CN102352388B - Chemical enzyme method for preparing L-2-amino adipic acid - Google Patents
Chemical enzyme method for preparing L-2-amino adipic acid Download PDFInfo
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- CN102352388B CN102352388B CN201110297373.6A CN201110297373A CN102352388B CN 102352388 B CN102352388 B CN 102352388B CN 201110297373 A CN201110297373 A CN 201110297373A CN 102352388 B CN102352388 B CN 102352388B
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Abstract
The invention provides a chemical enzyme method for preparing L-2-amino adipic acid, which is characterized in that D-2-amino adipic acid is used as a raw material and is derived into D-N-phenylacetyl-2-amino adipic acid by using acylating agents; and then, DL-N-phenylacetyl-2-amino adipic acid is obtained through the congruent melting and racemization with aromatic acid. The DL-N-phenylacetyl-2-amino adipic acid is correspondingly and selectively hydrolyzed into L-2-amino adipic acid, phenylacetic acid and D-N-phenylacetyl-2-amino adipic acid in a water medium under the biological catalysis effect of immobilized penicillin acylase, and the L-2-amino adipic acid with high optical purity is further separated. The technical effect of the method is not in doubt, and the D-N-phenylacetyl-2-amino adipic acid is used for the cyclic dismounting after the congruent melting and racemization with the phenylacetic acid, and the yield and the optical purity of products of the L-2-amino adipic acid are high. The technical flow process of the method has the advantages that the environment-friendly effect is realized, and the method is suitable for being used for the scale production of the L-2-amino adipic acid.
Description
Technical field
The present invention relates to use the method for enzyme to prepare the optically active isomer, particularly a kind of chemo-enzymatic process of preparing L-2-aminoadipic acid of compound.
Background technology
The preparation method of L-2-aminoadipic acid mainly contains:
1) chemical synthesis.Szirtes etc. (J. Med. Chem., 1986,29,1654.) have proposed one and take the method for 1B as the synthetic L-2-aminoadipic acid of chirality.First 1B is converted into H-Lys(Z)-OH, under acidic conditions, with KMnO4, be oxidized to L-2-amino-5[(carbobenzoxy-(Cbz)) carbamyl] valeric acid, then acidolysis is L-2-aminoadipic acid, total recovery 33%.
Kondo etc. (Bull. Chem. Soc. Jpn., 1985,58,1171) have proposed one and have improved one's methods.L-N-acetyl-ethyl ester of lysine is under the effect of tertiary butyloxycarbonyl acyl chlorides, and the two chlorinations of epsilon-amino are then converted into itrile group under pyridine effect, and itrile group is hydrolyzed to carboxyl under acidic conditions, total recovery 60%.
2) biological process.The U.S. aromatic Co., Ltd. of Japan has proposed one and take the preparation (EP0819761) for L-2-aminoadipic acid of microbial method that 1B is raw material.Under Methionin-6-transaminase effect in Flavobacterium sp., 1B is converted into L-2-aminoadipic acid.
Mochizuki etc. (Agric. Biol. Chem., 1988,52 (5), 1113) have reported a method of simultaneously preparing L-2-aminoadipic acid and D-piperidines-2-carboxylic acid.DL-piperidines-2-carboxylic acid is under Alcaligenes sp. 309B1 effect, and L-enantiomorph assimilates into L-aminoadipic acid, yield 56%, and 95%D-piperidines-2-carboxylic acid retains.
Summary of the invention
The chemo-enzymatic process that the object of this invention is to provide a kind of L-2-of preparation aminoadipic acid, comprises the following steps:
1). acidylate: under-10～10 ℃, the condition of pH8～10, D-2-aminoadipic acid reacts 1:1～3 in molar ratio with phenyllacetyl chloride, stirs after 6～24h, filters, and obtains solid D-N-phenylacetyl-AAA;
2). racemization: the prepared D-N-phenylacetyl-AAA of step 1) and aromatic acid are pressed after the mixed in molar ratio of 1:1, heat to 150～200 ℃ of congruent meltings, after 10-60min, the racemization of D-N-phenylacetyl-AAA obtains DL-N-phenylacetyl-AAA;
3). hydrolysis: under 20～40 ℃, the condition of pH8～10, step 2) gained DL-N-phenylacetyl-AAA is under the katalysis of immobilized penicillin acylated enzyme (IPGA), be hydrolyzed after reaction, filtration, to remove immobilized penicillin acylated enzyme (IPGA), obtains the mixture of L-2-aminoadipic acid, toluylic acid, D-N-phenylacetyl-AAA;
4). purifying: in the mixture described in step 3), add concentrated hydrochloric acid adjust pH to 1～2, separated to separate out toluylic acid and D-N-phenylacetyl-AAA, obtain pure L-2-aminoadipic acid.
Above-mentioned steps 1) in, before D-2-aminoadipic acid reacts with phenyllacetyl chloride, first in D-2-aminoadipic acid solution, add sodium hydroxide, regulate pH value to 8～10, then add gradually phenyllacetyl chloride.
