CN1095832C - Splitting of DL-threo-p-methylsulfonyl methyl serine ester - Google Patents
Splitting of DL-threo-p-methylsulfonyl methyl serine ester Download PDFInfo
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- CN1095832C CN1095832C CN00134953A CN00134953A CN1095832C CN 1095832 C CN1095832 C CN 1095832C CN 00134953 A CN00134953 A CN 00134953A CN 00134953 A CN00134953 A CN 00134953A CN 1095832 C CN1095832 C CN 1095832C
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- China
- Prior art keywords
- shi
- ester
- methylsulfonyl
- methylsulfonyl phenserine
- phenserine
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention belongs to the split technology of DL-threo-p-methylsulfonyl methyl serine ester. In the split technology, (R)-tetrahydrothiazole-2-thione-4-carboxylic acid ((R)-TTCA) as a splitting reagent is used for splitting the DL-threo-p-methylsulfonyl methyl serine ester. Raw materials for synthesizing the (R) TTCA is easy to acquire, the cost is low and a split process is simple. The optical purity of D-(+)-threo-p-methylsulfonyl methyl serine ester and L-(-)-threo-p-methylsulfonyl methyl serine ester which are obtained by splitting can reach 98.0%, and the yield is more than 85.0%.
Description
The present invention belongs to DL-Su Shi-to the disassemble technique of methylsulfonyl Phenserine ester.
Having optically active D-(+)-Su Shi-to methylsulfonyl Phenserine ester is the important intermediate of the active and thiamphenicol medicine that scope is similar to paraxin of synthetic antimicrobial; Therefore, about the DL-Su Shi-method for splitting of methylsulfonyl Phenserine ester is subject to people's attention.
DL-Su Shi-to the fractionation of methylsulfonyl Phenserine ester generally is to adopt (+)-tartrate [Japan's special permission is open, clear 50-137,952 (1975); Chinese Journal of Pharmaceuticals, 1979,10 (5): 1] split for resolution reagent.The method of this fractionation is that the different solubility in methyl alcohol is successively separated out according to diastereomer (+) the tartrate ammonium salt that obtains.Its shortcoming is: (+) tartrate: the mol ratio of DL-amino ester is 1: 1, and the lock out operation in methyl alcohol is cumbersome, and influences the optical purity and the productive rate of product.
The present invention with (R)-thiazolidinethion-2-4-carboxylic acid [be called for short (R) TTCA] for resolution reagent to DL-Su Shi-methylsulfonyl Phenserine ester is split.Be characterized in: (R) TTCA is that a kind of chiral reagent is used in the fractionation of DL-Su Shi-to methylsulfonyl Phenserine ester first; Its synthetic method is simple, and raw material is easy to get, and cost is low, and the mol ratio of reaction is 1: 2; Simple to operate, separate easily.
D-(+)-Su Shi that fractionation obtains-to methylsulfonyl Phenserine ester and L-(-)-Su Shi-to methylsulfonyl Phenserine ester productive rate is that optical purity reaches more than 98.0% more than 85.0%.
The present invention is dissolved in organic solvent ethanol or methyl alcohol, chloroform, ethyl acetate, acetone, dimethylbenzene etc. with (R) TTCA, 20～120 ℃ of reactions down, general temperature of reaction is under 40～80 ℃, be added drop-wise to the DL-Su Shi of corresponding organic solvent dissolution-in the methylsulfonyl Phenserine ester solution, drip the back and continue reaction 10～90 minutes, general continuation reaction was controlled at 30～50 minutes, generate a large amount of white precipitates, filter out white solid for (R) TTCAD-(+)-Su Shi-to the ammonium salt of methylsulfonyl Phenserine ester, productive rate reaches more than 98.0%.
Filtrate is used anhydrous Na
2SO
4Drying steams organic solvent, obtains that optically active L-(-)-Su Shi-to methylsulfonyl Phenserine ester, productive rate reaches more than 90.0%, and optical purity is more than 98.0%.
With (R) TTCAD-(+)-Su Shi-to methylsulfonyl Phenserine ester ammonium salt with water dissolution, with NH
4OH solution is neutralized to pH=7～8, has a large amount of white precipitates to separate out, and leaches precipitation, and filter cake is given a baby a bath on the third day after its birth time with less water, D-(+)-Su Shi-to methylsulfonyl Phenserine ester, productive rate reaches more than 85%, optical purity reaches more than 98.0%.
Embodiment 1: with 0.1640g (1mmol) (R) TTCA be dissolved in the 10mL ethanol, be added dropwise under 50 ℃ of stirrings in the ethanol that 10mL is dissolved with 0.5747g (2mmol) DL-Su Shi-to methylsulfonyl Phenserine ethyl ester, continue reaction 30 minutes after dripping, system produces a large amount of white precipitates, filter to such an extent that white solid is (R) TTCAD-(+)-Su Shi-to methylsulfonyl Phenserine ethyl ester ammonium salt, productive rate 98.20%, [a]
D 20-46.24 ° (c 0.20, H
2O), m.p.159～160 ℃.
Filtrate is with anhydrous Na
2SO
4Drying steams ethanol, L-(-)-Su Shi-to methylsulfonyl Phenserine ethyl ester, productive rate 94.60%, [a]
D 20-15.10 ° (c 0.20,1, the 4-dioxane), m.p.129～131 ℃.
