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Method for preparing lasofoxifene intermediate

A lasoxifene and intermediate technology, applied in the field of chemistry, can solve the problems of low overall yield, high production cost, and high requirements for production equipment, and achieve the effects of cheap raw materials, improved overall yield, and reduced production cost

Inactive Publication Date: 2012-01-11
WUHAN QR PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, the amount of cerium trichloride is large, the market price is expensive, and an ultra-low temperature condition of -78°C is required, which requires high production equipment
The overall yield of the method is not high, the production cost is high, and it is also unfavorable for industrialized production

Method used

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  • Method for preparing lasofoxifene intermediate
  • Method for preparing lasofoxifene intermediate
  • Method for preparing lasofoxifene intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of 1-(2-(4-(6-methoxy-3,4-dihydro-1-yl)phenoxy)ethyl)pyrrolidine hydrochloride (compound II')

[0031]

[0032] Put 2.7g (114mmol) of magnesium ribbon in a 500mL three-necked flask, add 10mL of tetrahydrofuran, add a few drops of 1,2-dibromoethane while stirring, add dropwise 114mL of a tetrahydrofuran solution of 31g (114mmol) of compound I, and after the dropwise addition Start to heat the reaction to reflux until all the magnesium bands are dissolved and disappear, then add 20 g (114 mmol) of 6-methoxytellone dropwise in 114 mL of tetrahydrofuran solution, and continue the reflux reaction overnight after the addition is complete. After the reaction, cool to room temperature, add 50mL of water and 200mL of ethyl acetate, stir for 10 minutes, filter with diatomaceous earth, rinse with ethyl acetate several times, concentrate the filtrate, add 200mL of 2N hydrochloric acid to the residue, and wash the aqueous solution with methanol base tert-butyl ether, ...

Embodiment 2

[0035] Preparation of 1-(2-(4-(6-methoxy-3,4-dihydro-1-yl)phenoxy)ethyl)pyrrolidine (Compound II)

[0036]

[0037] 5g of compound II' (refer to Example 1 for the preparation method) was dissolved in 50mL of dichloromethane, washed with 25mL of saturated aqueous sodium carbonate solution, and then washed with 25ml of saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, concentrated, vacuum- After drying, compound II (4.5 g, yield 99%) was obtained. Compound II Identification Parameters:

[0038] (MS: 350.2[P + +1]); 1 H NMR (400MHz, CDCl 3 ): δ7.28(d, J=8.4Hz, 2H), 6.95(m, 3H), 6.79(d, J=2.6Hz, 1H), 6.65(dd, J=8.4, 2.6Hz, 1H), 5.93 (t, J=4.6Hz, 1H), 4.18(t, J=6.0Hz, 2H), 3.82(s, 3H), 2.98(m, 2H), 2.83(m, 2H), 2.69(m, 4H) , 2.39(m, 2H), 1.86(m, 4H).

Embodiment 3

[0040] Preparation of 1-(2-(4-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy)ethyl)pyrrolidine hydrochloride (compound III')

[0041]

[0042]Compound II' 9.0g (25mmol, or equivalent compound II) was dissolved in 250mL tetrahydrofuran, and 8.0g (25mmol) of pyridinium tribromide was added, and stirred at room temperature for 3 days. The reaction solution was concentrated to dryness on a rotary evaporator, 100 mL of methyl tert-butyl ether was added to the residue, and filtered. The resulting solid was dissolved in 200 mL of dichloromethane, washed twice with 100 mL of 0.5N hydrochloric acid, then dried over anhydrous magnesium sulfate, and filtered. , and concentrated to obtain 12.4 g of a brownish-red solid, namely compound III', which was directly used in the next reaction. Identification parameters of compound III':

[0043] (MS: 428.2 / 430.2[P + +1]); 1 H NMR (400MHz, CDCl 3 ): δ11.77(br, 1H), 7.18(d, J=8.4Hz, 2H), 6.97(d, J=8.4Hz, 2H), 6.72(d, 1H), 6.57(m, 2H...

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Abstract

The invention relates to a method for preparing a lasofoxifene intermediate (namely, a compound IV) or an inorganic acid salt thereof. The method comprises the following steps: after a compound I is converted into a Grignard reagent, reacting the Grignard reagent with 6-methoxy tetralone so as to obtain a compound II or an inorganic acid salt thereof; carrying out bromination reaction on the obtained compound II or the inorganic acid salt thereof so as to obtain a compound III or an inorganic acid salt thereof; and then, carrying out coupling reaction on the obtained compound III or the inorganic acid salt thereof so as to obtain the lasofoxifene intermediate (namely, the compound IV) or the inorganic acid salt thereof. The compound IV or inorganic acid salt thereof is a key intermediate for preparing a medicament lasofoxifene for treating osteoporosis. The method provided by the invention is low in production cost, good for environmental protection, and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemistry, and relates to a new method for preparing lasofoxifene intermediates, in particular to a method for preparing 1-[2-[4-(6-methoxy-2-phenyl-3,4-di New methods of hydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (Nafoxidene) and its inorganic acid salts. Background technique [0002] Lasofoxifene (trade name: Fablyn) is a drug used to treat postmenopausal osteoporosis. Its chemical name is (-)cis-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8 -Tetralin-2-ol, such as the following structural formula: [0003] [0004] A variety of synthetic methods have been reported for lasofoxifene, involving a key intermediate 1-[2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalene-1-yl)benzene Oxygen] ethyl] pyrrolidine (namely Nafoxide, compound IV), as shown in the following structural formula. Nafoxidene easily combines with acid to form a stable salt, and existing literature has reported Nafoxidene hydr...

Claims

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Application Information

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IPC IPC(8): C07D295/088
Inventor 孙章辉廖文胜陈蔚江王朝东
Owner WUHAN QR PHARMA CO LTD
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