomer and chemical method for splitting are not reported.At present, optical purity Salvianic acidA is all to extract and obtain from the plant red sage root, and the method for chemosynthesis just prepares 3 of racemization, 4-DLA.Therefore, the present invention is by a large amount of experimental studies, found a kind ofly by chemical method for splitting, to be prepared and had 3 of high-optical-purity, 4-DLA.
Summary of the invention
The object of this invention is to provide a kind of from 3,4-DLA racemization intermediate (β-(3,4-benzyloxy phenenyl) lactic acid), utilize chemistry to split preparation optically pure R-(+)-3,4-DLA and S-(-)-3, the method for 4-DLA.
The intermediate β using in the present invention-(3,4-benzyloxy phenenyl) lactic acid be reference [Deng Xiling, Chen Xuemin, Jiang Fashou, Yao Xincheng. Salvianic acidA synthetic. Chinese Journal of Pharmaceuticals.2005,36 (9): 523-524] also improved and be prepared from.Concrete grammar is as follows:
First by raw material 3; 4-Dihydroxy benzaldehyde carries out benzyl protection (Theodora W.Greene; PeterG.M.Wuts.Protective Groups in Organic Synthesis; Third Edition.1999 John Wiley & Sons; Inc.); by literature method and acetyl glycine condensation, open loop, obtain α-acetamido-β-(3 again; 4-benzyloxy phenenyl) vinylformic acid; finally by sodium borohydride reduction [Luo Zhiwei; Zhang Yiwei; Lin Dongen. sodium borohydride system is made the reduction of reductive agent to carbonyl, Guangdong chemical industry.2005,3:12-14] and make intermediate β-(3,4-benzyloxy phenenyl) lactic acid.
The structural formula of the β in the present invention-(3,4-benzyloxy phenenyl) lactic acid and 3,4-DLA is as follows:
The present invention's chemical resolving agent used is phenylethylamine and derivative thereof, refers to furtherly the derivative of a series of D-phenylethylamines or L-phenylethylamine, and its structural formula can be as follows,
Wherein, R1, R2 or R3 can be following arbitrary groups: hydroxyl, methyl, phenyl, chlorine, nitro, itrile group, hydroxymethyl, hydroxyethyl, nitrophenyl; As being 1-(4-chloro-phenyl-) ethamine, 1-(p-tolyl) ethamine, red-2-amino-1,2-phenylbenzene ethanol, 1-(to cumyl) ethamine, 1-ethyl benzyl amine, N-(2-hydroxyl) ethyl-Alpha-Methyl benzylamine, 1-(1-how base) ethamine, 1-phenyl-2-(p-tolyl) ethamine, amino p-nitrophenyl-the 1,3-PD of 2-phenyl-3-methylbutylamine or D-(-)-Su-Type-2--.The best is phenylethylamine.
Preparation method of the present invention is 3,4-DLA intermediate β-(3,4-benzyloxy phenenyl) lactic acid and phenylethylamine derivative are dissolved in organic solvent, the diastereoisomeric salt of the β that solubleness is little-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine derivative, this salt of purifying are separated out in placement, be hydrolyzed optically active β-(3 of dissociating, 4-benzyloxy phenenyl) lactic acid, then through catalytic hydrogenation, can make optically pure 3,4-DLA.
Preparation method of the present invention can also be concentrated into dry by splitting for the first time mother liquor, be hydrolyzed the β-(3 that the part of dissociating splits, 4-benzyloxy phenenyl) lactic acid, be dissolved in organic solvent with the phenylethylamine derivative of another configuration, β-(3 are separated out in placement, 4-benzyloxy phenenyl) diastereoisomeric salt of lactic acid-phenylethylamine derivative, this salt of purifying, be hydrolyzed optically active β-(3 of dissociating, 4-benzyloxy phenenyl) lactic acid, through catalytic hydrogenation, can prepare the optically pure 3 of another configuration, 4-DLA.
