CN102863326A - Preparation method of antiepileptic drug intermediate - Google Patents
Preparation method of antiepileptic drug intermediate Download PDFInfo
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- CN102863326A CN102863326A CN201210073587XA CN201210073587A CN102863326A CN 102863326 A CN102863326 A CN 102863326A CN 201210073587X A CN201210073587X A CN 201210073587XA CN 201210073587 A CN201210073587 A CN 201210073587A CN 102863326 A CN102863326 A CN 102863326A
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Abstract
The invention relates to a preparation method of an antiepileptic drug intermediate 3-isobutyl glutaric acid. The preparation method includes that cyanoacetic acid ester ammonia is decomposed to obtain cyanoacetamide, condensation is performed on the cyanoacetamide and isovaleraldehyde to generate 2, 4-dicyan-3-isobutyl glutaric acid amide, the 2, 4-dicyan-3-isobutyl glutaric acid amide is hydrolysed and decarboxylated to obtain the 3-isobutyl glutaric acid, and total yield in the three steps can reach 77%. The preparation method of the antiepileptic drug intermediate is simple to operate, intermediate products and end products can be separated out easily from reaction, and the preparation method is low in cost and suitable for industrial production.
Description
Technical field:
The present invention relates to a kind of preparation method of antiepileptic drug pregabalin intermediate 3-isobutylglutaric acid, belong to medical technical field.
Background technology:
Lyrica (pregabalin, PGB) is novel γ-aminobutyric acid (GABA) receptor stimulant by Pfizer's exploitation.(S)-and lyrica, with trade(brand)name LYRICA listing, be a kind of to the sick specific neurotransmitter conditioning agent for the treatment of neuropathic pain, epilepsy and anxiety.
It is reported that the anticonvulsant action of racemize lyrica mainly is attributed to (S)-isomer (Bioorg.Med.Chem.Lett., 1994,4,823), (R)-the isomer lyrica almost do not have anticonvulsant action.Therefore, commercial applications requires to prepare high optically pure (S)-lyrica with effective means.
The preparation method of (the S)-lyrica of bibliographical information mainly contains following several:
Method one: US Patent No. 5599973 has been reported and has been used stoichiometric 4-methyl-5-phenyl-2-oxazolidone as chiral auxiliary(reagent) preparation (S)-lyrica, chiral auxiliary(reagent) can reclaim, but reaction scheme is long, multistep needs low temperature, side reaction is many, total recovery is low, so this route is not suitable for suitability for industrialized production.
Method two: reported in the US Patent No. 0212290 take the acrylonitrile that replaces as substrate and carried out asymmetric hydrogenation, obtain the cyano group precursor of 8-(S)-3-(amino methyl)-5-methylhexanoic acid, then hydrolysis, the cyano group that reduces at last obtains (S)-lyrica, and synthetic route is as follows:
The method needs expensive asymmetric catalyst, and need under high pressure use carbon monoxide, therefore is not suitable for suitability for industrialized production.
Method three: US Patent No. 5616793, reported take ethyl cyanoacetate as starting raw material, through Knoevenage, Michael addition, hydrolysis decarboxylation obtain 3-isobutylglutaric acid, then cyclization, the ammonia solution, Hoffmann degradation, hand-type splits and obtains final product (S)-lyrica, and synthetic route is as follows:
This synthetic route is the route that generally adopts in the present industrialization, but the first step Knoevenage condensation difficulty is carried out, need long-time dehydration, product directly carries out Michael addition without separating, then hydrolysis obtains the 3-isobutylglutaric acid, causing 3-isobutylglutaric acid purity low is oily matter, is difficult for separating out, and has therefore limited large-scale commercial production.
Lyrica is list marketing, therefore in the urgent need to a kind of simple to operate, cost is low, be fit to scale operation and can guarantee the method for the synthetic 3-isobutylglutaric acid of quality product.
Summary of the invention:
The technical problem that the present invention mainly solves: develop a kind of method for preparing lyrica important intermediate 3-isobutylglutaric acid, the method requires simple to operate, and equipment requirements is low, and cost is low, good product quality, and be applicable to suitability for industrialized production.
