CN102432413A - Purification method for improving chiral purity of D-amino acid - Google Patents
Purification method for improving chiral purity of D-amino acid Download PDFInfo
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- CN102432413A CN102432413A CN2011102917736A CN201110291773A CN102432413A CN 102432413 A CN102432413 A CN 102432413A CN 2011102917736 A CN2011102917736 A CN 2011102917736A CN 201110291773 A CN201110291773 A CN 201110291773A CN 102432413 A CN102432413 A CN 102432413A
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Abstract
The invention provides a purification method for improving the chiral purity of D-amino acid. In the method, the D-amino acid with low chiral purity is prepared into D-amino acid hydrochloride; L-amino acid hydrochloride is removed in the modes of stirring at room temperature, filtering, washing and the like by utilizing the solubility difference of two enantiomers of amino acid hydrochloride in an organic solvent to obtain the D-amino acid hydrochloride with high chiral purity; and the D-amino acid hydrochloride with high chiral purity is prepared by performing salt solution by adopting propylene oxide. The method provided by the invention has the characteristics of simple process, high yield and high chiral purity, and is suitable for large-scale production of the D-amino acid with high chiral purity.
Description
Technical field
The present invention relates to a kind of purification process of the D-of raising amino acid chiral purity, belong to chiral drug intermediate preparation technical field.
Background technology
D-amino acid is present in mikrobe, the animal and plant, and kind more than 30 is arranged approximately, accounts for to find amino acid whose about 10%.D-amino acid in the organism is found by scientist the seventies in 20th century, but is not caused enough attention.Along with medical science and biological development, find that the amino acid of two kinds of configurations has different physiological actions.Amino acid whose function of D-and physiological action are just illustrated gradually, and some human disease such as cataract, early dementia, nephropathy etc. are closely related with the D-content of amino acids.Experimentation on animals shows that the D-amino acid of excess can be blocked the synthetic of some biological substances, thereby suppresses the growth of cell, organism, so D-amino acid is very important to disease and old and feeble Study on Mechanism.The polypeptide that D-amino acid constitutes usually can not or can only be by the slow hydrolysis of peptase, so D-amino acid has been used for synthetic beta-lactam antibiotics, antibiotic and antiviral polypeptide more and more.D-amino acid and verivate D-amino alcohol, D-alcohol acid also are the key intermediates of chiral drug, chirality agricultural chemicals, chirality foodstuff additive, are widely used at medicine, agricultural chemicals and field of food.Table 1 has been listed the amino acid whose application example of some D-.
The amino acid whose commercial applications of table 1 D-
| D-amino acid | Purposes |
| The D-L-Ala | My Rayleigh of dermorphin, pain relieving analgesic polypeptide, endometriosis medicine, sterilant Metalaxyl-M, sweeting agent CP-54802 (sugariness is 2000 times of sucrose for day third dipeptides, Alitame, in the listing of states such as Australia and New Zealand) midbody. |
| The D-Xie Ansuan | My smooth midbody of sterilant fluorine amine nitrile chrysanthemum ester (the D-enantiomorph of this sterilant is active higher 5000 times than L-enantiomorph, and animal toxicity is merely 1/10, Eli Lilly company), antibiotics of animal valnemulin, sweeting agent. |
| The D-leucine | Endometriosis medicine leuprorelin midbody. |
| The D-Serine | Antitubercular agent seromycin (Tubiserin), antiepileptic drug SPM927 midbody. |
| The D-halfcystine | Microbiotic cephalo miaow promise midbody. |
| D-Methionin | The AI midbody. |
| The D-ornithine | Depilitant and antitumor drug D-alpha-difluoromethyl ornithine midbody |
| The D-phenylalanine(Phe) | , diarrhoea medicine acetate Sostatin, zymoplasm, Chymotrypsin, angiotonin proenzyme and retroviral protease suppressor factor, beautiful fertile gram (U.S. defends moral nutrition global group), diabetes medicament Nateglinides (Ajinomoto, Yamanouchi company, 1999 in Japan's listing), antitumor drug hundred scholars glad (1998 in China's listing), the sexual dysfunction medicine melanotan midbody of giving birth to of diet pill. |
