CN1900052A - Method for preparing levo-serine and dextro serine by induced crystallizing method - Google Patents
Method for preparing levo-serine and dextro serine by induced crystallizing method Download PDFInfo
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- CN1900052A CN1900052A CN 200610082016 CN200610082016A CN1900052A CN 1900052 A CN1900052 A CN 1900052A CN 200610082016 CN200610082016 CN 200610082016 CN 200610082016 A CN200610082016 A CN 200610082016A CN 1900052 A CN1900052 A CN 1900052A
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Abstract
The present invention relates to preparation of chiral organic compound, and is especially process of preparing levo-serine and dextro serine with recemized serine. Through mixing recemized serine and dextro serine in certain ratio, adding water, heating for dissolving, cooling, throwing certain amount of levo-serine or dextro serine crystal seed, lowering the temperature, filtering and stoving, crude levo-serine or dextro serine product is obtained. Through further dissolving the crude levo-serine or dextro serine product in deionized water through heating, decolorizing, hot filtering, concentrating filtrate, adding anhydrous alcohol, lowering the temperature to about 10 deg.c, stirring and stilling, filtering and stoving, levo-serine or dextro serine product is obtained.
Description
Technical field
The present invention is a kind of preparation method of chiral organic compound, especially a kind of method that is prepared levo-serine and dextrorotation Serine by the racemize Serine.
Background technology
Serine has another name called 2-amino-3-hydroxy-propionic acid.Serine is a kind of neutral amino acids of hydroxyl, and promptly it is amino identical with carboxyl quantity.Have 1 chiral carbon atom in its molecular structure, i.e. 1 chiral centre, thereby have the existence of a pair of enantiomorph, i.e. dextrorotation Serine (D type Serine) and levo-serine (L type Serine), its structure as shown in the formula:
Levo-serine dextrorotation Serine
Serine is a kind of glycogenic amino acid, in animal body participation-SH and-biosynthesizing of the conversion of OH and purine, pyrimidine, can change choline or phosphatide composition into.Therefore, Serine series product (racemize Serine, dextrorotation Serine, levo-serine) not only can be used for food and feed additive, and it is synthetic also to be widely used in medicine at present.Can be used as the synthesizing amino acid specifics as the racemize Serine; Levo-serine not only is used for Biochemical Research now as important biochemical reagents and medicament, and as the composition of third generation amino acid transfusion, and owing to its special wettability is used for cosmetic industry; The derivative of levo-serine such as carbobenzoxy-(Cbz)-L-Serine, tolysulfonyl-L-Serine, L-serine methylester (ethyl ester) hydrochloride etc. are used as medicine; The dextrorotation Serine can be used as the synthetic intermediate that synthesizes medicines such as D-seromycin, also can be used for synthetic peptide gene medicine.
The preparation method of known levo-serine and dextrorotation Serine has following several:
(1) by microbial process, generate N-formamyl-D-Serine by DL-hydroxymethyl glycolylurea, hydrolysis then obtains the method (spy opens clear 61-152291) of D-Serine.In this method, the yield that generates N-formamyl-D-Serine from DL-hydroxymethyl glycolylurea is very low, has only about 40%, and this method needs a large amount of bacterium as catalyzer simultaneously.
(2) in the substratum of DL-serine, cultivate mycocandida (Candida), torulopsis (Torulopsis), genera cryptococcus (Cryptococcus), multiple film spore saccharomyces (Saccharomycopsis), Hansenula (Hansenula), escherich's bacillus element (Escherichia), Klebsiella pneumoniae element (Klebsiella), Providencia (Providencia), assimilation L-Serine in microbot rhzomorph (Microbacterium) or the serratia (Serratia) and do not assimilate the microorganism of D-Serine, the method (spy opens clear 64-2594) of from nutrient solution, separating the D-Serine.After anabolic reaction finishes, D-Serine in the separation and Culture liquid and L-Serine.
(3) microorganism with tyrosinase activity and the reaction solution that contains DL-serine and phenol are interacted, convert the L-Serine to L-tyrosine, extract the method (spy opens flat 5-91895) of remaining D-Serine.This method mesostroma concentration has only about 1%, and needs to use deleterious phenols in the reaction process.
