CN102250976A - Synthesis method of chiral tert-leucine and final product obtained in method - Google Patents
Synthesis method of chiral tert-leucine and final product obtained in method Download PDFInfo
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- CN102250976A CN102250976A CN2011101162531A CN201110116253A CN102250976A CN 102250976 A CN102250976 A CN 102250976A CN 2011101162531 A CN2011101162531 A CN 2011101162531A CN 201110116253 A CN201110116253 A CN 201110116253A CN 102250976 A CN102250976 A CN 102250976A
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Abstract
The invention provides a synthesis method of chiral tert-leucine, and the synthesis method is characterized by comprising the following steps: adding raw materials and water to a reaction kettle; adding ammonium formate solid and adding a pH regulator to regulate the pH value after completely dissolving; then sequentially adding an ammonium formate buffer of catalyst oxidized coenzyme, a buffer solution of formic dehydrogenase and a buffer solution of chiral leucine dehydrogenase; stirring to start reaction while controlling the reaction temperature at 10-40 DEG C and the pH value of the reaction system at 6.0-10.0; and after the reaction is finished, acquiring a final product, namely deuterated chiral tertleucine. The synthesis method provided by the invention has the advantages that: the used raw materials are easily available and inexpensive; the used raw materials are commercial raw materials or easily prepared raw materials, and can meet the needs of large-scale production; and the product is obtained by one-step reaction, water is used as the solvent, enzyme protein is used as the catalyst, and the product has a yield more than 80% and both chemical purity and chiral purity greater than 99%.
Description
(1) technical field:
The present invention relates to the synthetic method and the product thereof of compound, especially a kind of synthetic method of chirality Terleu and final product thereof.
(2) background technology:
Amino acid and as important compound and organic drug intermediate is widely used in aspects such as medicine, food, feed, makeup, agricultural and chemical industry.In the generation and evolutionary process of life, caused biological intravital protein, nucleic acid, enzyme and cell surface receptor have specific chiral structure, therefore organism has different physiology and chemical reaction to the three-dimensional chiral molecules of difference, thereby causes the different chiral molecules of optical activity to have different pharmacology and toxicological effect.
Terleu is a kind of chiral amino acid of non-protein source, because the special construction and the character of the tertiary butyl are the important medicine intermediate and the chiral induction template and the catalyzer of asymmetric synthesis.The L-Terleu both can be used as nutrition-fortifying agent, animal additive agent for feeding, also can be used for synthetic drugs.
Along with the increase in demand of chipal compounds, chiral drug and intermediates preparation have also had very great development, and the method that present stage prepares this compounds generally is divided into four big classes, mainly contains:
(1) fractionation of DL body, the characteristics of this method are that technology is simple, adapt to large-scale industrial production, but shortcoming is the control of operation difficulty, needs the unwanted enantiomorph of purified product and racemization, it is lower to split efficient, and its prerequisite that can split with this method is that the DL body must be left-handed and mixed crystal dextrorotatory form, the resolving agent costliness, and the investment recovery time is longer, and resolving agent and choice of Solvent comparison blindly mainly be intuitively and experience, do not have rule to seek;
(2) chiral source is synthetic, this method be the most traditional also be the synthetic method of the most frequently used chipal compounds; Be divided into two kinds, a kind of is the chiral centre that directly utilizes chiral source, and chirality source compound is as the synthetic new chipal compounds of reactant, and another kind is that chirality source compound is induced as appurtenant and produced into the synthetic new compound of new chiral centre; But this product is only to be used for synthesizing chiral compound as chiral substrates and appurtenant;
(3) chemical catalysis comprises the chemical catalysis asymmetric synthesis, the kinetic resolution of chemical catalysis and the Dynamic Kinetic Resolution of chemical catalysis; Theoretically, adopting chemical catalysis, is the most economical route that is converted into chiral compound with high optical purity that makes dive chipal compounds or DL height yield; But also exist at present many problems as: need the special substrate of preparation, chiral catalyst is somewhat expensive, and the operation operation stability is relatively poor sometimes etc. during amplification;
(4) biological catalysis comprises fermentation method, enzyme catalysis asymmetric synthesis, enzymatic kinetic resolution and enzymatic Dynamic Kinetic Resolution; Along with development of biology, the performance of enzyme catalyst has had large increase in recent years, and the price of enzyme also has substantial degradation simultaneously; The characteristics of enzymic catalytic reaction are that the reaction stereoselectivity is strong, and reaction conditions gentleness, major part are to carry out at water, are a kind of asymmetric synthesis technology of green, and along with the enhancing of people's environmental consciousness, the enzyme catalysis synthesizing chiral compound more and more is subjected to people and payes attention to.
