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Efficient preparation method of bazedoxifene

A bazedoxifene and high-efficiency technology, applied in the field of efficient preparation of bazedoxifene, can solve the problems of hydrogen ignition, unfavorable preparation of bazedoxifene, unfavorable large-scale production of bazedoxifene, etc.

Active Publication Date: 2017-06-09
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] However, the above-mentioned preparation method of bazedoxifene has the following defects in many aspects: (1) need to use expensive Pd / C as a catalyst, so that the cost of this synthetic route is very high; (2) another serious defect is that, Need to adopt the hydrogen of certain pressure in the reaction, and maintain pressure temperature is more difficult to control, thus cause the preparation difficulty of bazedoxifene is very high; Very unfavorable for the preparation of bazedoxifene, especially, unfavorable for the large-scale production of bazedoxifene

Method used

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  • Efficient preparation method of bazedoxifene
  • Efficient preparation method of bazedoxifene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] The synthetic route of this experimental example is as follows:

[0080]

[0081] In the formula, Bn refers to benzyl (C 6 h 6 CH 2 -).

[0082] 1. Preparation of 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole

[0083]Weigh 10g of 4'-benzyloxy-2-bromopropiophenone (II-a), 15g of p-benzyloxyaniline hydrochloride (II-b), 50mL of N,N-dimethylformamide and 8 mL of triethylamine was reacted at 115°C for 4 hours. Thin-layer chromatography (TLC) detected that the reaction was complete, and the reaction solution was poured into 250 mL of ice water to precipitate solids, filtered by suction, and the obtained crude product was stirred and beaten with 20 mL of methanol, and vacuum-dried at 40 ° C for 24 hours to obtain 12.5 g of a yellow-brown solid product, namely It is 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (intermediate II), and the yield is 94.6%.

[0084] MS [M+H]: 420.52.

[0085] 1 HNMR (DMSO-d 6 ): 2.30ppm(s,3H), 5.21ppm(m,4H), 6.73ppm(d...

Embodiment 2

[0095] 1. Preparation of 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole

[0096] Weigh 10g of 4'-benzyloxy-2-bromopropiophenone (II-a), 15g of p-benzyloxyaniline hydrochloride (II-b), 50mL of N,N-dimethylformamide and 8 mL of triethylamine was reacted at 118°C for 3 hours. Thin-layer chromatography (TLC) detected that the reaction was complete. Pour the reaction solution into 250 mL of ice water to precipitate a solid, and filter it with suction. The obtained crude product was stirred and beaten with 20 mL of methanol, and the wet product was vacuum-dried at 42°C for 24 hours to obtain 12.5 g of a yellow-brown solid product. , namely 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (intermediate II), with a yield of 94.6%.

[0097] 2. Preparation of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl) -3-Methyl-1H-indole

[0098] Weigh 3g of 60% NaH, 8g of 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (intermediate II), 7g of 1-[ ...

Embodiment 3

[0102] 1. Preparation of 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole

[0103] Weigh 10g of 4'-benzyloxy-2-bromopropiophenone (II-a), 15g of p-benzyloxyaniline hydrochloride (II-b), 50mL of N,N-dimethylformamide and 8 mL of triethylamine was reacted at 115°C for 4 hours. Thin-layer chromatography (TLC) detected that the reaction was complete. Pour the reaction solution into 250 mL of ice water to precipitate a solid, and filter it with suction. The obtained crude product was stirred and beaten with 20 mL of methanol, and the wet product was vacuum-dried at 40°C for 24 hours to obtain 12.5 g of a yellow-brown solid product. , namely 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (intermediate II), with a yield of 94.6%.

[0104] 2. Preparation of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl) -3-Methyl-1H-indole

[0105] Weigh 3g of 60% NaH, 8g of 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (intermediate II), 7g of 1-[ ...

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Abstract

The invention discloses a preparation method of bazedoxifene. The preparation method comprises the following steps: (a) taking 1-(4-(2-(azepane-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole, adding a polar organic solvent, an aprotic lewis acid organic solution and a hydrogen ion provider, and stirring at 0-40 DEG C to obtain a reaction liquid; and (b) separating and purifying the reaction liquid obtained in the step (a) to obtain bazedoxifene. In the method disclosed by the invention, the low-cost and easily available aprotic lewis acid such as boron trifluoride is adopted as a catalyst for preparing bazedoxifene, the reaction conditions are mild, the operation is convenient, the safety is high, and the energy consumption is low; the obtained bazedoxifene has high yield and high purity, and the preparation difficulty and production cost of bazedoxifene are lowered; and the method brings a remarkable positive effect and is very suitable for industrialized use.

Description

technical field [0001] The invention relates to a high-efficiency preparation method of bazedoxifene. Background technique [0002] Bazedoxifene, chemical name: 1-[4-(2-azepan-1-yl-ethoxy-benzyl)]-2-(4-hydroxy-phenyl)-3-methanol Base-1H-indole-5-ol is mainly used for postmenopausal women without hysterectomy to treat moderate to severe menopause-related vasomotor symptoms (hot flashes) and prevent postmenopausal osteoporosis. [0003] At present, the existing technology is mainly to prepare bazedoxifene (namely compound 45) through compound 44 under the process conditions of palladium carbon catalyst and hydrogen gas, and its synthetic route is as follows; it is reported in patent WO2001019839 and so on. [0004] [0005] However, the above-mentioned preparation method of bazedoxifene has the following defects in many aspects: (1) need to use expensive Pd / C as a catalyst, so that the cost of this synthetic route is very high; (2) another serious defect is that, Need to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 张生烈姚中伟葛建华刘丽王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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