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New preparation method of silodosin compound

A silodosin and compound technology, which is applied in the new preparation field of silodosin, can solve the problems of being unsuitable for industrial scale production, having many impurities or side reactions, and low product purity, avoiding functional group protection and deprotection, The effect of reducing the purification and impurity removal process and simplifying the process operation

Active Publication Date: 2016-11-09
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Although there are currently patent documents CN200910194691.2, CN201210199199.6, CN201310340656.3 and the journal Tetrahedron etc. have disclosed various preparation methods, which have greatly improved the reaction conditions, but there are still many impurities or side reactions, and the reaction cycle is long and the operation is cumbersome. , Product purity is not high, low yield, high cost, not suitable for industrial scale production and other defects

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  • New preparation method of silodosin compound
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  • New preparation method of silodosin compound

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Experimental program
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Effect test

Embodiment 1

[0031] Add 10.0 g (42.7mmol) of compound II, 13.0 g (47.0mmol, 1.1eq) of compound III to 200ml of methanol, add 130 mg (2.1mmol, 0.05eq) of acetic acid, and then add 54.0g (256mmol, 6.0eq) of three Sodium acetoxyborohydride, stir and react at 20~30℃ for 0.5~1h; adjust the pH of the reaction solution to 7~8 with 1mol / L sodium hydroxide solution, add 1L ethyl acetate to extract the layers, and concentrate the organic phase to 70ml by subtracting evaporation , The temperature was lowered to 0-10 ℃ and crystallized to obtain 18.1 g of xerodoxine, the yield was 85.6%, the HPLC purity was 99.85%, and the impurity P1 content was 0.02%.

Embodiment 2

[0033] 1.0 g (4.27mmol) of compound II and 2.4 g (8.54mmol, 2.0eq) of compound III were added to 20ml of methanol, 0.74g (4.27 mmol, 1.0eq) of p-toluenesulfonic acid was added, and 1.1g (17.1 mmol, 4.0eq) Sodium cyanoborohydride, stirred at 20~30℃ for 0.5~1h; adjust the pH of the reaction solution to 7~8 with 1mol / L sodium hydroxide solution, add 100ml ethyl acetate to extract the layers, and concentrate the organic phase by distillation To 10ml, the reduced distillate was cooled to 0~10°C and crystallized to obtain 1.4g of xerodoxine, the yield was 66.2%, the HPLC purity was 99.89%, and the content of impurity P1 was 0.01%.

Embodiment 3

[0035] Add 1.0 g (4.27mmol) of compound II, 1.3 g (4.70 mmol, 1.1eq) of compound III to 20ml of ethanol, add 25mg (0.42mmol, 0.1eq) of acetic acid, and then add 0.65g (17.1 mmol, 4.0eq) of boron Sodium hydride, stirring at 20~30℃ for 0.5~1h; adjust the pH of the reaction solution to 7~8 with 1mol / L sodium hydroxide solution, add 100ml ethyl acetate to extract the layers, the organic phase is subtracted and concentrated to 10ml, and the reduced distillate The temperature was lowered to 0-10°C to crystallize to obtain 1.5g of xerodoxine, the yield was 70.9%, the HPLC purity was 99.86%, and the impurity P1 content was 0.02%.

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Abstract

The invention belongs to the technical field of medical chemistry, and concretely relates to a new preparation method of silodosin. A compound III reacts with a compound II to generate an imine intermediate IV, and the imine intermediate IV is reduced to obtain silodosin, so impurity P1 is effectively removed, the content of the impurity P1 is reduced, and the product quality is improved. The preparation method has the advantages of simplicity in operation, mild reaction conditions, good safety and controllability, good product purity, and suitableness for industrial production.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a new preparation method of xerodoxine. The preparation method has simple operation, mild reaction conditions, safety and controllability, high reaction yield, good product purity, and is more suitable for industrial production. Background technique [0002] Silodosin (Silodosin), chemical name 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) Phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide, with a chemical structure as shown in formula I, is produced by Japan Haraken Tachibana and No. 1 in Japan A new generation of α1-adrenergic blocker jointly developed and sold by Sankyo Pharmaceuticals has outstanding selectivity for α1A-subtype adrenergic receptors, and can selectively relax urethral smooth muscle. For the other two subtypes α 1 The affinity of the receptor is much weaker than that of other drugs, which reduces the incidence of h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 冷传新范传文陈洪忠房玺林栋刘培元
Owner QILU PHARMA HAINAN
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