Therefore, be to solve a difficult problem that exists in the prior art, the practicable synthetic route that provides one to carry out large-scale production is provided technical problem to be solved by this invention.
(3) summary of the invention:
The object of the present invention is to provide a kind of synthetic method of chirality Terleu, this method obtains product by single step reaction, and yield is greater than 80%, and chemical purity and chiral purity are all greater than 99%; Starting raw material is synthetic by the commercialization raw material, adopts water to make solvent, and zymoprotein carries out catalysis, and raw material is easy to get, the purity and the yield of reaction are higher, and processing condition are gentle stable, operate fairly simple, the generation three wastes are few, and are very friendly to environment, are highly suitable for large-scale production; Another technology to be solved by this invention is to provide the final product deuterium of above-mentioned synthetic method for the chirality Terleu.
Technical scheme of the present invention: a kind of synthetic method of chirality Terleu is characterized in that it may further comprise the steps:
(1) in reactor, adds raw material
And water, water consumption is every gram raw material
2～8mL;
(2) add the ammonium formiate solid, all after the dissolving, add the pH regulator agent and regulate pH to 6.5～8.5; Raw material
With the ammonium formiate mass ratio be 1: 1.5～3.0;
(3) accent is finished, and adds the ammonium formiate damping fluid of catalyst oxidation type coenzyme, the buffered soln and the chirality leucine dehydrogenase buffered soln of hydrogenlyase successively; Wherein, raw material
With the quality amount ratio of oxidized coenzyme be 1: (0.010 ± 0.003), raw material
With the quality amount ratio of hydrogenlyase be 1: (0.002 ± 0.0004), raw material
With the quality amount ratio of chirality leucine dehydrogenase be 1: (0.0009 ± 0.0003);
(4) stir, begin reaction, control reaction temperature is 10～40 ℃, and the pH of reaction system is 6.0～10.0;
(5) reaction finishes, and a step generates product
Above-mentioned described product
The ammonia chiral centre is S or R configuration, promptly
Or
Above-mentioned described raw material
Middle R
1For-CD
3Described product
Middle R
1For-CD
3, promptly
The ammonia chiral centre is S or R configuration.
Above-mentioned described product is that deuterium is for the chirality Terleu
1H-NMR:3.4ppm, s, 1H;
2D-NMR:1.0ppm, s, 9D.
Above-mentioned described raw material
Middle R
1For-CH
3Described product
Middle R
1For-CH
3, the ammonia chiral centre is S or R configuration.
Water consumption is every gram raw material in the above-mentioned described step (1)
3～5mL; The pH regulator agent is 10%～28% ammonia soln, 0.05M～0.5M Sodium phosphate dibasic/phosphate sodium dihydrogen buffer solution or 0.05M～0.5M dipotassium hydrogen phosphate/potassium phosphate buffer in the described step (2), raw material
With the ammonium formiate mass ratio be 1: 1.5～3.0; Raw material in the described step (3)
With the quality amount ratio of oxidized coenzyme be 1: (0.010 ± 0.002), raw material
With the quality amount ratio of hydrogenlyase be 1: (0.002 ± 0.0003), raw material
With the quality amount ratio of chirality leucine dehydrogenase be 1: (0.0009 ± 0.0002); Temperature of reaction is 20～38 ℃ in the described step (4); The pH of reaction system is 6.0～9.0.
Water consumption is every gram raw material in the above-mentioned described step (1)
2.5～5.0mL; The pH regulator agent is 10%～28% ammonia soln or 0.05M～0.5M dipotassium hydrogen phosphate/potassium phosphate buffer in the described step (2), raw material
With the ammonium formiate mass ratio be 1: 1.5～3.0; Raw material in the described step (3)
With the quality amount ratio of oxidized coenzyme be 1: (0.010 ± 0.001), raw material
With the quality amount ratio of hydrogenlyase be 1: (0.002 ± 0.0002), raw material
With the quality amount ratio of chirality leucine dehydrogenase be 1: (0.0009 ± 0.0001); Temperature of reaction is 25～35 ℃ in the described step (4); The pH of reaction system is 7.0～8.5.
Above-mentioned described chirality leucine dehydrogenase is L-leucine dehydrogenase or D-leucine dehydrogenase.
Above-mentioned described pH regulator agent is 10%～28% ammonia soln, 0.05M～0.5M Sodium phosphate dibasic/phosphate sodium dihydrogen buffer solution or 0.05M～0.5M dipotassium hydrogen phosphate/potassium phosphate buffer.