With (R) TTCAD-(+)-Su Shi-to methylsulfonyl Phenserine ethyl ester ammonium salt water dissolution, with dense NH
4OH pH=7～8 that neutralize leach white solid and are product D-(+)-Su Shi-to methylsulfonyl Phenserine ethyl ester, and productive rate is more than 85%, [a]
D 20+ 15.21 ° (c 0.25,1, the 4-dioxane), 129～131 ℃ of m.p.
Embodiment 2: changing solution ethanol is methyl alcohol, other prescription, reaction conditions are fully identical with embodiment 1, result (R) TTCAD-(+)-Su Shi-to methylsulfonyl Phenserine ethyl ester ammonium salt, productive rate 98.40%, L-(-)-Su Shi-to methylsulfonyl Phenserine ethyl ester, productive rate 98.00%.
Embodiment 3: changing solution ethanol is chloroform, other prescription, reaction conditions are fully identical with embodiment 1, result (R) TTCAD-(+)-Su Shi-to methylsulfonyl Phenserine ethyl ester ammonium salt, productive rate 98.30%, L-(-)-Su Shi-to methylsulfonyl Phenserine ethyl ester, productive rate 97.00%.
Embodiment 4: changing solution ethanol is ethyl acetate, other prescription, reaction conditions are fully identical with embodiment 1, result (R) TTCAD-(+)-Su Shi-to methylsulfonyl Phenserine ethyl ester ammonium salt, productive rate 98.30%, L-(-)-Su Shi-to methylsulfonyl Phenserine ethyl ester, productive rate 96.10%.
Embodiment 5: changing solution ethanol is acetone, other prescription, reaction conditions are fully identical with embodiment 1, result (R) TTCAD-(+)-Su Shi-to methylsulfonyl Phenserine ethyl ester ammonium salt, productive rate 98.25%, L-(-)-Su Shi-to methylsulfonyl Phenserine ethyl ester, productive rate 95.00%.
Embodiment 6: changing solution ethanol is dimethylbenzene, other prescription, reaction conditions are fully identical with embodiment 1, result (R) TTCAD-(+)-Su Shi-to methylsulfonyl Phenserine ethyl ester ammonium salt, productive rate 98.20%, L-(-)-Su Shi-to methylsulfonyl Phenserine ethyl ester, productive rate 94.10%.
Claims (2)
1, a kind of DL-Su Shi-to the method for splitting of methylsulfonyl Phenserine ester, it is characterized in that: with resolution reagent (R)-thiazolidinethion-2-4-hydroxy acid to DL-Su Shi-methylsulfonyl Phenserine ester is split, (R)-thiazolidinethion-2-4-hydroxy acid and DL-Su Shi-be 1: 2 to the reaction mol ratio of methylsulfonyl Phenserine ester; Temperature of reaction is 20～120 ℃; Reaction medium is selected from: CH
3OH, C
2H
5OH, CHCl
3, CH
3COOC
2H
5, CH
3COCH
3Or the organic solvent of dimethylbenzene; Reacted 10～90 minutes, and generated a large amount of white precipitates, filter out white solid and be (R)-thiazolidinethion-2-4-hydroxy acid D-(+)-Su Shi-the ammonium salt of methylsulfonyl Phenserine ester; Filtrate is washed with the saturated NaCl aqueous solution, the organic layer anhydrous Na
2SO
4Drying steams organic solvent and obtains optically active L-(-)-Su Shi-to methylsulfonyl Phenserine ester; (R)-thiazolidinethion-2-4-hydroxy acid D-(+)-Su Shi-to the ammonium salt of methylsulfonyl Phenserine ester is with water dissolution, uses NH
4OH solution transfers to pH=7～8, and to leach white solid be product D-(+)-Su Shi-to methylsulfonyl Phenserine ester.
2, DL-Su Shi as claimed in claim 1-to the method for splitting of methylsulfonyl Phenserine ester, it is characterized in that temperature of reaction is 40～80 ℃, the reaction times is 30～50 minutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00134953A CN1095832C (en) | 2000-12-12 | 2000-12-12 | Splitting of DL-threo-p-methylsulfonyl methyl serine ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00134953A CN1095832C (en) | 2000-12-12 | 2000-12-12 | Splitting of DL-threo-p-methylsulfonyl methyl serine ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1302798A CN1302798A (en) | 2001-07-11 |
| CN1095832C true CN1095832C (en) | 2002-12-11 |
Family
ID=4596498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00134953A Expired - Fee Related CN1095832C (en) | 2000-12-12 | 2000-12-12 | Splitting of DL-threo-p-methylsulfonyl methyl serine ester |
Country Status (1)
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| CN (1) | CN1095832C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104326901B (en) * | 2014-10-16 | 2016-09-07 | 安徽扬子化工有限公司 | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production |
| CN104355990B (en) * | 2014-10-16 | 2016-09-07 | 安徽扬子化工有限公司 | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production |
| CN107417585B (en) * | 2017-06-22 | 2019-05-03 | 浙江海翔川南药业有限公司 | A kind of synthetic method of pharmaceutical intermediate |
| CN108642120A (en) * | 2018-05-23 | 2018-10-12 | 山东汉兴医药科技有限公司 | A kind of preparation method of D- D-4-methylsulfonylphserine serine ethyl esters |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05202471A (en) * | 1992-01-28 | 1993-08-10 | Fujitsu Ltd | Magnetron sputtering apparatus |
-
2000
- 2000-12-12 CN CN00134953A patent/CN1095832C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05202471A (en) * | 1992-01-28 | 1993-08-10 | Fujitsu Ltd | Magnetron sputtering apparatus |
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| CN1302798A (en) | 2001-07-11 |
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