Preparation method of salt formation of silodosin intermediate

A compound and high-purity technology, which is applied in the field of silodosin intermediate salt preparation, can solve the problems of poor purification effect, cumbersome steps, and unsuitability for industrial production.

Active Publication Date: 2012-03-21
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are problems such as cumbersome steps and being unsuitable for industrialized production, especially the purification effect of the by-product represented by the following formula is not good in the scale-up production process:

Method used

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  • Preparation method of salt formation of silodosin intermediate
  • Preparation method of salt formation of silodosin intermediate
  • Preparation method of salt formation of silodosin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the preparation of compound (1) maleate

[0026] 10 g of compound (1) and 1.94 g of maleic acid were dissolved in 30 ml of tetrahydrofuran / 60 ml of isopropyl ether, and the mixture was dissolved by heating under reflux. Cool down to 0-15°C and stir, a large amount of solids are precipitated, continue to add 60ml of isopropyl ether. Stir at 5°C for 2h, filter, and dry to obtain solid compound (1) 1-(3-(4-fluorobenzoyl)hydroxypropyl)-5-((2R)-2-(2-(2-( 2,2,2-Trifluoroethoxy)phenoxy)ethylamino)propyl)indoline-7-cyano monomaleate. At this time, the content of the by-product compound (3) in the obtained product was less than 1%, and 10.99 g (yield 92%) was obtained by drying. It can be directly put into the next step reaction.

[0027] The monomaleic acid salt of the compound (1) obtained above was beaten with 100ml isopropyl ether, stirred at 20°C for 3h, filtered and dried to obtain 10.56g of the monomaleic acid salt of the pure compound (1) (yield 88%) )....

Embodiment 2

[0029] Embodiment 2: the preparation of compound (1) maleate

[0030] 10 g of compound (1) and 1.94 g of maleic acid were dissolved in 30 ml of tetrahydrofuran / isopropyl ether, and the mixture was dissolved by heating under reflux. Cool down to 0-5°C and stir, then slowly add 100ml of methyl tert-butyl ether dropwise, a large amount of solids precipitated, continue to add 100ml of methyl tert-butyl ether. Stir at 5°C for 2h, filter, and dry to obtain solid compound (1) 1-(3-(4-fluorobenzoyl)hydroxypropyl)-5-((2R)-2-(2-(2-( 2,2,2-Trifluoroethoxy)phenoxy)ethylamino)propyl)indoline-7-cyano monomaleate. At this time, the content of the by-product compound (3) in the obtained product was less than 0.8%, and 10.38 g (yield 87%) was obtained by drying. It can be directly put into the next step reaction.

[0031] The monomaleic acid salt of the compound (1) obtained above was beaten with 100ml of isopropyl ether, stirred at 20°C for 3h, filtered and dried to obtain 10.03g of the mo...

Embodiment 3

[0032] Embodiment 3: the preparation of silodosin

[0033] Dissolve 8 g of compound (1) monomaleic acid obtained in Example 1 or 2 with 100 ml of DMSO, add 12 ml of 5 mol / L sodium hydroxide, slowly add 7 g of 30% hydrogen peroxide dropwise at 18 to 20° C., and then react at 30° C. , 4h reaction was complete, extracted with ethyl acetate, combined organic layers, extracted with 2N HCl, the obtained aqueous layer was neutralized with sodium hydroxide, extracted with ethyl acetate, washed with saturated sodium bicarbonate, anhydrous sodium sulfate Dry, concentrate under reduced pressure, dissolve in ethyl acetate, cool and crystallize naturally, filter, and dry to obtain 4.9g (88%), with a purity of >99%.

[0034] Mp105~108℃

[0031] The monomaleic acid salt of the compound (1) obtained above was beaten with 100ml of isopropyl ether, stirred at 20°C for 3h, filtered and dried to obtain 10.03g of the monomaleic acid salt of the pure compound (1) (yield 84% ). At this time, the ...

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Abstract

The invention relates to a method of maleate formation of a silodosin intermediate indoline compound 1 - (3 - (4 - fluoro benzoyl) hydroxypropyl) -5 - ((2R) -2 - (2 - (2 - (2,2,2 - trifluoroethoxyl) phenoxy) ethylamine) propyl) indoline -7 - cyano (compound (1)), i.e., a crude product of the compound (1) forms a salt with maleic acid in a mixed solvent of a good solvent and a poor solvent. The maleate of the compound can be stably obtained by the method, and the method has the advantages of good impurity removal effect, stable process, high yield, simpleness in operation and the like.

Description

technical field [0001] The invention mainly relates to a salt-forming and purifying method for an intermediate of silodosin, a drug for treating benign prostatic hyperplasia. technical background [0002] Silodosin has a selective inhibitory effect on the contraction of urethral smooth muscle, and reduces the intraurethral pressure, but has no great effect on blood pressure, and is used for the treatment of benign prostatic hyperplasia. [0003] Chinese patent CN101048376 reports 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}propane Base]-2,3-dihydro-1H-indol-1-yl}propyl ester (compound 1) synthesis: [0004] [0005] This patent also provides a method for purifying the above compound by crystallization into oxalates. In this method, the yield of oxalate is low, and seed crystals need to be added, and it needs to be placed for a long time. There are problems such as cumbersome steps and being unsuitable for industrialized production, especially the p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
Inventor 郭起颜峰峰
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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