Summary of the invention
The purpose of this invention is to provide a kind of is raw material with the racemize Serine, prepares the method for dextrorotation Serine and levo-serine simultaneously by induced crystallization.
For achieving the above object, the present invention has adopted following technical scheme:
At first the racemize Serine is mixed by a certain percentage with the dextrorotation Serine, the water that adds 2-5 times of weight, be warming up to and make its whole dissolvings about 95 ℃, cooling cooling then, and a certain proportion of dextrorotation Serine of input racemize Serine weight crystal seed, slowly cool to certain temperature, filter, obtain dextrorotation Serine crude product after the crystal oven dry that obtains;
In filtrate, replenish the racemize Serine of the dextrorotation Serine crude product equivalent that adds and obtain, repeat above intensification, temperature-fall period, drop into a certain proportion of levo-serine crystal seed of material total amount in the solution, slowly cool to certain temperature, filter, the crystal that obtains obtains the levo-serine crude product after oven dry;
Above repeatedly operating process can obtain dextrorotation Serine and levo-serine crude product;
The above dextrorotation Serine crude product that obtains is dropped in the deionized water of 2-5 times of weight, be heated to 90 ℃, stirring and dissolving, add a certain proportion of discoloring agent, at 70-80 ℃ of insulated and stirred 0.5-1 hour, heat filtering, about vacuum concentration to 1/5, the dehydrated alcohol of adding and remaining liq equivalent is cooled to about 10 ℃ filtrate at a certain temperature, stirred 2-3 hour, left standstill 1-2 hour, and filtered, crystal is with a small amount of absolute ethanol washing 2-3 time, oven dry obtains dextrorotation Serine product;
Repeat above operating process and handle the levo-serine crude product, can obtain the levo-serine product.
The blending ratio of racemize Serine and dextrorotation Serine is 5-20: 1, the ratio that the crystal seed that drops into accounts for Serine total amount in the solution is 0.5-2: 100, Tc behind the input crystal seed is 20-40 ℃, bake out temperature is 60-90 ℃, used discoloring agent is adsorptivity discoloring agents such as gac, carclazyte in the refining decolorization, and the discoloring agent ratio is the 0.1-2% that accounts for material gross weight in the solution.
The present invention proposes with the racemize Serine is raw material, prepares the novel process of dextrorotation Serine and levo-serine simultaneously by induced crystallization.This method has made full use of the effective constituent in the racemize Serine raw material, and solution can recycle, has improved raw material availability; Whole process of preparation only needs subsidiary material such as a spot of ethanol, gac, does not have " three wastes " discharging substantially; This method can prepare dextrorotation Serine and levo-serine simultaneously.
Specific embodiments
The induced crystallization method is meant the crystal seed that adds an enantiomer in saturated or oversaturated racemic modification solution, make this enantiomer excessive slightly thereby cause asymmetric environment, in Jiang Wen the process, the isomer that opticity is identical with this crystal seed will crystallize out from solution a little.This is a kind of method for splitting efficiently, simply and efficiently, and the adding of crystal seed causes 2 enantiomers to have different crystallization rates, thereby reaches the purpose of fractionation by the change condition.The yield that the influence of the length of crystalline temperature and crystallization time once splits and the optical purity of product: that Tc reduces is many more, crystallization time is long more, and once the yield of Chai Fening is high more, but the reduction of the optical purity of product; Otherwise then the yield of Chai Fening is low, the optical purity height of product.For solving above contradiction, the present invention takes the Crystallization Separation and the recrystallization method that move in circles, to reach the optical purity that improves resolution yield and product.
Below the present invention is described in further detail by specific embodiment.
Embodiment 1
The racemize Serine of 25Kg and the dextrorotation Serine of 4Kg are put in the 200L reactor, added the 75L deionized water, stir and be warmed up to 95 ℃, make its whole dissolvings.Slowly cool to 45 ℃, drop into 0.58Kg dextrorotation Serine crystal seed, slowly cool to 35 ℃, filter, the crystal that obtains obtains dextrorotation Serine crude product 6.8Kg 80 ℃ of oven dry.In solution, replenish the racemize Serine that adds 6.8Kg, stir and be warmed up to 95 ℃, make its whole dissolvings.Slowly cool to 45 ℃, drop into 0.58Kg levo-serine crystal seed, slowly cool to 35 ℃, filter, the crystal that obtains obtains levo-serine crude product 4.0Kg 80 ℃ of oven dry.Above repeatedly operating process can obtain dextrorotation Serine and levo-serine crude product.