For overcoming the above problems, the invention provides following technological line:
The preparation method of formula (I) Malonamide nitrile: comprise that cyanoacetate compounds and the nitrogenous reagent of alkalescence carry out the ammonia solution at a certain temperature, make Malonamide nitrile (I).The cyanoacetate compounds refers to methyl cyanoacetate, ethyl cyanoacetate, cyanoacetic acid isopropyl ester, the cyanoacetic acid tert-butyl ester, cyanoacetic acid benzyl ester in the method; Described alkaline nitrogenous reagent is selected from ammoniacal liquor, urea, bicarbonate of ammonia and ammonium acetate; The mol ratio 1 of cyanoacetate and alkali: 0.5-2; Ammonia solution temperature is 0-100 ℃.In the method for more preferred preparation formula (I), the cyanoacetate compounds is methyl cyanoacetate and ethyl cyanoacetate; Described alkali is ammoniacal liquor; The mol ratio of cyanoacetate and alkali is 1: 0.8-1.2; Ammonia solution temperature is 0-10 ℃.
Formula (II) 2, the preparation method of 4-dicyano-3-isobutyl-glutaramide: comprise that Malonamide nitrile and isovaleric aldehyde carry out condensation reaction under alkaline condition.Used alkali is selected from ammoniacal liquor, triethylamine, diethylamine, sodium hydroxide, potassium hydroxide, sodium ethylate, alkaline ammonium salt in the method; The alkalescence ammonium salt is selected from bicarbonate of ammonia, ammonium acetate; The mol ratio of Malonamide nitrile and isovaleric aldehyde and alkali is 1: 0.05-1: 0.05-2; Used solvent is methyl alcohol, ethanol, Virahol, propyl carbinol, water, ethyl acetate in the method; Described setting-up point is-5 ℃-100 ℃.More preferably in the method for preparation formula (II), used alkali is selected from ammoniacal liquor, triethylamine, diethylamine; The mol ratio of Malonamide nitrile and isovaleric aldehyde and alkali is 1: 0.1-0.8: 0.05-1; Selected solvent is methyl alcohol, ethanol, Virahol, propyl carbinol, water; Described setting-up point is-5 ℃-50 ℃.In the method for more preferred preparation formula (II), used alkali is selected from triethylamine, diethylamine; The mol ratio of Malonamide nitrile and isovaleric aldehyde and alkali is 1: 0.3-0.6: 0.05-0.1; Selected solvent is methyl alcohol, ethanol, water; Described setting-up point is-5 ℃-10 ℃.
The preparation method of formula (III) 3-isobutylglutaric acid: comprise the reaction that in acid, under suitable temperature, is hydrolyzed of 2,4-dicyano-3-isobutyl-glutaramide (II).Described acid is selected from sulfuric acid, hydrochloric acid, Hydrogen bromide, glacial acetic acid; Hydrolysis temperature is 0-100 ℃; The mol ratio of 2,4-dicyano-3-isobutyl-glutaramide and acid is 1: 1-10.In the method for more preferred preparation formula (III), described acid is hydrochloric acid; Hydrolysis temperature is 80-110 ℃; The mol ratio of 2,4-dicyano-3-isobutyl-glutaramide and acid is 1: 8-10.
The present invention prepares the method for lyrica important intermediate 3-isobutylglutaric acid, and have three class advantages: 1) the method is simple to operate, need not specific installation, such as the low-temp reaction still, reaction conditions is gentle, and without the larger solvent of toxicity, solvent for use all is alcohol or the water of low carbon chain.2) do not have difficult intermediate or the end product that separates in the preparation process of the present invention, gained intermediate product and end product are all easily separated out from reaction solvent.3) to prepare 3-isobutylglutaric acid cost low for this route, and what the inventive method was used all is raw materials cheap and easy to get, thereby is suitable for suitability for industrialized production.The present invention includes a kind of new compound 2,4-dicyano-3-isobutyl-glutaramide, its hydrolyzable is pregabalin intermediate 3-isobutylglutaric acid.
Embodiment:
Help to understand the present invention by following embodiment, but do not limit content of the present invention.Raw material and reagent related among the embodiment are commercially available.
