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Preparation methods of 3-[N-(2-pyridyl)-3-amino-4-methylamino benzamido]-ethyl propionate

A kind of technology of methylaminobenzamide and methylaminobenzoyl chloride, applied in 3-[N-(2-pyridyl)-3-amino-4-methylaminobenzamide]-propionic acid In the field of preparation of ethyl ester, it can solve the problems of increased cost, decreased efficiency, slowness, etc., and achieve the effect of simplifying the production process, promoting the reaction, and reacting quickly and efficiently.

Inactive Publication Date: 2014-01-29
SHANGHAI AOBO PHARMTECH INC LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] But when preparing compound (I) with this method, there is the problem that cannot enlarge: when substrate>100g, the abnormal slowness that reaction carries out even can stop; Must filter and remove palladium / carbon, and replace fresh palladium / carbon, just can Complete conversion of compound (IV); for larger reactions, multiple palladium / carbon changes may be required
Moreover, this method is only suitable for small-scale reactions (raw material intake is no more than 20g), and for larger-scale reactions, it is not mentioned in the patent
[0011] Due to the defects in the preparation of compound (I) in the prior art, the efficiency of industrial production is reduced and the cost is greatly increased, which also prompted us to conduct in-depth research on the preparation process of this intermediate

Method used

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  • Preparation methods of 3-[N-(2-pyridyl)-3-amino-4-methylamino benzamido]-ethyl propionate
  • Preparation methods of 3-[N-(2-pyridyl)-3-amino-4-methylamino benzamido]-ethyl propionate
  • Preparation methods of 3-[N-(2-pyridyl)-3-amino-4-methylamino benzamido]-ethyl propionate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: Synthesis of 3-[N-(2-pyridyl)-3-nitro-4-methylaminobenzamido]-propionic acid ethyl ester (IV)

[0043] Add 1.3Kg of compound (II), 678g of triethylamine and 12L of dichloromethane into the reaction flask. Add 1.1 Kg of compound (III) dissolved in 12 L of dichloromethane at room temperature, stir at room temperature for 2 hours, and the reaction is complete. 12L of water and 1L of dichloromethane were added for extraction and separation, and the obtained organic phase was washed with 12L of saturated potassium carbonate solution. The separated organic phase was dried and the organic solvent was removed under reduced pressure to obtain 2.1 Kg of crude compound (IV), which was directly carried out to the next reaction.

Embodiment 2

[0044] Example 2: Synthesis of 3-[N-(2-pyridyl)-3-amino-4-methylaminobenzamido]-propionic acid ethyl ester (I)

[0045] Add the compound (IV) prepared in Example 1 and a mixed solvent consisting of 24L acetic acid and 6L water into the reaction flask. Add 1.3Kg of iron powder at room temperature, and react at room temperature for 4 hours, and the reaction is complete. Remove insoluble matter by filtration, remove acetic acid under reduced pressure, add saturated sodium bicarbonate solution to neutralize the system until the system is weakly alkaline. Add 6L of ethyl acetate for extraction, separate the layers, and remove the ethyl acetate under reduced pressure to obtain an oil. The oil was crystallized in tertiary methyl ether, filtered and dried to obtain 1.25Kg of compound (I), with a yield of 65% and a purity of 95%.

Embodiment 3

[0046] Example 3: Synthesis of 3-[N-(2-pyridyl)-3-amino-4-methylaminobenzamido]-propionic acid ethyl ester (I)

[0047] Add the compound (IV) prepared in Example 1 and a mixed solvent consisting of 20L acetic acid and 2L water into the reaction bottle. Add 2.05Kg of zinc powder at room temperature, react at room temperature for 1 hour, and the reaction is complete. Remove insoluble matter by filtration, remove acetic acid under reduced pressure, add saturated sodium bicarbonate solution to neutralize the system until the system is weakly alkaline. Add 4L of ethyl acetate for extraction, separate the layers, and remove the ethyl acetate under reduced pressure to obtain an oily substance. The oil was crystallized in tertiary methyl ether, filtered and dried to obtain 1.35Kg of compound (I), with a yield of 70% and a purity of 95%.

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Abstract

The invention discloses two methods of preparing a dabigatran etexilate intermediate 3-[N-(2-pyridyl)-3-amino-4-methylamino benzamido]-ethyl propionate (I).

Description

technical field [0001] The invention relates to two methods for preparing dabigatran etexilate key intermediate 3-[N-(2-pyridyl)-3-amino-4-methylaminobenzamido]-ethyl propionate (I) . Background technique [0002] Dabigatran etexilate (V) 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] [0004] At present, many documents and patents have reported ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 陈欢生梁俊陈宇竺伟
Owner SHANGHAI AOBO PHARMTECH INC LTD
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