CN101538251B - Novel method for synthesizing 2-amino-2-thiazoline-4-carboxylic acid - Google Patents
Novel method for synthesizing 2-amino-2-thiazoline-4-carboxylic acid Download PDFInfo
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- CN101538251B CN101538251B CN2009100149087A CN200910014908A CN101538251B CN 101538251 B CN101538251 B CN 101538251B CN 2009100149087 A CN2009100149087 A CN 2009100149087A CN 200910014908 A CN200910014908 A CN 200910014908A CN 101538251 B CN101538251 B CN 101538251B
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Abstract
The invention discloses a method for preparing 2-amino-2-thiazoline-4-carboxylic acid. 3-X-lactamine hydrochloride and sodium sulfocyanate react in medium water to generate 3-X-2-thioureido monoprop, and the 3-X-2-thioureido monoprop has a ring-closure reaction to prepare the 2-amino-2-thiazoline-4-carboxylic acid. The method is simple, convenient to operate, has high yield coefficient which is more than 95 percent, and greatly enhances the quality of products.
Description
Technical field
The present invention relates to a kind of synthetic method of fermentation precursor 2-amino-2-thiazoline-4-carboxylic acid (being called for short ATC) of L-halfcystine.
Background technology
2-amino-2-thiazoline-4-carboxylic acid, English name 2-amino-2-thiazoline-4-carboxylicacid, structural formula is as follows:
2-amino-2-thiazoline-4-carboxylic acid is a kind of racemic modification, hereinafter to be referred as (dl-ATC) ATC.ATC is widely used in field of medicaments as the precursor of synthetic halfcystine.Halfcystine is to use the hair of animal to pass through acid, alkali, enzymic hydrolysis as raw material at first, and after separating purification processes, reduction, crystallization generate halfcystine again, but there is synthetic route long, the shortcoming of complex operation, and the animal hair source is few, and raw material sources are subjected to bigger restriction.
Develop the synthetic halfcystine of a kind of route easy and simple to handle, that cost is low, will bring huge social benefit and economic benefit.At present, in the technology of report both domestic and external, relevant for the method for enzyme process catalytic hydrolysis ATC high efficiency production L-halfcystine.As, adopt the isolating voluntarily pseudomonas TS1138 of China bacterial strain, ATC produces the L-halfcystine expeditiously through the enzyme process catalytic hydrolysis, has broken for a long time offshore company to the monopolization of this technology, the transformation efficiency that DL-ATC is converted into the L-halfcystine continuously is 90%, is in technology leading in the world.In conjunction with advanced extracting method, L-halfcystine extraction yield is 86%, is better than traditional extracting method.The exploitation of enzyme process catalysis technique is promoting the Continual Improvement and the development of ATC production technology, and lot of domestic and foreign research institution is to the synthetic report widely that carried out of ATC.
U.S. Pat 4072687 (1978), the ATC synthetic method of report: with 2, use sodium-hydroxide treatment under the 3-dichloro methyl propionate room temperature, preparation 2-Lv Daibingxisuan methyl esters.Without separation, under acidic conditions, with 70 ℃ of reactions of thiocarbamide 2h, addition takes place and eliminate reaction, generate S-(2-carboxyl-2-chloroethyl) isothiourea.Use alkali (NaOH or yellow soda ash or strong aqua) in 60 ℃ of ring-closure reactions again, generate ATC, the yield of reaction reaches about 75%.Reaction formula is as follows
In " fine chemistry industry " 2002,19 (5), the 264-265 page or leaf has been reported the synthetic method of ATC: set out by vinylformic acid, through chlorination, dehydrochlorination, addition, cyclization, make amino 2-thiazoline-4 carboxylic acid (dl-ATC) of compound 2-.With the tetracol phenixin is solvent, and vinylformic acid mixes with the self-control copper base composite polymerzation inhibitor of its quality 0.23%, feeds chlorine under 50 ℃, and chlorination makes 2, the 3-Tripon.Polymerization side reactions when this method adopts self-control copper base composite polymerzation inhibitor to greatly reduce the vinylformic acid chlorination, yield reaches 86%, is 2.47 times of literature value.To react in 3 steps of back and the reaction of one-tenth one kettle way simultaneously, simplify operation.2, the 3-Tripon earlier with the sodium hydroxide of 2 times of amount of substances at 35 ℃ of reaction 5h, the thiocarbamide that adds the concentrated hydrochloric acid of 3 times of amount of substances then and wait amount of substance is in 80～83 ℃ of reaction 3h, again with the yellow soda ash of 1.5 times of amount of substances react product.Yield is brought up to more than 90% by 63% of literature value. set up method in addition, ω (dl-ATc)=96% with high performance liquid chromatography quantitative assay dl-ATc.Reaction formula is as follows
Though above several method can make 2-amino-2-thiazoline-4-carboxylic acid, but the step complexity, and yield is lower, and the quality product of preparation is lower.