Embodiment one
1) preparation of Malonamide nitrile:
Ethyl cyanoacetate (100.0g, 0.88mol) and dehydrated alcohol (100mL, 1.72mol) are placed reaction flask, system is cooled to 5 ℃ with ice bath.Begin to pass into ammonia, remove ice bath, along with the temperature of reaction that passes into of ammonia slowly raises, the speed of the logical people's ammonia of control is not overflowed ammonia, reaches 32 ℃ of temperature, continues water bath heat preservation reaction 5h.Cooling, suction filtration, and with the on a small quantity repeatedly drip washing of dehydrated alcohol of cooling, product is dried, and obtains white solid 71.6g, yield: 96.4%, m.p.119-120 ℃.
2) 2, the preparation of 4-dicyano-3-isobutyl-glutaramide:
With above-mentioned Malonamide nitrile (100.0g, 1.2mol) and water 650mL place reaction flask, heating for dissolving, ice bath cools off near 0 ℃, adds triethylamine 34mL and the isovaleric aldehyde (52.0g of catalytic amount, 0.6mol), the reaction system heat release keeps temperature of reaction at 3-5 ℃ with ice bath, uses TLC in the reaction process and monitors that (developping agent is ethyl acetate: methyl alcohol: sherwood oil=4: 1: 1), reaction 4h, the continuous adularescent solid of reaction system is separated out in reaction process.Suction filtration, cold water washing, oven dry obtains white solid 126.0g, yield: 90.5%, m.p.153-155 ℃.
3) preparation of 3-isobutylglutaric acid:
Get the condenses (75.0g of above-mentioned preparation, 0.39mol), and concentrated hydrochloric acid and water difference 185mL, under constantly stirring, reflux 8h, reaction solution is cooled to 0 ℃, separates out a large amount of inorganic salt, suction filtration, filter cake extracts with ethyl acetate backflow, heat filtering, filtrate is used ethyl acetate extraction 4-5 time, merges organic phase and also uses anhydrous magnesium sulfate drying.Reclaim solvent after siccative filtered, be concentrated into and product proportion 1: 1, be cooled to-15 ℃, product is separated out, suction filtration, and with the washing of cold ethyl acetate, filtration cakes torrefaction gets white solid 3-isobutylglutaric acid 53.0g, yield: 90.4%, purity: 99.5%, m.p.43-45 ℃.
Embodiment two
1) preparation of Malonamide nitrile:
Ethyl cyanoacetate (100.0g, 0.88mol) and water (500mL) are placed reaction flask, system is cooled to 5 ℃ with ice bath.Begin to splash into ammoniacal liquor (100ml, 25%), remove ice bath, along with the adding temperature of reaction of ammoniacal liquor slowly raises, the speed that control splashes into ammoniacal liquor makes temperature of reaction be lower than 32 ℃, continues water bath heat preservation reaction 5h.Cooling, suction filtration, and with the on a small quantity repeatedly drip washing of dehydrated alcohol of cooling, product is dried, and obtains white solid 56g, yield: 80%, m.p.119-120 ℃.
2) 2, the preparation of 4-dicyano-3-isobutyl-glutaramide:
With above-mentioned Malonamide nitrile (100.0g, 1.2mol) and water 650mL place reaction flask, heating for dissolving, ice bath cools off near 0 ℃, adds diethylamine 34mL and the isovaleric aldehyde (52.0g of catalytic amount, 0.6mol), the reaction system heat release keeps temperature of reaction at 3-5 ℃ with ice bath, uses TLC in the reaction process and monitors that (developping agent is ethyl acetate: methyl alcohol: sherwood oil=4: 1: 1), reaction 4h, the continuous adularescent solid of reaction system is separated out in reaction process.Suction filtration, cold water washing, oven dry obtains white solid 120.0g, yield: 88.5%; M.p.153-155 ℃.
3) preparation of 3-isobutylglutaric acid:
Get the condenses (75.0g of above-mentioned preparation, 0.39mol), and concentrated hydrochloric acid and water difference 250mL, under constantly stirring, reflux 8h, reaction solution is cooled to 0 ℃, separates out a large amount of inorganic salt, suction filtration, filter cake extracts with ethyl acetate backflow, heat filtering, filtrate is used ethyl acetate extraction 4-5 time, merges organic phase and also uses anhydrous magnesium sulfate drying.Reclaim solvent after siccative filtered, be concentrated into and product proportion 1: 1, be cooled to-15 ℃, product is separated out, suction filtration, and with the washing of cold ethyl acetate, filtration cakes torrefaction gets white solid 3-isobutylglutaric acid 57.0g, yield: 95.4%, purity: 99.5%, m.p.43-45 ℃.
