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The preparation method of dabigatran etexilate intermediate

A technology of dabigatran etexilate and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of increasing process complexity, increasing production costs, and being unsuitable for industrialized large-scale production, and achieves low production costs, short synthetic routes, The effect of easy operation

Active Publication Date: 2017-06-06
CHANGZHOU SUNLIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The method disclosed in the above literature needs to use relatively expensive benzyl chloroacetate for group protection, and then high-pressure catalytic hydrogenation to remove the benzyl group, which not only increases the production cost, but also increases the complexity of the process, and is not suitable for large-scale industrial production.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0025] This embodiment is the synthesis of 4-(N'-(n-hexyl formate) amidino)aniline hydrochloride, the specific method is as follows:

[0026] a. Add 53.6g of 4-aminobenzamidine dihydrochloride (0.258mol) and 215mL of acetone into a 1000mL four-neck flask, start stirring, cool down to 0-10°C in an ice-water bath, and drop 200mL of Add 16wt% sodium hydroxide aqueous solution for about 1 hour, control the temperature of the material at 0-10°C, add 42.5g of n-hexyl chloroformate (0.258mol) dropwise, drop it for about 2 hours, continue stirring for 1-2 hours after dropping, and take samples Central control until the raw materials disappear, the reaction is ended, the stirring is stopped, and the liquid is separated by standing.

[0027] b. Add 25mL of concentrated hydrochloric acid to the organic phase and stir evenly, then concentrate in vacuo to dryness to obtain 72.1g of light yellow solid (4-(N'-(n-hexylformyl)amidino)aniline hydrochloride) with a purity of 98.5% and a yield of...

Embodiment 2）

[0029] This example is the synthesis of 4-(N'-(n-hexylformyl)amidino)aniline sulfate, and its step a is the same as in Example 1, except that step b: add 25mL of 40wt% to the organic phase The sulfuric acid was stirred evenly and concentrated in vacuo to dryness to obtain 86.9 g of light yellow solid (4-(N'-(n-hexylformyl)amidino)aniline sulfate) with a purity of 98.5% and a yield of 92.0%.

Embodiment 3）

[0031] This example is the synthesis of 4-(N'-(n-hexylformyl)amidino)aniline, the step a of which is the same as that of Example 1, except that step b: the organic phase is directly concentrated in vacuo to dryness to obtain a light yellow solid (4-(N'-(n-hexylformyl)amidino)aniline) 63.3 g, purity 98.5%, yield 92.0%.

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PUM

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Abstract

The invention discloses a preparation method of a dabigatran etexilate intermediate. The method comprises the following steps: 1, condensing 4-aminobenzamidine or a salt thereof and hexyl chloroformate to obtain N-n-hexyl-4-aminobenzamidine-carbamate; and 2, condensing N-hexyl-4-aminobenzamidine-carbamate obtained in step 1 and R1CH2COOH to obtain 2-(4-(N'-(n-hexyl formate)amidino)aniline)acetic acid, or condensing N-hexyl-4-aminobenzamidine-carbamate and R2CH2COR2, and hydrolyzing to obtain 2-(4-(N'-(n-hexyl formate)amidino)aniline)acetic acid. The preparation method has the advantages of short synthesis route, simple technology, simple operation, mild conditions, low production cost, and suitableness for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a dabigatran etexilate intermediate. Background technique [0002] The chemical name of dabigatran etexilate is: 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1- Methyl-1H-benzimidazol-5-yl] carbonyl] (pyridin-2-yl) amino] ethyl propionate, its chemical structure is as described in formula 1: [0003] . [0004] Chinese patent document CN103626740A discloses a preparation method of dabigatran etexilate, the method is to first obtain compound VI by condensation of compound VII and benzyl chloroacetate, then obtain compound V by aminolysis of compound VI, and then obtain compound V by compound V and chlorine N-hexyl formate is condensed to obtain compound IV, followed by hydrogenation debenzylation of compound IV to obtain compound III, and finally compound I (ie dabigatran etexilate) is synthesized from ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/64C07C269/06
Inventor 胡锦平胡国宜郑建龙
Owner CHANGZHOU SUNLIGHT PHARMA