Preparation method for varespladib

A technology of Padil and solvent, applied in the field of drug preparation, can solve the problems of low yield, unsuitable for industrial production, and high preparation cost

Active Publication Date: 2010-09-22
ZENJI RES LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In the synthesis of compounds 5 to 6, the yield is low, only about 30%
In the synthesis from compound 5 to 4, selective debenzylation, the yield is low, only about 40%
High preparation cost, not suitable for industrial production

Method used

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  • Preparation method for varespladib
  • Preparation method for varespladib
  • Preparation method for varespladib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of 4-benzyloxy-1H-indole(II)

[0031]

[0032] Add 4-hydroxyindole (10.0g, 0.0752mol) to a 500ml three-necked flask, dissolve it with 300ml of acetone, then add potassium carbonate powder (31.1g, 0.226mol), add benzyl bromide (15.3g, 0.0902mol) under mechanical stirring ), the temperature is raised to reflux, and the reaction is stopped after the completion of the TLC monitoring reaction. Cooling, filtering, evaporating the filtrate, and column chromatography with 20% ethyl acetate / petroleum ether to obtain 13.0 g of pure product with a yield of 77.5%.

Embodiment 2

[0034] Preparation of 1-benzenesulfonyl-4-benzyloxy-1H-indole(III)

[0035]

[0036] Add 4-benzyloxy-1H-indole(II) (10.0g, 0.0448mol) into a 250ml single-necked flask, dissolve it with 100ml N,N-dimethylformamide, stir magnetically, and add sodium hydride ( 60%, 2.15g, 0.0537mol), add benzenesulfonyl chloride (9.47g, 0.0537mol), remove the ice bath and stir at 25°C, stop the reaction after TLC monitoring the reaction is complete. The reaction solution was poured into 300ml of ice water, 200ml of ethyl acetate was added, and it was allowed to stand. The organic layer was separated. The organic layer was washed twice with 300ml of water and once with 200ml of saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain an oily liquid. 300ml petroleum ether was added under stirring, a large amount of solids precipitated out, filtered, the filter cake was washed with 100ml petroleum ether, and after vacuum drying, 12.0g of light yellow solid was obtained with a yie...

Embodiment 3

[0038] Preparation of 2-acetyl-1-benzenesulfonyl-4-benzyloxy-1H-indole(IV)

[0039]

[0040] Add 1-benzenesulfonyl-4-benzyloxy-1H-indole(III) (10.0g, 0.0275mol) in a 250ml single-necked flask, dissolve it with tetrahydrofuran (100ml), and add 2.5M butyl at -78℃. Lithium n-hexane solution (13.2ml, 0.0331mol), stirred for 30 minutes, and then added acetic anhydride (3.65g, 0.0358mol), the reaction was stopped after the completion of TLC monitoring. The reaction solution was poured into 200ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate was added, and it was allowed to stand. The organic layer was separated. The organic layer was washed twice with 50ml of water and once with 50ml of saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain An oily liquid. 20% ethyl acetate / petroleum ether column chromatography to obtain a white solid. (Rf=0.3, ethyl acetate / petroleum ether)

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Abstract

The invention discloses a preparation method for varespladib. 4-oxyindole is adopted as starting material, phenylsulfonyl is used for protecting the N atom after hydroxy group protection, so that an acetyl group is introduced to the site 2 of indole, 2-ethyl-4-oxyindole is obtained by reduction and deprotection, tert-butyl acetate is introduced to the hydroxyl group, the site 3 of the indole is acylated by oxalyl chloride and then ammonolyzed after N is protected by a benzyl group, and finally, tert-butyl ester is hydrolyzed, so that the varespladib is obtained. The invention has the advantages of cheap and easily-obtained starting material, mild reaction conditions, simple operation process, low cost and high yield.

Description

(1) Technical field [0001] The invention relates to a method for preparing a medicine, in particular to a method for preparing varespladib. (2) Background technology [0002] Varespladib is an indole derivative, its chemical name is (3-aminooxalyl-1-benzyl-2-ethyl-1H-indole-4-oxo)-acetic acid. The latest research shows that varespladib is a selective inhibitor of secreted phosphatase 2 and can significantly reduce the levels of secreted phosphatase 2 and LDL-C. More importantly, varespladib can significantly reduce small and dense LDL-C and reduce the degree of LDL-C oxidation. Its chemical structure is as follows: [0003] [0004] WO01 / 44185, EP0675110 and JMC 2006, 49(10), 2858, etc. respectively disclose the preparation method of varespladib. [0005] In WO01 / 44185, the following method (schemel) was used to synthesize varespladib. [0006] [0007] The more expensive allyltriphenylphosphonium bromide is used from compound B to D, and the total yield of B to F is low, only 14%,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/24
Inventor 葛敏胡春晨付明伟
Owner ZENJI RES LAB
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