Embodiment three
1) preparation of Malonamide nitrile:
With embodiment one, middle step 1).
2) 2, the preparation of 4-dicyano-3-isobutyl-glutaramide:
With above-mentioned Malonamide nitrile (100.0g, 1.2mol) and water 650mL place reaction flask, heating for dissolving, ice bath cools off near 0 ℃, adds ammoniacal liquor 34mL and the isovaleric aldehyde (52.0g of catalytic amount, 0.6mol), the reaction system heat release keeps temperature of reaction at 3-5 ℃ with ice bath, uses TLC in the reaction process and monitors that (developping agent is ethyl acetate: methyl alcohol: sherwood oil=4: 1: 1), reaction 4h, the continuous adularescent solid of reaction system is separated out in reaction process.Suction filtration, cold water washing, oven dry obtains white solid 100.0g, yield: 71.5%, m.p.153-155 ℃.
3) preparation of 3-isobutylglutaric acid:
Get the condenses (75.0g of above-mentioned preparation, 0.39mol), and vitriol oil 30mL and water 185mL, under constantly stirring, reflux 8h, reaction solution is cooled to 0 ℃, separates out a large amount of inorganic salt, suction filtration, filter cake extracts with ethyl acetate backflow, heat filtering, filtrate is used ethyl acetate extraction 4-5 time, merges organic phase and also uses anhydrous magnesium sulfate drying.Reclaim solvent after siccative filtered, be concentrated into and product proportion 1: 1, be cooled to-15 ℃, product is separated out, suction filtration, and with the washing of cold ethyl acetate, filtration cakes torrefaction gets white solid 3-isobutylglutaric acid 42.0g, yield: 70.4%, purity: 99.5%, m.p.43-45 ℃.
Claims (5)
1. the preparation method of antiepileptic drug pregabalin intermediate 3-isobutylglutaric acid comprises the steps:
1) the cyanoacetate compounds carries out the ammonia solution at a certain temperature with the nitrogenous reagent of alkalescence, makes Malonamide nitrile (I);
2) Malonamide nitrile and isovaleric aldehyde carry out condensation reaction under the alkaline condition in solvent, make 2,4-dicyano-3-isobutyl-glutaramide (II);
3) 2, the reaction that is hydrolyzed under suitable temperature in acid of 4-dicyano-3-isobutyl-glutaramide (II) makes 3-isobutylglutaric acid (III).
2. the preparation method of pregabalin intermediate 3-isobutylglutaric acid in the claim 1, wherein
1) the cyanoacetate compounds refers to methyl cyanoacetate, ethyl cyanoacetate, cyanoacetic acid isopropyl ester, the cyanoacetic acid tert-butyl ester, cyanoacetic acid benzyl ester in the step; Described alkaline nitrogenous reagent is selected from ammoniacal liquor, ammonia, urea, bicarbonate of ammonia and ammonium acetate; The mol ratio 1 of cyanoacetate and alkali: 0.5-2; Ammonia solution temperature is 0-100 ℃; Described solvent is methyl alcohol, ethanol, Virahol, water;
2) alkali described in the step is selected from ammoniacal liquor, triethylamine, diethylamine, sodium hydroxide, potassium hydroxide, sodium ethylate, alkaline ammonium salt; The alkalescence ammonium salt is selected from bicarbonate of ammonia, ammonium acetate; The mol ratio of Malonamide nitrile and isovaleric aldehyde and alkali is 1: 0.05-1: 0.05-2; Described solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, water, ethyl acetate; Described setting-up point is-5 ℃-100 ℃;
3) acid described in the step is selected from sulfuric acid, hydrochloric acid, Hydrogen bromide, glacial acetic acid; Hydrolysis temperature is 0-100 ℃; The mol ratio of 2,4-dicyano-3-isobutyl-glutaramide and acid is 1: 1-10.
