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Preparation method of novel silodosin chiral intermediate

A technology for intermediates and organic ligands is applied in the field of preparation of silodosin chiral intermediates, and can solve the problems of affecting the purity of silodosin, low optical purity of intermediates, large material loss and the like

Pending Publication Date: 2022-07-29
SICHUAN QINGMU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is a chiral carbon in the structure of silodosin, and the pharmacological activity is mainly the structure of the R configuration, and the enantiomer of the S configuration exists in the silodosin as an impurity, which will not only affect the The purity of silodosin may also bring non-therapeutic toxic side effects, so determining a preparation method of high optical purity silodosin or a key chiral intermediate is of great significance for effectively controlling the quality of silodosin
[0004] At present, there are many preparation methods for optically pure silodosin intermediates, which can be summarized into three categories: one is to obtain silodosin chiral intermediates through the resolution method described in patents JP2002265444, WO2013056842, JP2002265444, and CN101759627, This method has low yield and large material loss; the second is the chiral induction method described in patents JP2001199956, CN109305932, and CN101993406A, which uses chiral auxiliary agents expensively, and the optical purity of the intermediate obtained is not high; the third is patents WO2016139773, WO2011030356, CN106045895A, CN103420893A, CN103554003A, KR20150066777, CN106045895 describe the method of docking with a chiral compound to construct a chiral center. The optical purity of the intermediate obtained by this method is directly derived from the raw material, but multi-step reactions are required to construct and the yield is low

Method used

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  • Preparation method of novel silodosin chiral intermediate
  • Preparation method of novel silodosin chiral intermediate
  • Preparation method of novel silodosin chiral intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] The preparation of embodiment 1 compound IV

[0024]

[0025] Dissolve 10g II-1 and 8.9g III-1 in 100ml 1,4-dioxane, add 11g potassium phosphate and 1.9g [1,1'-bis(diphenylphosphino)ferrocene]bis Palladium chloride, replaced by nitrogen for 3 times, reacted at 80°C under nitrogen protection, after the reaction was detected by TLC, filtered, 100 ml of filtrate was added, extracted with 100 ml of ethyl acetate, the liquid was separated, and the aqueous phase was washed with ethyl acetate Three times (50ml*3), the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a solid which was recrystallized with ethyl acetate and petroleum ether to obtain 9.6g of white solid with a yield of 80%.

[0026] 1 H-NMR (300MHz, d 6 -MDSO): δ8.02(d, 2H); 7.63(t, 1H); 7.52(t, 2H); 7.19(s, 1H); 7.06(s, 1H); 6.72(d, 1H); 4.31( t, 2H); 4.22-4.17(m, 1H); 3.75(t, 2H); 3.60(t, 2H); 2.89(t, 2H); 2.81(d, 1H); 2.57(d, 1H); 1.98 -1.88 (m, 2H); 1.32 (s, 9H), 1.10 (s,...

Embodiment 2

[0027] The preparation of embodiment 2 compound IV

[0028]

[0029] Dissolve 10g II-1 and 8.9g III-1 in 100ml 1,4-dioxane, add 5.8g potassium tert-butoxide, 1.5g tricyclohexylphosphine and 0.7g bis-(1,5-cyclooctane Diene) nickel, replaced by nitrogen for 3 times, reacted at 90°C under nitrogen protection, after TLC detected the reaction, filtered, added 100 ml to the filtrate, extracted with 100 ml of ethyl acetate, separated the water, and then used ethyl acetate for the aqueous phase. Washed three times (50ml*3), the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a solid which was recrystallized with ethyl acetate and petroleum ether to obtain 7.2g of white solid with a yield of 60%. NMR and mass spectrometry were consistent with Example 1.

Embodiment 3

[0030] The preparation of embodiment 3 compound IV

[0031]

[0032] Dissolve 10g II-1 and 6.3g III-2 in 100ml 1,4-dioxane, add 11g potassium phosphate and 1.1g [1,1'-bis(diphenylphosphino)ferrocene]dichloride The palladium dichloromethane complex was replaced with nitrogen for 3 times, and the reaction was carried out at 80°C under the protection of nitrogen. Washed with ethyl acetate three times (50ml*3), the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a solid which was recrystallized with ethyl acetate and petroleum ether to obtain 8.7g of white solid with a yield of 72%. NMR and mass spectrometry were consistent with Example 1.

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Abstract

The invention discloses a preparation method of a silodosin chiral intermediate, the structural formula of the intermediate is as shown in formula I. The compound can be used as an intermediate compound for synthesizing silodosin. The preparation method has the characteristics of simple operation, low cost, high yield, high optical purity of the product, stable process and the like, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical synthesis, in particular to a preparation method of a silodosin chiral intermediate. Background technique [0002] Benign prostatic hyperplasia (BPH) is one of the common diseases in middle-aged and elderly men. More than 50% of the elderly over the age of 60 suffer from this disease, and over 90% of the elderly over the age of 85 suffer from this disease. [0003] Silodosin, chemical name: 1-(3-hydroxypropyl)-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)phenoxy ]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide, a highly selective α1A-adrenoceptor antagonist for the treatment of benign prostatic hyperplasia It was first successfully developed by Kissei Pharmaceutical Company of Japan, which was approved for marketing in Japan in May 2006, and was subsequently approved for marketing in the United States and Europe. There is a chiral carbon in the silodosin structure, and the pharmacolog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
CPCC07D209/08C07B2200/07
Inventor 陈峰徐佳瑜李建国李晓迅胡同军
Owner SICHUAN QINGMU PHARMA CO LTD
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