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Preparation method of amlodipine base

A technology of amlodipine base and chlorophenyl, which is applied in the field of preparation of amlodipine base, can solve the problems of unstable intermediates, high equipment requirements, poor safety, etc., and achieve a simple route, reduced production cost, and low price. Effect

Pending Publication Date: 2020-12-01
SHANDONG HUIHAI PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods have the disadvantages of high cost, unstable intermediates or the use of flammable and explosive reagents. In actual production, the requirements for equipment are high and the safety is poor.

Method used

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  • Preparation method of amlodipine base
  • Preparation method of amlodipine base
  • Preparation method of amlodipine base

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Add 6-methyl-2-(2-chloroethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid methyl ethyl to the 10L reaction flask 1.0 mol of ester, 0.1 mol of potassium iodide and 5L of acetone were dissolved by stirring, then 1.5 mol of sodium nitrite was added, the reaction liquid was heated to 50°C and stirred for 6 hours; suction filtered while it was hot, the filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized with water to obtain Yellow solid product, yield 81.1%.

[0025] Under the protection of nitrogen, ethyl 6-methyl-2-(2-nitroethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate 0.5mol, dissolved in 5L of dichloromethane, added 2.5mol of triethylamine, cooled to -5°C with ice-brine, slowly pressed 1.5mol of trichlorosilane from the cylinder, and then the reaction solution was slowly raised to 25°C and stirred for 24 Hour. Slowly add 3L saturated aqueous solution of sodium bicarbonate dropwis...

Embodiment 2

[0027] Add 6-methyl-2-(2-chloroethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid methyl ethyl to the 10L reaction flask Add 1.0mol of ester, 0.01mol of tetrabutylammonium iodide and 5L of acetonitrile and acetone mixed solvent, stir to completely dissolve, add 1mol of sodium nitrite, heat the reaction solution to 60°C and stir for 6 hours; filter while hot, and concentrate the filtrate under reduced pressure , the resulting residue was recrystallized from water to obtain a yellow solid product with a yield of 80.7%.

[0028] Under the protection of nitrogen, ethyl 6-methyl-2-(2-nitroethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate Dissolve 1mol in 5L of acetonitrile, add 3mol of diisopropylethylamine, cool down to -5°C in ice brine, slowly press in 4mol of trichlorosilane from the cylinder, then slowly raise the reaction solution to 25°C and stir for 24 hours . Slowly add 3L saturated aqueous solution of sodium bicarbonate dropw...

Embodiment 3

[0030] Add 6-methyl-2-(2-chloroethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid methyl ethyl to the 10L reaction flask Add 1.0 mol of ester, 0.2 mol of sodium iodide and 5 L of N, N-dimethylformamide, stir to completely dissolve, add 1.8 mol of sodium nitrite, heat the reaction solution to 40°C and stir for 6 hours; suction filter while hot, and depressurize the filtrate After concentration, the resulting residue was recrystallized from water to obtain a yellow solid product with a yield of 80.9%.

[0031] Under the protection of nitrogen, ethyl 6-methyl-2-(2-nitroethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate 1mol, dissolved in 5L tetrahydrofuran, add 7mol of diisopropylethylamine, cool down to -5°C in ice brine, slowly press 2mol of trichlorosilane from the cylinder, then slowly raise the reaction solution to 25°C and stir for 24 hours . Slowly add 3L saturated aqueous solution of sodium bicarbonate dropwise, stir for 2 hou...

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Abstract

The invention relates to a preparation method of amlodipine base. Ethyl 6-methyl-2-(2-chloroethoxy)methyl-4-(2-chlorphenyl)-1, 4-dihydro-3, 5-pyridine dicarboxylate and sodium nitrite react in an organic solvent at the temperature of 40-70 DEG C with iodide as a catalyst to generate ethyl 6-methyl-2-(2-nitroethoxy)methyl-4-(2-chlorphenyl)-1, 4-dihydro-3, 5-pyridine dicarboxylate; and under the protection of nitrogen, the ethyl 6-methyl-2-(2-nitroethoxy) methyl-4-(2-chlorphenyl)-1, 4-dihydro-3, 5-pyridine dicarboxylate is dissolved into an organic solvent, an organic alkali is added, and trichlorosilane is reacted at room temperature to obtain amlodipine. Trichlorosilane is adopted as a green nitro-reduction reagent without metal participation, amlodipine is successfully synthesized, and the method is different from a previous synthesis method; and meanwhile, trichlorosilane is wide in industrial source and low in price.

Description

technical field [0001] The invention belongs to the technical field of chemical industry and pharmacy, and in particular relates to a preparation method of amlodipine base. Background technique [0002] Amlodipine is a calcium channel blocker used for essential hypertension and chronic stable angina and variant angina (alone or in combination with other drugs). Compared with other calcium antagonists, in addition to the advantages of low incidence of side effects and long half-life, it also has a strong vasodilator effect. The compound contains a dihydropyridine ring and a free amino group, and is called amlodipine base in synthesis; it is often converted into a salt form for clinical use in preparation, such as besylate, maleate, tartrate, Aspartic acid, citrate, hydrobromide, fumarate, methanesulfonate, etc. Since the launch of amlodipine, the domestic and foreign market sales have continued to grow, and it has become one of the leading drugs in the world. In particular,...

Claims

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Application Information

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IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 孟令栋钟强王乐强张世凤张国辉田希星
Owner SHANDONG HUIHAI PHARMA & CHEM
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