CN1609097A

CN1609097A - Serine synthesizing process

Info

Publication number: CN1609097A
Application number: CN 200310110759
Authority: CN
Inventors: 蔡艳
Original assignee: Individual
Current assignee: Individual
Priority date: 2003-10-21
Filing date: 2003-10-21
Publication date: 2005-04-27

Abstract

The present invention reveals new serine synthesizing process. Cheap cystine used as initial material is synthesized into serine in high value through esterification, halogenation and saponification. The said process is simple, practical and suitable for industrial production, and has the ultimate product L-serine without needing splitting, low production cost, and overall serine yield over 80 %.

Description

A kind of synthetic method of Serine

The present invention relates to a kind of synthetic method of amino acid whose synthetic method, especially Serine.

The production technology of L-Serine comprises that roughly precursor adds fermentation method, chemical synthesis, useless silk hydrolysis extraction method at present.The L-Serine is in the mid-way of amino acid metabolism, participate in the synthetic of many biological substances, the metabolism running speed is exceedingly fast, therefore, very difficult (" technical study of fermentative Production Serine ", " biological medicine technology of preparing " of direct fermentation production, Li Liangzhu, Chinese Medicine science and technology press, 2000,11, P127).Chemical synthesis can only obtain DL-serine, obtain the L-Serine and also must carry out the chemistry fractionation.Concrete synthetic method is broadly divided into three classes: be the synthesis method of raw material with the glycollic aldehyde; Utilize the synthesis method of various condensation reactions; With the vinyl compound is the synthesis method of raw material.In addition, also have some synthesis methods not in these three class methods (" synthetic method of Serine ", Wuhan University biological study chamber, " amino acid industry magazine ", 1986,12, P25).The L-serine content is the abundantest in the useless silk cocoon, therefore, can extract the L-Serine with hydrolysis method.This method also is the main method that China produces the L-Serine.But because silk cocoon costs an arm and a leg (about 45000 yuan/ton), its production cost is very high, and yield is low excessively, and acid production rate has only about 4%; Other production technique are ubiquity cost height also, the problem that yield is low, and final product is a DL-serine, to on the basis of this raceme, split and produce L-Serine technical sophistication, cost is too high, cause China up to the present,, rely on external import basically still belonging to blank aspect the research of the very big L-Serine of the market requirement and the production.

Purpose of the present invention is exactly in order to overcome so far cost height in the synthetic production of Serine both at home and abroad, the low deficiency that waits of yield, with cheap Gelucystine is the starting point raw material, by esterification, halo, the method of the simple and feasible and suitable industrial mass manufacture of the Serine of the synthetic high price of saponification reaction when improving yield, also greatly reduces production cost.

The present invention is to be raw material with the Gelucystine, through the synthetic method of intermediate product cystine dimethyl dihydrochloride and β-chloro alanine methyl ester hydrochloride.Wherein the preparation of cystine dimethyl dihydrochloride is that methyl alcohol (technical grade) is placed three mouthfuls of reaction flasks of exsiccant, bathe under the refrigerative situation at cryosel, add Gelucystine and sulfur oxychloride, stirring reaction is about 12 hours, remove cooling system, heating in water bath refluxes, and makes it to react completely, and follows the tracks of with TLC (thin-layer chromatography) and detects, after reacting completely (about 16 hours reaction times), when being evaporated to original volume 1/2, leave standstill crystallization, collect dry.The preparation of β-chloro alanine methyl ester hydrochloride is that the cystine dimethyl dihydrochloride is dissolved in the chloroform medium, feed chlorine, carry out chlorination under the low-temperature atmosphere-pressure, finishing of halogenating reaction can be passed through TLC (thin-layer chromatography) tracking and measuring, the time of halogenating reaction is about 48 hours, adds a small amount of ether after halogenating reaction is finished in reaction solution, blasts dry air, drive unnecessary halogen and HCL away, separate out product under the normal temperature.The synthetic of Serine is that the β-chloro alanine methyl ester hydrochloride that will make is dissolved among the 2N NaOH, slough ester group after, regulate pH to 6.5 with rare HCL again, the upper prop desalination, concentrated crystallization promptly gets the L-Serine.

Wherein in the preparation of cystine dimethyl dihydrochloride, the consumption mol ratio of methyl alcohol and Gelucystine is 5: 1, and the consumption mol ratio of sulfur oxychloride and Gelucystine is 1～0.7: 1.The temperature of reaction of preparation β-chloro alanine methyl ester hydrochloride be-15 ℃-5 ℃, and cystine dimethyl dihydrochloride and halogen consumption such as are at mol ratio, and the volume of adding ether is roughly 15% of reaction solution in reaction solution.

The present invention is raw materials used to be Gelucystine, cheap, and final product is exactly the L-Serine, need not split, and production cost is significantly reduced.The first step reaction purity of the present invention can reach 99%, and yield reaches 96%, and the W-response acid production rate reaches 80% at least, and its technology maintains the leading position.

Now every index of the present invention and at present domestic and international various production methods are done one relatively, see the following form.

