CN102352392A - Chemical-enzyme method for preparing D-tyrosine - Google Patents
Chemical-enzyme method for preparing D-tyrosine Download PDFInfo
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- CN102352392A CN102352392A CN2011102924918A CN201110292491A CN102352392A CN 102352392 A CN102352392 A CN 102352392A CN 2011102924918 A CN2011102924918 A CN 2011102924918A CN 201110292491 A CN201110292491 A CN 201110292491A CN 102352392 A CN102352392 A CN 102352392A
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Abstract
The invention provides a chemical-enzyme method for preparing D-tyrosine. The method comprises the following steps: based on DL-tyrosine as a raw material, deriving DL-tyrosine into DL-N-phenylacetyltyrosine in an acidic medium by using an acylating agent; based on immobilized penicillin acylase as a biocatalyst, carrying out enantiomorphous selective hydrolysis so as to form L-tyrosine, phenylacetic acid and D-N-phenylacetyltyrosine; and carrying out acidolysis on D-N-phenylacetyltyrosine so as to obtain phenylacetic acid and D-tyrosine. According to the chemical-enzyme method, the yield of D-tyrosine is 40%, and enantiomeric excess is larger than 99%. The method provided by the invention has the characteristics of high yield and optical purity of product, simple process and the like, and is suitable for large-scale production of D-tyrosine.
Description
Technical field
The present invention relates to a kind of chemical enzyme process of the D-of preparation tyrosine, belong to biocatalysis and prepare chiral drug intermediate technical field.
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Background technology
D-tyrosine is a kind of non-protein source chiral amino acid, in chiral drug is synthetic, has extensive use.For example; With D-tyrosine is that chiral intermediate synthetic polypeptide drugs Atosiban is a kind of tocolytic agent; Synthetic takes off the acetyl Anisomycin and has protozoacide, resistance to deformation worm, antimycotic, the anti-effect of swelling and ache, prevent plant mycosis; The treatment that the synthetic polypeptide drugs are used for malignant tumour has special efficacy, also can be used for antiphlogistic drug that lung, central nervous system, joint, endocardium, eye, ear, skin, stomach, Urinary system inflammation is had fabulous curative effect etc.
The preparation method of D-tyrosine mainly contains chemical resolution method, biological Split Method, asymmetric transformation approach etc.
1) chemical resolution method.Document (J.Bio.Chem., 1946,166 (1), 1.) reported that a kind of brucine that adopts splits the method that the DL-N-Acetyl tyrosine prepares D-tyrosine, yield 31 filter back filter cakes wash with small amount of deionized water, and oven dry obtains D-tyrosine 22.5g33%.He Quan, etc. (CN1569818) discloses a resolution using L-tartaric acid DL-tyrosine ethyl ester The method of preparation of D-tyrosine, 25% yield.The main drawback that chemistry splits is the phenomenon of carrying secretly that has L-tyrosine, and not only resolution yield is low, and the optical purity of D-tyrosine is poor, and resolution process is complicated.
2) biological Split Method.Patent (EP119275) discloses a kind of method of utilizing glycolylurea enzyme/carbamyl hydrolysis enzyme to prepare D-tyrosine.Glycolylurea enzyme selectivity catalytic hydrolysis DL-5-hydroxyl benzyl glycolylurea is the D-N-formyltyrosine, realizes the racemization of L-5-hydroxyl benzyl glycolylurea simultaneously.Carbamyl hydrolysis enzyme catalysis D-N-formyltyrosine is hydrolyzed to D-tyrosine.Lv Zhixian etc. (CN101153300) a kind of L-of utilization L-Aminoacylase catalysis DL-that openly knows clearly
15N-Acetyl tyrosine hydrolysis preparation is used for the tracer agent-D-of drug metabolism study
15The method of N-tyrosine.Ma Yunfeng etc. (CN1900298) disclose a kind of method of utilizing immobilization D-L-Aminoacylase catalysis DL-N-Acetyl tyrosine to prepare D-tyrosine.Using hydantoinase needs chemosynthesis DL-5-hydroxyl benzyl glycolylurea, and cost is higher.The L-Aminoacylase method adopts the enzyme of free form, can not recycle, and D-L-Aminoacylase especially, price is very high, is not suitable for the large-scale production of D-tyrosine.
3) asymmetric conversion method.Ma Yunfeng etc. (CN1876631) disclose a kind of asymmetric transformation approach of the D-of preparation tyrosine.In the presence of salicylic aldehyde, DL-tyrosine, L-tartrate form D-tyrosine L-tartrate in propionic acid, separate salt then and obtain D-tyrosine, and total recovery is greater than 60%.The shortcoming that asymmetric transformation approach prepares D-tyrosine is to carry a spot of L-tyrosine L-tartrate in the D-tyrosine L-tartrate easily secretly, causes the optical purity of product not high, and in addition, the L-tartrate of coexistence is difficult to remove fully.