Preparation method of the present invention is by racemic β-(3,4-benzyloxy phenenyl) ratio of lactic acid and optically pure phenylethylamine derivative resolving agent 1: 0.1 in molar ratio~5, the best is 1: 0.9~1.5, at 0~100 ℃, be dissolved in organic solvent, the best is 40~90 ℃, then at-20~100 ℃, the best is-10~30 ℃, diastereomeric salt solid is separated out in placement, collects this solid, recrystallization purifying it.Acid hydrolysis optically pure β-(3,4-benzyloxy phenenyl) lactic acid that dissociates: (R)-β-(3,4-benzyloxy phenenyl) lactic acid or (S)-β-(3,4-benzyloxy phenenyl) lactic acid.
Above-mentioned mother liquor is concentrated into dry, be hydrolyzed β-(3,4-benzyloxy phenenyl) lactic acid that the part of dissociating splits, and the ratio of corresponding optically pure phenylethylamine derivative resolving agent 1: 0.1 in molar ratio~5, the best is 1: 0.9~1.5, at 0~100 ℃, be dissolved in organic solvent, the best is 40~90 ℃, then at-20~100 ℃, the best is-10~30 ℃, diastereomeric salt solid is separated out in placement, collects this solid, recrystallization purifying it.Acid hydrolysis optically pure β-(3,4-benzyloxy phenenyl) lactic acid that dissociates: (R)-β-(3,4-benzyloxy phenenyl) lactic acid or (S)-β-(3,4-benzyloxy phenenyl) lactic acid.
Optically pure β-(3,4-benzyloxy phenenyl) lactic acid after catalytic hydrogenation, is prepared into optically pure 3 in organic solvent or in water, 4-DLA, i.e. (R)-3,4-DLA and (S)-3,4-DLA.
Do not reach optically pure β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine derivative salt can improve optical purity by the method for recrystallization, be purified to after e.e value is greater than 99.9% and just can carry out the next step, if still do not reach optical purity through recrystallization repeatedly, β-(3 of its acidifying can being dissociated, 4-benzyloxy phenenyl) lactic acid, then prepare according to the method described above the β that optical purity is higher-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine derivative salt with resolving agent phenylethylamine.
Organic solvent described in the present invention and recrystallization solvent are one or more of methyl alcohol, ethanol, Virahol, acetone, chloroform, methylene dichloride, ethyl acetate, ether, methyl tertiary butyl ether, benzene, toluene or tetrahydrofuran (THF), and the best is ethyl acetate.
Described acid is common strong acid example hydrochloric acid, sulfuric acid, trifluoroacetic acid etc.
The present invention has following beneficial effect: first, adopt the chiral reagent method for splitting in the present invention to prepare optically pure β-3,4-DLA, has filled up and there is no R-3 both at home and abroad, 4-DLA and S-3, the blank of 4-DLA synthetic method;
Secondly, compound R-3 that prepare by this method, 4-DLA and S-3,4-DLA, can be used as a kind of cardiovascular medicament and further develops;
Finally, the preparation method who adopts in this invention is easy and simple to handle, is a kind of method that is suitable for suitability for industrialized production.
Embodiment
By the following example, will contribute to understand the present invention, but not limit content of the present invention.
