Industrialized compounding method of N-alkyl substituted-5-cyanoimidazole compound

A cyanoimidazole and synthetic method technology, applied in the direction of organic chemistry, etc., can solve the problems of long route, expensive raw materials, low yield, etc., and achieve the effect of low preparation cost and easy reaction

Inactive Publication Date: 2009-10-07
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved in the present invention is: to solve the problem of expensive raw materials, long route, low yield, difficult purification, inability to effectively prepare, let alone scale-up in the existing preparation process of N-alkyl substituted-5-cyano-imidazole compounds The problem of production; provide an effective method for laboratory preparation of N-alkyl substituted-5-cyanoimidazoles; and provide a lower N-alkyl substituted-5-cyanide with higher overall yield Method for industrialized preparation of imidazole compounds

Method used

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  • Industrialized compounding method of N-alkyl substituted-5-cyanoimidazole compound

Examples

Experimental program
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Effect test

Embodiment 1

[0017] Synthesis of N-(((dimethylamino)methenylamino)methenyl)-N-dimethylammonium chloride (golden reagent)

[0018] Add cyanuric chloride (280g) and N,N-dimethylformamide (720g) to 1,4-dioxane (1500mL), heat to 65°C, react for one hour, then heat to 75-85°C, React for two hours. Cool to room temperature, filter, wash the filter cake with 1,4-dioxane (1000 mL), and dry under vacuum at low temperature to obtain 650 g of product, yield: 81%. 1 H NMR (400MHz, CDCl 3 ): δ9.58(s, 2H, CH, CH), 3.35(s, 6H, C 2 h 6 ), 3.17(s, 6H, CH 3 , CH 3 )

[0019] Synthesis of 1-methyl-5-cyanoimidazole

[0020] Acetonitrile hydrochloride (110 g) was added to tert-butyl methyl ether (2000 mL), followed by dimethyl oxalate (30 g) and freshly prepared 30% sodium methoxide in methanol (720 mL). Nitrogen was fed into the system, and gold reagent (240 g) was added simultaneously, allowing the reaction to take place in a nitrogen stream. Heated to 30°C for 24 hours. Cool to room temperatur...

Embodiment 2

[0022] Synthesis of Ethylaminoacetamide Hydrochloride

[0023] Ethylamine (18 g) was dissolved in ethanol (100 mL), and potassium carbonate (14 g) was added. Acetyl bromide (24 g) was slowly added dropwise under ice-bath conditions, and reacted at room temperature for 3 hours after the dropwise addition was complete. Filter, evaporate the organic solvent to dryness, add methyl tert-butyl ether solution (100 mL), let stand to separate the layers, and separate the lower aqueous phase. Add 5N hydrogen chloride in dioxane solution (30mL) to the organic matter in the upper layer, stir at room temperature for half an hour, filter, wash with dioxane (50mL) to obtain 17.5g product, yield: 63%. 1 H NMR (400MHz, DMSO-d 6 ): δ10.06(s, 2H, NH, HCl), 4.29(s, 2H, CH 2 ), 3.00 (m, 2H, CH 2 ), 1.21 (m, 3H, CH 3 ).

[0024] Synthesis of 1-ethyl-5-cyanoimidazole

[0025] Ethylaminoacetate hydrochloride (62.4 g) was added to tert-butyl methyl ether (1500 mL), followed by dimethyl oxal...

Embodiment 3

[0027] Synthesis of N-(((dimethylamino)methenylamino)methenyl)-N-dimethylammonium chloride (golden reagent)

[0028] Cyanuric chloride (28g) and N,N-dimethylformamide (72g) were added into tetrahydrofuran (150mL), heated to 65°C, reacted for one hour, then heated to reflux, reacted for two hours. Cool to room temperature, filter, wash the filter cake with tetrahydrofuran (100 mL), and dry under vacuum at low temperature to obtain 70 g of product, yield: 87%. Analysis data see embodiment 1.

[0029] Synthesis of 1-methyl-5-cyanoimidazole

[0030] Acetonitrile hydrochloride (10 g) was added to tetrahydrofuran (200 mL), followed by dimethyl oxalate (3 g) and potassium tert-butoxide (5 g). Nitrogen was passed into the system, and gold reagent (24 g) was added simultaneously, allowing the reaction to take place in a nitrogen stream. Heated to 40°C for 24 hours. After cooling to room temperature, the filtrate was evaporated to dryness and distilled under reduced pressure (80...

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Abstract

The invention relates to an industrialized compounding method of an N-alkyl substituted-5-cyanoimidazole compound, which uses conventional and easily-obtained cyanuric chloride as the raw material to react with DMF to generate a gold reagent and react with alkyl-substituted aminoacetonitriles to obtain the N-alkyl substituted-5-cyanoimidazole compound under an alkali condition in a loop closure way. The chemical reaction formula is as the right formula. The invention solves the problems of long line, low yield, difficult purification, no effective compounding method and no scale production of the prior art and can realize the scale industrialized production.

Description

Technical field: [0001] The invention relates to an industrialized method for effectively synthesizing N-alkyl substituted-5-cyanoimidazole compounds. Background technique: [0002] Imidazoles are the most commonly used drug intermediates, and 1-N-alkyl substituted-5-cyanoimidazoles are an important class, but so far there is no effective synthetic method for preparing this product, and more Several preparation methods have been reported in the literature without effective industrial synthetic methods. Method one, using imidazole carboxamide as raw material, through phosphorus oxychloride (US 3991072A1) or phenyl phosphorus dichloride (Leone-Bay, Andrea, Synth .Commun.; EN; 17; 12; 1987; 1409-1412) dehydration to generate cyano group but this method raw material is not easy to get; Siliconization effect, through transposition to generate 1-N-alkyl substituted-cyanoimidazole compound (Alcazar, Jesus; J.Org.Chem.; EN; 61; 20; 1996; 6971- 6973), but it is obvious that the sep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/90
Inventor 张福贵施峰顾虹唐苏翰李革
Owner 上海药明康德新药开发有限公司
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