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Preparation method of pharmaceutical intermediate 2-amine methylpyrazine hydrochloride

A technology of aminomethylpyrazine hydrochloride and chloromethylpyrazine, applied in the field of medicine and chemical industry, can solve the problems of harsh reaction conditions, low yield of 2-aminomethylpyrazine, difficult control of the reaction process, etc. Simple and inexpensive post-processing effects

Inactive Publication Date: 2012-01-11
ZAOZHUANG UNIV
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Problems solved by technology

However, this method needs to be catalyzed by Raney Ni at high temperature and high pressure. The reaction conditions are harsh and the reaction equipment is expensive. The hydrogenation reduction product is accompanied by the formation of secondary amine and the reduction product of the double bond in the pyrazine ring. The reaction process is not easy to control.
(3) The literature "Pharmaceutical Progress" 2007, 31 (6): 277-279 reported the use of red aluminum-toluene solution as a reducing agent to reduce the cyano group in cyanopyrazine to prepare 2-aminomethylpyrazine oxazine, but the yield of 2-aminomethylpyrazine obtained by reduction is low

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  • Preparation method of pharmaceutical intermediate 2-amine methylpyrazine hydrochloride

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preparation example Construction

[0035] A kind of preparation method of pharmaceutical intermediate 2-aminomethylpyrazine hydrochloride of the present invention, the steps of its preparation method are as follows:

[0036] (1) Under the protection of nitrogen, 2-methylpyrazine, dibenzoyl peroxide and N-chlorosuccinimide with a molar ratio of 1:0.01~0.1:1~1.3 were added to the solvent anhydrous tetrachloride In carbonization, reflux reaction makes α-chloromethylpyrazine;

[0037](2) After mixing the α-chloromethylpyrazine prepared above with catalyst potassium iodide and solvent anhydrous toluene, cool to below 15°C, and the molar ratio of α-chloromethylpyrazine to potassium iodide is 1: 0.01~0.1; Then add hexamethylenetetramine (hexamethylenetetramine) under stirring according to the molar ratio of α-chloromethylpyrazine and hexamethylenetetramine as 1: 1.0~1.3, control the temperature below 28°C, add After completion, the reaction temperature is 0-100°C, and the reaction time is 1-20 hours to obtain 2-chlor...

Embodiment 1

[0040] 1) Under nitrogen protection, add 2-methylpyrazine, dibenzoyl peroxide and N-chlorosuccinimide with a molar ratio of 1:0.01:1.2 into anhydrous carbon tetrachloride, and reflux The reaction makes α-chloromethylpyrazine;

[0041] 2) Mix the above-prepared α-chloromethylpyrazine with potassium iodide and anhydrous toluene and cool to below 15°C. The molar ratio of α-chloromethylpyrazine to potassium iodide is 1:0.1. Then, according to the molar ratio of α-chloromethylpyrazine and hexamethylenetetramine as 1:1, add hexamethylenetetramine (hexamethylenetetramine) under stirring, control the temperature below 28°C, and complete the addition Afterwards, the reaction temperature is 0° C., and the reaction time is 20 hours to obtain 2-chloromethylpyrazine hexamethylenetetramine double salt. Add concentrated hydrochloric acid and ethanol to the above reaction mixture, react at 30°C for 5 hours, cool, filter, wash, and dry to obtain the crude product of 2-aminomethylpyrazine hydr...

Embodiment 2

[0044] 1) Under nitrogen protection, add 2-methylpyrazine, dibenzoyl peroxide and N-chlorosuccinimide at a molar ratio of 1:0.1:1.0 to anhydrous carbon tetrachloride, and reflux The reaction makes α-chloromethylpyrazine;

[0045] 2) Mix the above-prepared α-chloromethylpyrazine with potassium iodide and anhydrous toluene and cool to below 15°C. The molar ratio of α-chloromethylpyrazine to potassium iodide is 1:0.05. Then add hexamethylenetetramine (hexamethylenetetramine) under stirring according to the molar ratio of α-chloromethylpyrazine and hexamethylenetetramine as 1:1.1, control the temperature below 28°C, after adding The temperature is 100° C. and the reaction time is 3 hours to obtain 2-chloromethylpyrazine hexamethylenetetramine double salt. Add concentrated hydrochloric acid and ethanol to the above reaction mixture, react at 10°C for 8 hours, cool, filter, wash, and dry to obtain the crude product of 2-aminomethylpyrazine hydrochloride.

[0046] 3) Recrystallize ...

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Abstract

The invention discloses a preparation method of pharmaceutical intermediate 2-amine methylpyrazine hydrochloride, comprising the following steps: (1) under the protection of nitrogen, 2-methylpyrazine, dibenzoyl peroxide and N-chlorosuccinimide at the molar ratio of 1:0.01-0.1:1-1.3 are added into anhydrous carbon tetrachloride to prepare alpha-chlorine methylpyrazine by reflux reaction; (2) after prepared alpha-chlorine methylpyrazine is mixed with potassium iodide and anhydrous methylbenzene, the mixture is cooled to be below 15 DEG C; then, hexamine is added under stirring, temperature is controlled below 28 DEG C, reaction is carried out when temperature is 0-100 DEG C after adding for 1-20 hours to obtain 2-chlorine methylpyrazine hexamine complex salt; superfluous concentrated hydrochloric acid and solvent alcohol are added into the reaction mixture to react, cool, filter, wash and dry to obtain the coarse product of the 2-amine methylpyrazine hydrochloride; and (3) recrystallization is carried out on the above coarse product in methanol-chloroform to obtain the pharmaceutical intermediate 2-amine methylpyrazine hydrochloride of the invention. The invention has cheap and abundant raw material resource, high overall yield and simple after-treatment and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of 2-aminomethylpyrazine pharmaceutical intermediates, in particular to a preparation method of 2-aminomethylpyrazine pharmaceutical intermediate 2-aminomethylpyrazine hydrochloride . Background technique [0002] Pyrazine compounds not only widely exist in nature, but also have many physiological activities. Synthesizing physiologically active natural products from pyrazine nuclei or deriving a large number of compounds for activity screening has always been the core of pyrazine chemistry research, so the research on them is very extensive and in-depth. Among various pyrazine derivatives, 2-aminomethylpyrazine is a commonly used pharmaceutical intermediate and raw material, and is often used as an important side chain or synthetic building block of drugs, for example, in the histamine H1 receptor antagonist thiadiol In the preparation process of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/12
Inventor 周峰岩刘雪静郝银燕
Owner ZAOZHUANG UNIV