A kind of final product of synthetic method of chirality Terleu is characterized in that it is that deuterium is for the chirality Terleu, promptly
The ammonia chiral centre is S or R configuration.
Above-mentioned described deuterium for the chirality Terleu is
1H-NMR:3.4ppm, s, 1H;
2D-NMR:1.0ppm, s, 9D.
Superiority of the present invention: 1, the raw material of the present invention's employing all is easy to get, and low price; The raw materials used raw material that is business-like raw material or easily prepares can satisfy needs of scale production; 2, this method obtains product by single step reaction, adopts water to make solvent, and zymoprotein carries out catalysis, and yield is greater than 80%, and chemical purity and chiral purity are all greater than 99%; 3, chemical reaction condition gentleness of the present invention, stable process conditions is operated fairly simplely, and it is few to produce the three wastes, very friendly to environment, is highly suitable for large-scale production.
(4) description of drawings:
Accompanying drawing is related synthetic for the present invention
The chemical reaction process of (the ammonia chiral centre is S or R).
(5) embodiment:
Embodiment 1:
Prepare deuterium for the L-Terleu,
In the 200L reactor, add 20kg raw material deuterium for the trimethylammonium pyruvic acid
Pure water 60L adds 36kg ammonium formiate solid, all after the dissolving, regulates pH to 6.5～8.5 with saturated ammoniacal liquor.Transfer and finish, the buffered soln and the 18g L-leucine dehydrogenase buffered soln of hydrogenlyase that adds ammonium formiate damping fluid, the 40g of catalyzer 200g oxidized coenzyme successively, stir 0.5h, system is warming up to 20 ± 2 ℃, and temperature control begins reaction, 2D-NMR tracks to reaction to be finished, cooling, concentrate system, centrifugal oven dry, obtain the product deuterium for the L-Terleu
17.6kg, yield 87%, HPLC:＞99%, ee
1H-NMR:3.4ppm, s, 1H;
2D-NMR:1.0ppm, s, 9D;
Embodiment 2:
Preparation L-Terleu,
In the 200L reactor, add 15kg raw material trimethylammonium pyruvic acid
Pure water 75L adds 37.5kg ammonium formiate solid, all after the dissolving, regulates pH to 6.5～8.5 with 0.1M Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC.Transfer and finish, the buffered soln and the 10.5g L-leucine dehydrogenase buffered soln of hydrogenlyase that adds ammonium formiate damping fluid, the 25.5g of catalyzer 120g oxidized coenzyme successively, stir 0.5h, system is warming up to 38 ± 2 ℃, and temperature control begins reaction, 2D-NMR tracks to reaction to be finished, cooling, concentrate system, centrifugal oven dry, obtain product preparation L-Terleu
13.6kg, yield 90%, HPLC:＞99%, ee
(
1H-NMR：3.4ppm，s，1H，1.0ppm，s，9H；)
Embodiment 3:
Prepare deuterium for the D-Terleu,
In the 200L reactor, add 15kg raw material deuterium for the trimethylammonium pyruvic acid
Pure water 60L adds 30kg ammonium formiate solid, all after the dissolving, regulates pH to 6.5～8.5 with 0.2M dipotassium hydrogen phosphate/potassium primary phosphate.Transfer and finish, the buffered soln and the 16.5g D-leucine dehydrogenase buffered soln of hydrogenlyase that adds ammonium formiate damping fluid, the 34.5g of catalyzer 180g oxidized coenzyme successively, stir 0.5h, system is warming up to 20 ± 2 ℃, and temperature control begins reaction, 2D-NMR tracks to reaction to be finished, cooling, concentrate system, centrifugal oven dry, obtain the product deuterium for the D-Terleu
13.4kg, yield 89%, HPLC:＞99%, ee
1H-NMR:3.4ppm, s, 1H;
2D-NMR:1.0ppm, s, 9D;
Embodiment 4
Preparation D-Terleu,
In the 200L reactor, add 15kg raw material trimethylammonium pyruvic acid
Pure water 52.5L adds 16.5kg ammonium formiate solid, all after the dissolving, regulates pH to 6.5～8.5 with 0.1M Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC.Transfer and finish, the buffered soln and the 15g D-leucine dehydrogenase buffered soln of hydrogenlyase that adds ammonium formiate damping fluid, the 29g of catalyzer 160g oxidized coenzyme successively, stir 0.5h, system is warming up to 30 ± 2 ℃, and temperature control begins reaction, 2D-NMR tracks to reaction to be finished, cooling, concentrate system, centrifugal oven dry, obtain product preparation D-Terleu
14.4kg, yield 95%, HPLC:＞99%, ee
(
1H-NMR：3.4ppm，s，1H，1.0ppm，s，9H；)
This shows, disclosed deuterium can obtain the high target product of purity for the synthetic method of L-Terleu among the present invention, the products obtained therefrom optical purity is stabilized in more than 98%, and the raw material that described synthetic method adopts is easy to get, and method is simple, the chemical reaction condition gentleness, the purity of yield and enantiomorph (ee) value is all very high, and is in the whole process of production, simple to operate, be synthesis technique feasible, that pollution is lower, for the preparation deuterium provides a kind of new thinking and method for the L-Terleu.
