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A kind of preparation method of raloxifene hydrochloride and its intermediate

A technology for raloxifene hydrochloride and an intermediate, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of difficult preparation of starting materials, unfavorable industrial production, and large environmental impact, and achieves the advantages of controlling impurities, improving atom utilization, Less side effects

Active Publication Date: 2021-02-02
江苏美迪克化学品有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0028] The reactions involved in the above method 7 and method 8 all need to use heavy metal catalysts, which not only has high cost but also has a great impact on the environment. At the same time, the starting materials are not easy to prepare, which is not conducive to industrial production

Method used

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  • A kind of preparation method of raloxifene hydrochloride and its intermediate
  • A kind of preparation method of raloxifene hydrochloride and its intermediate
  • A kind of preparation method of raloxifene hydrochloride and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] A) Preparation of 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2-benzylthio-4-methoxyphenyl)ethanone (formula 3) :

[0065] (3-Methoxyphenyl) benzyl sulfide (50.0g, Formula 5) was dissolved in acetonitrile (700mL), cooled in an ice bath, and periodic acid (75.0g) and ferric chloride (1.1g, 6.8 mmol), reacted at 25°C for 6h, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with saline and 5% sodium thiosulfate solution successively, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, the obtained sulfide The crude sulfone compound (Formula 4) was mixed with 1-[2-(4-ethynylphenoxy)ethyl]piperidine (50.0g) and trifluoromethanesulfonic acid (163g, 1.09mol), and reacted at 70°C for 6h. After the reaction is completed, the reaction mixture is post-treated, and recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2- Benzylthio-4-methoxypheny...

Embodiment 2

[0073] A) Preparation of 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2-benzylthio-4-methoxyphenyl)ethanone (formula 3) :

[0074] (3-Methoxyphenyl) benzyl sulfide (65.0g, Formula 5) was dissolved in toluene (850mL), cooled in an ice bath, and periodic acid (170.0g) and ferric chloride (0.9g, 5.5 mmol), reacted at 27°C for 4h, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with saline and 5% sodium thiosulfate solution successively, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, the obtained sulfide The crude sulfone compound (Formula 4) was mixed with 1-[2-(4-ethynylphenoxy)ethyl]piperidine (43.0g) and trifluoromethanesulfonic acid (422g, 2.8mol), and reacted at 80°C for 4h. After the reaction is completed, the reaction mixture is post-treated, and recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2- Benzylthio-4-methoxyphenyl)eth...

Embodiment 3

[0082] A) Preparation of 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2-benzylthio-4-methoxyphenyl)ethanone (formula 3) :

[0083] (3-Methoxyphenyl) benzyl sulfide (300.0g, formula 5) was dissolved in methyl tert-butyl ether (4000mL), cooled in an ice bath, and periodic acid (700.0g, 3.07mol) and three Ferric chloride (5.0g, 0.03mol), reacted at 30°C for 2h, rotary evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with saline and 5% sodium thiosulfate solution successively, dried over anhydrous sodium sulfate, and dried under reduced pressure Rotary evaporation to dryness, the obtained sulfoxide compound (formula 4) crude product was mixed with 1-[2-(4-ethynylphenoxy)ethyl]piperidine (230.0g), trifluoromethanesulfonic acid (1500.0g, 10mol ) mixed, reacted at 100°C for 2h, after the reaction was completed, the reaction mixture was post-treated, and recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 1-{4-[2-(piperidin-...

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Abstract

The invention discloses a preparation method of raloxifene hydrochloride and an intermediate thereof. ‑4‑methoxyphenyl) ethanone (intermediate 1) and 4‑methoxybenzoyl halide to prepare raloxifene hydrochloride precursor (intermediate 2), demethylation protection, and hydrochloric acid to prepare hydrochloric acid Raloxifene; intermediate 1 is converted from intermediate 3 (1‑{4‑[2‑(piperidin‑1‑yl)ethoxy]phenyl}‑2‑(2‑benzylthio‑4‑methoxy phenyl) ethyl ketone) in trifluoroacetic acid to remove benzyl protection reaction to generate (3-methoxyphenyl) benzyl sulfide oxidation to generate sulfoxide compound, and then with 1‑[2‑(4‑ Ethynylphenoxy)ethyl]piperidine reacts to generate intermediate 3; the reaction conditions of the present invention are milder, the side reactions are few, and the yield is high, while the reagent raw materials adopted are cheaper and easy to recycle and easy to prepare, and are suitable for large-scale industrialization. mass production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of raloxifene hydrochloride and an intermediate thereof. Background technique [0002] Raloxifene hydrochloride (Raloxifene hydrochloride) is a selective estrogen receptor modulator first developed by Lilly Company in the United States. It was approved by the FDA in December 1997 and listed in the United States in January 1998. It is used for the prevention of postmenopausal women osteoporosis. The chemical name of raloxifene hydrochloride is [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]{4-[2-(piperidin-1-yl)ethoxy ] phenyl} ketone hydrochloride, its chemical structural formula is: [0003] [0004] The preparation method of relevant raloxifene hydrochloride at present has the different processing methods of multiple documents and patent reports, each has its own characteristics and advantages and disadvantages. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/56C07D295/088
CPCC07D295/088C07D333/56
Inventor 杨盟徐肖洁景亚婷
Owner 江苏美迪克化学品有限公司
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