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Preparing method for osteoporosis preventing medicine

A compound, benzo technology, applied in the field of preparation of drugs for the prevention of osteoporosis, can solve the problem of short synthetic routes

Inactive Publication Date: 2016-07-13
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In summary, this area still lacks a short synthetic route, simple operation, mild conditions, high yield, good efficiency, environmentally friendly raloxifene synthetic route

Method used

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  • Preparing method for osteoporosis preventing medicine
  • Preparing method for osteoporosis preventing medicine
  • Preparing method for osteoporosis preventing medicine

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0052] The invention provides a [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl ] the preparation method of ketone hydrochloride, described method comprises the steps:

[0053]

[0054] (1) In an inert solvent, in the presence of a base, a ligand and a palladium catalyst, react a compound of formula II with a compound of formula III to obtain 6-methoxy-2-(4-methoxyphenyl)benzo[ b] thiophene (IV);

[0055] (2) In an inert solvent, in the presence of a Lewis acid, the compound of formula IV is reacted with the compound of formula V to obtain the compound of formula (VI);

[0056] (3) In an inert solvent, in the presence of a Lewis acid, demethylation reaction is carried out with the compound of formula (VI) and thioethanol; after the reaction is completed, the reaction system is acidified with hydrochloric acid to obtain the compound of formula I;

[0057] Wherein, said X is selected from the group consisting of chlorine, bromine and i...

Embodiment 1

[0102] (1), the preparation of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (Ⅳ)

[0103] 2-Bromo-6-methoxybenzothiophene (II) (10g, 41.1mmol), 4-methoxyphenylboronic acid (III) (6.25g, 41.1mmol), potassium carbonate (8.53g, 61.7mmol) , Rac-BINAP (1.15g, 1.8mmol) and toluene (200mL), stirred and mixed for 15min, replaced nitrogen three times, then added PdCl 2 (0.22g, 1.2mmol), nitrogen was replaced, under the protection of nitrogen, the temperature was raised to 110°C, and the reaction was stirred for 4.0 hours. TLC detects that the reaction is over, cools down, recovers toluene, heats and dissolves the residual mixture with ethyl acetate, filters off the insoluble solids while it is hot, uses activated carbon to remove impurities and decolorizes the filtrate, and then filters with suction. Solid, 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (IV) (10.6 g, 95%).

[0104] (2), [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol ...

Embodiment 2

[0107] (1), the preparation of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (Ⅳ)

[0108] 2-Bromo-6-methoxybenzothiophene (II) (10g, 41.1mmol), 4-methoxyphenylboronic acid (III) (6.25g, 41.1mmol), cesium carbonate (20.1g, 61.7mmol) , S-phos (0.68g, 1.64mmol) and ethanol (200mL), stirred and mixed for 15min, replaced nitrogen three times, then added PdCl 2 (0.15g, 0.82mmol), nitrogen was replaced, under the protection of nitrogen, the temperature was raised to 80°C, and the reaction was stirred for 6.5 hours. TLC detects that the reaction is over, cool down, recover ethanol, heat and dissolve the residual mixture with ethyl acetate, filter off the insoluble solids while hot, use activated carbon to remove impurities and decolorize the filtrate, and then filter with suction. Solid, 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (IV) (10.1 g, 91%).

[0109] (2), [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol Preparation of keto...

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Abstract

The invention relates to a preparing method for osteoporosis preventing medicine. Particularly, the invention relates to a preparing method for [6-hydroxy-2-(4-hydroxyphenyl) benzo-[b] thiophene-3-base] [4-[2-(1-piperidyl) ethyoxyl] phenyl] ketone hydrochloride. According to the preparing method, 2-halogenate-6-metoxybenzene thiophthene (II) as a beginning raw material, and a target product (I) can be prepared through coupling, fridel-crafts reaction, deprotection and salifying. The method has the advantages of being shorter in synthetic route, simple to operate, moderate in condition, high in efficiency and suitable for industrial production. (see the description).

Description

technical field [0001] The present invention relates to a preparation method for preventing osteoporosis medicine, in particular to a chemical drug [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4 - the preparation method of [2-(1-piperidinyl) ethoxy] phenyl] ketone hydrochloride. Background technique [0002] Raloxifenehydrochloride, whose trade name is Evista, is used in the prevention and treatment of postmenopausal osteoporosis in women, and it is used in combination with calcium preparations to prevent bone loss. Raloxifene is the first selective estrogen receptor modulator approved for clinical use with the chemical name [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride. Raloxifene was developed by Lilly Company of the United States, and was listed in the United States through the FDA in 1998. The drug not only has the dual effects of target organ selective and specific estrogen agonist and antagoni...

Claims

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Application Information

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IPC IPC(8): C07D333/56
CPCC07D333/56
Inventor 李函璞李健之刘海池王胄翟志军李建勋
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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