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Preparation method of cimetidine

A technology for cimetidine and imidazole, applied in the field of preparation of cimetidine, can solve the problems of difficulty in obtaining imidazol-4-yl) acetate, difficulty in large-scale production, difficulty in large-scale production and the like, and avoid odor Problems, high productivity, environmental friendliness and improved safety effects

Active Publication Date: 2021-05-25
YANCHENG KAILI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Since the listing of cimetidine, a large number of synthetic methods have been developed, but most of them have problems such as low yield, serious environmental pollution and complex production process.
In US4381395, cimetidine is prepared by the reaction of N-cyano-N'-methyl-N"-halogen and 4-((2-aminoethyl) thiomethyl)-5-methylimidazole, because N- The cyano-N'-methyl-N"-halogen intermediate is unstable, and it is easy to eliminate a part of cyanogen halide. At the same time, it is difficult to obtain the market and it is difficult to produce on a large scale
In US4413129, cimetidine is prepared as raw material with N-cyano-O-hydrocarbyl-S-hydrocarbyl and 4-((2-aminoethyl) thiomethyl)-5-methylimidazole, and this reaction produces volatile Odor-smelling mercaptans, difficult to produce on a large scale
In CN101838241A, react 4-methylimidazole and formaldehyde to prepare 4-methylimidazolol, then react with cysteamine hydrochloride to prepare a condensate, then react with dimethyl cyanamide to form a condensate, and formaldehyde The amine reacts to generate cimetidine. This scheme produces a large amount of volatile, toxic and odorous methyl mercaptan during the generation and amination of the dicondensate, which causes serious pollution to the environment and
In CN110372596A, 1,3-dioxoisoquinolin-2-yl 2-(5-methyl-4H-imidazol-4-yl) acetate and N-cyano-N'-methyl-N" -Mercaptoethylguanidine or its ether is used as raw material to prepare cimetidine, but raw material 1,3-dioxoisoquinolin-2-yl 2-(5-methyl-4H-imidazol-4-yl)acetic acid It is very difficult to obtain esters, and the reaction needs to be carried out under light, which is inconvenient to operate

Method used

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  • Preparation method of cimetidine
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  • Preparation method of cimetidine

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Add (5-methyl-1H-imidazol-4-yl)methanol (1.12g, 10.0mmol), 50mL of methanol, and 10mL of acetic anhydride into a 100mL three-necked flask, stir and mix; cool down to 10°C, at this temperature Sodium nitrite (0.76 g, 11.0 mmol) was added in batches, the temperature was naturally raised to room temperature and stirring was continued. The reaction progress was monitored by TLC until the raw material (5-methyl-1H-imidazol-4-yl)methanol completely disappeared, and then the reaction was continued for 0.5h, and the total reaction time was about 3h. After the reaction was finished, the reaction solution was naturally cooled to room temperature, then it was poured into 100 mL of water, the precipitate was collected, recrystallized from ethanol to obtain (5-methyl-1H-imidazol-4-yl) methyl nitrate 1.44 g , yield 92.0%. ESI-MS: m / z 158 [M+H]+.

[0035] Under nitrogen protection, (5-methyl-1H-imidazol-4-yl)methyl nitrate (1.26g, 8.0mmol), absolute ethanol (75mL), triethylamine (0....

Embodiment 2

[0037](5-Methyl-1H-imidazol-4-yl)methyl nitrate was synthesized in the same manner as in Example 1. Then, under nitrogen protection, (5-methyl-1H-imidazol-4-yl)methyl nitrate (1.26g, 8.0mmol), anhydrous methanol (80mL), pyridine (0.5mL ), stirred to dissolve, then added cobalt chloride (0.152 g, 1.2 mmol) and continued stirring for 15 min. Subsequently, the ether of N-cyano-N'-methyl-N"-mercaptoethylguanidine (i.e. 1,1'-(dithiodiylbis(ethane-2,1-diyl))bis( 2-cyano-3-methylguanidine)) (1.50g, 4.8mmol) was dissolved in anhydrous methanol (30mL) and slowly added dropwise, stirring was continued during the dropwise addition, and stirring was continued at room temperature after the dropwise addition was completed. .TLC monitors the reaction process, disappears completely to the point of raw material (5-methyl-1H-imidazol-4-yl) methyl nitrate, then continues to react for 1h, and the total reaction time is about 6h. After the reaction finishes, make the reaction solution Naturally ...

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Abstract

The invention provides a preparation method of cimetidine. The method comprises the steps of firstly, converting (5-methyl-1H-imidazole-4-yl) methanol into nitrate of (5-methyl-1H-imidazole-4-yl) methanol, and then reacting with N-cyano-N'-methyl-N''-mercaptoethylguanidine ether to prepare cimetidine. The reaction conditions are mild, the yield is high, by-products are few, the aftertreatment is simple, volatile methyl mercaptan is not generated, the environmental friendliness and safety are greatly improved, and the method is particularly suitable for industrial application to produce cimetidine.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to a preparation method of cimetidine. Background technique [0002] Cimetidine, also known as Cimetidine (CIM for short), is an imidazole H2 receptor antagonist, and is currently a more commonly used drug for inhibiting gastric acid and anti-ulcer. Cimetidine was listed in the United Kingdom in 1976 and was approved by the FDA in the United States in 1979. [0003] Since the listing of cimetidine, a large number of synthetic methods have been developed, but most of them have problems such as low yield, serious environmental pollution and complex production process. In US4381395, cimetidine is prepared by the reaction of N-cyano-N'-methyl-N"-halogen and 4-((2-aminoethyl) thiomethyl)-5-methylimidazole, because N- The cyano-N'-methyl-N"-halogen intermediate is unstable, and it is easy to eliminate a part of cyanogen halide. At the same time, it is difficult ...

Claims

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Application Information

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IPC IPC(8): C07D233/64
CPCC07D233/64
Inventor 马向东黄伟杨毅跃
Owner YANCHENG KAILI PHARMA
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