CN1900053A - Process for preparing D-alpha-amino isovaleric acid - Google Patents
Process for preparing D-alpha-amino isovaleric acid Download PDFInfo
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- CN1900053A CN1900053A CN 200610041056 CN200610041056A CN1900053A CN 1900053 A CN1900053 A CN 1900053A CN 200610041056 CN200610041056 CN 200610041056 CN 200610041056 A CN200610041056 A CN 200610041056A CN 1900053 A CN1900053 A CN 1900053A
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- valine
- acetyl
- alpha
- alcohol
- isovaleric acid
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Abstract
The present invention is enzyme catalyzed process of preparing D-alpha-amino isovaleric acid, and aims at reducing environmental pollution and raising product purity. The enzyme catalyzed process of preparing D-alpha-amino isovaleric acid includes selective hydrolyzing N-acetyl-DL-alpha- amino isovaleric acid as material with amino acylatase as catalyst to obtain N-acetyl-L-alpha- amino isovaleric acid, separating L-alpha- amino isovaleric acid and N-acetyl-D-alpha-amino isovaleric acid in alcohol solvent, hydrolyzing with hydrochloric acid N- acetyl-D-alpha-amino isovaleric acid to obtain crude D-alpha-amino isovaleric acid product, and refining to obtain D-alpha-amino isovaleric acid. The L-alpha- amino isovaleric acid may be racemized to obtain N-acetyl-DL-alpha- amino isovaleric acid capable of being used as separating material for further use.
Description
Technical field
The present invention relates to the preparation method of in medicine, agricultural chemicals and fine chemical product chiral centre and biological polypeptide useful D-valine in synthetic.
Background technology
The D-valine is a kind of important organic chiral source, is mainly used in fields such as chiral drug, chiral additives, chiral auxiliary(reagent), at pharmaceutical industry as chirality synthetic chiral source.It is synthetic to carry out medicine and agricultural chemicals with the D-valine as chiral centre; and can in polypeptide is synthetic, connect other amino acid; guarantee that peptides has enough amino acid chain length, the D-valine is noticeable as chiral centre and the protectant future of amino acid.
The trade(brand)name of D-valine is: D-Xie Ansuan, chemical name are again: D-2-amino-3 Methylbutanoic acid, English by name: D-Valine, molecular formula is: C
5H
11NO
2
Preparation method as the D-valine, known have a chemical method for splitting, Benzoyl chloride and the reaction of D-tartrate generate D-2,3-dibenzoyl tartaric acid acid anhydride, hydrolysis obtains resolving agent D-2 in aqueous acetone solution, the 3-dibenzoyl tartaric acid, under the catalysis of aldehyde, the racemization of L-valine obtains the DL-valine, then in the presence of mineral acid with D-2, the reaction of 3-dibenzoyl tartaric acid generates non-corresponding body salt, is reduced to 15 ℃ in temperature, D-2, the salt that 3-dibenzoyl tartaric acid and D-valine form is precipitated out, with obtaining the D-valine after this salt of alkaline purification, yield 70%～80%, optical purity only 95%.
The D-valine is carried out medicine and agricultural chemicals when synthetic as chiral centre, requiring it is high purity, but, in the prior preparation method, because above-mentioned chemical split process chemistry resolving agent and solvent use, make and the refining complexity that becomes effectively to prepare highly purified D-valine.And, behind use resolving agent and the solvent, bring the environment protection treating problem among this preparation method, quite important in the actual mechanical process labour protection.
Summary of the invention
For solving above-mentioned environmental pollution, and the goods purity problem that is difficult to guarantee, the present invention will provide-kind prepare the method for D-valine with enzyme technology.
For achieving the above object, the concrete technical scheme of the present invention's employing is: the preparation method of described D-valine may further comprise the steps:
(1) split: with N-acetyl-DL-valine is raw material, and in N-acetyl-DL-valine: the weight ratio of water is that 1: 10～1: 14 ratio is mixed with solution, temperature of reaction is controlled at 30 ℃～40 ℃, add L-Aminoacylase as catalyzer, carry out enzymic catalytic reaction;
(2) concentrate: split the liquid reduced vacuum completely through enzymic catalytic reaction and concentrate above-mentioned, when crystallization is separated out, be cooled to 30 ℃ ± 5 ℃, separate out the crystallization of L-valine with alcohol as solvent, the mother liquor recovery;
(3) hydrolysis: the alcohol that above-mentioned alcohol is analysed in the mother liquor evaporates, after freezing, obtain N-acetyl-D-valine again, again with concentration be the hydrochloric acid of 3.0～4.0mol/L as the solvent reaction that is hydrolyzed, and the concentration of N-acetyl-D-valine is 10%～15% in the control material; After reacting completely, remove hydrochloric acid, place crystallisation by cooling and obtain the crystallization of D-valine crude product;
(4) refining: as to use recrystallization method, it is 8%～12% the aqueous solution that above-mentioned D-valine crude product is mixed with concentration, and behind activated carbon decolorizing, vacuum concentration liquid reaches hypersaturated state, crystallisation by cooling obtains D-valine highly finished product again.