| D-tyrosine | Tocolytic agent RWJ-22164 midbody. |
| The D-tryptophane | Treatment erection problem disease drug Tadalafil (Eli Lilly company), diarrhoea medicine acetate Sostatin, amicine octapeptide analogue gastrointestinal drug,, endometriosis medicine triptorelin midbody. |
D-amino acid is non-protein source amino acid, can not adopt fermentative Production as natural L-amino acid.The amino acid whose preparation method of D-mainly comprises chemical method and biological process at present.Chemical method comprises chemical asymmetric synthesis method and chemical resolution method.Chemistry asymmetric synthesis method adopts chiral source, chiral auxiliary(reagent) or chiral catalyst to prepare D-amino acid; It is the chiral separation agent that chemical resolution method adopts chiral acid or chiral base, through forming diastereo-isomerism salt, separating step such as salt and prepare D-amino acid.Biological process comprises biological Split Method and biotransformation method.Biological Split Method serves as to split catalyzer with lytic enzymes such as acylase or lypase, and the deutero-dl aminoadipic acid is a raw material, prepares D-amino acid through the stereoselectivity enzymatic hydrolysis.Biotransformation method mainly comprises using hydantoinase, amino acid dehydrogenase method, transaminase method, microbial degradation method etc.
D-amino acid has high requirements to its chiral purity as the chiral drug midbody, requires enantiomeric excess (ee) usually>99% even higher.Adopt chemical asymmetric synthesis or chemistry to split preparation D-amino acid, owing to carry phenomenon secretly in selectivity of catalyst or the salification process, the D-amino acid chiral purity that often causes preparing is lower; Need adopt repeatedly methods such as recrystallization to carry out chirally purified; Acylase splits to adopt biology to split especially, although have very high enantioselectivity, owing to relate to the amino acid whose acidolysis step of the D-that derives; Be prone to racemization reaction takes place, cause the D-amino acid chiral purity of preparation not high.Therefore, be necessary to propose new D-amino acid chiral purification process.
Summary of the invention
The purification process that the purpose of this invention is to provide a kind of D-of raising amino acid chiral purity.The D-amino acid that optical purity is lower is converted into hydrochloride, mixes with organic solvent, stirs, and utilizes D-amino acid salts hydrochlorate and the dissolubility difference of L-amino acid salts hydrochlorate in organic solvent, realizes that D-is amino acid whose chirally purified.
The present invention includes the following step:
1) D-amino acid salts hydrochlorate preparation: D-amino acid adds in ethanol or the methyl alcohol, stirs down and drips concentrated hydrochloric acid until dissolving, and evaporated under reduced pressure gets D-amino acid salts hydrochlorate.
2) D-amino acid salts hydrochlorate is chirally purified: D-amino acid salts hydrochlorate mixes with ETHYLE ACETATE, stir process under the room temperature, and suction filtration, washing gets high chiral purity D-amino acid salts hydrochlorate.
3) high chiral purity D-amino acid preparation: the D-amino acid salts hydrochlorate after chirally purified is dissolved in ethanol or the methyl alcohol, adds the propylene oxide desalination, separates out D-amino acid, washing, dry high chiral purity D-amino acid.
The amino acid whose enantiomeric excess ee of the D-that chiral purity is lower described in the step (1) is 80～97%.
Souring agent in the step (1) is a hydrochloric acid, and organic solvent is an ethanol; D-amino acid and alcoholic acid mol ratio 1:5～10
Organic solvent in the step (2) is an ETHYLE ACETATE, and the mol ratio of D-amino acid salts hydrochlorate and ETHYLE ACETATE is 1:10～15.
Temperature in the step (2) is 30～40 ℃, and churning time is 1～3h.
Organic solvent in the step (3) is an ethanol, the D-amino acid salts hydrochlorate of high chiral purity and the D-amino acid of organic solvent and alcoholic acid mol ratio 1:5～10.
