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Efficient and scalable synthesis of 2-(1'H-Indole-3'-Carbonyl)-thiazole-4-carboxylic acid methyl ester and its structural analogs

a technology of thiazole and methyl ester, which is applied in the direction of organic active ingredients, cyano group formation/introduction, organic chemistry, etc., can solve the problems of inability to efficiently produce ite at levels, severe limits the efficiency of the entire synthesis, and unpredictable success of other cyclization reactions, etc., to achieve easy synthesis, increase the efficiency and scalability of synthesis, and low cost

Inactive Publication Date: 2019-03-21
ARIAGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This disclosed patent describes methods for quickly and efficiently synthesizing a compound called 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and its analogs. These methods use a series of reactions to create the desired compound, eliminating a slow step in the original process. The methods are also safe, controllable, and use cheap and readily available materials. Overall, these methods make it easier and faster to produce ITE and its analogs.

Problems solved by technology

However, the original synthesis scheme is not capable of efficiently producing ITE at levels required for clinical studies in large animals and human subjects or therapies.
The inefficiency of this key step severely limits the efficiency of the entire synthesis.
Due to the presence of the carbonyl group, success using other cyclization reactions is unpredictable.

Method used

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  • Efficient and scalable synthesis of 2-(1'H-Indole-3'-Carbonyl)-thiazole-4-carboxylic acid methyl ester and its structural analogs
  • Efficient and scalable synthesis of 2-(1'H-Indole-3'-Carbonyl)-thiazole-4-carboxylic acid methyl ester and its structural analogs
  • Efficient and scalable synthesis of 2-(1'H-Indole-3'-Carbonyl)-thiazole-4-carboxylic acid methyl ester and its structural analogs

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0102]Example 1 shows a method of synthesizing ITE from 1H-indole via a number of intermediates, as depicted in Scheme A of FIG. 1.

Intermediate 1 (ITE-1): 1H-indol-3-yl(oxo)acetyl chloride

[0103]

[0104]1H-Indole (50 g, 0.43 mol.) and methyl tert-butyl ether (MTBE, 375 mL) were added to a three-necked round-bottom flask under stirring. The solution was cooled to −10° C., and then oxalyl chloride (56.9 g, 0.45 mol., 1.05 eq.) was added drop-wise while keeping the temperature between −10° C. and −5° C. The reaction mixture was then warmed to room temperature (−20° C.) and stirred at ˜20° C. for 1 hour. Petroleum ether (PE, 375 mL) was added to the reaction mixture. The suspension was stirred at ˜20° C. for 30 min. and then filtered. The filter cake was washed with PE (100 mL) and solvents in the cake were evaporated to give 108 g of product as a yellow solid. LC / MS: 208.6[M+1]

Intermediate 2 (ITE-2): 2-(1H-indol-3-yl)-2-oxoacetamide

[0105]

[0106]ITE-1 (108 g, 0.52 mol.) was added portion-wi...

example 2

[0114]Example 2 shows methods of synthesizing ITE from 1H-indol-3-yl(oxo)acetonitrile (ITE-3) in one container (“one-pot”) without purification of intermediate 2-(1′H-indole-3′-carbonyl)-4,5-dihydro-thiazole-4-carboxylic acid methyl ester (ITE-4), as depicted in Scheme B of FIG. 1. The process is presented in two sets of conditions.

example 2a

Product (ITE): 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester

[0115]

[0116]ITE-3 (1 g, 5.88 mmol.), L-cysteine methyl ester hydrochloride (1.01 g, 5.88 mmol.), pyridine (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 90 mg, 0.587 mmol.) were added to a three-necked round-bottom flask under stirring. After stirring at 40° C. for 2 hours, the reaction mixture was diluted with dichloromethane (DCM, 140 mL), then cooled to 0°. To the mixture was added DBU (1.79 g, 1.18 mmol.), followed by N-bromosuccinimide (NBS, 1.15 g, 6.46 mmol.) portion-wise. After stirring at 0° C. for 1 hour, the mixture was quenched with IN aqueous hydrochloric acid (100 mL) and extracted with DCM (20 mL) twice. The combined DCM layers were washed with IN aqueous hydrochloric acid (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give 1.71 g of crude product as a pale yellow solid (yield: 86.9%). Dimethyl sulfoxide (DMSO) and NaHCO3 were tested as solvent and base, ...

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Abstract

Methods of synthesizing 2−(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and structural analogs thereof. The methods include condensation reactions or condensation and oxidation reactions to form the thiazoline or thiazole moiety of ITE or its structural analogs.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 15 / 509,722, filed Mar. 8, 2017, which is a national stage entry of International Patent Application PCT / US2015 / 049302, filed Sep. 10, 2015, which claims priority from U.S. Provisional Application 62 / 049,804, filed Sep. 12, 2014. The disclosures of the aforementioned priority applications are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The invention is directed to the synthesis of 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester and structural analogs thereof.BACKGROUND[0003]The aryl hydrocarbon receptor (Ah receptor or AhR) is a ligand-inducible transcription factor that mediates a number of important biological and pharmacological processes. 2-(1′H-Indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) (Song et al. 2002, U.S. Pat. No. 6,916,834) is an endogenous ligand for the receptor. ITE can be used to study ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D277/20
CPCC07D277/20C07C67/47C07D417/06C07D209/12C07B43/08A61K31/404A61K31/427
Inventor SONG, JIASHENGZHANG, SUOMINGLI, GUODONGYANG, LUQING
Owner ARIAGEN INC
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