CN101735085B - Method for preparing D-serine by kinetic resolution - Google Patents
Method for preparing D-serine by kinetic resolution Download PDFInfo
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- CN101735085B CN101735085B CN 200910201315 CN200910201315A CN101735085B CN 101735085 B CN101735085 B CN 101735085B CN 200910201315 CN200910201315 CN 200910201315 CN 200910201315 A CN200910201315 A CN 200910201315A CN 101735085 B CN101735085 B CN 101735085B
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- ANSUDRATXSJBLY-GSVOUGTGSA-N COC([C@@H](CO)N)=O Chemical compound COC([C@@H](CO)N)=O ANSUDRATXSJBLY-GSVOUGTGSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N N[C@H](CO)C(O)=O Chemical compound N[C@H](CO)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 2
- ANSUDRATXSJBLY-UHFFFAOYSA-N COC(C(CO)N)=O Chemical compound COC(C(CO)N)=O ANSUDRATXSJBLY-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N NC(CO)C(O)=O Chemical compound NC(CO)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
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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 with racemization catalyst, carry out the method that Dynamic Kinetic Resolution prepares D-Ser.
Background technology
D-Ser 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 Wu Liuyang etc. " take DL-serine prepares the novel method of D-Ser for raw material ", take DL-serine as raw material, prepare the method for D-Ser through esterification, fractionation and hydrolysis, at resolving agent L-2, split the DL-serine methyl esters under the effect of 3-dibenzoyl tartaric acid (L-DBTA), obtain D-Ser methyl esters L-DBTA disalt, then through salt acid dissociation and hydrolysis, obtain D-Ser.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, resolution yield is only 48.8%.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of method of preparing D-serine by kinetic resolution, adopts racemization catalyst to carry out the method that Dynamic Kinetic Resolution prepares D-Ser, 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 take DL-serine as raw material, under the catalysis of Amberlyst-15 ion exchange resin, with methanol esterification, obtains the DL-serine methyl esters; Then DL-serine methyl esters and resolving agent L-DBTA carry out Dynamic Kinetic Resolution under the effect of racemization catalyst, obtain D-Ser methyl esters L-DBTA disalt; Finally with hydrochloric acid, this disalt is dissociated, hydrolysis, obtain target product D-Ser of the present invention.
The method of described preparing D-serine by kinetic resolution specifically comprises the following steps:
(1) prepare the DL-serine methyl esters:
DL-serine, anhydrous methanol and Amberlyst-15 ion exchange resin, at the temperature of 20-70 ℃, reaction 1-4 hour, filter the solid formation obtained and regulate pH=8 with ammoniacal liquor, and the ethyl acetate extraction obtains the DL-serine methyl esters after steaming desolventizes.
(2) prepare D-Ser methyl esters L-DBTA disalt:
The DL-serine methyl esters that step (1) obtains, solvent methanol, racemization catalyst is at the temperature of 35-65 ℃, splashed into resolving agent L-DBTA in 1-3 hour, reaction 0.5-3 hour, reaction solution is through cooling, filter, drying, obtain the crystallization of D-Ser methyl esters L-DBTA disalt.
(3) prepare D-Ser:
The D-Ser methyl esters L-DBTA disalt that step (2) obtains at room temperature reacts 10-30 minute with hydrochloric acid, reacting liquid filtering, and filtrate and hydrochloric acid, at 60-100 ℃ of lower hydrolysis reaction 0.5-4 hour, are then collected the target product D-Ser 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, the bromo-4-aldehyde radical of 2-pyridine, the bromo-5-aldehyde radical of 2-pyridine, preferably 4-aldehyde radical pyridine.
DL-serine in 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.
DL-serine methyl esters in 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.
In described step (2), also use the L-DBTA methanol solution to be dripped, L-DBTA and methanol solvate are prepared according to weightmeasurement ratio 1: 2-5g/ml.
D-Ser methyl esters L-DBTA disalt in described step (3) and the mol ratio of hydrochloric acid are 1: 6-12.
Described step (3) is collected the target product D-Ser and is also comprised the steps: that reaction product dewaters from reaction product, adds alcohol solvent, and triethylamine is regulated pH=7, filters, and precipitate ethanol drip washing, obtain the D-Ser white crystals after drying.