The adding weight of L-Aminoacylase is 1 ‰～3 ‰ of the described aqueous solution weight that is mixed with in the above-mentioned steps (); The time of enzymic catalytic reaction was controlled at 30～36 hours.
Alcohol described in the above-mentioned steps (two) is methyl alcohol or ethanol; Vacuum degree control-0.085Mpa～-0.1Mpa.
In step (three), the alcohol that evaporates is reclaimed; Freezing temp is controlled at 0 ℃～-10 ℃; When removing hydrochloric acid, adjusting pH value with alkali lye is between 5.5～7.0.
In addition, also the L-valine crystallization that obtains in the step (two) can be mixed with concentration and be 3%～8% the aqueous solution, holding temperature is 35 ℃～45 ℃, constantly use the aceticanhydride racemization, make the solution specific optical rotation transfer to 0 ± 1 degree, freezing and crystallizing gets N-acetyl-DL-valine, can be used as the raw material in the step ().
The present invention utilizes biotechnology high efficiency and specificity, to N-acetyl-DL-valine hydrolyzing N-acetyl-L-valine optionally, reaction needed is kept certain temperature, and needs just can finish through the long period, and transformation efficiency is almost 100%.In preparation method of the present invention; to producing the L-valine, to realize separating fully with N-acetyl-D-valine dissolubility difference in alcohol according to it, alcohol can be common solvent such as methyl alcohol, ethanol; can select methyl alcohol from economic angle; low price, it is little to influence cost factor, but from the labour protection angle; ethanol is less to the human injury; alcohol is only made solvent and is used in the preparation process, and the usage quantity of alcohol is not particularly limited, and can use repeatedly after reclaiming.Relatively with mixture, as long as alcohol can thoroughly separate this two kinds of compounds, in order to guarantee the centrifugation of alcohol, must not have water treatment before alcohol is analysed, reason is that these two kinds of compounds all to a certain degree dissolve in water.
As the starting raw material acetyl-DL-valine that uses among the present invention; both can be from market purchasing; also can utilize by product L-valine to form through the aceticanhydride racemization; therefore the processing of by product is more convenient; and the initial L-valine that uses fermentative production that extends to of raw material; this reaction belongs to typical acylation reaction, considers from the viewpoints such as control complexity of reaction conditionss such as operability, temperature of reaction, and reaction is than being easier to control.
Advantage of the present invention is: the present invention has efficiently, cheap, public hazards are few, cost is low advantage, the resolving agent and the solvent problem of chemical method for splitting have been avoided, and utilize the single-minded selectivity of biological enzyme, solved the optical purity difficult problem in the D-valine production process, its suitability for industrialized production optical purity can be reached more than 99.0%.
Embodiment
The invention will be further described below by specific embodiment, but the present invention not should be these embodiment and any restriction is arranged.
Embodiment 1
Batching: in flask by weight N-acetyl-DL-valine: the ratio preparation of water=1: 12 splits substrate solution 240ml.
Split: temperature of reaction is maintained 30 ℃; add L-Aminoacylase then as catalyzer; adding weight is 2 ‰ of above-mentioned fractionation substrate weight; time of enzymatic reacting 30 hours; the mode that reaction solution is analysed with ply of paper detects the wherein content of L-valine; and the calculating hydrolysis conversion, result almost 100% ground is generated as the L-valine with N-acetyl-L-valine hydrolysis.
Concentrate: will split the liquid reduced vacuum completely through enzymic catalytic reaction and concentrate, vacuum tightness is-0.095MPa.When crystallization is separated out, be cooled to about 30 ℃, separate out the crystallization of L-valine with methyl alcohol, mother liquor reclaims.
Hydrolysis: the alcohol evaporation that alcohol is analysed in the mother liquor is reclaimed, after freezing, obtain the wet product 12g of N-acetyl-D-valine again, freezing temp is controlled at about-6 ℃, use 3.0～3.5mol/L hydrochloric acid 120ml hydrolysis again, after reacting completely, remove hydrochloric acid repeatedly, transferring pH value with alkali lye is 6.0, places crystallisation by cooling and obtains D-valine crude product crystallization 8.3g.
Refining: the concentration preparation D-valine crude product solution by 10%, reach hypersaturated state through activated carbon decolorizing final vacuum concentrated liquid, crystallisation by cooling obtains D-valine highly finished product again, and oven dry obtains finished product D-valine 6.9g.
The racemization of L-valine is handled
The L-valine solution of preparation 5%, 40 ℃ of holding temperatures are constantly used the aceticanhydride racemization, make the solution specific optical rotation transfer to 0 ± 1 degree, and freezing and crystallizing gets N-acetyl-DL-valine, can be used as the fractionation raw material and continues to use.
