Method for synthesizing dabigatran etexilate intermediate

A synthesis method and dropwise addition technology, applied in the direction of organic chemistry, etc., can solve the problems of high impurities in intermediates, difficult separation and purification, low yield of synthesis route 1, etc., and achieve the effect of high atomic economic benefit.

Inactive Publication Date: 2016-07-13
江西胜富化工有限公司
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  • Abstract
  • Description
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Problems solved by technology

[0015] It is precisely because there is a problem with the synthesis method of this key intermediate in the above-mentioned synthetic route 1 that the obtained i

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  • Method for synthesizing dabigatran etexilate intermediate
  • Method for synthesizing dabigatran etexilate intermediate
  • Method for synthesizing dabigatran etexilate intermediate

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preparation example Construction

[0073] In a preferred embodiment, the synthesis method comprises the following steps:

[0074] (1) Using 3-nitro-4-methylaminobenzoic acid (II) as the starting material, dissolve it in a solvent, and treat it with thionyl chloride to obtain acid chloride; then esterify with methanol in the presence of a base Reaction generates 3-nitro-4-methylaminobenzoic acid methyl ester (Ⅲ);

[0075] Wherein, the solvent is selected from any one of toluene, benzene or chlorobenzene, and the base is selected from any one of triethylamine, diisopropylethylamine or N, N-dimethylaminopyridine;

[0076] (2) Methyl 3-nitro-4-methylaminobenzoate (Ⅲ) is dissolved in a solvent, and palladium carbon or Raney nickel is used as a catalyst, and catalytic hydrogenation is carried out under a hydrogen pressure of 1-10 times the atmospheric pressure Reduction reaction generates 3-amino-4-methylaminobenzoic acid methyl ester (Ⅳ);

[0077] Wherein, the solvent is selected from any one of tetrahydrofuran, e...

Embodiment 1

[0107] Synthesis of Methyl 3-Nitro-4-Methylaminobenzoate (Ⅲ)

[0108] Under nitrogen protection, put 3-nitro-4-methylaminobenzoic acid (100g, 0.51mol), N,N-dimethylformamide (catalytic amount: 2 drops), toluene (500mL ). Turn on the heating and raise the temperature to 90°C. When the system is at 60°C, start to add thionyl chloride (91g, 0.76mol) dropwise, and the dropwise addition is completed in about half an hour. After dropping, keep warm at 90°C for reaction, and continue stirring for 1 hour after the system is clarified. Then toluene and thionyl chloride were concentrated. After the concentration, methanol (300 mL) was added to the concentrate. The temperature was raised to 60-65° C., and triethylamine (154.8 g, 1.53 mol) was added dropwise. After dropping the incubation reaction, HPLC followed the reaction for about 1 hour. The reaction solution was concentrated to dryness, and the concentrate was dissolved in dichloromethane (500 mL). It was washed successively w...

Embodiment 2

[0113] Synthesis of Methyl 3-Amino-4-Methylaminobenzoate (Ⅳ)

[0114] Methyl 3-nitro-4-methylaminobenzoate (95 g, 0.45 mol) and tetrahydrofuran (950 mL) were put into a hydrogenation reactor. The temperature was raised to 60° C., and after the system was clarified, 10% palladium carbon (9.5 g) was added. First replace the air in the reactor with nitrogen, and then replace the nitrogen with hydrogen. The hydrogenation was started, and the reaction progress was tracked by TLC, and the reaction was completed in 2 hours. The temperature of the system was lowered to below 40°C. Palladium carbon was filtered off, and the filter cake was washed twice with a small amount of tetrahydrofuran (50 mL). The filtrates were combined and concentrated to dryness under vacuum at 50° C. to obtain 76 g of methyl 3-amino-4-methylaminobenzoate as an off-white solid, with a yield of 93.3%.

[0115] MP: 148.1-153.6°C

[0116] LC-MS: Theoretical C 9 h 12 N 2 o 2 (M+1)181, the actual value is ...

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Abstract

The invention provides a method for synthesizing a dabigatran etexilate intermediate, comprising: esterifying 3-nitro-4-methylaminobenzoic acid as a starting material with methanol to generate 3-nitro-4-methyl-(methylamino)benzoate, and carrying out catalytic hydrogenation reduction to obtain 3-amino-4-methyl-(methylamino)benzoate; carrying out closed-ring reaction to generate 1-methyl-2-chloromethylbenzimidazole-5-methyl formate; subjecting 1-methyl-2-chloromethylbenzimidazole-5-methyl formate to substitution reaction with 4-cyanoaniline to generate 1-methyl-2-(4-cyanophenylamino)methylbenzimidazole-5-methyl formate, and hydrolyzing to obtain 1-methyl-2-(4-cyanophenylamino)methylbenzimidazole-5-formic acid; amidating to generate a target product.The target product is synthesized through a converging synthetic process, reactive operations are simple, and the method is easy for industrial production.

Description

technical field [0001] The invention belongs to the field of compound synthesis, in particular to a synthetic method of an intermediate of dabigatran etexilate, wherein the intermediate of dabigatran etexilate is 3-{2-[(4-cyanoanilino) Methyl]-1-methyl-benzimidazole-5-[N-(2-pyridyl)carboxamido]}-propionic acid ethyl ester. Background technique [0002] Dabigatran etexilate, a direct thrombin inhibitor, was first launched in Germany and the UK in April 2008. The drug is a prodrug of dabigatran, a non-peptide thrombin inhibitor. Wherein, the structural formulas of the dabigatran etexilate and the dabigatran are as follows respectively: [0003] [0004] Dabigatran etexilate is converted into dabigatran with direct anticoagulant activity after gastrointestinal absorption after oral administration. Dabigatran etexilate is the first new class of oral anticoagulant drugs marketed in the past 50 years after warfarin. stroke risk in tremor patients. In October 2015, the US F...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 叶敏刘锐叶方国
Owner 江西胜富化工有限公司
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