Preparation method of intermediate compound of pregabalin

A technology of pregabalin and compounds, applied in the field of preparation of intermediate compounds, can solve the problems of high cost, dangerous operation and the like

Active Publication Date: 2012-05-23
JIANGXI LONGLIFE BIO PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The technical problem to be solved by the present invention is to provide a method for preparing pregabalin completely different from the existing method in order to overcome defects such as high cost and danger

Method used

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  • Preparation method of intermediate compound of pregabalin
  • Preparation method of intermediate compound of pregabalin
  • Preparation method of intermediate compound of pregabalin

Examples

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Embodiment 1

[0055] Embodiment 1: Synthesis of intermediate I (3-cyano-3-(diethoxyphosphoryl) ethyl propionate)

[0056] Sodium hydride (13.5 g, 60%, 339 mmol) and toluene (500 mL) were added into a three-necked reaction flask equipped with a thermometer and a stirrer under nitrogen protection. To the obtained suspension was added dropwise a solution of diethyl cyanomethylphosphate (30.0 g, 169 mmol) dissolved in 40 mL of toluene at -5-0°C. After the addition, keep within this temperature range, stir and react for 1 hour to obtain a thick mixture. Ethyl chloroacetate (41.5 g, 339 mmol) was dissolved in 40 mL of toluene solution and added dropwise to the above system, and the reaction mixture gradually became clear. After the dropwise addition, the temperature was raised to 10-15°C, followed by TLC or GC detection, and the reaction was complete in about 3 hours. The reaction was quenched with 0.1M aqueous HCl, the layers were separated and the organic layer was collected. The aqueous pha...

Embodiment 2

[0058] Example 2: Synthesis of intermediate II (3-cyano-5-methyl-3-ene-hexanoic acid ethyl ester)

[0059] Sodium hydride (1.73 g, 60%, 43.2 mmol) and toluene (40 mL) were added into a three-necked reaction flask equipped with a thermometer and a stirrer under nitrogen protection. Stir. Intermediate I (9.3 g, 35.4 mmol) dissolved in 30 ml toluene was added dropwise to the obtained suspension at -5-0°C. After the addition was complete, the temperature was maintained and stirring was continued for 1 hour. To the reaction mixture was added a solution of isobutyraldehyde (2.8 g, 38.9 mmol) dissolved in 30 ml of toluene. After the addition, the stirring reaction was continued for 2 hours, and detected by TLC or GC. When the phosphate ester reaction was complete, it was quenched by the careful addition of water 0.1M aqueous HCl. The organic layer was separated, and the aqueous phase was extracted with toluene. The organic phases were combined and dried over anhydrous sodium sul...

Embodiment 3

[0061] Example 3: One-pot synthesis of intermediate II (3-cyano-5-methyl 3-ene-hexanoic acid ethyl ester)

[0062] In a three-necked reaction flask equipped with a thermometer and a stirrer, under nitrogen protection, sodium hydride (27.1 g, 60%, 678 mmol) and toluene (1200 mL) were added. To the obtained suspension was added dropwise a solution of diethyl cyanomethylphosphate (100.0 g, 565 mmol) dissolved in 250 ml of toluene at -5-0°C. After the addition, keep within this temperature range, stir and react for 1 hour to obtain a thick mixture. Ethyl chloroacetate (83.1 g, 678 mmol) was slowly added dropwise to the above system, and the reaction mixture gradually became clear. After the dropwise addition, the temperature was raised to 10-15°C. After 1 hour, the temperature was lowered to 0°C. At 0-5°C, sodium hydride (22.6g, 60%, 565mmol) was added in batches, and the temperature was raised to 10-15°C after the addition was completed. The reaction was continued at ℃, followe...

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Abstract

The invention discloses a preparation method for preparing an intermediate compound II of pregabalin. The preparation method of the intermediate compound II comprises the following steps of: (1) undergoing an SN2 substitution reaction on a compound VI and XCH2COOR2 to obtain a compound I; and (2) undergoing a Wittig-Hornor reaction on the compound I obtained in the step (1) and isobutylaldehyde, wherein R1 is alkoxyl with 1-6 carbon atoms or aryl with 6-10 carbon atoms; X is halogen; and R2 is alkyl with 1-6 carbon atoms. The invention further relates to a preparation method for preparing an intermediate compound V of pregabalin. The preparation method of the intermediate compound V comprises the following step of: undergoing an asymmetric hydrogenation reaction on the compound IV and hydrogen gas in a solvent under the action of [Rh((Sc,Rp)-Duanpos)(COD)]BF4, wherein M is H, alkyl with 1-6 carbon atoms or t-BuNH<3+>.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an intermediate compound of pregabalin. Background technique [0002] Pregabalin (pregabalin, formula I), chemical name (3S)-3-aminomethyl-5-methylhexanoic acid, is a gamma-aminobutyric acid (GABA) receptor antagonist developed by American Pfizer Company, clinical For the treatment of diabetic neuralgia, postherpetic neuralgia, and adjuvant treatment of partial insufficiency seizures in adult patients. It is the first drug approved by the FDA for the treatment of more than 2 types of neuropathic pain, with less frequent administration and fewer adverse reactions. [0003] [0004] There are many reports on the synthesis of this compound. Organic Process Research & Development, 1997, 1, 26 summarizes various technological methods for synthesizing pregabalin. According to the method of preparing chiral compounds, these methods ...

Claims

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Application Information

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IPC IPC(8): C07C255/23C07C253/30C07C255/19
Inventor 刘自军苗艳陆辉李文革
Owner JIANGXI LONGLIFE BIO PHARM CO LTD
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