Embodiment 2-4
Except that it is as shown in the table temperature, time of enzymatic reaction change, other is operated similarly to Example 1, the gained result is as shown in table 1.In addition, the transformation efficiency in the table is meant that the mode of analysing by ply of paper calculates, and expression N-acetyl-L-valine is converted into the ratio of L-valine.Yield is that D-valine finished product calculates with respect to the theoretical product of N-acetyl-DL-valine, and optical purity is the purity that detects with chiral column according to high performance liquid chromatograph (HPLC).
Table 1
| Embodiment | Enzymatic temperature ℃ | Enzymatic time hr | Transformation efficiency % | Yield % | Optical purity % |
| 1 | 30 | 30 | 99.5 | 94 | 99.2 |
| 2 | 33 | 32 | 99.3 | 91 | 99.1 |
| 3 | 36 | 34 | 99.8 | 96 | 99.3 |
| 4 | 40 | 36 | 99.6 | 92 | 99.0 |
Claims (5)
1, the preparation method of D-valine is characterized in that: may further comprise the steps:
(1) split: with N-acetyl-DL-valine is raw material, and in N-acetyl-DL-valine: the weight ratio of water is that 1: 10～1: 14 ratio is mixed with solution, temperature of reaction is controlled at 30 ℃～40 ℃, add L-Aminoacylase as catalyzer, carry out enzymic catalytic reaction;
(2) concentrate: split the liquid reduced vacuum completely through enzymic catalytic reaction and concentrate above-mentioned, when crystallization is separated out, be cooled to 30 ℃ ± 5 ℃, separate out the crystallization of L-valine with alcohol as solvent, the mother liquor recovery;
(3) hydrolysis: the alcohol that above-mentioned alcohol is analysed in the mother liquor evaporates, after freezing, obtain N-acetyl-D-valine again, again with concentration be the hydrochloric acid of 3.0～4.0mol/L as the solvent reaction that is hydrolyzed, and the concentration of N-acetyl-D-valine is 10%～15% in the control material; After reacting completely, remove hydrochloric acid, place crystallisation by cooling and obtain the crystallization of D-valine crude product;
(4) refining: as to use recrystallization method, it is 8%～12% the aqueous solution that above-mentioned D-valine crude product is mixed with concentration, and behind activated carbon decolorizing, vacuum concentration liquid reaches hypersaturated state, crystallisation by cooling obtains D-valine highly finished product again.
2, the preparation method of D-valine as claimed in claim 1 is characterized in that: the adding weight of L-Aminoacylase is 1 ‰～3 ‰ of the described aqueous solution weight that is mixed with in the step (); The time of enzymic catalytic reaction was controlled at 30～36 hours.
3, the preparation method of D-valine as claimed in claim 1 or 2 is characterized in that: the alcohol described in the step (two) is methyl alcohol or ethanol; Vacuum degree control-0.085Mpa～-0.1Mpa.
4, the preparation method of D-valine as claimed in claim 1 or 2 is characterized in that: in step (three), the alcohol that evaporates is reclaimed; Freezing temp is controlled at 0 ℃～-10 ℃; When removing hydrochloric acid, adjusting pH value with alkali lye is between 5.5～7.0.
5, the preparation method of D-valine as claimed in claim 1 or 2, it is characterized in that: it is 3%～8% the aqueous solution that the L-valine crystallization that obtains in the step (two) is mixed with concentration, holding temperature is 35 ℃～45 ℃, constantly use the aceticanhydride racemization, make the solution specific optical rotation transfer to 0 ± 1 degree, freezing and crystallizing gets N-acetyl-DL-valine, can be used as the raw material in the step ().
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610041056 CN1900053A (en) | 2006-07-21 | 2006-07-21 | Process for preparing D-alpha-amino isovaleric acid |
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|---|---|---|---|
| CN 200610041056 CN1900053A (en) | 2006-07-21 | 2006-07-21 | Process for preparing D-alpha-amino isovaleric acid |
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| CN 200610041056 Pending CN1900053A (en) | 2006-07-21 | 2006-07-21 | Process for preparing D-alpha-amino isovaleric acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671704B (en) * | 2009-09-25 | 2011-12-21 | 王小松 | Method for preparing L-selenomethionine by using enzyme separation method |
| CN104496806A (en) * | 2014-12-30 | 2015-04-08 | 濮阳天健生物科技有限公司 | Synthetic method of L-dibenzoyl tartaric acid |
| CN107488128A (en) * | 2016-06-13 | 2017-12-19 | 黄冈威尔曼生物科技有限责任公司 | It is a kind of that the method that D valines are extracted in mother liquor is split from DL valines |
-
2006
- 2006-07-21 CN CN 200610041056 patent/CN1900053A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671704B (en) * | 2009-09-25 | 2011-12-21 | 王小松 | Method for preparing L-selenomethionine by using enzyme separation method |
| CN104496806A (en) * | 2014-12-30 | 2015-04-08 | 濮阳天健生物科技有限公司 | Synthetic method of L-dibenzoyl tartaric acid |
| CN107488128A (en) * | 2016-06-13 | 2017-12-19 | 黄冈威尔曼生物科技有限责任公司 | It is a kind of that the method that D valines are extracted in mother liquor is split from DL valines |
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