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A kind of synthetic method of flupirtine maleate compound

A technology of flupirtine maleate and a synthesis method, applied in the field of medicine and chemical industry, can solve the problems of harmful environment, unstable product quality and high production cost, and achieve the effects of improving product yield, reducing product purity and easy reaction process

Active Publication Date: 2019-08-06
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to provide a synthetic method of flupirtine maleate compound to solve the problems of high production cost, harmful to the environment and unstable product quality in the prior art. The synthetic method has relatively simple process and easy-to-obtain raw materials , The operation is controllable, the generation of by-products can be avoided, the product yield and purity are high, and it is suitable for industrial production

Method used

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  • A kind of synthetic method of flupirtine maleate compound
  • A kind of synthetic method of flupirtine maleate compound
  • A kind of synthetic method of flupirtine maleate compound

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Example 1: Preparation of 2-amino-3-nitro-6-p-fluorobenzylaminopyridine (compound 3)

[0028] Add 200mL of methanol, 52.08g of compound 1, 37.54g of p-fluorobenzylamine, and 50.0mL of triethylamine into the reaction bottle, heat up to 80°C and react for 10 hours. After the reaction is completed, add the reaction solution to 10 times of water, precipitate a solid, and dry it by suction filtration. 76.47 g of compound 3 was obtained with a yield of 97.2% and a purity of 99.62% (HPLC).

Embodiment 2

[0029] Example 2: Preparation of 3-nitro-6-p-fluorobenzylaminopyridin-2-yl-acetic acid tert-butyl ester (compound 4)

[0030] Suspend 26.22g of compound 3 (100mmol) in 50ml of dry DMF, add 12.0g of sodium hydroxide at room temperature to obtain a brown solution, add 34.50ml of Boc 2 O (150mmol), after stirring for 10 minutes, the mixture was heated to 40°C overnight, the reaction mixture was poured into water, extracted with ethyl acetate (2×100mL), the aqueous phase was adjusted to pH 4-5 with 2M HCl aqueous solution, and Chloromethane (3×100 mL) was extracted, and the combined organic phases were concentrated to dryness under reduced pressure to obtain 24.27 g of compound 4 with a yield of 97.0% and a purity of 99.7% (HPLC).

Embodiment 3

[0031] Example 3: Preparation of 3-nitro-6-p-fluorobenzylaminopyridin-2-yl-acetic acid tert-butyl ester (compound 4)

[0032] Suspend 26.22g (100mmol) of compound 3 in 50ml of dry dioxane and water, add 41.73ml of triethylamine dropwise at room temperature to obtain a brown solution, add 23.00ml of Boc 2 O (100mmol) was stirred for 10 minutes, the mixture was heated to 50°C overnight, the reaction mixture was poured into water, extracted with ethyl acetate (2×100mL), the aqueous phase was adjusted to pH 4-5 with 2M HCl aqueous solution, and dichloro Methane (3×100 mL) was extracted, and the combined organic phases were concentrated to dryness under reduced pressure to obtain 23.77 g of compound 4 with a yield of 95.0% and a purity of 99.7% (HPLC).

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Abstract

The invention discloses a synthesis method for a flupirtine maleate compound. The method comprises the steps that 2-amino-3-nitro-6-chloropyridine (a first compound) is used as a starting material to react with fluorobenzylamine (a second compound) to generate 2-amino-3-nitro-6-p-fluorobenzylamine pyridine (a third compound), the third compound is processed through di-tert-butyl dicarbonate ester protection to obtain 2-amino-3-nitro-6-p-fluorobenzylamine pyridine-3-based-tert-butyl acetate (a fourth compound), the fourth compound is processed through hydrogenation reduction and then react with ethyl chloroformate, after reacting is finished, deprotection is performed to obtain flupirtine hydrochloride (a fifth compound), and the fifth compound is salified with maleic acid to obtain flupirtine maleate (the sixth compound). According to the synthesis method, the starting material is cheap and easy to obtain, byproduct generation is avoided through amino protection, therefore, the impurity content is decreased, and the product quality is improved; catalytic reduction is performed by adopting palladium chloride, the reaction condition is mild, the reaction process is easy to operate, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a method for synthesizing flupirtine maleate compound. Background technique [0002] Flupirtine Maleate is a new type of non-opioid pain reliever, which was launched in Germany in 1986 for the treatment of postoperative pain, toothache, wound and burn pain, and then re-marketed for the treatment of degenerative joints disease, nerve and cancer pain, migraine, headache and dysmenorrhea, and later launched in Brazil. In September 2006, my country approved the import of flupirtine maleate capsules from AWD Company in Germany. The trade name is Cordadelon Flupirtine is a new type of non-opioid analgesic, its mechanism of action is a selective neurogenic potassium channel opener, which has triple effects of analgesia, muscle relaxation and neuroprotection. Its chemical name is: 2-amino-6-[(p-fluorobenzyl)amino]-3-pyridine-urethane ethyl ester maleate, molecul...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 孙松朱丽萍杨静
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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