Claims (10)
1. the synthetic method of a chirality Terleu is characterized in that it may further comprise the steps:
(1) in reactor, adds raw material
And water, water consumption is every gram raw material
2～8mL;
(2) add the ammonium formiate solid, all after the dissolving, add the pH regulator agent and regulate pH to 6.5～8.5; Raw material
With the ammonium formiate mass ratio be 1: 1.5～3.0;
(3) accent is finished, and adds the ammonium formiate damping fluid of catalyst oxidation type coenzyme, the buffered soln and the chirality leucine dehydrogenase buffered soln of hydrogenlyase successively; Wherein, raw material
With the quality amount ratio of oxidized coenzyme be 1: (0.010 ± 0.003), raw material
With the quality amount ratio of hydrogenlyase be 1: (0.002 ± 0.0004), raw material
With the quality amount ratio of chirality leucine dehydrogenase be 1: (0.0009 ± 0.0003);
(4) stir, begin reaction, control reaction temperature is 10～40 ℃, and the pH of reaction system is 6.0～10.0;
(5) reaction finishes, and a step generates product
2. according to the synthetic method of the described a kind of chirality Terleu of claim 1, it is characterized in that described product
The ammonia chiral centre is S or R configuration, promptly
3. according to the synthetic method of the described a kind of chirality Terleu of claim 1, it is characterized in that described raw material
Middle R
1For-CD
3Described product
Middle R
1For-CD
3, promptly
The ammonia chiral centre is S or R configuration.
4. according to the synthetic method of claim 1,2 or 3 described a kind of chirality Terleus, it is characterized in that described product is that deuterium is for the chirality Terleu
1H-NMR:3.4ppm, s, 1H;
2D-NMR:1.0ppm, s, 9D;
5. according to the synthetic method of the described a kind of chirality Terleu of claim 1, it is characterized in that described raw material
Middle R
1For-CH
3Described product
Middle R
1For-CH
3, the ammonia chiral centre is S or R configuration.
6. according to the synthetic method of the described a kind of chirality Terleu of claim 1, it is characterized in that water consumption is every gram raw material in the described step (1)
3～5mL; The pH regulator agent is 10%～28% ammonia soln, 0.05M～0.5M Sodium phosphate dibasic/phosphate sodium dihydrogen buffer solution or 0.05M～0.5M dipotassium hydrogen phosphate/potassium phosphate buffer in the described step (2), raw material
With the ammonium formiate mass ratio be 1: 1.5～3.0; Raw material in the described step (3)
With the quality amount ratio of oxidized coenzyme be 1: (0.010 ± 0.002), raw material
With the quality amount ratio of hydrogenlyase be 1: (0.002 ± 0.0003), raw material
With the quality amount ratio of chirality leucine dehydrogenase be 1: (0.0009 ± 0.0002); Temperature of reaction is 20～38 ℃ in the described step (4); The pH of reaction system is 6.0～9.0.
7. according to the synthetic method of the described a kind of chirality Terleu of claim 1, it is characterized in that water consumption is every gram raw material in the described step (1)
2.5～5.0mL; The pH regulator agent is 10%～28% ammonia soln or 0.05M～0.5M dipotassium hydrogen phosphate/potassium phosphate buffer in the described step (2), raw material
With the ammonium formiate mass ratio be 1: 1.5～3.0; Raw material in the described step (3)
With the quality amount ratio of oxidized coenzyme be 1: (0.010 ± 0.001), raw material
With the quality amount ratio of hydrogenlyase be 1: (0.002 ± 0.0002), raw material
With the quality amount ratio of chirality leucine dehydrogenase be 1: (0.0009 ± 0.0001); Temperature of reaction is 25～35 ℃ in the described step (4); The pH of reaction system is 7.0～8.5.
