CN1569815A - Amino acid racemization method - Google Patents
Amino acid racemization method Download PDFInfo
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- CN1569815A CN1569815A CN 200410018050 CN200410018050A CN1569815A CN 1569815 A CN1569815 A CN 1569815A CN 200410018050 CN200410018050 CN 200410018050 CN 200410018050 A CN200410018050 A CN 200410018050A CN 1569815 A CN1569815 A CN 1569815A
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Abstract
Disclosed is an amino acid racemization method which consists of dissolving the L-amino acid in organic acid solvent, acylating with organic acid anhydride, thus achieving a L-amino racemization ratio of 100% with a fast reaction speed and high yield, the acid anhydride and organic acid solvent can be reclaimed for circulation use.
Description
Technical field
The present invention relates to amino acid whose a kind of racemization method, specifically be to use chemical process to produce racemic DL-amino acid.
Background technology
So-called racemization is meant optically active compounds generation part change of configuration, is transformed into the process of the steric isomer that does not have opticity.Amino acid is important chipal compounds, has natural L type and two kinds of configurations of non-natural D type, and under certain condition, all or part of process that changes into racemic modification (DL type) of a certain configuration is called the Racemization of Amino Acids effect.L-amino acid is a kind of natural amino acid, the amino acid that promptly usually said human body is necessary, and its performance is familiar with by people very early, has in fields such as medicine, food, chemical industry so far quite widely to use.Along with going deep into of scientific research in the last few years, it is found that the D-amino acid of thinking useless in the past, have the irreplaceable effect of L-amino acid in vital movement and the medication preparation.Non-natural D-amino acid has become the useful especially chiral source of a class, can synthesize a series of chiral drugs with special efficacy with it as chiral precurser.
In industrial production, the racemization of utilization L-amino acid prepares DL-amino acid, is the important channel that obtains D-amino acid single enantiomer through fractionation again.For L-amino acid, there is a large amount of production in China, wide material sources, so racemization technology is very crucial.Even utilize the DL amino acid of chemosynthesis, again through fractionation obtain D-amino acid single enantiomer technological process, in order to improve utilization ratio of raw materials, the L-amino acid after the fractionation still needs further to utilize after the racemization again, and therefore the amino acid racemization method of research and development practicality is significant.
The amino acid Study on Racemization situation of home and abroad existence at present is as follows:
Document (Fang Baiying, Feng Dayan. necessary amino acid racemization Study on Theory and nutrient protein science [J] .1997,18 (8): 12-17) amino acid has been carried out heating racemization under the alkaline condition, most of amino acid racemization rates are between 10-50%.
Document (Sasaji I., et al.US 3213106,1965) is in the pipe of sealing, and 150～250 ℃ and water heat together 12 seed amino acids is carried out the racemization experiment, and racemization has in various degree taken place most of amino acid.Document (Yamada Y, Hongo C, Yoshioka R..Method for the racemization ofoptically active amino acid[J] .J Org Chem.1983,48:843-846.) in the organic acid, racemization under the aldehyde catalyst action.
CN1034183C proposes a kind of acylamino acid recemase of using, and near neutral water racemize N-acyl-alpha--amino acid only at ordinary times, it combines application with D or L acidylate amidohydrolase and makes DL-acyl-alpha--aminocarboxylic production optically-active D or L-alpha amino acid at PH.This method is used two kinds of enzymes, because the specificity of enzyme and losing activity easily is difficult to widespread usage.
Summary of the invention
The objective of the invention is defective, research and develop a kind of chemical racemization method, make the optically active amino acid of tool become racemic DL-amino acid at the various racemization methods of present amino acid.
The technical solution used in the present invention is that the amino acid racemization method is dissolved in L-amino acid in the organic acid solvent, adds organic acid anhydride, heats acidylate takes place, and generates the amido-carboxylic acid of racemization, handles generating DL amino acid through the deacylated tRNA base
In the above-mentioned reaction, racemization occurs in the aminoacyl amination stage, destroyed the rock steady structure of chirality alpha-carbon, form carbanion, after alpha-carbon negative ion (Csp3) forms, because electron density is bigger on the carbon atom, so it is unstable, easily shift to carbonylic carbon atom, resonance is reset to there not to be the carbon alcohol configuration (Csp2) of chirality feature, thereby has realized Racemization of Amino Acidsization.