β in embodiment-(3,4-benzyloxy phenenyl) lactic acid e.e (enantiomer is excessive) value is with high effective liquid chromatography for measuring, and design parameter is as follows:
Chiral chromatographic column: Chiralcel AD post
Monitor: UV210nm
Moving phase: normal hexane: Virahol (0.1% trifluoroacetic acid)=70: 30
Embodiment 1
(R) preparation of-β-(3,4-benzyloxy phenenyl) lactic acid
5.64g (0.015mol) racemize β-(3,4-benzyloxy phenenyl) lactic acid, 1.99gD-(+)-phenylethylamine (0.0165mol) join in 60ml methyl alcohol and ethanolic soln, heating for dissolving, 60 ℃ of insulated and stirred are reacted three hours, slowly be down to room temperature, standing over night, filters, and collects mother liquor.Filter cake washs with cold ethyl acetate, is dried to obtain (R)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt crude product 3.16g (yield 87.6%).Re-crystallizing in ethyl acetate obtains (R)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt 2.31g twice, and e.e% is greater than 99%.。
2.31g (R)-β-(3,4-benzyloxy phenenyl) solution that lactic acid-phenylethylamine salt contains methyl alcohol, ethanol, Virahol, acetone, chloroform, methylene dichloride and ethyl acetate with 35ml dissolves, 1mol/ml hydrochloric acid soln regulates pH approximately 5, add about 25ml water, stir extraction, separatory, organic phase is after washing three times, steaming desolventizes to obtain yellow oil, i.e. (R)-β-(3,4-benzyloxy phenenyl) lactic acid 1.73g (based on raceme 30.7% yield), e.e% is greater than 99%.
Embodiment 2
R-3, the preparation of 4-DLA
1.73g (R)-β-(3,4-benzyloxy phenenyl) lactic acid is dissolved in the solution that 30ml contains methylene dichloride, ethyl acetate, ether and methyl tertiary butyl ether, add 0.2g10% palladium-charcoal, under normal temperature and pressure, pass into hydrogen, stirring reaction 2 hours, filter, filtrate evaporated under reduced pressure, obtains water white transparency oily thing, i.e. (R)-3,4-DLA 0.83g (yield 91.1%), e.e% is greater than 99%.
Embodiment 3
(S) preparation of-β-(3,4-benzyloxy phenenyl) lactic acid
In example 1, gained splits mother liquor and is concentrated into the solution dissolving that dry gains contain ethyl acetate, ether, methyl tertiary butyl ether, benzene, toluene and tetrahydrofuran (THF) with 35ml, 1mol/ml hydrochloric acid soln regulates pH approximately 5, add about 50ml water, stir extraction, separatory, organic phase, after washing three times, is steamed and is desolventized containing a small amount of (R)-β-(3,4-benzyloxy phenenyl) (the S)-β of lactic acid-(3,4-benzyloxy phenenyl) lactic acid 2.37g.
2.37g (0.006mol) (S)-β-(3,4-benzyloxy phenenyl) lactic acid crude product, 0.79gL-(-)-phenylethylamine (0.0066mol) join in 30ml ethyl acetate, heating for dissolving, 40 ℃ of insulated and stirred are reacted three hours, slowly be down to room temperature, standing over night, filters, and collects mother liquor.Filter cake washs with cold ethyl acetate, is dried to obtain (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt crude product 2.11g (yield 73.1%).Re-crystallizing in ethyl acetate obtains (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt 1.65g twice, and e.e% is greater than 99%.
1.65g (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt is with 30ml acetic acid ethyl dissolution, 1mol/ml hydrochloric acid soln regulates pH approximately 5, adds about 25ml water, stirs extraction, separatory, organic phase, after washing three times, is steamed and is desolventized to obtain yellow oil, i.e. (S)-β-(3,4-benzyloxy phenenyl) lactic acid 1.20g (based on raceme 21.3% yield), e.e% is greater than 99%.
Embodiment 4
S-3, the preparation of 4-DLA
1.20g (S)-β-(3,4-benzyloxy phenenyl) lactic acid is dissolved in 25ml ethyl acetate, add 0.18g10%Pd-C, under normal temperature and pressure, pass into hydrogen, stirring reaction 2 hours, filter, filtrate evaporated under reduced pressure, obtains water white transparency oily thing, i.e. (S)-3,4-DLA 0.59g (yield 93.0%), e.e% is greater than 99%.