Compare index item	The present invention	Extraction method (domestic)	Extraction method (abroad)	Fermentation method	The thanomin synthesis method	Propylene cyanogen synthesis method
Compare index item	The present invention	Extraction method (domestic)	Extraction method (abroad)	Fermentation method	The thanomin synthesis method	Propylene cyanogen synthesis method	Starting raw material	Gelucystine	Silk	Silk	Glycine	Thanomin	Propylene cyanogen
The unit cost of production (ten thousand yuan/ton)	＜20	≥60	≥50	≥70	50	50～55	Starting raw material	Gelucystine	Silk	Silk	Glycine	Thanomin	Propylene cyanogen
The unit cost of production (ten thousand yuan/ton)	＜20	≥60	≥50	≥70	50	50～55	Yield	＞80％	4％	4％～5％	2％～5％	60％	50％～60％
Toxicity	Less	Less	Less	Less	Very big	Very big	Yield	＞80％	4％	4％～5％	2％～5％	60％	50％～60％
Toxicity	Less	Less	Less	Less	Very big	Very big	Produce acid energy	Fine	Better	Better	Bad	Generally	Generally
Reaction time	4 days	7 days	7 days	10～11 days	10 days	10 days	Produce acid energy	Fine	Better	Better	Bad	Generally	Generally

As can be seen from the table, compare with production method both domestic and external, technical costs of the present invention is low, yield is high, toxicity is little, and over-all properties is splendid.

Embodiment

In reaction flask, add methyl alcohol 320mL, bathe under the refrigerative situation at cryosel, add Gelucystine 24g (0.1 mole) and sulfur oxychloride 67mL, about stirring reaction 12 hours, remove cooling system, heating in water bath refluxes, make it to react completely, follow the tracks of with TLC (thin-layer chromatography) and detect, after reacting completely (about 16 hours reaction times), when being evaporated to original volume 1/2, leave standstill and promptly get cystine dimethyl dihydrochloride crystal, collect drying, get its cystine dimethyl dihydrochloride 36.9g (0.11 mole) that makes and be dissolved in the 400mL trichloromethane, in below 0 ℃, feed 0.12 mole of chlorine, finishing of halogenating reaction can be passed through TLC (thin-layer chromatography) tracking and measuring, about 48 hours of halogenating reaction time, after finishing, halogenating reaction in reaction solution, adds the 60mL ether, blast dry air, drive unnecessary halogen and HCL away, separate out β-chloro alanine methyl ester hydrochloride under the normal temperature.β-chloro alanine methyl ester the hydrochloride that makes is dissolved among the 2N NaOH, slough ester group after, regulate pH to 6.5 with rare HCL again, the upper prop desalination, concentrated crystallization promptly gets the L-Serine.

Claims

1, a kind of synthetic method of Serine is characterized in that with the Gelucystine being raw material, through intermediate product cystine dimethyl dihydrochloride, and the synthetic method of β-chloro alanine methyl ester hydrochloride:

(1) preparation of cystine dimethyl dihydrochloride: methyl alcohol (technical grade) is placed three mouthfuls of reaction flasks of exsiccant, bathe under the refrigerative situation at cryosel, add Gelucystine and sulfur oxychloride, stirring reaction is about 12 hours, remove cooling system, heating in water bath refluxes, and makes it to react completely, and follows the tracks of with TLC (thin-layer chromatography) and detects, after reacting completely (about 16 hours reaction times), when being evaporated to original volume 1/2, leave standstill crystallization, collect dry;

(2) preparation of β-chloro alanine methyl ester hydrochloride: the cystine dimethyl dihydrochloride is dissolved in the chloroform medium, feed chlorine, carry out chlorination under the low-temperature atmosphere-pressure, finishing of halogenating reaction can be passed through TLC (thin-layer chromatography) tracking and measuring, the time of halogenating reaction is about 48 hours, adds a small amount of ether after halogenating reaction is finished in reaction solution, blasts dry air, drive unnecessary halogen and HCL away, separate out product under the normal temperature;

(3) Serine is synthetic: the β-chloro alanine methyl ester hydrochloride that makes is dissolved among the 2N NaOH, slough ester group after, again with rare HCL adjusting pH to 6.5, the upper prop desalination, concentrated crystallization promptly gets the L-Serine.

2, the synthetic method of Serine as claimed in claim 1 is characterized in that in the preparation of cystine dimethyl dihydrochloride that the consumption mol ratio of methyl alcohol and Gelucystine is 5: 1.

3,, the synthetic method of Serine as claimed in claim 1 is characterized in that in the preparation of cystine dimethyl dihydrochloride that the consumption mol ratio of sulfur oxychloride and Gelucystine is 1～0.7: 1.

4, the synthetic method of Serine as claimed in claim 1 is characterized in that the temperature of reaction for preparing β-chloro alanine methyl ester hydrochloride is-15 ℃-5 ℃.

5, the synthetic method of Serine as claimed in claim 1, when it is characterized in that preparing β-chloro alanine methyl ester hydrochloride, cystine dimethyl dihydrochloride and halogen consumption such as are at mol ratio.

6, the synthetic method of Serine as claimed in claim 1, after the halogenating reaction that it is characterized in that preparing β-chloro alanine methyl ester hydrochloride was finished, the volume that adds ether in reaction solution was roughly 15% of reaction solution.