The R of above-mentioned reaction represent aliphatics, aromatic series and heterocyclic group because of.As Threonine, Xie Ansuan, Isoleucine, Methionin, halfcystine, phenylalanine, tyrosine and proline(Pro) etc.
In the above-mentioned reaction, organic acid solvent is an anhydrous acetic acid, and organic acid anhydride is a diacetyl oxide, and mineral acid is a hydrochloric acid, and basic solution is a sodium hydroxide solution.
Marked improvement of the present invention and beneficial effect are the places: some amino acid, tyrosine for example, racemization chemically is a kind of of comparison difficulty in amino acid, and many racemization methods that other amino acid is suitable for are used for tyrosine, all do not obtain good racemization effect.The present invention adopts the method for acetic anhydride acylation racemization in pure acetic acid solvent, makes the racemization rate 100% of L-tyrosine.And then this method is applied to other amino acid, also obtained good racemization effect.The method of this monoamino-acid racemization has that racemization is complete, speed of response is fast, product yield is high, acid anhydrides and organic acid solvent can recycle and reuse, low cost and other advantages, has actual application value.This racemization method comprises that to most amino acid L-tyrosine, L-proline(Pro), L-Threonine, L-Xie Ansuan, L-Methionin, L-halfcystine, L-phenylalanine, L-Isoleucine all are suitable for.
Embodiment
Embodiment one: add 20gL-tyrosine in the there-necked flask of 250ml, 100ml Glacial acetic acid and 22ml diacetyl oxide stir, and oil bath is heated to 110 ℃.The initial time of record heating, system clarification after 10 minutes.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 10 minutes sampling 10ml surveys its optical value until being 0.Tyrosine reaches 100% racemization, and the required racemization time is 30min.
The solution decompression distillation removes and desolvates after the racemization that obtains, and obtains the thick material of burgundy, adds 100ml3NHCl solution, refluxes two hours, makes the ethanoyl complete hydrolysis.Be about 3 with sodium hydroxide solution regulator solution pH value, add activated carbon decolorizing, remove by filter gac, continue the iso-electric point (pH ≈ 5～6) of dropping sodium solution to DL-tyrosine, filter, drying obtains flaxen DL-tyrosine.Yield is 90% (is that benchmark calculates with raw material L-tyrosine).
Embodiment two: add 20gL-tyrosine in the there-necked flask of 250ml, 100ml Glacial acetic acid and 22ml diacetyl oxide stir, and oil bath is heated to 100 ℃.The initial time of record heating, after 40 minutes, the system clarification.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 10 minutes sampling 10ml surveys its optical value until being 0.Tyrosine reaches 100% racemization, and the required racemization time is 60min.
Embodiment three: add 20gL-tyrosine in the there-necked flask of 250ml, 100ml Glacial acetic acid and 22ml diacetyl oxide stir, and oil bath is heated to 80 ℃.The initial time of record heating, system clarification after 80 minutes.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 30 minutes sampling 10ml surveys its optical value until being 0.Tyrosine reaches 100% racemization, and the required racemization time is 140min.
Embodiment four: add 20gL-tyrosine in the there-necked flask of 250ml, 100ml Glacial acetic acid and 33ml diacetyl oxide stir, and oil bath is heated to 80 ℃.The initial time of record heating, treated the system clarification in 70 minutes after.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 10 minutes sampling 10ml surveys its optical value until being 0.Tyrosine reaches 100% racemization, and the required racemization time is 90min.
Embodiment five: add 20gL-tyrosine in the there-necked flask of 250ml, 100ml Glacial acetic acid and 15.6ml diacetyl oxide stir, and oil bath is heated to 80 ℃.The initial time of record heating, treated the system clarification in 120 minutes after.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 1 hour sampling 10ml surveys its optical value until being 0.Tyrosine reaches 100% racemization, and the required racemization time is 600min.