Said D-amino acid is D-L-Ala, D-2-propalanine, D-leucine, D-Xie Ansuan, D-halfcystine, D-phenylalanine(Phe), D-o-chlorobenzene glycine or D-2-aminoadipic acid; Said D-amino acid salts hydrochlorate is D-L-Ala hydrochloride, D-2-propalanine hydrochloride, D-leucine hydrochloride, D-Xie Ansuan hydrochloride, D-cysteine hydrochloride, D-phenylalanine(Phe) hydrochloride, D-o-chlorobenzene glycine hydrochloride or D-2-aminoadipic acid hydrochloride.
The amino acid whose enantiomeric excess ee of high chiral purity D-that step (3) obtains is 98.5～99.9%.。
Beneficial effect of the present invention
Compare with existing D-amino acid chiral purification technique, the method that the present invention proposes has the following advantages: 1) technology is simple.The D-amino acid that optical purity is lower uses conventional methods and is prepared as hydrochloride, realizes chirally purified with organic dissolving stirring; 2) universality is strong.It is alicyclic amino acid whose chirally purified that method is fit to D-neutral amino acids, D-basic aminoacids, D-acidic amino acid, D-die aromatischen Aminosaeuren, D-.
The chiral analysis method
The amino acid whose enantiomeric excess of D-adopts chiral high performance liquid chromatography to measure.(4.6 * 150mm), moving phase: (90～95:10～5, V/V), flow velocity: 0.5～1ml/min detects: UV, 210nm, temperature: 20-30 ℃ normal hexane/Virahol chiral column: Crownpak CR (+).
Embodiment
Below be the chirally purified embodiment of D-amino acid salts hydrochlorate, but the present invention is not limited to listed several instances.
Embodiment 1:D-L-Ala is chirally purified
17.8g (0.2mol ee95.3%) in the D-L-Ala adding 100ml ethanol, stirs and drips the dissolving of concentrated hydrochloric acid (36%) to solid down, and evaporated under reduced pressure gets D-L-Ala hydrochloride.D-L-Ala hydrochloride adds in the 200ml ETHYLE ACETATE, and 30 ℃ are stirred 2h down, and suction filtration gets D-L-Ala hydrochloride 24g.D-L-Ala hydrochloride behind the 24g purifying is added in the 100ml ethanol, adds propylene oxide 30ml, separate out solid under stirring, suction filtration, dry 17g D-L-Ala, yield 96%, ee99.5%.
Embodiment 2:D-2-propalanine is chirally purified
20.6g (0.2mol ee87%) in the D-2-propalanine adding 100ml ethanol, stirs and drips the dissolving of concentrated hydrochloric acid (36%) to solid down, and evaporated under reduced pressure gets D-2-propalanine hydrochloride.D-2-propalanine hydrochloride adds in the 200ml ETHYLE ACETATE, and 30 ℃ are stirred 2h down, and suction filtration gets D-2-propalanine hydrochloride 25g.D-2-propalanine hydrochloride behind the 25g purifying is added in the 100ml ethanol, adds propylene oxide 30ml, separate out solid under stirring, suction filtration, dry 18g D-2-propalanine, yield 87.4%, ee 99.5%.
Embodiment 3:D-leucine is chirally purified
26.2g (0.2mol ee93%) in the D-leucine adding 100ml ethanol, stirs and drips the dissolving of concentrated hydrochloric acid (36%) to solid down, and evaporated under reduced pressure gets D-leucine hydrochloride.D-leucine hydrochloride adds in the 200ml ETHYLE ACETATE, and 30 ℃ are stirred 2h down, and suction filtration gets D-leucine hydrochloride 31g.D-leucine hydrochloride behind the 31g purifying is added in the 100ml ethanol, adds propylene oxide 30ml, separate out solid under stirring, suction filtration, dry 24g D-leucine, yield 91.6%, ee99.8%.
