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Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate

A technology of methylaminobenzoyl and ethyl propionate, which is applied in the field of post-treatment purification of pharmaceutical intermediates 3-[amino] ethyl propionate and 3-[amino] ethyl propionate, and can solve post-treatment purification The method process is complicated, the product properties are not very good, and it is uneconomical, etc., to achieve significant creativity and practical value, improve production safety, and be easy to operate.

Inactive Publication Date: 2015-09-09
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] As can be seen from the above-mentioned existing disclosed technology, compound (1) is the key intermediate of dabigatran etexilate, it is a kind of amino compound, is obtained by reducing the corresponding nitro compound, and the post-treatment purification method process is complicated , involving the use of toxic drug toluene, the product properties are not very good, uneconomical and not environmentally friendly

Method used

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  • Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate
  • Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate
  • Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] This example dabigatran etexilate synthetic process intermediate 3-(pyridin-2-yl amino) ethyl propionate is synthetic, and described synthetic reaction equation is as follows:

[0036]

[0037] Including the following steps:

[0038] (1) Dissolve 5 g of ethyl 3-[(3-nitro-4-methylaminobenzoyl) (pyridin-2-yl) amino] propionate hydrochloride in 30 mL of HAC / H 2 O (15mL / 15mL);

[0039] (2) Add 3.5g of reduced zinc powder or Zn particles at one time or in batches;

[0040] (3) At room temperature, stir for 1-4h and keep reacting;

[0041] (4) After the reaction is completed, filter to remove unnecessary reduced metallic zinc;

[0042] (5) with H 2 O washing, get the organic phase;

[0043] (6) adding lye to the organic phase of step (5), adjusting the pH to 7-8;

[0044] (7) Extract 2-3 times with 50-300mL dichloromethane, concentrate and distill off the dichloromethane;

[0045] (8) Dissolve with 2-10mL ethyl acetate sonication;

[0046] (9) Under stirring, add 5...

Embodiment 2

[0050] This example dabigatran etexilate synthetic process intermediate 3-(pyridin-2-yl amino) ethyl propionate is synthetic, and described synthetic reaction equation is as follows:

[0051]

[0052] Including the following steps:

[0053] (1) Dissolve 10 g of ethyl 3-[(3-nitro-4-methylaminobenzoyl) (pyridin-2-yl) amino] propionate hydrochloride in 30 mL of HAC / H 2 O (30mL / 30mL);

[0054] (2) Add 7.0 g of reduced zinc powder or Zn particles at one time or in batches;

[0055] (3) At room temperature, stir for 1-4h and keep reacting;

[0056] (4) After the reaction is completed, filter to remove unnecessary reduced metal zinc;

[0057] (5) with H 2O washing, get the organic phase;

[0058] (6) adding lye to the organic phase of step (5), adjusting the pH to 7-8;

[0059] (7) Extract 2-3 times with 50-300mL dichloromethane, concentrate and distill off the dichloromethane;

[0060] (8) Dissolve with 2-10mL ethyl acetate sonication;

[0061] (9) Under stirring, add 10-...

Embodiment 3

[0065] This example dabigatran etexilate synthetic process intermediate 3-(pyridin-2-yl amino) ethyl propionate is synthetic, and described synthetic reaction equation is as follows:

[0066]

[0067] Including the following steps:

[0068] (1) Dissolve 15g of ethyl 3-[(3-nitro-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate hydrochloride in 30mL HAC / H 2 O (45mL / 45mL);

[0069] (2) Add 10.5g of reduced zinc powder or Zn particles at one time or in batches;

[0070] (3) At room temperature, stir for 1-4h and keep reacting;

[0071] (4) After the reaction is completed, filter to remove unnecessary reduced metal zinc;

[0072] (5) with H 2 O washing, get the organic phase;

[0073] (6) adding lye to the organic phase of step (5), adjusting the pH to 7-8;

[0074] (7) Extract 2-3 times with 50-300mL dichloromethane, concentrate and distill off the dichloromethane;

[0075] (8) Dissolve with 2-10mL ethyl acetate sonication;

[0076] (9) Under stirring, add 15-150 g o...

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Abstract

The invention discloses an aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate. The method comprises the following steps: reducing 3-[(3-nitro-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate hydrochloride with metal zinc in an acetic acid / water system so as to obtain a mother solution; and filtering and washing the mother solution, regulating the PH of the mother solution with alkali liquor, extracting the mother solution with a first organic solvent, condensing, dissolving the mother solution with a second organic solvent, absorbing by use of silica gel, eluting with a third organic solvent, and condensing to obtain a white solid, namely 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate. According to the aftertreatment purification method, a silica gel adsorption method and an eluting method are adopted to remove pigments and byproducts generated in reaction, so that aftertreatment is simple, the target organic product purity is improved and a high-purity target compound is obtained.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a pharmaceutical intermediate 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]ethyl propionate, specifically a 3-[(3-Amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propanoic acid ethyl ester post-treatment purification method. Background technique [0002] Ethyl 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate (compound (1)) is a key intermediate for the preparation of dabigatran etexilate. Dabigatran etexilate (English name Dabigatranetexilate, compound (2)) is a new type of direct thrombin inhibitor. This drug was invented by Boehringer Ingelheim of Germany, and it was first launched in Germany and the UK in April 2008. This is the first new class of oral anticoagulant drug launched in the past 50 years after warfarin. [0003] [0004] In the prior art, such as CN102612517A, the synthetic route of dabigatran etexilate is shown in formula 1: [0005]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 任玉杰王飞
Owner SHANGHAI INST OF TECH
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