Embodiment six: add the 10.36gL-proline(Pro) in the there-necked flask of 250ml, 75ml Glacial acetic acid and 18ml diacetyl oxide stir, and oil bath is heated to 100 ℃.The initial time of record heating, after 10 minutes, proline(Pro) dissolves fully, and the system clear is got the 10ml sample, is diluted to 25ml with deionized water and surveys its optical value.After this every mistake 10 minutes sampling 10ml surveys its optical value until being 0.Proline(Pro) reaches 100% racemization, and the required racemization time is 60min.
Embodiment seven: add the 16.07gL-Threonine in the there-necked flask of 250ml, 75ml Glacial acetic acid and 40ml diacetyl oxide stir, and oil bath is heated to 80 ℃.The initial time of record heating, system clarification after 20 minutes.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 20 minutes sampling 10ml surveys its optical value until being 0.Threonine reaches 100% racemization, and the required racemization time is 80min.
Embodiment eight: add the 10.54gL-Xie Ansuan in the there-necked flask of 250ml, 50ml Glacial acetic acid and 18ml diacetyl oxide stir, and oil bath is heated to 90 ℃.The initial time of record heating, system clarification in 12 minutes.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 10 minutes sampling 10ml surveys its optical value until being 0.Xie Ansuan reaches 100% racemization, and the required racemization time is 32min.
Embodiment nine: add 13.16gL-Methionin in the there-necked flask of 250ml, 150ml Glacial acetic acid and 27ml diacetyl oxide stir, and oil bath is heated to 100 ℃.The initial time of record heating, after the system clarification in 5 minutes, the time that the record dissolving is required.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 20 minutes sampling 10ml surveys its optical value until being 0.Methionin reaches 100% racemization, and the required racemization time is 124min.
Embodiment ten: add the 17.73gL-phenylalanine in the there-necked flask of 250ml, 100ml Glacial acetic acid and 18ml diacetyl oxide stir, and oil bath is heated to 60 ℃.The initial time of record heating, system clarification in 10 minutes.Get the 10ml sample, be diluted to 25ml with deionized water and survey its optical value.After this every mistake 10 minutes sampling 10ml surveys its optical value until being 0.Phenylalanine reaches 100% racemization, and the required racemization time is 60min.
Claims (10)
1, amino acid racemization method is dissolved in L-amino acid in the organic acid solvent, adds organic acid anhydride, and acidylate takes place in heating, generates the amido-carboxylic acid of racemization; Handle generation DL amino acid through the deacylated tRNA base
(R-CHCOOH)。
NH
3
2, amino acid racemization method according to claim 1 is characterized in that organic acid solvent is a Glacial acetic acid, and organic acid anhydride is a diacetyl oxide.
3, amino acid racemization method according to claim 1 and 2, the mole (mol) that it is characterized in that amino acid and diacetyl oxide is than being 1: 1～1: 3.
4, amino acid racemization method according to claim 1 is characterized in that the organic acid solvent consumption is a 5-10ml/g amino acid.
5, amino acid racemization method according to claim 1, it is characterized in that heating the acidylate temperature is 60～110 ℃.
6, amino acid racemization method according to claim 1 is characterized in that with the amino acid of diacetyl oxide and the racemization of amino acid acidylate L-tyrosine, L-proline(Pro), L-Threonine, L-Xie Ansuan, L-halfcystine, L-phenylalanine, L-Isoleucine being arranged.
7, amino acid racemization method according to claim 1 is characterized in that adding 20 gram L-tyrosine and 22ml diacetyl oxides in the 100ml Glacial acetic acid, is heated with stirring to 110 ℃, and the 100% racemization time of casein amino acid is 30 minutes.
8, amino acid racemization method according to claim 1; it is characterized in that the N-Acetyl tyrosine underpressure distillation after the racemization except that desolvating; add the 3N hydrochloric acid soln; 2 hours hydrolysis ethanoyl reflux; be neutralized to the pH value with sodium hydroxide solution again and be about 3; add activated carbon decolorizing, filtered liquid dropping sodium solution refilters the dry DL-tyrosine that gets to DL tyrosine iso-electric point PH5～6.