Embodiment 4:D-Xie Ansuan is chirally purified
23.4g (0.2mol ee90%) in the D-Xie Ansuan adding 100ml ethanol, stirs and drips the dissolving of concentrated hydrochloric acid (36%) to solid down, and evaporated under reduced pressure gets D-Xie Ansuan hydrochloride.D-Xie Ansuan hydrochloride adds in the 200ml ETHYLE ACETATE, and 30 ℃ are stirred 2h down, and suction filtration gets D-Xie Ansuan hydrochloride 27g.D-Xie Ansuan hydrochloride behind the 27g purifying is added in the 100ml ethanol, adds propylene oxide 30ml, stir down and separate out solid, suction filtration, dry 21g D-Xie Ansuan, yield 90%, it is 99.2% that employing HPLC method records ee.
Embodiment 5:D-halfcystine is chirally purified
24.2g (0.2mol ee80%) in the D-halfcystine adding 100ml ethanol, stirs and drips the dissolving of concentrated hydrochloric acid (36%) to solid down, and evaporated under reduced pressure gets the D-cysteine hydrochloride.The D-cysteine hydrochloride adds in the 200ml ETHYLE ACETATE, and 30 ℃ are stirred 2h down, and suction filtration gets D-cysteine hydrochloride 30g.D-cysteine hydrochloride behind the 30g purifying is added in the 100ml ethanol, adds propylene oxide 30ml, stir down and separate out solid, suction filtration, dry 21g D-halfcystine, yield 86.8%, it is 99.5% that employing HPLC method records ee.
Embodiment 6:D-phenylalanine(Phe) is chirally purified
(0.2mol ee92%) in the D-phenylalanine(Phe) adding 100ml ethanol, stirs and drips the dissolving of concentrated hydrochloric acid (36%) to solid down 33g, and evaporated under reduced pressure gets D-phenylalanine(Phe) hydrochloride.D-phenylalanine(Phe) hydrochloride adds in the 200ml ETHYLE ACETATE, and 40 ℃ are stirred 3h down, and suction filtration gets D-phenylalanine(Phe) hydrochloride 40g.D-phenylalanine(Phe) hydrochloride behind the 40g purifying is added in the 100ml ethanol, adds propylene oxide 30ml, stir down and separate out solid, suction filtration, dry 30g D-phenylalanine(Phe), yield 91%, it is 98.5% that employing HPLC method records ee.
Embodiment 7:D-o-chlorobenzene glycine is chirally purified
37.1g (0.2mol ee97%) in the D-o-chlorobenzene glycine adding 100ml methyl alcohol, stirs and drips the dissolving of concentrated hydrochloric acid (36%) to solid down, and evaporated under reduced pressure gets D-o-chlorobenzene glycine hydrochloride.D-o-chlorobenzene glycine hydrochloride adds in the 200ml ETHYLE ACETATE, and 40 ℃ are stirred 3h down, and suction filtration gets D-o-chlorobenzene glycine hydrochloride 43g.D-o-chlorobenzene glycine hydrochloride behind the 43g purifying is added in the 100ml methyl alcohol, adds propylene oxide 30ml, stir down and separate out solid, suction filtration, dry 35g D-o-chlorobenzene glycine, yield 94.3%, it is 99.9% that employing HPLC method records ee.
Embodiment 8:D-2-aminoadipic acid is chirally purified
32.2g (0.2mol ee96%) in the D-2-aminoadipic acid adding 100ml ethanol, stirs and drips the dissolving of concentrated hydrochloric acid (36%) to solid down, and evaporated under reduced pressure gets D-2-aminoadipic acid hydrochloride.D-2-aminoadipic acid hydrochloride adds in the 200ml ETHYLE ACETATE, and 30 ℃ are stirred 2h down, and suction filtration gets D-2-aminoadipic acid hydrochloride 38g.D-2-aminoadipic acid hydrochloride behind the 38g purifying is added in the 100ml ethanol, adds propylene oxide 30ml, stir down and separate out solid, suction filtration, dry 30g D-2-aminoadipic acid, yield 93.2%, it is 99.8% that employing HPLC method records ee.