Embodiment 5
(S) preparation of-β-(3,4-benzyloxy phenenyl) lactic acid
5.64g (0.015mol) racemize β-(3,4-benzyloxy phenenyl) lactic acid, 1.99gL-(-)-phenylethylamine (0.0165mol) join in 60ml ethyl acetate, heating for dissolving, 90 ℃ of insulated and stirred are reacted three hours, slowly be down to room temperature, standing over night, filters, and collects mother liquor.Filter cake washs with cold ethyl acetate, is dried to obtain (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt crude product 3.24g (yield 89.8%).Re-crystallizing in ethyl acetate obtains (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt 2.44g twice, and e.e% is greater than 99%.。
2.44g (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt is with 35ml acetic acid ethyl dissolution, 1mol/ml hydrochloric acid soln regulates pH approximately 5, adds about 25ml water, stirs extraction, separatory, organic phase, after washing three times, is steamed and is desolventized to obtain yellow oil, i.e. (S)-β-(3,4-benzyloxy phenenyl) lactic acid 1.45g (based on raceme 25.7% yield), e.e% is greater than 99%.
Embodiment 6
S-3, the preparation of 4-DLA
1.45g (S)-β-(3,4-benzyloxy phenenyl) lactic acid is dissolved in 30ml ethyl acetate, add 0.22g10% palladium-charcoal, under normal temperature and pressure, pass into hydrogen, stirring reaction 2 hours, filter, filtrate evaporated under reduced pressure, obtains water white transparency oily thing, i.e. (S)-3,4-DLA 0.70g (yield 91.8%), e.e% is greater than 99%.
Embodiment 7
(R) preparation of-β-(3,4-benzyloxy phenenyl) lactic acid
In example 5, gained splits mother liquor and is concentrated into dry gains with 35ml acetic acid ethyl dissolution, 1mol/ml hydrochloric acid soln regulates pH approximately 5, add about 50ml water, stir extraction, separatory, organic phase, after washing three times, is steamed and is desolventized containing a small amount of (S)-β-(3,4-benzyloxy phenenyl) (the R)-β of lactic acid-(3,4-benzyloxy phenenyl) lactic acid 2.23g.
2.23g (0.005mol) (R)-β-(3,4-benzyloxy phenenyl) lactic acid crude product, 0.67gD-(+)-phenylethylamine (0.0055mol) join in 30ml ethyl acetate, heating for dissolving, 0 ℃ of insulated and stirred is reacted three hours, slowly be down to room temperature, standing over night, filters, and collects mother liquor.Filter cake washs with cold ethyl acetate, is dried to obtain (R)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt crude product 2.11g (yield 73.9%).Re-crystallizing in ethyl acetate obtains (R)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt 1.71g twice, and e.e% is greater than 99%.
1.71g (R)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt is with 30ml acetic acid ethyl dissolution, 1mol/ml hydrochloric acid soln regulates pH approximately 5, adds about 25ml water, stirs extraction, separatory, organic phase, after washing three times, is steamed and is desolventized to obtain yellow oil, i.e. (R)-β-(3,4-benzyloxy phenenyl) lactic acid 1.33g (based on raceme 23.6% yield), e.e% is greater than 99%.
Embodiment 8
R-3, the preparation of 4-DLA
1.33g (R)-β-(3,4-benzyloxy phenenyl) lactic acid is dissolved in 25ml ethyl acetate, add 0.19g10%Pd-C, under normal temperature and pressure, pass into hydrogen, stirring reaction 2 hours, filter, filtrate evaporated under reduced pressure, obtains water white transparency oily thing, i.e. (R)-3,4-DLA 0.65g (yield 92.6%), e.e% is greater than 99%.