In step 1), before filtering, with hydrochloric acid adjust pH to 1～2.
Step 2) described aromatic acid is phenylformic acid, toluylic acid, phenylpropionic acid or benzenebutanoic acid.
Step 2) mixture obtaining after eutectic racemization, with hot hexanaphthene extraction, to remove aromatic acid.
After step 4) purifying, gained filtrate is concentrated, adjust iso-electric point to separate out L-2-aminoadipic acid.
In step 4), separate out to remove the liquid after toluylic acid and D-N-phenylacetyl-AAA, concentrating under reduced pressure at 60 ℃, adjust pH to 3.2, the freezing L-2-aminoadipic acid solid of separating out at 5 ℃, then by gained solid absolute ethanol washing, dry, obtain pure L-2-aminoadipic acid.
The toluylic acid that step 4) is separated out is as step 2) aromatic acid used to be to recycle.
D-N-phenylacetyl-AAA that step 4) is separated out is as step 2) D-N-phenylacetyl-AAA used to be to recycle.
Method provided by the present invention is owing to having above-mentioned steps, and its advantage is:
1) take cheap Cephalosporin C fermentation by product D-2-aminoadipic acid prepares L-2-aminoadipic acid as raw material, efficiently solves raw material sources.
2) enantioselectivity of immobilized penicillin acylated enzyme height, has guaranteed the high optical activity of L-2-aminoadipic acid.
3) using the toluylic acid that produces in enzyme reaction process as the organic acid of D-N-phenylacetyl-AAA racemization, not only effectively utilized byproduct of reaction, and the racemization time is short, racemization rate and racemization yield are high.
4) the circulation fractionation of invalid enantiomorph and recycling of immobilized penicillin acylated enzyme, greatly reduce process cost.
Accompanying drawing explanation
The indefiniteness embodiment that method of the present invention can provide by accompanying drawing further illustrates.
Fig. 1 is process route chart of the present invention.
Embodiment
Below in conjunction with drawings and Examples, the invention will be further described, but should not be construed the above-mentioned subject area of the present invention, only limits to following embodiment.Without departing from the idea case in the present invention described above, according to ordinary skill knowledge and customary means, make various replacements and change, all should be included in the scope of the present invention.
Referring to accompanying drawing: a kind of chemo-enzymatic process of preparing L-2-aminoadipic acid, is characterized in that: comprise the following steps:
1). acidylate: under-10～10 ℃, the condition of pH8～10, D-2-aminoadipic acid reacts 1:1～3 in molar ratio with phenyllacetyl chloride, stirs after 6～24h, filters, and obtains solid D-N-phenylacetyl-AAA;
2). racemization: the prepared D-N-phenylacetyl-AAA of step 1) and aromatic acid are pressed after the mixed in molar ratio of 1:1, heat to 150～200 ℃ of congruent meltings, after 10-60min, the racemization of D-N-phenylacetyl-AAA obtains DL-N-phenylacetyl-AAA;
3). hydrolysis: under 20～40 ℃, the condition of pH8～10, step 2) gained DL-N-phenylacetyl-AAA is under the katalysis of immobilized penicillin acylated enzyme (IPGA), be hydrolyzed after reaction, filtration, to remove immobilized penicillin acylated enzyme (IPGA), obtains the mixture of L-2-aminoadipic acid, toluylic acid, D-N-phenylacetyl-AAA;
4). purifying: in the mixture described in step 3), add concentrated hydrochloric acid adjust pH to 1～2, separated to separate out toluylic acid and D-N-phenylacetyl-AAA, obtain pure L-2-aminoadipic acid.
In an embodiment, better implementation is in step 1), before D-2-aminoadipic acid reacts with phenyllacetyl chloride, first in D-2-aminoadipic acid solution, adds sodium hydroxide, regulates pH value to 8～10, then adds gradually phenyllacetyl chloride.
Further, in step 1), before filtering, with hydrochloric acid adjust pH to 1～2.
Of the present invention when implementing, step 2) described aromatic acid is phenylformic acid, toluylic acid, phenylpropionic acid or benzenebutanoic acid.
For step 3) obtains pure reactant, in embodiment, step 2) mixture obtaining after eutectic racemization, with hot hexanaphthene extraction, to remove aromatic acid.
Better mode is, after step 4) purifying, gained filtrate is concentrated, adjusts iso-electric point to separate out L-2-aminoadipic acid.
For realizing recycling economy, the toluylic acid that step 4) is separated out is as step 2) aromatic acid used to be to recycle.
In like manner, D-N-phenylacetyl-AAA that step 4) is separated out is as step 2) D-N-phenylacetyl-AAA used to be to recycle.
