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Bazedoxifene intermediate and preparation method thereof

An intermediate and oxygen technology, which is applied to the intermediates prepared by the selective estrogen receptor modulator bazedoxifene and its preparation field, can solve the problems of rare raw materials, bromination reaction pollution, and many reaction steps, etc., and achieve The preparation process is quick and convenient, and the product yield and product purity are high.

Active Publication Date: 2016-04-06
XUZHOU LIXIN IRRIGATION & DRAINAGE EQUIP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the disadvantages of rare raw materials, many reaction steps and serious pollution of bromination reaction, it is very meaningful to seek new intermediates and their preparation methods for the economic and technological development of bazedoxifene raw materials

Method used

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  • Bazedoxifene intermediate and preparation method thereof
  • Bazedoxifene intermediate and preparation method thereof
  • Bazedoxifene intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Under an inert atmosphere and anhydrous environment, silver trifluoromethanesulfonate (0.032g, 0.1mmol), bis[dichloro(5-methylcyclopentadienyl) rhodium] (0.015g, 0.025mmol), Copper acetate monohydrate (0.42g, 2.1mmol) and N-(4-methoxyphenyl) acetamide (III) (0.17g, 1mmol) were added to the micro reaction vial, sealed and injected with 1-(4-methanol Oxy-phenyl) propyne (II) (0.15 g, 1 mmol) in 5 mL of tert-butanol was heated to 120° C., stirred for 1 hour, and then cooled to room temperature. TLC detected that the reaction was complete. Filtration, the filter cake was washed with diethyl ether, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (diethyl ether / petroleum ether=1 / 1) to obtain an off-white solid 2-(4-methoxyphenyl)-3-methyl-5 -Methoxy-1-acetyl-indole (I) 0.26g, yield 84.1%.

Embodiment 2

[0028] Under an inert atmosphere and anhydrous environment, silver trifluoromethanesulfonate (0.032g, 0.1mmol), bis[dichloro(5-methylcyclopentadienyl) rhodium] (0.015g, 0.025mmol), Copper acetate monohydrate (0.42g, 2.1mmol) and N-(4-benzyloxyphenyl) acetamide (III) (0.24g, 1mmol) were added to the micro reaction vial, and 1-(4-benzyl Oxy-phenyl) propyne (II) (0.22 g, 1 mmol) in 5 mL of tert-butanol was heated up to 125° C., stirred for 1 hour, cooled to room temperature, and the reaction was detected by TLC. Filtration, the filter cake was washed with diethyl ether, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (diethyl ether / petroleum ether=1 / 1) to obtain an off-white solid 2-(4-benzyloxyphenyl)-3-methyl-5 - Benzyloxy-1-acetyl-indole (I) 0.41 g, yield 89.0%.

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Abstract

The invention discloses a bazedoxifene intermediate, namely 2-[4-(Pg1 oxyl) phenyl]-3-methyl-5-(Pg2 oxyl)-1-acetyl-indol (I) and a preparation method thereof. The preparation method of the bazedoxifene intermediate comprises the step that 1-(4-Pg1 oxyl-phenyl)-allylene (II) and N-[4-(Pg2 oxyl) phenyl] acetamide (III) are subjected to oxidation ring-closure reaction so as to obtain the bazedoxifene intermediate, namely the 2-[4-(Pg1 oxyl) phenyl]-3-methyl-5-(Pg1 oxyl)-1-acetyl-indol (I) through one step. The intermediate is stable in natural. The preparation method is concise, economical and environment-friendly and can be used for providing a new effective intermediate for industrial production of bazedoxifene bulk drugs.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to an intermediate that can be used for the preparation of bazedoxifene, a selective estrogen receptor modulator, and a preparation method thereof. Background technique [0002] Bazedoxifene is a small molecule drug originally developed by Wyeth and later acquired by Pfizer. Bazedoxifene was first listed in Italy and Spain through the approval of the European Medicines and Drug Administration (EMEA) in April 2009, with the trade name Conbriza; in July 2010, it was launched in Japan with the trade name Viviant; in October 2013, it was approved by the US Food and Drug Administration. Approved by the Food and Drug Administration (FDA), it is marketed in the United States under the trade name Duavee for the treatment of moderate to severe menopause-related vasomotor symptoms (hot flashes) and the preven...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 许学农
Owner XUZHOU LIXIN IRRIGATION & DRAINAGE EQUIP CO LTD
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