Method for preparing and purifying dabigatran etexilate intermediate

A compound, the technology of ethyl propionate, which is applied in the field of preparation and purification of dabigatran etexilate intermediates, can solve the problems of no yield and purity, and achieve the effect of simple operation and high yield

Active Publication Date: 2013-02-06
SHANGHAI AOBO PHARMTECH INC LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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  • Method for preparing and purifying dabigatran etexilate intermediate
  • Method for preparing and purifying dabigatran etexilate intermediate
  • Method for preparing and purifying dabigatran etexilate intermediate

Examples

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Embodiment 1

[0048] Example 1: 3-{2-[(4-cyanoanilino)methyl]-1-methyl-benzimidazole-5-[N-(2-pyridyl)formamido]}-propionic acid Synthesis of ethyl ester (I)

[0049] Add 687g of 2-(4-cyanoanilino)acetic acid and 10L of tetrahydrofuran into the reaction flask, add 632g of carbonyldiimidazole under stirring, and stir at room temperature for 1 hour. Add 1334g of 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido]-acrylic acid ethyl ester (III), stir at room temperature for 12 hours, the raw material disappears and a condensate intermediate is formed. Tetrahydrofuran was removed under reduced pressure, and 10 L of ethyl acetate was added. Wash with saturated potassium carbonate solution, extract and separate the organic phase. Add 468g of glacial acetic acid, reflux reaction for 12 hours, the condensate intermediate disappears, and the ethyl acetate solution of the obtained compound (I) is washed with a saturated potassium carbonate solution, and then directly proceeds to the next step of react...

Embodiment 2

[0051] Example 2: 3-{2-[(4-cyanoanilino)methyl]-1-methyl-benzimidazole-5-[N-(2-pyridyl)formamido]}-propionic acid Synthesis of Ethyl Estersuccinate (V)

[0052] Add 460 g of succinic acid to the ethyl acetate solution containing compound (I) in Example 1, and stir at room temperature for 3 hours. The precipitated solid was filtered out and dried to obtain 2015 g of compound (V), with a two-step total yield of 86% and a purity of 99%.

[0053] 1 H NMR (400MHz, d-DMSO) δ1.10(t, J=7.2Hz, 3H), 2.39(s, 4H), 2.65(t, J=7.2Hz, 2H), 3.73(s, 3H), 3.95 (q, J=7.2Hz, 2H), 4.20(t, J=7.2Hz, 2H), 4.57(d, J=5.6Hz, 2H), 6.79(d, J=8.0Hz, 2H), 6.87(d , J=8.0Hz, 1H), 7.09(dd, J=4.8, 7.2Hz, 1H), 7.14(d, J=8.0, 1H), 7.22(t, J=4.8, 1H), 7.38(d, J =8.0, 1H), 7.42-7.46(m, 3H), 7.52(t, J=8.0Hz, 1H), 8.36(d, J=2.8, 1H), 12.11(brs, 2H)

Embodiment 3

[0054] Example 3 3-{2-[(4-cyanoanilino)methyl]-1-methyl-benzimidazole-5-[N-(2-pyridyl)formamido]}-propionic acid ethyl Preparation of pure ester (I)

[0055] 1000 g of compound (V) obtained in Example 2 was added to a mixed solvent composed of 3 L of ethyl acetate and 3 L of water. Add 230 g of potassium carbonate and stir at room temperature for 1 hour. Separate the liquid to obtain the organic phase. After the organic phase was dried, the organic solvent was removed under reduced pressure to obtain 780 g of pure compound (I), with a yield of 97% and a purity of 99%.

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Abstract

The invention discloses a method for preparing and purifying a dabigatran etexilate key intermediate 3-{2-[(4-cyanoanilino)methyl]-1-methyl-benzimidazolyl-5-[N-(2-pyridyl)formamido]}-ethyl propionate (I). The preparation process comprises the following steps: reacting 2-( 4-cyanoanilino)acetic acid (IV) and 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido-]-ethyl acrylate (III) in the presence of a condensing agent to form a condensate; and carrying out cyclization reaction under the catalytic action of acetic acid to prepare the 3-{2-[(4-cyanoanilino)methyl]-1-methyl-benzimidazolyl-5-[N-(2-pyridyl)formamido]}-ethyl propionate (I). The purification process comprises the following steps: reacting the compound (I) and succinic acid to form 3-{2-[(4-cyanoanilino)methyl]-1-methyl-benzimidazolyl-5-[N-(2-pyridyl)formamido]}-ethyl propionate succinate (V), and finally, adding alkali for dissociation to obtain the high-purity compound (I).

Description

technical field [0001] The invention relates to a preparation and purification of dabigatran etexilate key intermediate 3-{2-[(4-cyanoanilino)methyl]-1-methyl-benzimidazole-5-[N-(2 -pyridyl)formamido]}-propionic acid ethyl ester (I) method. Background technique [0002] Dabigatran etexilate (II) is a kind of oral thrombin inhibitor developed by Boehringer Ingelheim Pharmaceutical Company of Germany, which was approved for marketing in Europe in March 2008. The drug is mainly used for venous thromboembolism after surgery and in specific patient populations. This is the first new class of oral anticoagulant drugs to be marketed in more than 50 years since warfarin. Dabigatran etexilate is converted in vivo to the active dabigatran, which exerts its anticoagulant effect by directly inhibiting thrombin. The launch of the drug is a major development in the field of anticoagulant therapy and the prevention of potentially fatal thrombosis, which is a milestone. [0003] [0...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 陈宇梁俊竺伟陈欢生
Owner SHANGHAI AOBO PHARMTECH INC LTD
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