Above-mentioned dextrorotation Serine crude product 7.5Kg that obtains and 30L deionized water are put in the 50L reactor together, be warmed up to 90 ℃, stirring makes its whole dissolvings, add the 100g gac, 75 ℃ of insulated and stirred 45 minutes, filtered while hot, filtrate to having only about 8L, adds the 8L dehydrated alcohol at 60-70 ℃ of vacuum concentration, be cooled to 10 ℃, stirred 2 hours, left standstill 1.5 hours, filter, crystal is with a small amount of absolute ethanol washing 3 times, in 80 ℃ of oven dry, obtain dextrorotation Serine elaboration 7.25Kg, yield is 96.67%.Detecting specific rotation is [α]
D 20=-15.2 ° (C=8,1N HCl), optical purity of products 99.94%.
Above-mentioned levo-serine crude product 7.5Kg that obtains and 60L deionized water are put in the 50L reactor together, be warmed up to 90 ℃, stirring makes its whole dissolvings, add the 100g gac, 75 ℃ of insulated and stirred 45 minutes, filtered while hot, filtrate to having only about 8L, adds the 8L dehydrated alcohol at 60-70 ℃ of vacuum concentration, be cooled to 10 ℃, stirred 2 hours, left standstill 1.5 hours, filter, crystal is with a small amount of absolute ethanol washing 3 times, in 80 ℃ of oven dry, obtain levo-serine elaboration 7.2Kg, yield is 96.0%.Detecting specific rotation is [α]
D 20=+15.1 ° (C=8,1NHCl), optical purity of products 99.89%.
Embodiment 2
The racemize Serine of 25Kg and the dextrorotation Serine of 5Kg are put in the 200L reactor, added the 75L deionized water, stir and be warmed up to 95 ℃, make its whole dissolvings.Slowly cool to 40 ℃, drop into 0.28Kg dextrorotation Serine crystal seed, slowly cool to 30 ℃, filter, the crystal that obtains obtains dextrorotation Serine crude product 5.76Kg 80 ℃ of oven dry.In solution, replenish the racemize Serine that adds 5.76Kg, stir and be warmed up to 95 ℃, make its whole dissolvings.Slowly cool to 40 ℃, drop into 0.28Kg levo-serine crystal seed, slowly cool to 30 ℃, filter, the crystal that obtains obtains levo-serine crude product 3.92Kg 80 ℃ of oven dry.Above repeatedly operating process can obtain dextrorotation Serine and levo-serine crude product.
Above-mentioned dextrorotation Serine crude product 7.5Kg that obtains and 30L deionized water are put in the 50L reactor together, be warmed up to 90 ℃, stirring makes its whole dissolvings, add 100g from soil, 70 ℃ of insulated and stirred 1 hour, filtered while hot, filtrate to having only about 7.5L, adds the 7.5L dehydrated alcohol at 60-70 ℃ of vacuum concentration, be cooled to 10 ℃, stirred 2 hours, left standstill 1.5 hours, filter, crystal is with a small amount of absolute ethanol washing 3 times, in 80 ℃ of oven dry, obtain dextrorotation Serine elaboration 6.95Kg, yield is 92.7%.Detecting specific rotation is [α]
D 20=-14.8 ° (C=8,1N HCl), optical purity of products 98.6%.
Above-mentioned levo-serine crude product 7.5Kg that obtains and 30L deionized water are put in the 50L reactor together, be warmed up to 90 ℃, stirring makes its whole dissolvings, add the 100g carclazyte, 70 ℃ of insulated and stirred 1 hour, filtered while hot, filtrate to having only about 7.5L, adds the 7.5L dehydrated alcohol at 60-70 ℃ of vacuum concentration, be cooled to 10 ℃, stirred 2 hours, left standstill 1.5 hours, filter, crystal is with a small amount of absolute ethanol washing 3 times, in 80 ℃ of oven dry, obtain levo-serine elaboration 7.05Kg, yield is 94.0%.Detecting specific rotation is [α]
D 20=+14.7 ° (C=8,1N HCl), optical purity of products 98.83%.
