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New synthesis method of endogenous ligand 2-(1'H3'-indolyl carbonyl) thiazole-4-carboxylic acid methyl ester of arylhydrocarbon receptor (AHR)

A technology of methyl carboxylate and indole carbonyl, applied in the field of medicine, can solve the problems of unindustrialization, harsh conditions for ring closure of titanium tetrachloride, difficult separation of acylation, etc.

Inactive Publication Date: 2012-11-14
CGENETECH (SUZHOU CHINA) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The existing process acylation is not easy to separate, and the conditions for ring closure with titanium tetrachloride are harsh, the yield is low (about 20%), it needs to pass through the column many times, the cost is high, and it cannot be industrialized

Method used

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  • New synthesis method of endogenous ligand 2-(1'H3'-indolyl carbonyl) thiazole-4-carboxylic acid methyl ester of arylhydrocarbon receptor (AHR)
  • New synthesis method of endogenous ligand 2-(1'H3'-indolyl carbonyl) thiazole-4-carboxylic acid methyl ester of arylhydrocarbon receptor (AHR)
  • New synthesis method of endogenous ligand 2-(1'H3'-indolyl carbonyl) thiazole-4-carboxylic acid methyl ester of arylhydrocarbon receptor (AHR)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1: Indole (117 g, 1 mole) was dissolved in 1170 liters of anhydrous ether in a two-liter three-necked flask, cooled in an ice-salt bath, and the temperature was controlled at 0 to 5 degrees, and 1 ml of N,N-di Methylformamide, slowly add oxalyl chloride (254 g, 2 moles) dropwise within 2 hours, slowly rise to room temperature after dropping, continue stirring for 2 hours, filter, wash with 200 ml of ether, and dry in vacuo to obtain a yellow solid 168 G, the yield is 95% (used directly in the next step).

Embodiment 2

[0019] Example 2: The yellow solid (104 g, 0.5 mol) obtained in the previous step was dissolved in 1 liter of anhydrous tetrahydrofuran, and tributyltin (160 g, 0.55 mol) was slowly added dropwise while controlling the temperature below 35 degrees. React at room temperature for 24 hours, remove most of the solvent with a rotary evaporator, add 500 ml of water after cooling, extract three times with ethyl acetate (500 ml), mix the organic phase, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and spin. 76 g of off-white solid was obtained by drying, with a yield of 88%.

Embodiment 3

[0020] Example 3: The reduced white solid (34.6 g, 0.2 mol) was dissolved in a mixed solvent of 350 ml tetrahydrofuran and 350 ml water, and L-cysteine ​​methyl ester hydrochloride (31.4 g, 0.2 mol) was added And sodium bicarbonate (16.8 g, 0.2 mol), stirred at room temperature for 24 hours, extracted three times with ethyl acetate (500 ml), combined the organic phases, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a white solid (55 g), the yield is 95%. 1 H NMR (500MHz, CD 3 COCD 3 )δ11.27 (1H, m, NH), 8.82 (1H, d, J=3.2Hz, 2'-H), 8.34 (1H, m, 4'-H), 7.56 (1H, m, 7'- H), 7.27 (2H, m, 5'-and 6'-H), 5.59 (1H, t, J = ca. 9.5 Hz, 4-H), 3.80 (3H, s, CO 2 Me), 3.67(1H, dd, J=11.3, 10.1Hz, one of 5-H 2 ), 3.58(1H, dd, J=11.3, 8.9Hz, one of 5-H 2 )

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Abstract

The invention discloses a new synthesis method of 2-(1'H3'-indolyl carbonyl) thiazole-4-carboxylate. The synthesis method mainly comprises the following steps of: reacting (1H-indole-3-yl) carboxylic acetaldehyde with -L-cysteine methyl ester hydrochloride for one-step ring closure; and then oxidizing. With the adoption of the new synthesis method, the defects that the reaction of indole-3-acetaldehyde acyl chloride and the-L-cysteine methyl ester hydrochloride on the basis of the traditional process is low in yield and column passing purification is needed are avoided without ring closure in a next step, and the disadvantages of strict conditions, low yield, difficulty in purification and the like due to ring closure through TiCl4 are avoided.

Description

Technical field [0001] The invention relates to an improvement in the synthesis process technology of 2-(1'H3'-indolecarbonyl)thiazole-4-carboxylic acid methyl ester, and belongs to the technical fields of medicine and chemical industry. Background technique [0002] 2-(1′H3′-Indolecarbonyl)thiazole-4-carboxylic acid methyl ester is a pale yellow solid, which is an endogenous ligand, and has been widely used in wound fibrosis and other negative aspects. Now due to the biological importance of the ligand Because of its chemical synthesis structure distribution and research to confirm its physiological activity, large-scale synthesis and industrialization are obviously necessary. [0003] The existing 2-(1'H3'-indolecarbonyl)thiazole-4-carboxylic acid methyl ester synthesis technology is mainly indolecarbonyl acid chloride and 1-cysteine ​​methyl ester hydrochloride acylation, and then in tetrachloride The ring is oxidized in the presence of titanium oxide. The route is [0004] [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06
Inventor 张福治张仁延丁炬平余强
Owner CGENETECH (SUZHOU CHINA) CO LTD