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A kind of preparation method of asymmetric synthesis pregabalin
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A pregabalin, asymmetric technology, applied in the field of asymmetric synthesis of pregabalin, can solve the problems of low yield, need to split, long synthesis route of pregabalin, etc., achieves less steps, mild reaction conditions, Novel effect of synthetic route
Active Publication Date: 2020-11-10
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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[0017] In order to solve the problems of long synthetic route of pregabalin, low yield in the production process, and the need for resolution in the preparation process, the present invention provides an asymmetric synthetic route with few synthetic steps, high yield and no need for chiral resolution
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Embodiment 1
[0040] 1. Catalytic asymmetric alcoholysis
[0041] Take a 100 mL three-necked flask, add 3-isobutylglutaric anhydride (1.70 g, 0.01 mol), bromide ( S )-2-(3(3,5-bis(trifluoromethyl)phenyl)thioureido)- N , N , 4-trimethyl- N -(4-nitrobenzyl)pentan-1-ammonium (630 mg, 1.0 mmol), and 50 mL of tetrahydrofuran was added to dissolve the solid, and benzylmercaptan (1.50 g, 0.012 mol) was added under stirring at -10°C, and the reaction After 16 h, the solvent was removed under reduced pressure, and purified by column chromatography to obtain 2.80 g of thiol ester with a yield of 95% and an ee value of 94%.
[0042] 2. Synthesis of benzyloxycarbamide methyl thiol ester
[0043]Take a 100 mL three-necked flask, dissolve thiol ester (2.80 g, 9.5 mmol) in dry toluene at 25 °C, add triethylamine (0.97 g, 9.6 mmol) and diphenylphosphoryl azide (2.64 g , 9.6 mmol), stirred for 15 min and then slowly raised the temperature to 85 °C. When no bubbles emerged from the system, benzyl alcoho...
Embodiment 2
[0049] 1. Catalytic asymmetric alcoholysis
[0050] Take a 100 mL three-necked flask, add 3-isobutylglutaric anhydride (1.70 g, 0.01 mol), chloride ( S )-2-(3(3,5-bis(trifluoromethyl)phenyl)thioureido)- N , N , 4-trimethyl- N -(4-nitrobenzyl)pentan-1-ammonium (590 mg, 1.0 mmol), and 50 mL of methyl tert-butyl ether was added to dissolve the solid, and benzylthiol (1.50 g, 0.012 mol), reacted for 16 h, removed the solvent under reduced pressure, and purified by column chromatography to obtain 2.84 g of thiol ester, with a yield of 96% and an ee value of 95%.
[0051] 2. Synthesis of benzyloxycarbamide methyl thiol ester
[0052] Take a 50 mL three-necked flask, dissolve thiol ester (1.42 g, 4.8 mmol) in dry toluene at 25 °C, add triethylamine (0.49 g, 4.8 mmol) and diphenylphosphoryl azide (1.324 g , 4.8 mmol), stirred for 15 min and then slowly raised the temperature to 85 °C. When no bubbles emerged from the system, benzyl alcohol (0.54 g, 5.0 mmol) was slowly added drop...
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Abstract
The invention discloses a preparation method for asymmetric synthesis of pregabalin.The preparation method includes: using 3-isobutylglutaric anhydride as a starting raw material; under catalytic action of chiral thioureaammonium salt, enabling the starting raw material to be in asymmetric alcoholysis with mercaptan to generate mercaptide; enabling mercaptide to react with diphenylphosphoryl azide and benzyl alcohol sequentially to generate benzyloxy carbonyl methyl mercaptide; obtaining pregabalin through hydrolysis and hydrogenation reduction.The synthetic method is adopted to synthesize pregabalin, asymmetric catalysis is adopted to synthesize a key intermediate, a chemical resolution reagent is not used, total yield is greater than 50%, and ee value is greater than 94%.The preparation method has the advantages of novel synthesis path, few steps, mild reaction condition and the like.
Description
technical field [0001] The invention relates to the field of chemical synthesis, more specifically, to a preparation method for asymmetrically synthesizing pregabalin. Background technique [0002] Pregabalin (CAS: 148553-50-8) is a gamma-aminobutyric acid (GABA) analogue, similar in structure and action to gabapentin, with antiepileptic, analgesic and anxiolytic activities. The mechanism of antiepileptic action of this drug is not clear. In laboratory studies, the drug has anticonvulsant activity on various epilepsy models; the activity spectrum of animal models is similar to that of gabapentin, but the activity is 3 to 10 times that of gabapentin. [0003] The drug was applied for registration by Pfizer in 2003, and the FDA approved it for listing in December, 2004, and the preparation is a capsule. This variety is widely used in the treatment of epilepsy, neuropathic pain and anxiety disorders, generalized anxiety disorder, diabetic peripheral neuropathy, post-herpetic ...
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