CN101735085A - Method for preparing D-serine by kinetic resolution - Google Patents
Method for preparing D-serine by kinetic resolution Download PDFInfo
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- CN101735085A CN101735085A CN200910201315A CN200910201315A CN101735085A CN 101735085 A CN101735085 A CN 101735085A CN 200910201315 A CN200910201315 A CN 200910201315A CN 200910201315 A CN200910201315 A CN 200910201315A CN 101735085 A CN101735085 A CN 101735085A
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Abstract
The invention discloses a method for preparing D-serine by kinetic resolution. The method takes DL-serine as raw material and is implemented by esterifying DL-serine with methanol under catalysis of Amberlyst-15 ion exchange resin to obtain DL-serinemethylester, carrying out dynamic kinetic resolution on DL-serinemethylester and resolving agent L-DBTA under action of racemization catalyst to obtain dibasic DL-serinemethylester.L-DBTA, dissociating with hydrochloric acid, and hydrolyzing to obtain D-serine, the target product of the invention. Compared with the prior art, by using the racemization catalyst in the invention, the dynamic continuous conversion of dibasic L-serinemethylester.L-DBTA into dibasic DL-serinemethylester.L-DBTA can be realized with the theoretic conversion rate being approximate to 100%, thus greatly enhancing yield of resolution, reducing operation cost, stabilizing product quality and being suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of method of preparing D-serine by kinetic resolution, be specifically related to a kind ofly carry out the method that Dynamic Kinetic Resolution prepares the D-Serine with racemization catalyst.
Background technology
The D-Serine is a kind of important medicine intermediate, can be applicable to biochemical reagents and prepares tissue culture medium (TCM), pharmaceutically is used as amino acids nutritional drugs etc.Its structural formula is as follows:
Existing document " amino acid and Biological resources " 2007,29 (2): 40-41 has reported that Southeast China University's chemical is " are the novel method of feedstock production D-Serine with the DL-serine " such as Wu Liuyang, with the DL-serine is raw material, prepare the method for D-Serine through esterification, fractionation and hydrolysis, promptly at resolving agent L-2, the effect of 3-dibenzoyl tartaric acid (L-DBTA) splits the DL-serine methyl esters down, obtain D-serine methylester L-DBTA disalt, obtain the D-Serine through salt acid dissociation and hydrolysis then.But this classical resolution process can only split the half D-type thing of measuring in the DL-serine methyl esters, relative DL-serine methyl esters, and resolution yield only is 48.8%.
Summary of the invention
Technical problem to be solved by this invention provides a kind of method of preparing D-serine by kinetic resolution, promptly adopts racemization catalyst to carry out the method that Dynamic Kinetic Resolution prepares the D-Serine, to overcome deficiency of the prior art.
In order to achieve the above object, the present invention realizes by the following technical solutions:
A kind of method of preparing D-serine by kinetic resolution at first is raw material with the DL-serine, obtains the DL-serine methyl esters with methanol esterification under the catalysis of Amberlyst-15 ion exchange resin; DL-serine methyl esters and resolving agent L-DBTA carry out Dynamic Kinetic Resolution under the effect of racemization catalyst then, obtain D-serine methylester L-DBTA disalt; With hydrochloric acid this disalt is dissociated at last, hydrolysis obtains target product D-Serine of the present invention.
The method of described preparing D-serine by kinetic resolution specifically may further comprise the steps:
(1) preparation DL-serine methyl esters:
DL-serine, anhydrous methanol and Amberlyst-15 ion exchange resin under 20-70 ℃ temperature, reacted 1-4 hour, filtered the solid formation that obtains and regulated pH=8 with ammoniacal liquor, and ethyl acetate extraction obtains the DL-serine methyl esters after steaming desolventizes.
(2) preparation D-serine methylester L-DBTA disalt:
The DL-serine methyl esters that step (1) obtains, solvent methanol, racemization catalyst is under 35-65 ℃ temperature, splashed into resolving agent L-DBTA in 1-3 hour, reacted 0.5-3 hour, reaction solution is through cooling, filter, drying obtains the crystallization of D-serine methylester L-DBTA disalt.
(3) preparation D-Serine:
D-serine methylester L-DBTA disalt and hydrochloric acid that step (2) obtains at room temperature reacted 10-30 minute, and reacting liquid filtering, filtrate and hydrochloric acid were collected target product D-Serine then at 60-100 ℃ of following hydrolysis reaction 0.5-4 hour from reaction product.