8. according to the synthetic method of claim 1,6 or 7 described a kind of chirality Terleus, it is characterized in that described chirality leucine dehydrogenase is L-leucine dehydrogenase or D-leucine dehydrogenase.
9. according to the synthetic method of the described a kind of chirality Terleu of claim 1, it is characterized in that described pH regulator agent is 10%～28% ammonia soln, 0.05M～0.5M Sodium phosphate dibasic/phosphate sodium dihydrogen buffer solution or 0.05M～0.5M dipotassium hydrogen phosphate/potassium phosphate buffer.
10. the final product of the synthetic method of a chirality Terleu is characterized in that it is that deuterium is for the chirality Terleu, promptly
The ammonia chiral centre is S or R configuration; Wherein
1H-NMR:3.4ppm, s, 1H;
2D-NMR:1.0ppm, s, 9D.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102978248A (en) * | 2012-12-03 | 2013-03-20 | 苏州汉酶生物技术有限公司 | Method for regulating pH of enzyme reaction system |
| CN102978251A (en) * | 2012-12-03 | 2013-03-20 | 苏州汉酶生物技术有限公司 | Method for producing L-tert-leucine |
| WO2013167088A2 (en) * | 2013-07-29 | 2013-11-14 | 凯莱英医药集团（天津）股份有限公司 | Synthesis method for l-cyclic alkyl amino acid and pharmaceutical composition having said acid |
| WO2013167012A2 (en) * | 2013-06-27 | 2013-11-14 | 凯莱英医药集团（天津）股份有限公司 | Synthesis method for l-heterocyclic amino acid and pharmaceutical composition having said acid |
| CN112831532A (en) * | 2021-03-29 | 2021-05-25 | 洛阳华荣生物技术有限公司 | Method for enzymatic synthesis of D-leucine |
-
2011
- 2011-05-06 CN CN2011101162531A patent/CN102250976A/en not_active Withdrawn
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102978248A (en) * | 2012-12-03 | 2013-03-20 | 苏州汉酶生物技术有限公司 | Method for regulating pH of enzyme reaction system |
| CN102978251A (en) * | 2012-12-03 | 2013-03-20 | 苏州汉酶生物技术有限公司 | Method for producing L-tert-leucine |
| WO2013167012A2 (en) * | 2013-06-27 | 2013-11-14 | 凯莱英医药集团（天津）股份有限公司 | Synthesis method for l-heterocyclic amino acid and pharmaceutical composition having said acid |
| WO2013167012A3 (en) * | 2013-06-27 | 2014-04-03 | 凯莱英医药集团（天津）股份有限公司 | Synthesis method for l-heterocyclic amino acid and pharmaceutical composition having said acid |
| WO2013167088A2 (en) * | 2013-07-29 | 2013-11-14 | 凯莱英医药集团（天津）股份有限公司 | Synthesis method for l-cyclic alkyl amino acid and pharmaceutical composition having said acid |
| WO2013167088A3 (en) * | 2013-07-29 | 2014-07-24 | 凯莱英医药集团（天津）股份有限公司 | Synthesis method for l-cyclic alkyl amino acid and pharmaceutical composition having said acid |
| CN112831532A (en) * | 2021-03-29 | 2021-05-25 | 洛阳华荣生物技术有限公司 | Method for enzymatic synthesis of D-leucine |
| CN112831532B (en) * | 2021-03-29 | 2023-12-08 | 洛阳华荣生物技术有限公司 | Method for enzymatic synthesis of D-leucine |
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Address after: 300457, No. 6 Dongting street, Seventh Street, Tianjin economic and Technological Development Zone Applicant after: Asymchem Medical Group (Tianjin) Inc. Co-applicant after: Asymchem Life Science and Tecnology (Tianjin) Co., Ltd. Co-applicant after: Tianjin Asymchem Pharmaceutical Co., Ltd. Co-applicant after: Asymchem Medical Chemical (Fuxin) Technology Co., Ltd. Co-applicant after: Jilin Asymchem Medicinal and Pharmaceutical Chemistry Co., Ltd. Address before: 300457, No. 6 Dongting street, Seventh Street, Tianjin economic and Technological Development Zone Applicant before: Kailaiying Medical Chemical (Tianjin) Co., Ltd. Co-applicant before: Asymchem Life Science and Tecnology (Tianjin) Co., Ltd. Co-applicant before: Tianjin Asymchem Pharmaceutical Co., Ltd. Co-applicant before: Asymchem Medical Chemical (Fuxin) Technology Co., Ltd. Co-applicant before: Jilin Asymchem Medicinal and Pharmaceutical Chemistry Co., Ltd. |
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Application publication date: 20111123 |