Claims (2)

1. prepare optically pure β-3 for one kind, the method of 4-DLA, it is characterized in that, (1) joins 5.64g racemize β-(3,4-benzyloxy phenenyl) lactic acid, 1.99gD-(+)-phenylethylamine in 60ml methyl alcohol and ethanolic soln, heating for dissolving, 60 ℃ of insulated and stirred are reacted three hours, are slowly down to room temperature, standing over night, filter, collect mother liquor; Filter cake washs with cold ethyl acetate, be dried to obtain (R)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt crude product 3.16g, re-crystallizing in ethyl acetate obtains (R)-β-(3 twice, 4-benzyloxy phenenyl) lactic acid-phenylethylamine salt 2.31g, e.e% is greater than 99%;
(2) 2.31g (R)-β-(3,4-benzyloxy phenenyl) solution that lactic acid-phenylethylamine salt contains methyl alcohol, ethanol, Virahol, acetone, chloroform, methylene dichloride and ethyl acetate with 35ml dissolves, it is 5 that 1mol/ml hydrochloric acid soln regulates pH, adds 25ml water, stirs extraction, separatory, organic phase, after washing three times, is steamed and is desolventized to obtain yellow oil, i.e. (R)-β-(3,4-benzyloxy phenenyl) lactic acid 1.73g, e.e% is greater than 99%;
(3) 1.73g (R)-β-(3,4-benzyloxy phenenyl) lactic acid is dissolved in the solution that 30ml contains methylene dichloride, ethyl acetate, ether and methyl tertiary butyl ether, add 0.2g10% palladium-charcoal, under normal temperature and pressure, pass into hydrogen, stirring reaction 2 hours, filter, filtrate evaporated under reduced pressure, obtains water white transparency oily thing, i.e. (R)-3,4-DLA 0.83g, e.e% is greater than 99%;
(4) gained in step (1) is split to mother liquor and be concentrated into the solution dissolving that dry gains contain ethyl acetate, ether, methyl tertiary butyl ether, benzene, toluene and tetrahydrofuran (THF) with 35ml, it is 5 that 1mol/ml hydrochloric acid soln regulates pH, add 50ml water, stir extraction, separatory, organic phase, after washing three times, is steamed and is desolventized containing a small amount of (R)-β-(3,4-benzyloxy phenenyl) (the S)-β of lactic acid-(3,4-benzyloxy phenenyl) lactic acid 2.37g;
(5) 2.37g (S)-β-(3,4-benzyloxy phenenyl) lactic acid crude product, 0.79gL-(-)-phenylethylamine join in 30ml ethyl acetate, heating for dissolving, 40 ℃ of insulated and stirred are reacted three hours, are slowly down to room temperature, standing over night, filter, collect mother liquor; Filter cake washs with cold ethyl acetate, be dried to obtain (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt crude product 2.11g, re-crystallizing in ethyl acetate obtains (S)-β-(3 twice, 4-benzyloxy phenenyl) lactic acid-phenylethylamine salt 1.65g, e.e% is greater than 99%;
(6) 1.65g (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt is with 30ml acetic acid ethyl dissolution, it is 5 that 1mol/ml hydrochloric acid soln regulates pH, adds 25ml water, stirs extraction, separatory, organic phase, after washing three times, is steamed and is desolventized to obtain yellow oil, i.e. (S)-β-(3,4-benzyloxy phenenyl) lactic acid 1.20g, e.e% is greater than 99%;
(7) 1.20g (S)-β-(3,4-benzyloxy phenenyl) lactic acid is dissolved in 25ml ethyl acetate, add 0.18g10%Pd-C, under normal temperature and pressure, pass into hydrogen, stirring reaction 2 hours, filter, filtrate evaporated under reduced pressure, obtains water white transparency oily thing, i.e. (S)-3,4-DLA 0.59g, e.e% is greater than 99%.