Can also be, in step 4), separate out to remove the liquid after toluylic acid and D-N-phenylacetyl-AAA, concentrating under reduced pressure at 60 ℃, adjust pH to 3.2, the freezing L-2-aminoadipic acid solid of separating out at 5 ℃, then by gained solid absolute ethanol washing, dry, obtain pure L-2-aminoadipic acid.
embodiment:
1) by the D-2-aminoadipic acid raw material 80.5g and the 50g NaOH(1.25mol that contain 0.5mol) add in 800ml water stirring and dissolving.Under condition of ice bath, drip the raw material 73.3ml that contains 0.55mol phenyllacetyl chloride.After dropwising, under room temperature, react.With concentrated hydrochloric acid, adjust pH1～2, under stirring, separate out D-N-phenylacetyl-AAA solid.Suction filtration, dries to obtain D-N-phenylacetyl-AAA 125.5g, yield 90%.
2) get the prepared D-N-phenylacetyl-AAA of above-mentioned steps solid 111.6g, wherein, the D-N-phenylacetyl-AAA that contains 0.4mol.It is mixed with the raw material that 54.4g contains toluylic acid 0.4mol, and oil bath is heated to 170 ℃, insulation 20min, and sampling is dissolved in methyl alcohol, and surveying specific rotation is 0, racemization rate 100%.Congruent melting racemic mixture is removed toluylic acid with hot hexanaphthene extraction 3 times (200ml * 3), and solid is dried to obtain DL-N-phenylacetyl-AAA 106g, racemization yield 95%.
3) product 83.7g above-mentioned steps is prepared, DL-N-phenylacetyl-AAA of containing 0.3mol adds in 600ml water, with ammoniacal liquor, adjusts pH8.0.Add 16.7g immobilized penicillin acylated enzyme, stirring reaction 24h at 30 ℃.Suction filtration, removes immobilized penicillin acylated enzyme.Filtrate is adjusted pH1～2 with concentrated hydrochloric acid, suction filtration, and solid hot wash, dries to obtain D-N-phenylacetyl-AAA 37.7g, yield 45%.Concentrating under reduced pressure at 60 ℃ of filtrates, adjusts pH to 3.2, the freezing solid of separating out at 5 ℃.Solid absolute ethanol washing, dries, and obtains 21.7g L-2-aminoadipic acid, and yield 90% adopts HPLC to record ee99.5%.
Claims (3)
1. a chemo-enzymatic process of preparing L-2-aminoadipic acid, is characterized in that:
Comprise the following steps:
1) acidylate: under-10～10 ℃, the condition of pH8～10, D-2-aminoadipic acid reacts 1:1～3 in molar ratio with phenyllacetyl chloride, stirs after 6～24h, filters, and obtains solid D-N-phenylacetyl-AAA; Before D-2-aminoadipic acid reacts with phenyllacetyl chloride, first in D-2-aminoadipic acid solution, add sodium hydroxide, regulate pH value to 8～10, then add gradually phenyllacetyl chloride; Before filtering, with hydrochloric acid adjust pH to 1～2;
2) racemization: the prepared D-N-phenylacetyl-AAA of step 1) and aromatic acid are pressed after the mixed in molar ratio of 1:1, heat to 150～200 ℃ of congruent meltings, after 10-60min, the racemization of D-N-phenylacetyl-AAA obtains DL-N-phenylacetyl-AAA; The mixture obtaining after eutectic racemization, with hot hexanaphthene extraction, to remove aromatic acid; Described aromatic acid is phenylformic acid, toluylic acid, phenylpropionic acid or benzenebutanoic acid;
3) hydrolysis: under 20～40 ℃, the condition of pH8～10, step 2) gained DL-N-phenylacetyl-AAA is under the katalysis of immobilized penicillin acylated enzyme IPGA, reaction is hydrolyzed, afterwards, filtration, to remove immobilized penicillin acylated enzyme IPGA, obtains the mixture of L-2-aminoadipic acid, toluylic acid, D-N-phenylacetyl-AAA;
4) purifying: in the mixture described in step 3), add concentrated hydrochloric acid adjust pH to 1～2, separated to separate out toluylic acid and D-N-phenylacetyl-AAA; Separate out to remove the liquid after toluylic acid and D-N-phenylacetyl-AAA, concentrating under reduced pressure at 60 ℃, adjusts pH to 3.2, the freezing L-2-aminoadipic acid solid of separating out at 5 ℃, by gained solid absolute ethanol washing, dry again, obtain pure L-2-aminoadipic acid.
2. a kind of chemo-enzymatic process of preparing L-2-aminoadipic acid according to claim 1, is characterized in that: the toluylic acid that step 4) is separated out is as step 2) aromatic acid used to be to recycle.
3. a kind of chemo-enzymatic process of preparing L-2-aminoadipic acid according to claim 1, is characterized in that: D-N-phenylacetyl-AAA that step 4) is separated out is as step 2) D-N-phenylacetyl-AAA used to be to recycle.
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Citations (2)
| 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 |
| 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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| 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 |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| 酶法拆分D,L-苯丙氨酸制备D-苯丙氨酸;黄冠华等;《合成化学》;20071231;第15卷(第1期);69-72 * |
| 黄冠华等.酶法拆分D L-苯丙氨酸制备D-苯丙氨酸.《合成化学》.2007 |
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