Embodiment 3
The racemize Serine of 25Kg and the dextrorotation Serine of 1.5Kg are put in the 200L reactor, added the 75L deionized water, stir and be warmed up to 95 ℃, make its whole dissolvings.Slowly cool to 35 ℃, drop into 0.53Kg dextrorotation Serine crystal seed, slowly cool to 25 ℃, filter, the crystal that obtains obtains dextrorotation Serine crude product 3.65Kg 80 ℃ of oven dry.In solution, replenish the racemize Serine that adds 3.65Kg, stir and be warmed up to 95 ℃, make its whole dissolvings.Slowly cool to 35 ℃, drop into 0.15Kg levo-serine crystal seed, slowly cool to 30 ℃, filter, the crystal that obtains obtains levo-serine crude product 4.7Kg 80 ℃ of oven dry.Above repeatedly operating process can obtain dextrorotation Serine and levo-serine crude product.
Above-mentioned dextrorotation Serine crude product 7.5Kg that obtains and 30L deionized water are put in the 50L reactor together, be warmed up to 90 ℃, stirring makes its whole dissolvings, add the 200g gac, 70 ℃ of insulated and stirred 1 hour, filtered while hot, filtrate to having only about 6L, adds the 6L dehydrated alcohol at 60-70 ℃ of vacuum concentration, be cooled to 10 ℃, stirred 2 hours, left standstill 1.5 hours, filter, crystal is with a small amount of absolute ethanol washing 3 times, in 80 ℃ of oven dry, obtain dextrorotation Serine elaboration 6.4Kg, yield is 85.3%.Detecting specific rotation is [α]
D 20=-14.0 ° (C=8,1NHCl), optical purity of products 96.2%.
Above-mentioned levo-serine crude product 7.5Kg that obtains and 30L deionized water are put in the 50L reactor together, be warmed up to 90 ℃, stirring makes its whole dissolvings, add the 200g gac, 70 ℃ of insulated and stirred 1 hour, filtered while hot, filtrate to having only about 6L, adds the 6L dehydrated alcohol at 60-70 ℃ of vacuum concentration, be cooled to 10 ℃, stirred 2 hours, left standstill 1.5 hours, filter, crystal is with a small amount of absolute ethanol washing 3 times, in 80 ℃ of oven dry, obtain levo-serine elaboration 6.2Kg, yield is 82.67%.Detecting specific rotation is [α]
D 20=+14.1 ° (C=8,1N HCl), optical purity of products 96.5%.
Claims (10)
1, a kind of induced crystallization legal system is equipped with the method for levo-serine and dextrorotation Serine, may further comprise the steps:
At first with racemize Serine and dextrorotation Serine mixed, the water that adds 2-5 times of weight, be warming up to and make its whole dissolvings about 95 ℃, cooling cooling then, and a certain proportion of dextrorotation Serine of input racemize Serine weight crystal seed, slowly cooling is filtered, and obtains dextrorotation Serine crude product after the crystal oven dry that obtains;
Replenish the racemize Serine of the dextrorotation Serine crude product equivalent that adds and obtain in filtrate, repeat above intensification, temperature-fall period, drop into the levo-serine crystal seed, slowly cooling is filtered, and the crystal that obtains obtains the levo-serine crude product after oven dry;
Above repeatedly operating process can obtain dextrorotation Serine and levo-serine crude product;
The above dextrorotation Serine crude product that obtains is dropped in the deionized water of 2-5 times of weight, be heated to 90 ℃, stirring and dissolving, add discoloring agent, at 70-80 ℃ of insulated and stirred 0.5-1 hour, heat filtering, filtrate is about following vacuum concentration to 1/5, and the dehydrated alcohol of adding and remaining liq equivalent is cooled to about 10 ℃, stirred 2-3 hour, left standstill 1-2 hour, and filtered, crystal is with a small amount of absolute ethanol washing 2-3 time, oven dry obtains dextrorotation Serine product;
Repeat above operating process and handle the levo-serine crude product, can obtain the levo-serine product.
2, induced crystallization legal system according to claim 1 is equipped with the method for levo-serine and dextrorotation Serine, it is characterized in that: the blending ratio of racemize Serine and dextrorotation Serine is 5-20: 1.