2. prepare optically pure β-3 for one kind, the method of 4-DLA, it is characterized in that, (1) 5.64g racemize β-(3,4-benzyloxy phenenyl) lactic acid, 1.99gL-(-)-phenylethylamine join in 60ml ethyl acetate, heating for dissolving, 90 ℃ of insulated and stirred are reacted three hours, are slowly down to room temperature, standing over night, filter, collect mother liquor; Filter cake washs with cold ethyl acetate, be dried to obtain (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt crude product 3.24g, re-crystallizing in ethyl acetate obtains (S)-β-(3 twice, 4-benzyloxy phenenyl) lactic acid-phenylethylamine salt 2.44g, e.e% is greater than 99%;
(2) 2.44g (S)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt is with 35ml acetic acid ethyl dissolution, it is 5 that 1mol/ml hydrochloric acid soln regulates pH, adds 25ml water, stirs extraction, separatory, organic phase, after washing three times, is steamed and is desolventized to obtain yellow oil, i.e. (S)-β-(3,4-benzyloxy phenenyl) lactic acid 1.45g, e.e% is greater than 99%;
(3) 1.45g (S)-β-(3,4-benzyloxy phenenyl) lactic acid is dissolved in 30ml ethyl acetate, add 0.22g10% palladium-charcoal, under normal temperature and pressure, pass into hydrogen, stirring reaction 2 hours, filter, filtrate evaporated under reduced pressure, obtains water white transparency oily thing, i.e. (S)-3,4-DLA 0.70g, e.e% is greater than 99%;
(4) gained in step (1) is split to mother liquor and be concentrated into dry gains with 35ml acetic acid ethyl dissolution, it is 5 that 1mol/ml hydrochloric acid soln regulates pH, add 50ml water, stir extraction, separatory, organic phase, after washing three times, is steamed and is desolventized containing a small amount of (S)-β-(3,4-benzyloxy phenenyl) (the R)-β of lactic acid-(3,4-benzyloxy phenenyl) lactic acid 2.23g;
(5) 2.23g (R)-β-(3,4-benzyloxy phenenyl) lactic acid crude product, 0.67gD-(+)-phenylethylamine join in 30ml ethyl acetate, heating for dissolving, 0 ℃ of insulated and stirred is reacted three hours, is slowly down to room temperature, standing over night, filter, collect mother liquor; Filter cake washs with cold ethyl acetate, be dried to obtain (R)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt crude product 2.11g, re-crystallizing in ethyl acetate obtains (R)-β-(3 twice, 4-benzyloxy phenenyl) lactic acid-phenylethylamine salt 1.71g, e.e% is greater than 99%;
(6) 1.71g (R)-β-(3,4-benzyloxy phenenyl) lactic acid-phenylethylamine salt is with 30ml acetic acid ethyl dissolution, it is 5 that 1mol/ml hydrochloric acid soln regulates pH, adds 25ml water, stirs extraction, separatory, organic phase, after washing three times, is steamed and is desolventized to obtain yellow oil, i.e. (R)-β-(3,4-benzyloxy phenenyl) lactic acid 1.33g, e.e% is greater than 99%;
(7) 1.33g (R)-β-(3,4-benzyloxy phenenyl) lactic acid is dissolved in 25ml ethyl acetate, add 0.19g10%Pd-C, under normal temperature and pressure, pass into hydrogen, stirring reaction 2 hours, filter, filtrate evaporated under reduced pressure, obtains water white transparency oily thing, i.e. (R)-3,4-DLA 0.65g, e.e% is greater than 99%.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1433393A (en) * 1999-12-03 2003-07-30 阿斯特拉曾尼卡有限公司 New process
CN1443153A (en) * 2000-07-18 2003-09-17 辛根塔有限公司 Process for preparation of enantiomerically pure pyrethroid insecticides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1433393A (en) * 1999-12-03 2003-07-30 阿斯特拉曾尼卡有限公司 New process
CN1443153A (en) * 2000-07-18 2003-09-17 辛根塔有限公司 Process for preparation of enantiomerically pure pyrethroid insecticides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Man Xu et al.,.Structural characterization of metabolites of salvianolic acid B from Salvia miltiorrhiza in normal and antibiotic-treated rats by liquid chromatography–mass spectrometry.《Journal of Chromatography B》.2007,第858卷第184-198页.
Structural characterization of metabolites of salvianolic acid B from Salvia miltiorrhiza in normal and antibiotic-treated rats by liquid chromatography–mass spectrometry;Man Xu et al.,;《Journal of Chromatography B》;20070830;第858卷;第184-198页 *
童元峰等,.dl-丹参素的合成.《中国药物化学杂志》.2007,第17卷(第2期),第93页Figure 1和2.6. *

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