Industrialized preparation method of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound

A technology for ester compounds and alkyl groups, which is applied in the field of effectively synthesizing N-alkyl-substituted-imidazole-5-carboxylic acid/ester compounds, can solve the problems of long route, difficult purification, low yield and the like, and achieves the preparation cost. Low, reasonable selection of reaction process, easy reaction effect

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

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems of long route, low yield, difficult purification and incapable of large-scale production in the existing preparation process of N-alkyl substituted-imidazole-5-carboxylic acid / ester compounds

Method used

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  • Industrialized preparation method of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound
  • Industrialized preparation method of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound
  • Industrialized preparation method of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis of N-(((dimethylamino)methenamino)methenyl)-N-dimethylammonium chloride (gold reagent)

[0032] Add 1,4-dioxane (1500mL) to cyanuric chloride (280g) and N,N-dimethylformamide (720g), heat to 65°C, react for one hour, and then heat to 75-85°C to react Two hours. Cooled to room temperature, filtered, washed the filter cake with 1,4 dioxane (1000 mL), and dried at low temperature under vacuum 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 )

[0033] Synthesis of 1-methylimidazole-5-ethyl carboxylate

[0034] Add methyl glycine ethyl ester hydrochloride (100 g) to tert-butyl methyl ether (2500 mL), then add dimethyl oxalate (30 g) and a freshly prepared 30% sodium ethoxide ethanol solution (900 mL). Nitrogen gas was introduced into the system and gold reagent (150 g) was added at the same time to allow the reaction to occur in a nitrogen stream. Heat to 30°C to react for 24 h...

Embodiment 2

[0036] Synthesis of ethyl glycine ethyl ester hydrochloride

[0037] Ethyl ammonia (45 g) was dissolved in ethanol (400 mL), and potassium carbonate (70 g) was added. Ethyl bromoacetate (83g) was slowly added dropwise in an ice bath, and reacted at room temperature (10-15°C) for 3 hours after completion of the dropwise addition. Filter, evaporate the organic solvent, stand still and separate into layers, and separate the lower aqueous phase. Add 2N hydrogen chloride 1,4-dioxane solution (500 mL) to the upper organic matter, stir at room temperature for half an hour, filter, and wash with 1,4-dioxane (500 mL) to obtain 60 g of product, yield: 72%. 1 H NMR(400MHz, DMSO-d 6 ): δ9.48 (s, 2H, NH, HCl), 4.20 (m, 2H, CH 2 ), 3.90(m, 2H, CH 2 ), 2.93(m, 2H, CH 2 ), 1.19(m, 6H, CH 3 , CH 3 )

[0038] Synthesis of ethyl 1-ethylimidazole-5-carboxylate

[0039] Ethyl glycine ethyl hydrochloride (60 g) was added to tert-butyl methyl ether (650 mL), followed by dimethyl oxalate (10 g) and a...

Embodiment 3

[0043] Synthesis of n-pentylglycine ethyl ester hydrochloride

[0044] Glycine ethyl ester hydrochloride (14 g) was dissolved in ethanol (200 mL), cooled to 0° C., and potassium carbonate (20 g) was added. Add n-pentyl bromide (15g) dropwise, and react for 3 hours at room temperature (0-5°C) after the dropwise addition is complete. Filter, evaporate the organic solvent, add methyl tert-butyl ether solution (100 mL), stand to separate the layers, and separate the lower aqueous phase. Add 5N hydrogen chloride in dioxane solution (30 mL) to the upper organic matter, stir at room temperature for half an hour, filter, and wash with methyl tert-butyl ether (50 mL) to obtain 15 g of product. Yield: 71.4%. 1 H NMR(400MHz, DMSO-d 6 ): δ9.40 (s, 2H, NH, HCl), 4.21 (m, 2H, CH 2 ), 3.91(m, 2H, CH 2 ), 2.94(m, 2H, CH 2 ), 1.97(m, 2H, CH 2 ), 1.29-1.32 (m, 7H), 0.92 (m, 3H, CH 3 )

[0045] Synthesis of 1-n-pentylimidazole-5-ethyl carboxylate

[0046] Add n-pentylglycine ethyl ester hydrochlor...

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Abstract

The invention relates to an industrialized preparation method of an N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound, which uses conventional and easily-obtained cranuric chloride as a raw material to react with DMF to generate a gold reagent, and react with alkyl-substituted glycinate to obtain N-alkyl substituted-imidazole-5-carboxylic ester under an alkali condition a loop closure way. N-alkyl substituted-imidazole-5-carboxylic acid can be obtained by hydrolysis. The invention solves the problems of long line, low yield, difficult purification 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-imidazole-5-carboxylic acid / ester compounds. Background technique: [0002] Imidazole compounds are the most commonly used pharmaceutical intermediates. N-alkyl substituted-imidazole-5-carboxylic acid / ester compounds are an important class of them, but so far there is no effective industrial synthesis method for preparing this product. . The following preparation methods have been reported in the literature. Method one is to use N-alkyl substituted-imidazole as the raw material, treat with butyl lithium, remove the active hydrogen, and pass in carbon dioxide to generate carboxylic acid (J.Am.Chem.Soc, 79, 1957, 4922-4926); Method two, 1-N-alkyl-substituted-imidazole-4,5-dicarboxylic acid is heated to reflux decarboxylation in acetic anhydride to obtain the target product (Synthesis; EN; 10, 1988, 767- 771). [0003] Literature synthesis route 1: [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/90
Inventor 神小明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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