Summary of the invention
Technical problem to be solved by this invention provides the method for a kind of 2-of preparation amino-2-thiazoline-4-carboxylic acid, and this method steps is simple, the yield height, and quality product obviously improves.
2-amino provided by the present invention-2-thiazoline-4-carboxylic acid synthetic method, may further comprise the steps: at first 3-X-L-Ala hydrochloride (X in the 3-X-L-Ala hydrochloride is Cl, Br or OH etc.) and Sodium Thiocyanate 99 are reacted in water medium, temperature of reaction 50-70 ℃, keep pH value in reaction 8.0-9.0, the alkali that keeps pH to use can be yellow soda ash, salt of wormwood, triethylamine or pyridine etc., reaction times 2.8-3.2h can make like this and contains 3-X-2-thioureido propionic acid (X is Cl, Br or OH etc.) reaction solution; Can separate and directly carry out the next step, be available hydrochloric acid conditioned reaction liquid pH value 6.0-7.5, be warmed up to 80-100 ℃, insulation ring-closure reaction 1.8-2.2h, be cooled to 35-45 ℃ of crystallization afterwards, crystallization can be adopted and add crystal seed or friction wall induced crystallization, continues to cool to 0-10 ℃ afterwards again, hold-time greater than 30min after, filtration washing gets product 2-amino-2-thiazoline-4-carboxylic acid.
With the oven dry of the product that obtains, in the dry product molar yield greater than 95%.
The association reaction equation, concrete preparation method is as follows:
The preparation of 3-X-2-thioureido propionic acid:
3-X-L-Ala hydrochloride (X is Cl, Br or OH etc.) is added and dissolves in the entry, the sodium sulfocynanate solid of amount such as interpolation again, can at room temperature carry out, mix 10-15min afterwards, regulate pH to 8.0-9.0, be warmed up to 50-70 ℃ as 60 ℃ with yellow soda ash, and keep the pH value to react 2.8-3.2h such as 3h down in 50-70 ℃, obtain the light yellow reaction solution of 3-X-2-thioureido propionic acid,, be directly used in the next step without isolation of intermediate products;
The preparation of 2-amino-2-thiazoline-4-carboxylic acid:
Dripping hydrochloric acid such as 6mol/L hydrochloric acid soln in the reaction solution that obtains, regulate pH to 6.0-7.5, continue to be warmed up to 80-100 ℃ again, keep temperature, carry out ring-closure reaction 1.8-2.2h such as 2h, cool to 35-45 ℃ afterwards, add crystal seed or friction wall induced crystallization, continue to cool to 0-10 ℃ again, keep more than the 30min, filter, a small amount of cold water washing of product obtains 2-amino-2-thiazoline-4-carboxylic acid.
The production method of 2-amino of the present invention-2-thiazoline-4-carboxylic acid, the 3-X-2-thioureido propionic acid that utilizes 3-X-L-Ala hydrochloride and Sodium Thiocyanate 99 to react generation in WATER AS FLOW MEDIUM carries out ring-closure reaction and prepares 2-amino-2-thiazoline-4-carboxylic acid, method is simple, be convenient to operation, the yield height, its yield has improved quality product greatly greater than 95%.
Embodiment
Below in conjunction with embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1:
After in the 500ml there-necked flask, adding 3-chloro-L-Ala hydrochloride 80g (0.5mol) and 300ml water stirring and dissolving, in reaction flask, add sodium sulfocynanate solid 41g (0.5mol) again, at room temperature continue to mix 15min, regulate pH8.0-9.0 with yellow soda ash, heating in water bath to 60 ℃, and continue to keep pH with yellow soda ash, yellow soda ash 29-30g consumed altogether, in 60 ℃ of reaction 3h, obtain the light yellow reaction soln of 3-chloro-2-thioureido propionic acid.In reaction solution, drip concentrated hydrochloric acid with constant pressure funnel, regulate pH to 6.0-7.5.Be warmed up to 90 ℃ again, keep 90 ℃ of reactions, carry out ring-closure reaction 2h, reaction finishes, when cooling to 40 ℃,, can add small amount of seeds or friction wall induced crystallization in order to accelerate crystallization speed, after having more crystallization to produce, continue to cool to 0-5 ℃ again, the maintenance temperature is filtered after continuing reaction 35min, use the 100ml cold water washing, obtain 2-amino-2-thiazoline-4-carboxylic acid.Product is at vacuum drying oven, and 50-60 ℃ dry down, obtains dry product 69.4g, yield 95%.