9, amino acid racemization method according to claim 1 is characterized in that adding 16.07 gram L-Threonine and 40ml diacetyl oxides in the 75ml Glacial acetic acid, is heated with stirring to 80 ℃, and the 100% racemization time of Threonine is 80 minutes
10, amino acid racemization method according to claim 1 is characterized in that adding 13.16 L-Methionin and the 27ml diacetyl oxides that restrain in the 150ml Glacial acetic acid, is heated with stirring to 100 ℃, and the 100% racemization time of Methionin is 124 minutes.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289410B (en) * | 2008-06-06 | 2011-03-16 | 山东奥克特化工有限公司 | Method for preparing D-phenylalanine |
| CN101560132B (en) * | 2009-05-14 | 2011-12-14 | 浙江普洛医药科技有限公司 | Method for racemizing chiral amino acid or derivatives of chiral amino acid |
| CN101575624B (en) * | 2009-06-03 | 2012-07-18 | 淮北新旗氨基酸有限公司 | Microbial enzymes racemization preparation method of DL-alanine |
| CN103664679A (en) * | 2013-12-16 | 2014-03-26 | 天津天成制药有限公司 | Synthetic method of N-acetyl-beta-alanine nitrate |
| CN104592083A (en) * | 2015-01-06 | 2015-05-06 | 宁波海硕生物科技有限公司 | Method for preparing N-acetyl-DL-thioproline |
| CN105063117A (en) * | 2015-07-21 | 2015-11-18 | 成都百事兴科技实业有限公司 | Preparation method of D-arginine monohydrochloride |
| CN109456220A (en) * | 2018-11-16 | 2019-03-12 | 浙江工业大学 | A kind of racemization method of chirality N- phenylacetylamino acid and its derivative |
| CN111836800A (en) * | 2020-06-18 | 2020-10-27 | 苏州园方生物科技有限公司 | Preparation method of DL-proline |
-
2004
- 2004-04-29 CN CN 200410018050 patent/CN1228311C/en not_active Expired - Fee Related
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289410B (en) * | 2008-06-06 | 2011-03-16 | 山东奥克特化工有限公司 | Method for preparing D-phenylalanine |
| CN101560132B (en) * | 2009-05-14 | 2011-12-14 | 浙江普洛医药科技有限公司 | Method for racemizing chiral amino acid or derivatives of chiral amino acid |
| CN101575624B (en) * | 2009-06-03 | 2012-07-18 | 淮北新旗氨基酸有限公司 | Microbial enzymes racemization preparation method of DL-alanine |
| CN103664679A (en) * | 2013-12-16 | 2014-03-26 | 天津天成制药有限公司 | Synthetic method of N-acetyl-beta-alanine nitrate |
| CN104592083A (en) * | 2015-01-06 | 2015-05-06 | 宁波海硕生物科技有限公司 | Method for preparing N-acetyl-DL-thioproline |
| CN105063117A (en) * | 2015-07-21 | 2015-11-18 | 成都百事兴科技实业有限公司 | Preparation method of D-arginine monohydrochloride |
| CN105063117B (en) * | 2015-07-21 | 2018-08-17 | 成都百事兴科技实业有限公司 | A kind of preparation method of D-Arg hydrochloride |
| CN109456220A (en) * | 2018-11-16 | 2019-03-12 | 浙江工业大学 | A kind of racemization method of chirality N- phenylacetylamino acid and its derivative |
| CN109456220B (en) * | 2018-11-16 | 2021-10-08 | 浙江工业大学 | Racemization method of chiral N-phenylacetyl amino acid and derivative thereof |
| CN111836800A (en) * | 2020-06-18 | 2020-10-27 | 苏州园方生物科技有限公司 | Preparation method of DL-proline |
| CN111836800B (en) * | 2020-06-18 | 2021-11-05 | 苏州园方生物科技有限公司 | Preparation method of DL-proline |
| WO2021253306A1 (en) * | 2020-06-18 | 2021-12-23 | 苏州园方生物科技有限公司 | Method for preparing dl-proline |
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