Described racemization catalyst is selected from a kind of in 2-aldehyde radical pyridine, 3-aldehyde radical pyridine, 4-aldehyde radical pyridine, 2-bromo-4-aldehyde radical pyridine, the 2-bromo-5-aldehyde radical pyridine, preferred 4-aldehyde radical pyridine.
The DL-serine in the described step (1) and the weightmeasurement ratio of anhydrous methanol are 1: 4-8g/ml, the weight ratio of DL-serine and Amberlyst-15 ion exchange resin is 1: 2-5.
The DL-serine methyl esters in the described step (2) and the weightmeasurement ratio of solvent methanol are 1: 2-8g/ml; DL-serine methyl esters, racemization catalyst, resolving agent L-DBTA three's mol ratio is 1: 0.01-0.1: 0.5.
Also use the L-DBTA methanol solution to drip in the described step (2), L-DBTA and methanol solvate are prepared according to weightmeasurement ratio 1: 2-5g/ml.
The D-serine methylester L-DBTA disalt in the described step (3) and the mol ratio of hydrochloric acid are 1: 6-12.
Described step (3) is collected target product D-Serine and is comprised the steps: that also reaction product dewaters from reaction product, add alcohol solvent, and triethylamine is regulated pH=7, filters, and precipitate ethanol drip washing obtains D-Serine white crystals after the drying.
Chemical equation of the present invention is as follows:
With the D-Serine that preparation method of the present invention obtains, fusing point: 220 ℃ (decomposition), specific rotatory power:
With the disclosed fusing point of ChemicalBook: 220 ℃,
Consistent.
The present invention compared with prior art, adopt racemization catalyst, realized when the DL-serine methyl esters is split as D-serine methylester L-DBTA disalt and L-serine methylester L-DBTA disalt, L-serine methylester L-DBTA disalt mobilism is converted into D-serine methylester L-DBTA disalt continuously, and the theoretical transformation rate is near 100%.Its optical purity of D-Serine, chemical purity that the inventive method obtains all reach more than 99%, and resolution yield is 78-88%, has improved resolution yield, greatly reduces running cost, and constant product quality is suitable for suitability for industrialized production.
Embodiment
The invention will be further described below by embodiment, but embodiment does not limit protection scope of the present invention.
Embodiment 1
(1) preparation DL-serine methyl esters:
In the reactor that has stirring, heating, thermometer, add 84.0g (0.80mol) DL-serine respectively, 400ml anhydrous methanol and 252.0g Amberlyst-15 ion exchange resin, heat temperature raising to 65 ℃ when stirring was kept this thermotonus 1 hour.Reaction solution is cooled to room temperature, filter, filtrate is reclaimed the back and is reused, solid formation is regulated pH=8 with 30% ammoniacal liquor, with each 200ml ethyl acetate solvent extraction 3 times, steam and remove ethyl acetate solvent (reusing after the solvent recuperation), obtain DL-serine methyl esters 91.6g, yield 96.2%, purity are 99.36% (HPLC).
(2) preparation D-serine methylester L-DBTA disalt:
Having stirring, heating, add the DL-serine methyl esters that 23.8g (0.20mol) step (1) obtains in the reactor of thermometer respectively, 50ml methyl alcohol, 1.1g (0.01mol) 2-aldehyde radical pyridine, heat temperature raising to 60 ℃ when stirring, splash into resolving agent L-DBTA methanol solution [formulated] in 2 hours by 35.8g (0.10mol) L-DBTA and 100ml methyl alcohol, drip off the synthermal reaction down in back 30 minutes, reaction solution is cooled to room temperature, filter, filtrate is applied mechanically, and crystallisate is with 3 after drying of each 30ml methanol solvate drip washing, obtain crystalloid D-serine methylester L-DBTA disalt 50.7g, resolution yield 85.2%, fusing point: 168.3 ℃, specific rotatory power
(3) preparation D-Serine:
Add the D-serine methylester L-DBTA disalt that 48.5g (0.081mol) step (1) obtains in the reactor that has stirring, heating, thermometer, 6N hydrochloric acid 108ml stirs under the room temperature, carries out replacement(metathesis)reaction 30 minutes.Reacting liquid filtering is removed resolving agent L-DBTA (reclaiming the back reuses), filtrate is stirred and heat the reaction 1 hour that is hydrolyzed down under 85 ℃, after dewatering, reactant adds 75ml ethanol, regulate pH=7 with triethylamine, separate out D-Serine crude product, after filtration, ethanol drip washing, dry D-Serine white crystals 15.1g, yield: 88.6%; Purity is 99.48% (HPLC); Optical purity: 99.39%; Fusing point: 219.8 ℃, (ChemicalBook value: 220 ℃); Specific rotatory power:
The ChemicalBook value:
Embodiment 2
(1) preparation DL-serine methyl esters is with embodiment 1.