Claims (7)
1. purification process that improves D-amino acid chiral purity is characterized in that may further comprise the steps:
(1) D-amino acid salts hydrochlorate preparation: the D-amino acid that chiral purity is lower adds in the organic solvent, drips concentrated hydrochloric acid to solid under stirring and dissolves, and evaporated under reduced pressure promptly gets D-L-Ala hydrochloride;
(2) D-amino acid salts hydrochlorate is chirally purified: D-amino acid salts hydrochlorate is mixed with organic solvent at a certain temperature, and stir process, suction filtration, washing gets high chiral purity D-amino acid salts hydrochlorate;
(3) high chiral purity D-amino acid preparation: the D-amino acid salts hydrochlorate of high chiral purity is dissolved in the organic solvent, adds propylene oxide and separate demineralizing acid, separate out D-amino acid, washing, dry high chiral purity D-amino acid.
2. D-amino acid chiral purification process according to claim 1 is characterized in that the amino acid whose chiral purity ee% of D-that chiral purity is lower described in the step (1) is 80%～97%.
3. D-amino acid chiral purification process according to claim 1 is characterized in that the souring agent in the step (1) is a hydrochloric acid, and organic solvent is methyl alcohol or ethanol, preferred alcohol; D-amino acid and alcoholic acid mol ratio are 1:5～10.
4. D-amino acid chiral purification process according to claim 1; It is characterized in that the organic solvent in the step (2) is the carboxylic acid esters solvent; Be selected from ethyl formate, ETHYLE ACETATE or butylacetate, ethyl acetate, the mol ratio of D-amino acid salts hydrochlorate and ETHYLE ACETATE are 1:10～15.
5. D-amino acid chiral purification process according to claim 1 is characterized in that the temperature in the step (2) is 30～40 ℃, and churning time is 1～3h.
6. D-amino acid chiral purification process according to claim 1 is characterized in that said D-amino acid is D-L-Ala, D-2-propalanine, D-leucine, D-Xie Ansuan, D-halfcystine, D-phenylalanine(Phe), D-o-chlorobenzene glycine or D-2-aminoadipic acid; Said D-amino acid salts hydrochlorate is D-L-Ala hydrochloride, D-2-propalanine hydrochloride, D-leucine hydrochloride, D-Xie Ansuan hydrochloride, D-cysteine hydrochloride, D-phenylalanine(Phe) hydrochloride, D-o-chlorobenzene glycine hydrochloride or D-2-aminoadipic acid hydrochloride.
7. D-amino acid chiral purification process according to claim 1 is characterized in that the amino acid whose enantiomeric excess ee of high chiral purity D-that step (3) obtains is 98.5～99.9%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58188853A (en) * | 1982-04-30 | 1983-11-04 | Ajinomoto Co Inc | Process for optical resolution of dl-cysteine hydrochloride |
| US4667054A (en) * | 1985-02-13 | 1987-05-19 | Nippon Kayaku Kabushiki Kaisha | Process for producing optically active valine |
| US6008403A (en) * | 1996-09-27 | 1999-12-28 | Tosoh Corporation | Method for producing optically active amino acid of derivative thereof having high optical purity |
| 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 |
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2011
- 2011-09-29 CN CN201110291773.6A patent/CN102432413B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58188853A (en) * | 1982-04-30 | 1983-11-04 | Ajinomoto Co Inc | Process for optical resolution of dl-cysteine hydrochloride |
| US4667054A (en) * | 1985-02-13 | 1987-05-19 | Nippon Kayaku Kabushiki Kaisha | Process for producing optically active valine |
| US6008403A (en) * | 1996-09-27 | 1999-12-28 | Tosoh Corporation | Method for producing optically active amino acid of derivative thereof having high optical purity |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 廖晓垣: "D-赖氨酸盐酸盐的研制", 《D-赖氨酸盐酸盐的研制》 * |
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Application publication date: 20120502 Assignee: Bafeng Pharmaceutical Co., Ltd., Hubei Prov. Assignor: Chongqing University of Posts and Telecommunications Contract record no.: 2015420000067 Denomination of invention: Purification method for improving chiral purity of D-amino acid Granted publication date: 20140219 License type: Exclusive License Record date: 20150504 |
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