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Synthesis method of lasofoxifene precursor of nafoxidine

A technology of nafaxidine and its synthesis method, which is applied in the field of chemical synthesis, can solve the problems of different process conditions, reaction temperature and separation method, etc., and achieve the effects of mild reaction conditions, easy control of reaction conditions, and solution to source problems

Active Publication Date: 2015-01-07
FUZHOU NEPTUNUS FUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] U.S. Patent US2012 / 0045648 A1 adopts the same route, but the process conditions of the first step reaction are different, using Grignard reagent instead of organolithium reagent for reaction, but specific Reaction temperature and separation method not mentioned

Method used

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  • Synthesis method of lasofoxifene precursor of nafoxidine
  • Synthesis method of lasofoxifene precursor of nafoxidine
  • Synthesis method of lasofoxifene precursor of nafoxidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] 6-methoxy-2-phenyl-1-tetralone ( 2 ) (15.0 g, 59.5 mmol) was dissolved in dichloromethane (120 mL), and DBU (12.6 g, 83.3 mmol) was added. Perfluorobutylsulfonyl fluoride (25.2 g, 83.3 mmol) was slowly added to the reaction solution, and the addition was completed in about 20 minutes. Stir at room temperature for 16h. Add 120mL of distilled water × 2 to the reaction liquid to wash, and add 167mL of 0.5N hydrochloric acid solution, separate the water phase, and extract with 100mL of dichloromethane × 2, combine the organic phases, wash with 100mL of saturated sodium chloride solution, and dry over anhydrous sodium sulfate , filter, and concentrate the filtrate to obtain 6-methoxy-2-phenyl-3,4-dihydronaphthalene-1-perfluorobutanesulfonate ( 3 ) 30.0g, pale yellow oil, yield 94.3%.

[0042] 6-methoxy-2-phenyl-3,4-dihydronaphthalene-1-perfluorobutanesulfonate ( 3 )of 1 H NMR (500 MHz, CDCl 3 )See figure 1 : δ 7.51 (d, J = 8.5 Hz, 1H), 7.49 – 7.43 (m, 4H), 7.43 – ...

Embodiment 2

[0045] 6-methoxy-2-phenyl-1-tetralone ( 2 ) (3.00 g, 11.9 mmol) was dissolved in THF (25 mL), and DBU (2.53 g, 16.7 mmol) was added. Perfluorobutylsulfonyl fluoride (5.03 g, 16.7 mmol) was slowly added to the reaction solution, and the addition was completed in about 15 minutes. Stir at room temperature for 16h. THF was evaporated under reduced pressure, 30 mL of dichloromethane was added to the residue, washed with 30 mL of distilled water × 2, and 33.3 mL of 0.5N hydrochloric acid solution was added, the aqueous phase was separated, extracted with 10 mL of dichloromethane, the organic phases were combined, saturated chlorinated Wash with 30 mL of sodium solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 6-methoxy-2-phenyl-3,4-dihydronaphthalene-1-perfluorobutylsulfonate ( 3 ) 5.89g, light yellow oil, yield 92.7%.

Embodiment 3

[0047] At 0°C, to (4-(2-(1-pyrrolidinyl)ethoxy)phenylmagnesium bromide ( 4 ) (M = MgBr) (11.2mmol) in THF solution (48mL), add CuCl (1.11g, 11.2mmol), anhydrous LiCl (0.940g, 22.5mmol), stir for 1h, add 6-methoxy- 2-Phenyl-3,4-dihydronaphthalene-1-perfluorobutanesulfonate ( 3 ) (6.00g, 11.2mmol) and iron acetylacetonate (3.97g, 11.2mmol), stirring was continued at 0°C for 2h. The reaction solution was poured into saturated ammonium chloride solution (50 mL), the solid was removed by filtration, and the filtrate was collected. The aqueous phase was separated and extracted with 20 mL of ethyl acetate × 2, the organic phases were combined, and the solvent was evaporated under reduced pressure. Add 40 mL of distilled water and 2N hydrochloric acid to the residue to make the pH 2~3, add 20 mL of a mixture of diethyl ether and methyl tetrahydrofuran (1:3 v / v) for extraction, separate the organic phase, and use 0.5 N Extract with 30mL of hydrochloric acid, combine the water phases...

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Abstract

The invention discloses a synthesis method of lasofoxifene precursor nafaxidine (1). Through the reaction of 6-methoxy-2-phenyl-1-tetralone (2) with perfluorobutylsulfonyl fluoride, 6-methoxy-2-phenyl-3,4-dihydrogenated Naphthalene-1-perfluorobutane sulfonate (3), then in the presence of cuprous chloride, lithium chloride and iron catalyst, carries out coupling reaction with the compound of general formula 4, obtains nafaxidine (1 ). The synthesis method of the invention is simple and efficient, the reaction conditions are mild and easy to control, the yield is high and the products are easy to separate.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthesis method of lasofoxifene precursor nafaxidine (1), a medicine for treating postmenopausal women with osteoporosis. Background technique [0002] Lasofoxifene D-tartrate D-tartrate (lasofoxifene D-tartrate) is a kind of estrogen partial agonist developed by Pfizer, and its marketed dosage form is film-coated tablet, trade name is Fablyn. It has the effect of blocking bone loss and lowering cholesterol. It is currently on the market in Europe, and the daily dose is only 0.5mg. It is currently the most powerful estrogen partial agonist with the effect of blocking bone loss and lowering cholesterol. [Wang Wei, Ai Min. Lasofoxifene, a new drug for the treatment of osteoporosis, Pharmaceutical progress , 2005, 29 (2): 2-3]. Its Phase II clinical trial compared the efficacy of D-Lasofifene tartrate and Raloxifene hydrochloride (raloxifene, 60mg / day) de...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/088
CPCC07D295/088
Inventor 赵学清陈韵翔李忠铭
Owner FUZHOU NEPTUNUS FUYAO PHARMA
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