Summary of the invention
The chemical enzyme process that the purpose of this invention is to provide a kind of new preparation D-tyrosine.Utilize the immobilized penicillin acylated enzyme of high enantioselectivity to split DL-N-phenylacetyl tyrosine, obtain L-tyrosine, toluylic acid and D-N-phenylacetyl tyrosine, the acidolysis of D-N-phenylacetyl tyrosine is toluylic acid and D-tyrosine.Technological line is following:
The present invention includes the following step:
1) DL-N-phenylacetyl tyrosine preparation: under 50～80 ℃ and pH2～3 conditions, be reaction medium with acetic acid, mol ratio is the DL-tyrosine and the acylating agent stirring reaction 10～20h of 1:1～3; Reaction is transferred pH1～2 with hydrochloric acid after accomplishing, and separates out DL-N-phenylacetyl tyrosine solid;
2) DL-N-phenylacetyl tyrosinase catalysis hydrolysis: under 20～40 ℃ and pH8～10 conditions, 0.1～0.5mol/L DL-N-phenylacetyl tyrosine hydrolysis 10～20h under immobilization penicillin acylated enzyme catalysis; The mass ratio of immobilized penicillin acylated enzyme and DL-N-phenylacetyl tyrosine is 1:3～10, and after reaction was accomplished, concentrated hydrochloric acid was transferred pH1～2, separates out toluylic acid and D-N-phenylacetyl tyrosine;
3) D-tyrosine preparation: D-N-phenylacetyl tyrosine is under nitrogen protection; In 3～8mol/L aqueous hydrochloric acid; 90～115 ℃ of following acidolysis 3～15h of temperature; Acid hydrolysis solution is concentrated into 1/5～1/10 of aqueous hydrochloric acid volume; Use and concentrated solution equal volume of ethyl acetate toluylic acid three times; Water is transferred pH5.6, the freezing D-tyrosine of separating out.
Beneficial effect of the present invention
Compared with prior art, the method that the present invention proposes has the following advantages: 1) substitute alkaline condition with acidic conditions and prepare DL-N-phenylacetyl tyrosine, avoided the formation of tyrosine hydroxyl phenylacetic acid ester, simplified follow-up enzymic catalytic reaction; 2) enantioselectivity of immobilized penicillin acylated enzyme height, the high optical activity of assurance D-tyrosine; 3) recycling of the circulation fractionation of invalid enantiomorph L-tyrosine and immobilized penicillin acylated enzyme greatly reduces process cost.
Embodiment
Below be to be biological catalyst with the immobilized penicillin acylated enzyme, prepare the embodiment of D-tyrosine through enantioselective hydrolysis, but the present invention be not limited to listed several instances.
Embodiment 1: the preparation of DL-N-phenylacetyl tyrosine
72.4g (0.4mol) DL-tyrosine and 48g acetic acid (0.8mol) are added in the 800ml water stirring and dissolving.Under condition of ice bath, drip 64ml (0.48mol) phenyllacetyl chloride.After dropwising, 60 ℃ of following reactions are spent the night.Be cooled to 5 ℃ in the ice bath, suction filtration is used the small amount of deionized water wash solids, gets DL-N-phenylacetyl tyrosine 110.2g, yield 92.1% after the drying.
Embodiment 2:The hydrolysis of DL-N-phenylacetyl tyrosinase catalysis
89.7g (0.3mol) DL-N-phenylacetyl tyrosine is added in the 1000ml water, transfer pH8.0 with ammoniacal liquor.Add the 17.9g immobilized penicillin acylated enzyme, 30 ℃ of following stirring reaction 10h.Suction filtration is removed immobilized penicillin acylated enzyme.Filtrating is transferred pH1～2 with concentrated hydrochloric acid, suction filtration, the solid cold water washing, dry D-N-phenylacetyl trorsine 14 0.4g, yield 45%.
Embodiment 3:The preparation of D-tyrosine
40.4g D-N-phenylacetyl tyrosine is dissolved in the 200mL 6 mol/L concentrated hydrochloric acids N
2Protection, 90 ℃ of following hydrolysis 12h add the 10g activated carbon decolorizing in the hydrolyzed solution.Destainer is concentrated into 40 ml, ethyl acetate (40ml * 3) extraction three times, and water layer is transferred pH to 5.6 with ammoniacal liquor; Under 0～5 ℃, standing over night is filtered the back filter cake and is washed with small amount of deionized water; Oven dry obtains D-tyrosine 22.5g, and yield is 92%, and adopting the HPLC method to record ee is 99.9%.