3, induced crystallization legal system according to claim 1 and 2 is equipped with the method for levo-serine and dextrorotation Serine, it is characterized in that: the blending ratio of racemize Serine and dextrorotation Serine is 10: 1.
4, induced crystallization legal system according to claim 1 is equipped with the method for levo-serine and dextrorotation Serine, it is characterized in that: the ratio that the crystal seed of input accounts for Serine total amount in the solution is 0.5-2: 100.
5, be equipped with the method for levo-serine and dextrorotation Serine according to claim 1 or 4 described induced crystallization legal systems, it is characterized in that: the ratio that the crystal seed of input accounts for Serine total amount in the solution is 0.5: 100.
6, induced crystallization legal system according to claim 1 is equipped with the method for levo-serine and dextrorotation Serine, it is characterized in that: the Tc behind the input crystal seed is 20-40 ℃.
7, be equipped with the method for levo-serine and dextrorotation Serine according to claim 1 or 6 described induced crystallization legal systems, it is characterized in that: the Tc that drops into behind the crystal seed is about 35 ℃.
8, induced crystallization legal system according to claim 1 is equipped with the method for levo-serine and dextrorotation Serine, it is characterized in that: bake out temperature is 60-90 ℃, and optimum temps is about 80 ℃.
9, induced crystallization legal system according to claim 1 is equipped with the method for levo-serine and dextrorotation Serine, it is characterized in that: used discoloring agent is adsorptivity discoloring agents such as gac, carclazyte in the refining decolorization, and used discoloring agent ratio is the 0.1-2% that accounts for material gross weight in the solution in the refining decolorization.
10, induced crystallization legal system according to claim 9 is equipped with the method for levo-serine and dextrorotation Serine, it is characterized in that: used discoloring agent ratio is to account for 0.15% of material gross weight in the solution in the refining decolorization.
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| CN100491337C CN100491337C (en) | 2009-05-27 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219705A (en) * | 2011-05-10 | 2011-10-19 | 常州工程技术职业学院 | Crystallization process of columnar crystal of L-serine and application of columnar crystal |
| CN102584613A (en) * | 2011-12-30 | 2012-07-18 | 宁波海硕生物科技有限公司 | Crystallization method for L-serine in stable crystal form |
| CN102633690A (en) * | 2012-04-11 | 2012-08-15 | 上海康福赛尔医药科技有限公司 | Method for preparing levo- and dextro-camphor sulfonic acid by induced crystallization and resolution of racemized camphor sulfonic acid |
| CN102633692A (en) * | 2012-04-11 | 2012-08-15 | 上海康福赛尔医药科技有限公司 | Method for preparing optically active L-D-3-bromocamphor-8-sulfonic acid |
-
2006
- 2006-07-17 CN CNB2006100820167A patent/CN100491337C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219705A (en) * | 2011-05-10 | 2011-10-19 | 常州工程技术职业学院 | Crystallization process of columnar crystal of L-serine and application of columnar crystal |
| CN102219705B (en) * | 2011-05-10 | 2013-07-31 | 常州工程职业技术学院 | Crystallization process of columnar crystal of L-serine and application of columnar crystal |
| CN102584613A (en) * | 2011-12-30 | 2012-07-18 | 宁波海硕生物科技有限公司 | Crystallization method for L-serine in stable crystal form |
| CN102633690A (en) * | 2012-04-11 | 2012-08-15 | 上海康福赛尔医药科技有限公司 | Method for preparing levo- and dextro-camphor sulfonic acid by induced crystallization and resolution of racemized camphor sulfonic acid |
| CN102633692A (en) * | 2012-04-11 | 2012-08-15 | 上海康福赛尔医药科技有限公司 | Method for preparing optically active L-D-3-bromocamphor-8-sulfonic acid |
| CN102633690B (en) * | 2012-04-11 | 2014-04-09 | 上海康福赛尔医药科技有限公司 | Method for preparing levo- and dextro-camphor sulfonic acid by induced crystallization and resolution of racemized camphor sulfonic acid |
| CN102633692B (en) * | 2012-04-11 | 2014-04-09 | 上海康福赛尔医药科技有限公司 | Method for preparing optically active L-D-3-bromocamphor-8-sulfonic acid |
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