Preparation method of 2-n-butyl-4-chloro-5-formylimidazole

A technology of formyl imidazole and n-butyl, applied in the field of preparation of losartan intermediate 2-n-butyl-4-chloro-5-formyl imidazole, can solve high production cost, poor product quality, difficult to purchase To achieve the effect of low production cost, less impurity generation and easy operation

Inactive Publication Date: 2017-08-01
滨海三甬药业化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The starting material 2-butyl-4-chloroimidazole raw material of this method is difficult to buy, and the production cost is h

Method used

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  • Preparation method of 2-n-butyl-4-chloro-5-formylimidazole
  • Preparation method of 2-n-butyl-4-chloro-5-formylimidazole

Examples

Experimental program
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Effect test

Embodiment 1

[0041] The preparation of embodiment 1 (1-iminopentyl) glycine tert-butyl ester

[0042]

[0043] Add pentamidine hydrochloride (1.36kg, 10mol) and glycine tert-butyl ester hydrochloride (1.67kg, 10mol) into DMF (10L), add triethylamine (3.54kg, 35mol) dropwise, and heat up to 60°C , stirred for 8 hours, cooled to room temperature, added water and ethyl acetate, separated the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give (1-iminopentyl) glycine tert-butyl ester, 1.35kg , Yield: 86.1%.

Embodiment 2

[0044] The preparation of embodiment 2 (1-iminopentyl) glycine tert-butyl ester

[0045] Add pentamidine hydrochloride (1.36kg, 10mol) and glycine tert-butyl ester hydrochloride (2.51kg, 15mol) into DMF (20L), add triethylamine (4.05kg, 40mol) dropwise, and heat up to 60°C , stirred for 10 hours, cooled to room temperature, added water and ethyl acetate, separated the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain (1-iminopentyl) glycine tert-butyl ester, 1.38kg , Yield: 86.7%.

Embodiment 3

[0046] Example 3 Preparation of 2-n-butyl-4-chloro-5-formyl imidazole

[0047]

[0048] (1-iminopentyl)glycine tert-butyl ester (1.35kg, 6.3mol) was added to 20L of 10% trifluoroacetic acid 1,2-dichloroethane solution, stirred at room temperature for 24 hours, the reaction was completed, evaporated to dryness , add toluene 15L, phosphorus oxychloride (9.64kg, 63mol) warm up to 80°C, stir for 2 hours, add DMF 4.6kg dropwise, heat up to 105°C, stir for 7 hours, the reaction is complete, cool down to 0°C, pour hydrogen Add ethyl acetate to the aqueous solution of sodium oxide, separate the layers, dry the organic layer over anhydrous sodium sulfate, evaporate to dryness, and recrystallize with ethyl acetate n-heptane to obtain 2-n-butyl-4-chloro-5-formyl imidazole , 1.05kg, purity 99.5%, yield 89.2%.

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Abstract

The invention provides a preparation method of 2-n-butyl-4-chloro-5-formylimidazole. The preparation method comprises the following steps of using pentanimidamide hydrochloride and tert-butyl glycine hydrochloride as initial raw materials to react, so as to obtain (1-imido amyl)tert-butyl glycinate; performing deprotection, ring closing, chlorinating and vilsemier reaction, and recrystallizing, so as to obtain the 2-n-butyl-4-chloro-5-formylimidazole. The preparation method has the advantages that the price of raw materials is low, the obtaining is easy, the cost is low, the content of impurities is low, and the purity is high; the organic solvent used in the preparation process can be recycled, the pollution is little, the environment-friendly effect is realized, and the preparation method is suitable for industrialized large-scale production.

Description

[0001] 1. Technical field [0002] The invention belongs to the technical field of pharmaceutical synthesis and relates to a preparation method of a losartan intermediate 2-n-butyl-4-chloro-5-formyl imidazole. [0003] 2. Background technology [0004] 2-n-butyl-4-chloro-5-formyl imidazole (CAS 83857-96-9) is the key intermediate of the first generation oral non-peptide angiotensin II receptor inhibitor losartan, the following formula ( I) shown. [0005] [0006] Chinese invention patent CN201010111705.2 discloses a preparation method of 2-n-butyl-4(5)-chloro-formaldehyde-1H-imidazole, as shown below, but the preparation method has a long reaction route and requires 4 steps of reaction. [0007] [0008] Chinese invention patent CN201010184934.7 discloses a synthetic method of 2-n-butyl-4-chloro-5-formyl imidazole, imidazolone shown in formula (II), bis(trichloro) shown in formula (III) Methyl)carbonate and the formamide shown in formula (IV) are reacted in an organic ...

Claims

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Application Information

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IPC IPC(8): C07D233/68
CPCC07D233/68
Inventor 张毅
Owner 滨海三甬药业化学有限公司
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