Claims (4)
1. chemo-enzymatic process for preparing D-tyrosine; It is characterized in that with DL-tyrosine be raw material; In acidic medium, adopt acylating agent to derive and obtain DL-N-phenylacetyl tyrosine; With the immobilized enzyme is biological catalyst; Enantioselectivity catalysis DL-N-phenylacetyl tyrosine is D-N-phenylacetyl tyrosine, toluylic acid and L-tyrosine in water medium; The acidolysis of D-N-phenylacetyl tyrosine is toluylic acid and D-tyrosine, obtains D-tyrosine through concentrated, extraction, iso-electric point adjusting, crystallization, filtration, drying and other steps; May further comprise the steps:
1) DL-N-phenylacetyl tyrosine preparation: under 50～80 ℃ and pH2～3 conditions, be reaction medium with acetic acid, mol ratio is the DL-tyrosine and the acylating agent stirring reaction 10～20h of 1:1～3; Reaction is transferred pH1～2 with hydrochloric acid after accomplishing, and separates out DL-N-phenylacetyl tyrosine solid;
2) DL-N-phenylacetyl tyrosinase catalysis hydrolysis: under 20～40 ℃ and pH8～10 conditions, 0.1～0.5mol/L DL-N-phenylacetyl tyrosine hydrolysis 10～20h under immobilization penicillin acylated enzyme catalysis; The mass ratio of immobilized penicillin acylated enzyme and DL-N-phenylacetyl tyrosine is 1:3～10, and after reaction was accomplished, concentrated hydrochloric acid was transferred pH1～2, separates out toluylic acid and D-N-phenylacetyl tyrosine;
3) D-tyrosine preparation: D-N-phenylacetyl tyrosine is in 3～8mol/L aqueous hydrochloric acid; 90～115 ℃ of following acidolysis 3～15h of temperature; Acid hydrolysis solution is concentrated into 1/5～1/10 of aqueous hydrochloric acid; Use and concentrated solution equal volume of ethyl acetate toluylic acid three times; Water is transferred pH5.6, the freezing D-tyrosine of separating out.
2. D-tyrosine preparation method according to claim 1 is characterized in that the acylating agent that the middle DL-tyrosine-derived of step (1) is a DL-N-phenylacetyl tyrosine is toluylic acid, methyl phenylacetate, phenyllacetyl chloride or phenylacetyl bromine.
3. D-tyrosine preparation method according to claim 1, the acidolysis that it is characterized in that D-N-phenylacetyl tyrosine in the step (3) is adopted 3～8mol/L concentrated hydrochloric acid, 90～115 ℃ of acidolysis temperatures, time 3～15h under nitrogen protection.
4. D-tyrosine preparation method according to claim 1; It is characterized in that acid hydrolysis solution activated carbon decolorizing in the step (3); The destainer ethyl acetate extraction; Water transfers pH to iso-electric point 5.6 with mineral alkali such as ammoniacal liquor, sodium hydroxide; Under 0～5 ℃; Standing over night, filter cake washs with small amount of deionized water behind the suction filtration, and oven dry obtains D-tyrosine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724217A (en) * | 2012-10-11 | 2014-04-16 | 上海交通大学 | Asymmetric syntheses method for D-tyrosine |
| CN109053797A (en) * | 2018-09-05 | 2018-12-21 | 成都百事兴科技实业有限公司 | A kind of improvement synthetic method of oxygen phosphoric acid-l-tyrosine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900298A (en) * | 2006-07-17 | 2007-01-24 | 安徽省恒锐新技术开发有限责任公司 | Method for preparing D-tyrosine by enzyme method |
| CN101003822A (en) * | 2006-07-05 | 2007-07-25 | 中国科学院成都有机化学有限公司 | Method for producing D amino acid by immobilizing acylation enzyme of penicillin |
| CN101368199A (en) * | 2008-10-14 | 2009-02-18 | 重庆邮电大学 | Method for preparing D-aminophenol with immobilization penicillin acylated enzyme catalysis |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101003822A (en) * | 2006-07-05 | 2007-07-25 | 中国科学院成都有机化学有限公司 | Method for producing D amino acid by immobilizing acylation enzyme of penicillin |
| CN1900298A (en) * | 2006-07-17 | 2007-01-24 | 安徽省恒锐新技术开发有限责任公司 | Method for preparing D-tyrosine by enzyme method |
| CN101368199A (en) * | 2008-10-14 | 2009-02-18 | 重庆邮电大学 | Method for preparing D-aminophenol with immobilization penicillin acylated enzyme catalysis |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724217A (en) * | 2012-10-11 | 2014-04-16 | 上海交通大学 | Asymmetric syntheses method for D-tyrosine |
| CN103724217B (en) * | 2012-10-11 | 2016-08-17 | 上海交通大学 | A kind of method of asymmetric synthesis of D-Tyrosine |
| CN109053797A (en) * | 2018-09-05 | 2018-12-21 | 成都百事兴科技实业有限公司 | A kind of improvement synthetic method of oxygen phosphoric acid-l-tyrosine |
| CN109053797B (en) * | 2018-09-05 | 2021-06-29 | 成都百事兴科技实业有限公司 | Improved synthesis method of oxyphosphoric acid-L-tyrosine |
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Inventor after: Xu Hongmei Inventor after: Xia Shiwen Inventor after: Fang Guolan Inventor before: Xia Shiwen Inventor before: Fang Guolan |
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