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Synthetic method of dabigatran etexilate key intermediate

A dabigatran etexilate and synthetic method technology, applied in the direction of organic chemistry, etc., can solve the problems of compound 8 being expensive, not meeting the needs of industrial production, and not easy to obtain, and achieve good industrial production prospects, stable properties, and short reaction time Effect

Active Publication Date: 2017-07-07
FUJIAN INST OF MICROBIOLOGY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] In this method, intermediate 7 is used as raw material, compound 8 is selected as the coupling reagent, the conditions are mild, and the reaction yield is improved compared with the above-mentioned patent WO2011061080, but compound 8 is expensive and difficult to obtain, and this method still needs to obtain intermediate 7 first. , does not solve the problem of difficult source of intermediate 7, so this method does not meet the needs of industrial production

Method used

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  • Synthetic method of dabigatran etexilate key intermediate
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  • Synthetic method of dabigatran etexilate key intermediate

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Experimental program
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Effect test

Embodiment 1

[0035] The synthetic method of dabigatran etexilate key intermediate (formula 6 compound), comprises the following steps:

[0036] 1. Preparation of formula 2 compound

[0037]

[0038] 30.2 g (0.2 mol) of p-methylaminobenzoic acid was mixed with 280 ml of dichloromethane at room temperature and stirred for 1 hour, then 32.2 mL (0.4 mol) of pyridine was added and cooled to -20 o C, slowly add bromine 10.76 mL (0.21 mol), keep the low temperature and continue the reaction for 5 hours, finish the reaction with 50 mL saturated sodium thiosulfate aqueous solution, add 100 mL ethyl acetate, separate the organic phase, and then use 300 mL saturated chlorine Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure to about 100 mL, add 50 mL of n-hexane, a solid precipitates, stir at room temperature for 2 hours, filter with suction, wash with 50 mL of dichloromethane, 50 o C was dried in vacuum for 1 hour to obtain 43.0 g o...

Embodiment 2

[0046] 1. Preparation of formula 2 compound

[0047]

[0048] 30.2 g (0.2 mol) of p-methylaminobenzoic acid was mixed with 280 ml of tetrahydrofuran at room temperature and stirred for 1 hour, then 55.7 mL (0.4 mol) of triethylamine was added and cooled to -20 o C, slowly add bromine 10.76 mL (0.21 mol), keep the low temperature and continue the reaction for 5 hours, finish the reaction with 50 mL saturated sodium thiosulfate aqueous solution, add 100 mL ethyl acetate, separate the organic phase, and then use 300 mL saturated chlorine Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure to about 100 mL, add 50 mL of n-hexane, a solid precipitates, stir at room temperature for 2 hours, filter with suction, wash with 50 mL of dichloromethane, 50 o C was dried in vacuum for 1 hour to obtain 43.0 g of white powdery solid, yield: 94%.

[0049] 2. Preparation of the compound of formula 4

[0050]

[0051] Mix 34.4 ...

Embodiment 3

[0056] 1. Preparation of formula 2 compound

[0057]

[0058] 30.2 g (0.2 mol) of p-methylaminobenzoic acid was mixed with 280 ml of 1,2-dichloroethane at room temperature and stirred for 1 hour, then 33.6 g (0.4 mol) of sodium bicarbonate was added and cooled to -20 o C, slowly add 37.4 g (0.21 mol) of N-bromosuccinimide, keep the low temperature and continue the reaction for 5 hours, finish the reaction with 50 mL of saturated aqueous sodium thiosulfate solution, add 100 mL of ethyl acetate, separate the organic phase, Then wash with 300 mL of saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure to about 100 mL, add 50 mL of n-hexane, a solid precipitates, stir at room temperature for 2 hours, filter with suction, and wash with 50 mL of dichloromethane wash, 50 o C was dried in vacuum for 1 hour to obtain 42.1 g of white powdery solid, yield: 92%.

[0059] 2. Preparation of the compound of formula 4

[0060] ...

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Abstract

The invention discloses a synthetic method of a dabigatran etexilate key intermediate, namely N-[[2-(Chloromethyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl-N-2-pyridyl-beta-alanine ethyl ester (a compound of formula 6). According to the synthetic method, the key intermediate is prepared from three components of a compound of formula 4, haloacetic acid and an ammoniation agent through one-step cyclization, so that the complicated synthetic steps are avoided; the compound of the formula 4 can be prepared from cheap raw materials with stable performance. Compared with the prior art, the synthetic method has the advantages that the problems in multiple aspects can be simultaneously solved; the adopted raw materials are low in cost and have stable performance, the reaction time is short, conditions are mild, the intermediate is easy to purify, and the total yield reaches above 72%, so that the low-cost and high-yield dabigatran etexilate key intermediate (the compound of formula 6) can be prepared, and the synthetic method has relatively good industrial production prospects.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a chemical synthesis method of a key intermediate of oral anticoagulant dabigatran etexilate. Background technique [0002] Dabigatran etexilate (trade name: Padaxa) is developed by Boehringer Ingelheim, Germany, and is the first new oral anticoagulant drug that has been marketed 50 years after warfarin. Dabigatran etexilate is a non-peptide thrombin inhibitor, which exerts an anticoagulant effect by specifically and selectively blocking the activity of thrombin (free or bound). Medication monitoring and few drug interactions are a major advance in the field of anticoagulant therapy and the prevention of potentially fatal thrombosis. In 2008, Europe and Canada approved dabigatran etexilate for the prevention and treatment of acute venous thrombosis (VTE). In September 2010, the US FDA approved the use of dabigatran etexilate for the prevention of stroke and systemi...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 郑治尧赵学清陈忠黄杨威林燕琴
Owner FUJIAN INST OF MICROBIOLOGY
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