Preparation method of micromolecule cathepsin D inhibitor

A technology of small molecules and inhibitors, which is applied in the field of preparation of small molecule cathepsin D inhibitors, can solve the problems of long reaction time, low yield, pollution and the like, and achieves the effects of simple operation, simple reaction conditions and simple post-treatment.

Active Publication Date: 2013-09-04
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to overcome the technical problems such as low yield, long reaction time and serious pollution in the preparation method of

Method used

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  • Preparation method of micromolecule cathepsin D inhibitor
  • Preparation method of micromolecule cathepsin D inhibitor
  • Preparation method of micromolecule cathepsin D inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] (I) Preparation of 4-(2-benzothiazylthio)aniline

[0022] First add 2-mercaptobenzothiazole (1.67g, 10mmol), p-aminoiodobenzene (2.63g, 12mmol), catalyst CuI (0.19g, 1mmol), Na 2 CO 3 (1.06g, 10mmol) and H 2 O (20mL), heated to 120°C and refluxed for 24h, the reaction was completed, cooled to room temperature, the reaction liquid was extracted with ethyl acetate, the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried, PE:EA= 2.09 g of 4-(2-benzothiazylsulfanyl)aniline was obtained by passing through the column at 6:1, with a yield of 86.0%.

[0023] (Π) Preparation of a small molecule cathepsin D inhibitor

[0024] Dissolve 4-(2-benzothiazylthio)aniline (1.29g, 5mmol) and 3,5-dichloro-2-hydroxybenzoic acid (1.04g, 5mmol) in CH 2 CL 2 (20mL), add the acylating agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.96g, 5mmol), heat to 40°C under reflux for 8h, After the reaction is complet...

Embodiment 2

[0026] (I) Preparation of 4-(2-(6-chlorobenzothiazylthio))aniline

[0027] First add 2-mercapto-6-chlorobenzothiazole (2.02g, 10mmol), p-aminoiodobenzene (2.63g, 12mmol), catalyst CuI (0.19g, 1mmol), Na 2 CO 3 (1.06g, 10mmol) and H 2 O (20mL), heated to 120°C and refluxed for 24h, the reaction was completed, cooled to room temperature, the reaction liquid was extracted with ethyl acetate, the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried, PE:EA= 2.46 g of 4-(2-(6-chlorobenzothiazylsulfanyl))aniline was obtained in a 6:1 column with a yield of 84.0%.

[0028] (Π) Preparation of a small molecule cathepsin D inhibitor

[0029] Dissolve 4-(2-(6-chlorobenzothiazylthio))aniline (1.46g, 5mmol) and 3,5-dichloro-2-hydroxybenzoic acid (1.04g, 5mmol) in CH 2 CL 2 (20mL), add the acylating agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.96g, 5mmol), heat to 40°C under reflux for 8h, After the re...

Embodiment 3

[0031] (I) Preparation of 4-(2-(6-methoxybenzothiazylthio))aniline

[0032] First add 2-mercapto-6-methoxybenzothiazole (1.97g, 10mmol), p-aminoiodobenzene (2.63g, 12mmol), catalyst CuI (0.19g, 1mmol), Na 2 CO 3 (1.06g, 10mmol) and H 2 O (20mL), heated to 120°C and refluxed for 24h, the reaction was completed, cooled to room temperature, the reaction liquid was extracted with ethyl acetate, the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried, PE:EA= 2.39 g of 4-(2-(6-methoxybenzothiazylsulfanyl))aniline was obtained by 6:1 column, with a yield of 83.2%.

[0033] (Π) Preparation of a small molecule cathepsin D inhibitor

[0034] 4-(2-(6-methoxybenzothiazylthio))aniline (1.44g, 5mmol) obtained in step 1 was dissolved in 3,5-dichloro-2-hydroxybenzoic acid (1.04g, 5mmol) in CH 2 CL 2 (20mL), add the acylating agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.96g, 5mmol), heat to 40°C under r...

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Abstract

The invention discloses a preparation method of a micromolecule cathepsin D inhibitor. The preparation method comprises the following steps that 2-mercaptobenzothiazole or its derivatives and 4-iodoaniline as starting materials undergo a reaction in a water phase by catalytic C-S coupling to produce 4-(2-benzothiazolylthio)aniline or its corresponding derivatives (A); and the 4-(2-benzothiazolylthio)aniline or its corresponding derivatives (A), and 3,5-dichloro-2-hydroxybenzoic acid undergo an amidation reaction to produce the micromolecule cathepsin D inhibitor (B). The preparation method has the advantages of easily available raw materials, simple reaction conditions, simple and convenient operation, low toxicity and pollution, simple post-treatment processes, high yield and high purity.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of a class of small molecule cathepsin D inhibitors. Background technique [0002] Cathepsin D is a lysosomal aspartic acid protease, and studies have shown that it is closely related to Alzheimer's disease, breast cancer and uterine cancer. Through high-throughput screening and optimization, Stephen Wong's research team obtained a class of compounds with strong inhibitory effects on cathepsin D, whose core structure is N-[4-(benzothiazole-2-thio)aryl]- 3,5-dichloro-2-hydroxybenzamide, the specific molecular structure formula is as follows: [0003] [0004] At present, there is no patent protection for the preparation of this type of compound. In the current literature reports, 2-(4-nitrophenylthio)benzothiazole is mainly prepared by 2-mercaptobenzothiazole and p-chloronitrobenzene. Complete in solvent DMF, post-pro...

Claims

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Application Information

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IPC IPC(8): C07D277/74
Inventor 韩世清何国珍张杰赵丹周双利
Owner NANJING UNIV OF TECH
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