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Preparation method for p-aminobenzamidine hydrochloride

A technology of aminobenzamidine hydrochloride and aminobenzamidine iminocarboxylic acid, which is applied in the field of pharmaceutical synthesis, can solve the problems of many side reactions, expensive raw materials and high cost, and achieves low price, simple reaction operation and easy control. Effect

Inactive Publication Date: 2016-02-17
INST OF PHARMACY SHANDONG PROV ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although this method has been widely used, it is not the best choice for industrial production because of its high cost, expensive raw materials, many side reactions and low yield.

Method used

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  • Preparation method for p-aminobenzamidine hydrochloride
  • Preparation method for p-aminobenzamidine hydrochloride
  • Preparation method for p-aminobenzamidine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] 1.1 Dissolve p-nitrobenzaldehyde (15.1 g, 0.1 mol) in N,N-dimethylacetamide, add hydroxylamine hydrochloride (8.4 g, 0.12 mol) and react at 100°C for 4 hours, after the reaction is complete, pour it into ice water, Suction filtration, washing with water, and drying gave 10.2 g of p-nitrobenzonitrile with a yield of 69%.

[0055] 1.2 Add 100mL of anhydrous methanol and 3.78g (0.07mol) of solid sodium methoxide into the reaction vessel, stir to dissolve, add 10g (0.068mol) of p-nitrobenzonitrile, and stir at 50°C for 5 hours. Then add 5.4 g (0.07 mol) of ammonium acetate, stir at 45°C for 18 hours, cool to room temperature and suction filter, rinse the filter cake with methanol, and dry in vacuo to obtain 6.6 g of p-nitrobenzamidine with a yield of 60.1%.

[0056] 1.3 Add 80mL of 30% potassium carbonate solution to the reaction vessel, stir and cool down to 0°C, add 15g (0.091mol) of p-nitrobenzamidine, 80mL of ethyl acetate, dropwise add 15g (0.091mol) of chloroformic ac...

Embodiment 2

[0062] 2.1 Dissolve p-nitrobenzaldehyde (15.1 g, 0.1 mol) in N,N-dimethylacetamide, add hydroxylamine hydrochloride (8.4 g, 0.12 mol), and ferric chloride (9.8 g, 0.06 mol) at 100°C for reaction After 3 hours, the reaction was completed, poured into ice water, filtered with suction, and dried to obtain 11.1 g of p-nitrobenzonitrile with a yield of 75%.

[0063] 2.2 Add 80mL of anhydrous methanol, stir and dissolve 4.4g (0.08mol) of solid sodium methoxide, then add 12g (0.08mol) of p-nitrobenzonitrile, stir at 30°C for 7 hours, add 6.3g (0.08mol) of ammonium chloride, 5ml ( 0.08mol) of acetic acid, stirred at 60°C for 8 hours, cooled to room temperature and suction filtered, the filter cake was rinsed with methanol, and dried in vacuo to obtain 8.4 g of p-nitrobenzamidine with a yield of 63.6%.

[0064] 2.3 Add 80mL of 4M sodium hydroxide solution, stir to cool down to 20°C, add 15g (0.091mol) of p-nitrobenzamidine, 20mL of acetone, and dropwise add 15g (0.091mol) of n-hexyl ch...

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Abstract

The invention discloses a preparation method for p-aminobenzamidine hydrochloride, and belongs to the field of drug synthesis. The preparation method comprises the following steps: taking p-aminobenzamidine as a starting raw material, and enabling the p-aminobenzamidine and hydroxylamine hydrochloride to generate nitrobenzonitrile; then, enabling the nitrobenzonitrile to react with ammonium salt to generate p-aminobenzamidine; carrying out acylation and reduction on the p-aminobenzamidine to obtain p-aminobenzamidine imidogen n-hexyl formate; finally, performing salifying on the p-aminobenzamidine imidogen n-hexyl formate and hydrogen chloride to obtain the p-aminobenzamidine hydrochloride. Compared with the prior art, the preparation method for the p-aminobenzamidine hydrochloride disclosed by the invention has the characteristics of being simple to operate, easy to control in reaction, low in production cost and the like, and has a very good popularization and application value.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of p-aminobenzamidine (n-hexyl iminoformate) hydrochloride, an intermediate of dabigatran etexilate. Background technique [0002] Dabigatran etexilate ( Trade name: Pradaxa) is a cutting-edge new generation of oral anticoagulants for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. So far, dabigatran etexilate has been approved in 81 countries around the world, and has become a new oral anticoagulant drug with the most extensive clinical application experience. At present, dabigatran etexilate has accumulated more than 1.3 million patients worldwide The use of experience, the global sales of more than 1 billion euros. [0003] P-aminobenzamidine (n-hexyl iminoformate) hydrochloride has another name called dabigatran etexilate intermediate 4, which is an important intermediate in the synthetic route of dabigatr...

Claims

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Application Information

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IPC IPC(8): C07C257/20
CPCC07C253/02C07C257/18C07C257/20C07C255/50
Inventor 孙捷李娜王晓静孙敬勇韩德凤解宝仙李慧娟
Owner INST OF PHARMACY SHANDONG PROV ACAD OF MEDICAL SCI
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