3. the preparation method of pregabalin intermediate 3-isobutylglutaric acid in the claim 2, wherein
1) most preferably methyl cyanoacetate and ethyl cyanoacetate of cyanoacetate compounds in the step; Described alkali most preferably is ammonia; The mol ratio of cyanoacetate and alkali most preferably is 1: 0.8-1.2; Ammonia solution temperature most preferably is 0-10 ℃; Described solvent most preferably is water;
2) alkali described in the step most preferably is triethylamine, diethylamine; The mol ratio of Malonamide nitrile and isovaleric aldehyde and alkali most preferably is 1: 0.5-0.6: 0.05-0.1; Described solvent most preferably is the first alcohol and water; Described setting-up point most preferably is-5 ℃-10 ℃;
3) acid described in the step most preferably is hydrochloric acid; Hydrolysis temperature most preferably is 80-110 ℃; The mol ratio of 2,4-dicyano-3-isobutyl-glutaramide and acid most preferably is 1: 8-10.
4. the preparation method of pregabalin intermediate 3-isobutylglutaric acid in the claim 1, wherein
1) the ammonolysis reaction time of cyanoacetate is 5h in the step;
2) condensation reaction time of Malonamide nitrile and isovaleric aldehyde is 4h in the step;
3) in the step 2, the hydrolysis time of 4-dicyano-3-isobutyl-glutaramide (II) is 8h.
5. the preparation method of pregabalin intermediate 3-isobutylglutaric acid in the claim 3, wherein the concentration of hydrochloric acid described in the step is 10%-36%, is preferably 10%-20%, most preferably is 18%.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105463037A (en) * | 2015-11-26 | 2016-04-06 | 太仓运通生物化工有限公司 | Method for synthesizing pregabalin with isobutyl butanedinitrile as intermediate |
| CN106278931A (en) * | 2016-08-17 | 2017-01-04 | 苏州英诺欣医药科技有限公司 | The preparation method of 3 isobutylglutaric acid monoamides |
| CN108912082A (en) * | 2018-07-23 | 2018-11-30 | 湖北宇阳药业有限公司 | A kind of preparation method of pregabalin intermediate |
| CN110128293A (en) * | 2019-04-09 | 2019-08-16 | 武汉武药制药有限公司 | A kind of medicine intermediate impurity and the preparation method and application thereof |
| CN110483317A (en) * | 2019-09-05 | 2019-11-22 | 黄冈鲁班药业股份有限公司 | The preparation method and application of high-purity 3- isobutylglutaric acid dimethyl ester |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5616793A (en) * | 1995-06-02 | 1997-04-01 | Warner-Lambert Company | Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
-
2012
- 2012-03-20 CN CN201210073587XA patent/CN102863326A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5616793A (en) * | 1995-06-02 | 1997-04-01 | Warner-Lambert Company | Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
Non-Patent Citations (2)
| Title |
|---|
| MARVIN S. HOEKSTRA, ET AL.: ""Chemical Development of CI-1008, an Enantiomerically Pure Anticonvulsant"", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, vol. 1, no. 1, 15 January 1997 (1997-01-15), pages 26 - 38 * |
| 孙志忠等: ""β-甲基戊二酸的合成工艺优化"", 《化学研究与应用》, vol. 23, no. 8, 31 August 2011 (2011-08-31), pages 1111 - 1116 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105463037A (en) * | 2015-11-26 | 2016-04-06 | 太仓运通生物化工有限公司 | Method for synthesizing pregabalin with isobutyl butanedinitrile as intermediate |
| CN106278931A (en) * | 2016-08-17 | 2017-01-04 | 苏州英诺欣医药科技有限公司 | The preparation method of 3 isobutylglutaric acid monoamides |
| CN108912082A (en) * | 2018-07-23 | 2018-11-30 | 湖北宇阳药业有限公司 | A kind of preparation method of pregabalin intermediate |
| CN110128293A (en) * | 2019-04-09 | 2019-08-16 | 武汉武药制药有限公司 | A kind of medicine intermediate impurity and the preparation method and application thereof |
| CN110128293B (en) * | 2019-04-09 | 2022-06-17 | 武汉武药制药有限公司 | Medical intermediate impurity and preparation method and application thereof |
| CN110483317A (en) * | 2019-09-05 | 2019-11-22 | 黄冈鲁班药业股份有限公司 | The preparation method and application of high-purity 3- isobutylglutaric acid dimethyl ester |
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