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Synthesis method of 2-(aminomethyl)-1, 3-thiazole-5-carboxylic acid methyl ester

A technology of methyl carboxylate and aminomethyl, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of unsuitable overall process, unavailable ring-closing raw materials, and strong taste of reagents, so as to improve consistency, reduce production costs, and protect the environment. The effect of little pollution

Pending Publication Date: 2022-01-18
凯美克(上海)医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Aiming at the problems of low yield, difficulty in purification, strong taste of reagents, difficulty in obtaining ring-closing raw materials and unsuitable industrial scale-up of the overall process in the synthesis of similar compounds in the prior art, the main purpose of the present invention is to provide a 2-(amino The synthetic method of methyl)-1,3-thiazole-5-carboxylic acid methyl ester adopts 2-methylthiazole-5-carboxylic acid as initial raw material, through esterification, bromination, single reduction, double Boc amination and The classic chemical reaction steps of removing Boc, under mild and suitable conditions, the target product 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester with a purity of more than 97% is obtained

Method used

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  • Synthesis method of 2-(aminomethyl)-1, 3-thiazole-5-carboxylic acid methyl ester
  • Synthesis method of 2-(aminomethyl)-1, 3-thiazole-5-carboxylic acid methyl ester
  • Synthesis method of 2-(aminomethyl)-1, 3-thiazole-5-carboxylic acid methyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0040] This example prepares methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate, and the synthetic route is as follows:

[0041]

[0042] Specific steps are as follows:

[0043] Step 1: Add compound A (100g, 0.70mol, 1eq) to 1000ml methanol, then add concentrated sulfuric acid (100g, 1mol, 1.4eq), heat to reflux overnight, TLC detection, the reaction is complete, pour into ice water, ethyl acetate After extraction, backwashing with sodium bicarbonate solution and spinning to dry, 106 g of compound B was obtained as a brown liquid with a yield of 91.8% and a purity of 95%.

[0044] Step 2: Add compound B (106g, 0.64mol, 1eq) to 1000ml of carbon tetrachloride, then add N-bromosuccinimide (214g, 2.12mol, 2.5eq), heat to reflux, batch by batch Add azobisisobutyronitrile (69.36, 0.42mol, 0.66eq), continue to reflux overnight after addition, TLC detects that the reaction is complete, cool and filter, wash the filter cake with dichloromethane, combine the organic phases to obtain ...

Embodiment 2

[0050] This example prepares methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate, and the specific steps are as follows:

[0051] Step 1: Add compound A (10g, 70mmol, 1eq) to 100ml of methanol, then add concentrated sulfuric acid (10g, 100mmol, 1.4eq), heat to reflux overnight, TLC detection, the reaction is complete, pour into ice water, and extract with ethyl acetate , backwashed with sodium bicarbonate solution and spin-dried to obtain 9.42 g of compound B as a brown liquid, with a yield of 78% and a purity of 91%.

[0052] Step 2: Add compound B (9.42g, 55mmol, 1eq) to 100ml of carbon tetrachloride, then add N-bromosuccinimide (19.58g, 110mmol, 2.0eq), heat to reflux, batch by batch Add azobisisobutyronitrile (2.71g, 16.5mmol, 0.3eq), continue to reflux overnight after the addition, TLC detection, the reaction is complete, cool and filter, wash the filter cake with dichloromethane, combine the organic phases to obtain 150ml of compound C solution, The quantitative content i...

Embodiment 3

[0057] This example prepares methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate, and the specific steps are as follows:

[0058] Step 1: Add compound A (10g, 70mmol, 1eq) to 100ml of methanol, then add concentrated sulfuric acid (5g, 50mmol, 0.7eq), heat to reflux overnight, TLC detection, the reaction is complete, pour into ice water, and extract with ethyl acetate , backwashed with sodium bicarbonate solution and spin-dried to obtain 6.2 g of compound B as a brown liquid with a yield of 50% and a purity of 89%.

[0059] Step 2: Add compound B (6.2g, 35mmol, 1eq) to 60ml of carbon tetrachloride, then add dibromohydantoin (22.02g, 77mmol, 2.2eq), heat to reflux, and add azobisiso Butyronitrile (3.79g, 23.1mmol, 0.66eq), continued to reflux overnight after addition. According to TLC detection, the reaction was complete, cooled and filtered, the filter cake was washed with dichloromethane, and the organic phases were combined to obtain 90 ml of compound C solution with a quantit...

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Abstract

The invention discloses a synthetic method of 2-(aminomethyl)-1, 3-thiazole-5-carboxylic acid methyl ester, and belongs to the technical field of drug intermediate synthesis. According to the synthetic method, 2-methylthiazole-5-carboxylic acid is adopted as an initial raw material and sequentially subjected to classical chemical reactions of esterification, bromination, single reduction, bis-Boc amination and Boc removal to obtain the target compound 2-(aminomethyl)-1, 3-thiazole-5-carboxylic acid methyl ester, wherein the purity is 97% or above, the total yield reaches up to 48.3%, and the stability is good; the problems of low yield, difficulty in purification, large reagent smell, difficulty in obtaining of ring closing raw materials and difficulty in amplification of the whole process in synthesis of similar compounds in the prior art are solved, and application of the target compound in the field of medicines is promoted.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester. Background technique [0002] Thiazoles and their derivatives are an important class of heterocyclic compounds, which have been proven to have superior pharmacological and biological activities. They can be used as key intermediates to synthesize antitumor, antiviral and antibacterial drugs, and are widely used in medicine, pesticides, etc. field. As an important thiazole derivative, 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester can be used as a key raw material to prepare HDAC6 inhibitors for the treatment of proliferative, inflammatory, infectious, neurological or Cardiovascular disease (as described in WO2011106627A1), so it is necessary to study its synthesis. [0003] There is no report on the synthesis of 2-(aminomethyl)-1,3-thiazole-5-carboxy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56A61P29/00A61P31/00A61P9/00A61P25/00
CPCC07D277/56A61P29/00A61P31/00A61P9/00A61P25/00
Inventor 王治国郦荣浩罗春艳许惠敏
Owner 凯美克(上海)医药科技有限公司
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