Chemical equation of the present invention is as follows:
The D-Ser obtained by preparation method of the present invention, fusing point: 220 ℃ (decomposition), specific rotatory power:
with the disclosed fusing point of ChemicalBook: 220 ℃,
unanimously.
The present invention compared with prior art, adopt racemization catalyst, realized when the DL-serine methyl esters is split as D-Ser methyl esters L-DBTA disalt and Serine methyl esters L-DBTA disalt, Serine methyl esters L-DBTA disalt mobilism is converted into D-Ser methyl esters L-DBTA disalt continuously, and the theoretical transformation rate approaches 100%.Its optical purity of the D-Ser that the inventive method obtains, chemical purity 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
Below by embodiment, the invention will be further described, but embodiment does not limit the scope of the invention.
Embodiment 1
(1) prepare the DL-serine methyl esters:
Add respectively 84.0g (0.80mol) DL-serine in the reactor with stirring, heating, thermometer, 400ml anhydrous methanol and 252.0g Amberlyst-15 ion exchange resin, be heated to 65 ℃ when stirring, maintain this thermotonus 1 hour.Reaction solution is cooled to room temperature, filter, filtrate is reused after reclaiming, solid formation is regulated pH=8 with 30% ammoniacal liquor, with each 200ml ethyl acetate solvent extraction 3 times, steam except ethyl acetate solvent (reusing after solvent recuperation), obtain DL-serine methyl esters 91.6g, yield 96.2%, purity is 99.36% (HPLC).
(2) prepare D-Ser methyl esters L-DBTA disalt:
With stirring, heating, the DL-serine methyl esters that adds respectively 23.8g (0.20mol) step (1) to obtain in the reactor of thermometer, 50ml methyl alcohol, 1.1g (0.01mol) 2-aldehyde radical pyridine, be heated to 60 ℃ when stirring, splash into resolving agent L-DBTA methanol solution [formulated by 35.8g (0.10mol) L-DBTA and 100ml methyl alcohol] in 2 hours, drip off rear synthermal lower reaction 30 minutes, reaction solution is cooled to room temperature, filter, filtrate is applied mechanically, crystallisate is with dry after each 30ml methanol solvate drip washing 3 times, obtain crystalloid D-Ser methyl esters L-DBTA disalt 50.7g, resolution yield 85.2%, fusing point: 168.3 ℃, specific rotatory power
(3) prepare D-Ser:
The D-Ser methyl esters L-DBTA disalt that adds 48.5g (0.081mol) step (1) to obtain in the reactor with stirring, heating, thermometer, 6N hydrochloric acid 108ml, stir under room temperature, carries out replacement(metathesis)reaction 30 minutes.Reacting liquid filtering is removed resolving agent L-DBTA (reusing after recovery), filtrate is stirred the lower reaction 1 hour that is hydrolyzed under 85 ℃ of heating, after dewatering, reactant adds 75ml ethanol, regulate pH=7 with triethylamine, separate out the D-Ser crude product, after filtration, ethanol drip washing, dry to obtain D-Ser 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) prepare the DL-serine methyl esters with embodiment 1.
(2) prepare D-Ser methyl esters L-DBTA disalt:
With stirring, heating, the DL-serine methyl esters 23.8g (0.20mol) that adds respectively step (1) to obtain in the reactor of thermometer, 180ml methyl alcohol, 2.1g (0.02mol) 4-aldehyde radical pyridine, be heated to 35 ℃ when stirring, splash into L-DBTA methanol solution [formulated by 35.8g (0.10mol) L-DBTA and 72ml methyl alcohol] in 3 hours, drip off rear synthermal lower reaction 3 hours, reaction solution is cooled to room temperature, filter, filtrate is applied mechanically, crystallisate is with dry after each 30ml methanol solvate drip washing 3 times, obtain crystalloid D-Ser methyl esters L-DBTA disalt 47.1g, resolution yield 79.2%, fusing point: 168.5 ℃, specific rotatory power
(3) prepare D-Ser:
With the method for embodiment 1 step (3), get 45.0g (0.075mol) D-Ser methyl esters L-DBTA disalt, use the salt acid dissociation, hydrolysis, obtain D-Ser 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) prepare the DL-serine methyl esters with embodiment 1.
