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Synthesis method of gabapentin hydrochloride

A technology of gabapentin hydrochloride and synthesis method, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry and other directions, can solve the problems of complicated operation, difficult separation of product gabapentin hydrochloride, large consumption and the like

Inactive Publication Date: 2013-11-06
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Among them, the existing patent situation of the second process route: using 1,1-cyclohexyloxalic acid monoamide as the starting material, through the Hofmann degradation reaction, the reaction solution is directly acidified to prepare gabapentin hydrochloride, and its disadvantage lies in the acidification To consume a large amount of inorganic acid, a large amount of inorganic salts and acidic organic impurities are generated at the same time, and it is difficult to separate the product gabapentin hydrochloride from the reaction solution, no matter the organic solvent extraction currently used, or concentration first and then extraction, or liquid-liquid extraction (US20080207945), its operation is all more loaded down with trivial details, is difficult to realize continuous production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Take 10 g of 1,1-cyclohexyloxalic acid monoamide and prepare 75 mL of an aqueous solution in the form of 1,1-cyclohexyloxalic acid monoamide sodium salt to obtain solution ①. Slowly add solution ① to 80.98g of sodium hypochlorite (6.60% available chlorine) and 50g of sodium hydroxide aqueous solution with a mass fraction of 10 to 20%, dropwise for 4 hours, and control the temperature at about -10 to 10°C . After the dropwise addition was completed, the temperature was raised to 60° C., and the reaction was carried out for 30 minutes. Then add 150mL of toluene, heat, the reaction temperature is 80-100°C, stir well, and react for 5 hours. Separate the toluene layer, add 120mL of 3mol / L hydrochloric acid, the reaction temperature is 85-100°C, fully stir, react for 5 hours, separate the water layer, concentrate to dryness, and obtain 5.30g of white solid, calculated as gabapentin hydrochloride, the yield was 56%. The product is compared with the gabapentin hydrochloride ...

Embodiment 2

[0020] Take 10 g of 1,1-cyclohexyloxalic acid monoamide and prepare 75 mL of an aqueous solution in the form of 1,1-cyclohexyloxalic acid monoamide sodium salt to obtain solution ②. The sodium hypochlorite (available chlorine is 6.60%) of 80.98g is mixed with the lye lye separated by cyclization in 50g embodiment 1, and solution 2. is slowly added dropwise in the sodium hypochlorite lye after mixing, and is added dropwise for 4 hours. The temperature is controlled at about -10 to 10°C. After the dropwise addition was completed, the temperature was raised to 60° C., and the reaction was carried out for 30 minutes. Then add the toluene separated by hydrolysis in Example 1, heat, the reaction temperature is 80-100° C., fully stir, and react for 5 hours. Separate the toluene layer, add 120mL of 3mol / L hydrochloric acid, the reaction temperature is 85-100°C, stir well, react for 8 hours, separate the water layer, and concentrate to dryness to obtain 8.34g of white solid, calculate...

Embodiment 3

[0022] Take 10 g of 1,1-cyclohexyloxalic acid monoamide and prepare 75 mL of an aqueous solution in the form of 1,1-cyclohexyloxalic acid monoamide sodium salt to obtain solution ③. The sodium hypochlorite (available chlorine is 6.60%) of 80.98g is mixed with the alkali lye separated by cyclization in 50g embodiment 2, and solution 3. is slowly added dropwise in the mixed sodium hypochlorite alkali, and is added dropwise for 4 hours. The temperature is controlled at about -10 to 10°C. After the dropwise addition was completed, the temperature was raised to 60° C., and the reaction was carried out for 30 minutes. Then add the toluene separated by hydrolysis in Example 2, heat, the reaction temperature is 80-100° C., fully stir, and react for 5 hours. Separate the toluene layer, add 120mL of 3mol / L hydrochloric acid, the reaction temperature is 85-100°C, stir well, react for 5 hours, separate the water layer, concentrate to dryness, and obtain 5.73g of white solid, calculated a...

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Abstract

The invention relates to a synthesis method of gabapentin hydrochloride. The method comprises the following steps of: with 1,1-cyclohexyldiacid monoacyl amine as a starting material, carrying out a Hoffman degradation reaction; dewatering and condensing; carrying out product phase transfer; and hydrolyzing. The method artfully integrates relevant processes in the prior art and realizes the preparation of the gabapentin hydrochloride through the generation and the phase transfer of 3,3-pentylidene butyrolactam in a reaction process; the reaction does not relate to an acidification process, avoids the consumption of a large quantity of inorganic acids and the generation of inorganic salts and thoroughly solves the problem of difficult separation of the gabapentin hydrochloride in the original process; and in the reaction process, an organic solvent is directly cycled and mechanically applied and closed in the reaction process all the time, which is hopeful to realize the zero organic solvent discharge of the process. The method has the advantages of reasonable process design, simpleness and convenience of operation, high raw material conversion rate and high yield.

Description

technical field [0001] The invention relates to a synthesis process of gabapentin hydrochloride, which belongs to the field of chemical synthesis. technical background [0002] The chemical name of Gabapentin (Gabapentin) is 1-(aminomethyl)-cyclohexylacetic acid, and its structure is similar to GABA. It can be used for the treatment of certain forms of epilepsy and hypokinesia. U.S. Patents US4024175 and US4087544 cover this compound and its use. Recent clinical applications have shown that the drug is effective in the treatment of various pains, especially in intractable neuropathic pain and postoperative pain. Due to less adverse reactions and no interaction with other drugs, this drug may become a promising analgesic or analgesic adjuvant drug. [0003] As the precursor of gabapentin, gabapentin hydrochloride is called 1-(aminomethyl)-cyclohexylacetic acid hydrochloride. Pentylglutarimide is used as a raw material, which is obtained through Lossen rearrangement and hyd...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/28C07C227/16
Inventor 李悦青赵伟杰宋其玲胡勇男
Owner DALIAN UNIV OF TECH