(2) preparation D-serine methylester L-DBTA disalt:
Having stirring, heating, add the DL-serine methyl esters 23.8g (0.20mol) that step (1) obtains in the reactor of thermometer respectively, 180ml methyl alcohol, 2.1g (0.02mol) 4-aldehyde radical pyridine, heat temperature raising to 35 ℃ when stirring, splash into L-DBTA methanol solution [formulated] in 3 hours by 35.8g (0.10mol) L-DBTA and 72ml methyl alcohol, drip off the synthermal reaction down in back 3 hours, reaction solution is cooled to room temperature, filter, filtrate is applied mechanically, and crystallisate is with 3 after drying of each 30ml methanol solvate drip washing, obtain crystalloid D-serine methylester L-DBTA disalt 47.1g, resolution yield 79.2%, fusing point: 168.5 ℃, specific rotatory power
(3) preparation D-Serine:
With the method for embodiment 1 step (3), get 45.0g (0.075mol) D-serine methylester L-DBTA disalt, use the salt acid dissociation, hydrolysis gets D-Serine white crystals 14.0g, yield 89.2%; HPLC:99.35%; Optical purity: 99.18%; Fusing point: 219.2 ℃ (ChemicalBook value: 220 ℃); Specific rotatory power:
The ChemicalBook value:
Embodiment 3
(1) preparation DL-serine methyl esters is with embodiment 1.
(2) preparation D-serine methylester L-DBTA disalt:
Having stirring, heating, add the DL-serine methyl esters 23.8g (0.20mol) that step (1) obtains in the reactor of thermometer respectively, 180ml methyl alcohol, 0.37g (0.002mol) 2-bromo-4-aldehyde radical pyridine, heat temperature raising to 55 ℃ when stirring, splash into L-DBTA methanol solution [formulated] in 1 hour by 35.8g (0.10mol) L-DBTA and 140ml methyl alcohol, drip off the synthermal reaction down in back 1.5 hours, reaction solution is cooled to room temperature, filter, filtrate is applied mechanically, and crystallisate is through each 3 after drying of 30ml methanol solvate drip washing, obtain crystalloid D-serine methylester L-DBTA disalt 52.2g, resolution yield 87.8%, fusing point: 168.1 ℃, specific rotatory power
(3) preparation D-Serine:
With the method for embodiment 1 step (3), get 50.0g (0.084mol) D-serine methylester L-DBTA disalt, use the salt acid dissociation, hydrolysis obtains D-Serine white crystals 15.0g, yield 85.9%; Purity: 99.61% (HPLC); Optical purity: 99.66%; Fusing point: 220.2 ℃ (ChemicalBook value: 220 ℃); Specific rotatory power:
The ChemicalBook value:
Claims (8)
1. the method for a preparing D-serine by kinetic resolution is characterized in that, comprises the steps:
(1) preparation DL-serine methyl esters:
DL-serine, anhydrous methanol and Amberlyst-15 ion exchange resin under 20-70 ℃ temperature, reacted 1-4 hour, filtered the solid formation that obtains and regulated pH=8 with ammoniacal liquor, and ethyl acetate extraction obtains the DL-serine methyl esters after steaming desolventizes;
(2) preparation D-serine methylester L-DBTA disalt:
The DL-serine methyl esters that step (1) obtains, solvent methanol, racemization catalyst splashed into resolving agent L-DBTA in 1-3 hour under 35-65 ℃ temperature, reacted 0.5-3 hour, reaction solution is through cooling, filter, drying obtains the crystallization of D-serine methylester L-DBTA disalt;
(3) preparation D-Serine:
D-serine methylester L-DBTA disalt and hydrochloric acid that step (2) obtains at room temperature reacted 10-30 minute, and reacting liquid filtering, filtrate and hydrochloric acid were collected target product D-Serine then at 60-100 ℃ of following hydrolysis reaction 0.5-4 hour from reaction product.
