Preparation method of antiepileptic drug intermediate

A technology of antiepileptic drugs and intermediates, applied in the field of medicine, can solve the problems of difficult Knoevenage condensation and precipitation, and achieve the effects of low cost, mild reaction conditions and simple operation

Inactive Publication Date: 2013-01-09
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This synthetic route is the route commonly used in industrialization now, but the first step Knoevenage condensation is more difficult to carry out, needs long-term dehydration, the product is directly subjected to Michael addition without separation, and then hydrolyzed to obtain 3-isobutylglutaric acid, resulting in 3-isobutylglutaric acid has low purity and is oily, which is not easy to separate out, thus limiting large-scale industrial production

Method used

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  • Preparation method of antiepileptic drug intermediate
  • Preparation method of antiepileptic drug intermediate
  • Preparation method of antiepileptic drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 1) preparation of cyanoacetamide:

[0023]

[0024] Ethyl cyanoacetate (100.0 g, 0.88 mol) and absolute ethanol (100 mL, 1.72 mol) were placed in a reaction flask, and the system was cooled to 5° C. with an ice bath. Start to feed ammonia gas, remove the ice bath, slowly increase the reaction temperature with the introduction of ammonia gas, control the speed of feeding ammonia gas so that the ammonia gas does not overflow, reach the temperature of 32 ° C, and continue the water bath insulation reaction for 5 hours. Cool, filter with suction, rinse with a small amount of cooled absolute ethanol several times, and dry the product to obtain 71.6g of white solid, yield: 96.4%, m.p.119-120°C.

[0025] 2) Preparation of 2,4-dicyano-3-isobutylglutaramide:

[0026]

[0027] Put the above-mentioned cyanoacetamide (100.0g, 1.2mol) and 650mL of water into a reaction flask, heat to dissolve, cool in an ice bath close to 0°C, add a catalytic amount of triethylamine 34mL and ...

Embodiment 2

[0032] 1) preparation of cyanoacetamide:

[0033] Ethyl cyanoacetate (100.0 g, 0.88 mol) and water (500 mL) were placed in a reaction flask, and the system was cooled to 5° C. with an ice bath. Start dripping ammonia water (100ml, 25%), remove the ice bath, slowly increase the reaction temperature with the addition of ammonia water, control the speed of dripping ammonia water so that the reaction temperature is lower than 32°C, and continue the water bath insulation reaction for 5h. Cool, filter with suction, rinse with a small amount of cooled absolute ethanol several times, and dry the product to obtain 56 g of white solid, yield: 80%, m.p.119-120°C.

[0034] 2) Preparation of 2,4-dicyano-3-isobutylglutaramide:

[0035] Put the above cyanoacetamide (100.0g, 1.2mol) and 650mL of water in a reaction flask, heat to dissolve, cool in an ice bath close to 0°C, add a catalytic amount of diethylamine 34mL and isovaleraldehyde (52.0g, 0.6mol) , the reaction system is exothermic, a...

Embodiment 3

[0039]1) preparation of cyanoacetamide:

[0040] With embodiment one, in step 1).

[0041] 2) Preparation of 2,4-dicyano-3-isobutylglutaramide:

[0042] The above-mentioned cyanoacetamide (100.0g, 1.2mol) and 650mL of water were placed in a reaction flask, heated to dissolve, cooled in an ice bath close to 0°C, and a catalytic amount of ammonia water 34mL and isovaleraldehyde (52.0g, 0.6mol) were added to react The system is exothermic, and the reaction temperature is kept at 3-5°C with an ice bath. During the reaction, TLC is used to monitor (developing agent is ethyl acetate: methanol: petroleum ether = 4: 1: 1), and the reaction is 4h. During the reaction White solids were continuously precipitated from the reaction system. Suction filtration, washing with cold water, drying to obtain 100.0 g of white solid, yield: 71.5%, m.p.153-155°C.

[0043] 3) Preparation of 3-isobutylglutaric acid:

[0044] Take the condensate prepared above (75.0g, 0.39mol), 30mL of concentrated ...

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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: [0001] The invention relates to a preparation method of an antiepileptic drug pregabalin intermediate 3-isobutylglutaric acid, which belongs to the technical field of medicine. Background technique: [0002] Pregabalin (PGB) is a novel γ-aminobutyric acid (GABA) receptor agonist developed by Pfizer. (S)-Pregabalin, marketed under the trade name LYRICA, is a neurotransmitter modulator with specific effects on the treatment of neuropathic pain, epilepsy and anxiety disorders. [0003] According to reports, the anticonvulsant effect of racemic pregabalin is mainly attributed to the (S)-isomer (Bioorg.Med.Chem.Lett., 1994, 4, 823), and the (R)-isomer pregabalin is almost No anticonvulsant effect. Therefore, commercial applications require efficient methods to prepare highly optically pure (S)-pregabalin. [0004] The preparation method of (S)-pregabalin reported in the literature mainly contains the following: [0005] Method 1: U.S. Patent US5599973 reports...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C55/02C07C51/09
Inventor 殷学治郭乙杰王小琴张艳计莹
Owner CHANGZHOU PHARMA FACTORY
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