(2) prepare D-Ser methyl esters L-DBTA disalt:
With stirring, heating, the DL-serine methyl esters 23.8g (0.20mol) that adds respectively step (1) to obtain in the reactor of thermometer, 180ml methyl alcohol, 0.37g (0.002mol) the bromo-4-aldehyde radical of 2-pyridine, be heated to 55 ℃ when stirring, splash into L-DBTA methanol solution [formulated by 35.8g (0.10mol) L-DBTA and 140ml methyl alcohol] in 1 hour, drip off rear synthermal lower reaction 1.5 hours, reaction solution is cooled to room temperature, filter, filtrate is applied mechanically, crystallisate is dry after each 30ml methanol solvate drip washing 3 times, obtain crystalloid D-Ser methyl esters L-DBTA disalt 52.2g, resolution yield 87.8%, fusing point: 168.1 ℃, specific rotatory power
(3) prepare D-Ser:
With the method for embodiment 1 step (3), get 50.0g (0.084mol) D-Ser methyl esters L-DBTA disalt, use the salt acid dissociation, hydrolysis, obtain D-Ser 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 (7)
1. the method for a preparing D-serine by kinetic resolution, is characterized in that, comprises the steps:
(1) prepare the DL-serine methyl esters:
DL-serine, anhydrous methanol and Amberlyst-15 ion exchange resin, at the temperature of 20-70 ℃, reaction 1-4 hour, filter the solid formation obtained and regulate pH=8 with ammoniacal liquor, and the ethyl acetate extraction obtains the DL-serine methyl esters after steaming desolventizes;
(2) prepare D-Ser methyl esters L-DBTA disalt:
The DL-serine methyl esters that step (1) obtains, solvent methanol, racemization catalyst, at the temperature of 35-65 ℃, splashed into resolving agent L-DBTA in 1-3 hour, reaction 0.5-3 hour, reaction solution is through cooling, filter, drying, obtain the crystallization of D-Ser methyl esters L-DBTA disalt;
Described catalyzer is a kind of in 2-aldehyde radical pyridine, 3-aldehyde radical pyridine, 4-aldehyde radical pyridine, the bromo-4-aldehyde radical of 2-pyridine, the bromo-5-aldehyde radical of 2-pyridine;
(3) prepare D-Ser:
The D-Ser methyl esters L-DBTA disalt that step (2) obtains at room temperature reacts 10-30 minute with hydrochloric acid, reacting liquid filtering, and filtrate and hydrochloric acid, at 60-100 ℃ of lower hydrolysis reaction 0.5-4 hour, are then collected the target product D-Ser from reaction product.
2. method according to claim 1, is characterized in that, described racemization catalyst is preferably 4-aldehyde radical pyridine.
3. method according to claim 1, is characterized in that, in described step (1), the weightmeasurement ratio of DL-serine and anhydrous methanol is 1:4-8g/ml, and the weight ratio of DL-serine and Amberlyst-15 ion exchange resin is 1:2-5.
4. method according to claim 1, it is characterized in that, in 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.
5. according to the described method of claim 1 or 4, it is characterized in that, in described step (2), use the L-DBTA methanol solution to be dripped, L-DBTA and methanol solvate are prepared according to weightmeasurement ratio 1:2-5g/ml.
6. method according to claim 1, is characterized in that, in described step (3), the mol ratio of D-Ser methyl esters L-DBTA disalt and hydrochloric acid is 1:6-12.
7. method according to claim 1, it is characterized in that, in described step (3), collect the target product D-Ser and comprise the steps: that reaction product dewaters from reaction product, add alcohol solvent, triethylamine is regulated pH=7, filters, precipitate ethanol drip washing, obtain the D-Ser white crystals after drying.
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| 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 |
| CN102533922B (en) * | 2011-12-14 | 2013-07-31 | 浙江大学 | Method for catalyzing dynamic kinetic resolution of arylamine via racemization catalyst |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (3)
| Title |
|---|
| 几种D-型氨基酸的制备研究;吴刘洋;《东南大学硕士学位论文》;20080829;第7-22页 * |
| 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》.2008, |
| 张占金等.路易斯酸碱催化的外消旋体（动态）动力学拆分反应.《化学进展》.2004,第16卷(第4期),第574-583页. * |
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