Embodiment 2:
In the 500ml there-necked flask, add 3-hydroxyl-L-Ala hydrochloride 52.6g (0.5mol) and 300mol water stirring and dissolving, in reaction flask, add sodium sulfocynanate solid 41g (0.5mol) again, mix 15min under the room temperature, regulate pH8.5-9.0 with yellow soda ash 29g approximately, be warmed up to 65 ℃, and keep temperature to continue reaction 2.8h, obtain the light yellow reaction soln of 3-hydroxyl-2-thioureido propionic acid, in reaction solution, drip concentrated hydrochloric acid, regulate pH to 7.0-7.5, be warmed up to 100 ℃ again, insulation ring-closure reaction 1.8h.Reaction finishes, and cools to 38 ℃, adds the crystal seed induced crystallization, continues to cool to 5-10 ℃ again, keep 32min, filter afterwards, product 100ml cold water washing obtains 2-amino-2-thiazoline-4-carboxylic acid, 50-60 ℃ of following vacuum-drying gets finished product 69.5g, yield 95.2%.
Embodiment 3:
In the 500ml there-necked flask, add 3-bromo-L-Ala hydrochloride 84g (0.5mol) and 300ml water stirring and dissolving, add sodium sulfocynanate solid 41g (0.5mol), mix 10min under the room temperature, regulate pH to 8.0-8.5 with yellow soda ash, be warmed up to 55 ℃, and keep pH, react 3.2h down in 55 ℃.Obtain the reaction soln of 3-bromo-2-thioureido propionic acid.In reaction solution, drip concentrated hydrochloric acid, regulate pH to 6.0-6.5.Be warmed up to 85 ℃, insulation ring-closure reaction 2.2h.Reaction finishes, and when cooling to 45 ℃, friction wall induced crystallization continues to cool to 4-6 ℃ again, keep 35min, filter, product 100ml cold water washing obtains 2-amino-2-thiazoline-4-carboxylic acid, 50-60 ℃ of following vacuum-drying obtains finished product 72g, product yield 97.3%.
Claims (3)
1.2-amino-2-thiazoline-4-carboxylic acid synthetic method is characterized in that may further comprise the steps: 3-X-L-Ala hydrochloride and Sodium Thiocyanate 99 are reacted in water medium, and temperature of reaction 50-70 ℃, reaction keeps pH value 8.0-9.0, reaction times 2.8-3.2h; Conditioned reaction liquid pH value 6.0-7.5 is warmed up to 80-100 ℃ then, and insulation ring-closure reaction 1.8-2.2h is cooled to 35-45 ℃ of crystallization afterwards, continues to cool to 0-10 ℃ again, the hold-time greater than 30min after, filtration washing gets 2-amino-2-thiazoline-4-carboxylic acid; Wherein, the X in the described 3-X-L-Ala hydrochloride is Cl, Br or OH.
2. 2-amino as claimed in claim 1-2-thiazoline-4-carboxylic acid synthetic method, it is characterized in that: react in water medium when keeping pH value in reaction 8.0-9.0 at 3-X-L-Ala hydrochloride and Sodium Thiocyanate 99, keeping the alkali of pH value use is yellow soda ash, salt of wormwood, triethylamine or pyridine.
3. 2-amino as claimed in claim 1 or 2-2-thiazoline-4-carboxylic acid synthetic method is characterized in that: crystallization is adopted and is added crystal seed or friction wall induced crystallization.
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Effective date of registration: 20160323 Address after: 262737 Shandong city of Weifang province Lingang Industrial Park, Binhai Economic Development Zone, Binhai Avenue No. 0199 Patentee after: SHANDONG SUNWIN BIOTECHNOLOGY CO., LTD. Address before: 261061 Shandong province Weifang city Weifang high tech Zone East Road Room 701 sail business in Hong Kong Patentee before: Sunwin Chemicals Co., Ltd. |