2. method according to claim 1 is characterized in that, described racemization catalyst is a kind of in 2-aldehyde radical pyridine, 3-aldehyde radical pyridine, 4-aldehyde radical pyridine, 2-bromo-4-aldehyde radical pyridine, the 2-bromo-5-aldehyde radical pyridine.
3. method according to claim 2 is characterized in that, described racemization catalyst is preferably 4-aldehyde radical pyridine.
4. method according to claim 1 is characterized in that, in the described step (1), the weightmeasurement ratio of DL-serine and anhydrous methanol is 1: 4-8g/ml, the weight ratio of DL-serine and Amberlyst-15 ion exchange resin is 1: 2-5.
5. method according to claim 1, it is characterized in that, in the described step (2), the weightmeasurement ratio of DL-serine methyl esters and solvent methanol is 1: 2-8g/ml, DL-serine methyl esters: racemization catalyst: the mol ratio of resolving agent L-DBTA is 1: 0.01-0.1: 0.5.
6. method according to claim 1 or 5 is characterized in that, in the described step (2), uses the L-DBTA methanol solution to drip, and L-DBTA and methanol solvate are prepared according to weightmeasurement ratio 1: 2-5g/ml.
7. method according to claim 1 is characterized in that, in the described step (3), the mol ratio of D-serine methylester L-DBTA disalt and hydrochloric acid is 1: 6-12.
8. method according to claim 1, it is characterized in that, in the described step (3), from reaction product, collect target product D-Serine and comprise the steps: that reaction product dewaters, add alcohol solvent, triethylamine is regulated pH=7, filters, precipitate ethanol drip washing obtains D-Serine white crystals after the drying.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010345A (en) * | 2010-11-24 | 2011-04-13 | 上海华谊（集团）公司 | Method for preparing D-phenylalanine through dynamic kinetic resolution |
| CN102533922A (en) * | 2011-12-14 | 2012-07-04 | 浙江大学 | Method for catalyzing dynamic kinetic resolution of arylamine via racemization catalyst |
| CN103274956A (en) * | 2013-05-29 | 2013-09-04 | 安徽省恒锐新技术开发有限责任公司 | Preparation method of D-serine |
| CN105646255A (en) * | 2016-02-18 | 2016-06-08 | 国药集团化学试剂有限公司 | Method for preparing L-serine with chiral separation method |
| CN110878029A (en) * | 2019-11-13 | 2020-03-13 | 上海星酶生物科技有限公司 | Preparation method of D-serine |
Citations (2)
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| CN1418862A (en) * | 2002-11-22 | 2003-05-21 | 东南大学 | Method for preparing dextrorotary phenylalanine by asymmetric conversion method |
| US20070015943A1 (en) * | 2003-07-25 | 2007-01-18 | Postech Foundation | Method of preparation of optically active alcohols |
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| CN1418862A (en) * | 2002-11-22 | 2003-05-21 | 东南大学 | Method for preparing dextrorotary phenylalanine by asymmetric conversion method |
| US20070015943A1 (en) * | 2003-07-25 | 2007-01-18 | Postech Foundation | Method of preparation of optically active alcohols |
Non-Patent Citations (2)
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| 吴刘洋: "几种D-型氨基酸的制备研究", 《东南大学硕士学位论文》 * |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010345A (en) * | 2010-11-24 | 2011-04-13 | 上海华谊（集团）公司 | Method for preparing D-phenylalanine through dynamic kinetic resolution |
| CN102010345B (en) * | 2010-11-24 | 2014-04-09 | 上海华谊（集团）公司 | Method for preparing D-phenylalanine through dynamic kinetic resolution |
| CN102533922A (en) * | 2011-12-14 | 2012-07-04 | 浙江大学 | Method for catalyzing dynamic kinetic resolution of arylamine via racemization catalyst |
| CN103274956A (en) * | 2013-05-29 | 2013-09-04 | 安徽省恒锐新技术开发有限责任公司 | Preparation method of D-serine |
| CN103274956B (en) * | 2013-05-29 | 2015-07-01 | 安徽省恒锐新技术开发有限责任公司 | Preparation method of D-serine |
| CN105646255A (en) * | 2016-02-18 | 2016-06-08 | 国药集团化学试剂有限公司 | Method for preparing L-serine with chiral separation method |
| CN110878029A (en) * | 2019-11-13 | 2020-03-13 | 上海星酶生物科技有限公司 | Preparation method of D-serine |
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