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Preparation method of bazedoxifene acetate and key intermediate thereof

A technology of bazedoxifene acetate and intermediates, applied in the direction of organic chemistry and the like, can solve problems such as hidden dangers, existing operation safety, difficulty in industrialization amplification, etc., and achieve the effect of improving yield and purity

Inactive Publication Date: 2014-04-09
万全万特制药江苏有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The main disadvantage is that the reaction requires high-pressure hydrogenation, which has potential safety hazards in operation and difficulties in industrial scale-up

Method used

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  • Preparation method of bazedoxifene acetate and key intermediate thereof
  • Preparation method of bazedoxifene acetate and key intermediate thereof
  • Preparation method of bazedoxifene acetate and key intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 : 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-acetoxy-phenyl)-3-methyl-5-acetoxy- 1 H - Preparation of indole (compound III).

[0029] I II III

[0030] In a 1000ml three-neck flask, add 32.3g (0.1mol) of compound I, 36.1g (0.11mol) of compound II, 500ml of toluene, stir, heat to 75°C for 4 hours, TLC spotting test shows that the reaction is complete, distill and remove the solvent , to obtain a residue, add 100ml of water, extract with ethyl acetate (200ml×3), dry over anhydrous sodium sulfate, filter off the desiccant, and distill under reduced pressure to obtain a light white solid 51.2, yield: 92.5%.

[0031] MS (+1): 555.2.

[0032] 1 HNMR: δ (ppm, CDCl 3 ), 7.45-7.46(d, 2H, Ar-H), 7.12-7.13(d, 2H, Ar-H), 7.06-7.10(m, 3H, Ar-H), 6.95-6.96(d, 2H, Ar-H) -H), 6.73-6.75(d, 2H, Ar-H), 5.11(s, 2H, CH 2 ), 4.10-4.12 (t, 2H, CH 2 ), 2.78-2.79(t, 2H, CH 2 ), 2.36-2.38(t, 4H, CH 2 ×2), 2.09(s, 3H, CH 3 ), 2.07(s, 3H, CH 3 ), 1.39-...

Embodiment 2

[0034] Example 2 : Preparation of Bazedoxifene Acetate (Compound TM)

[0035]

[0036] IIITM

[0037] In a 500ml three-neck flask, add 27.2g (0.05mmol) of compound III and 200ml of 1N (0.20mol) sodium hydroxide solution, stir, heat up to 55°C for 2 hours, TLC spotting test shows that the reaction is complete, cool to room temperature, and adjust the pH To neutrality, a solid was precipitated, and vacuum-dried to obtain 20.6g of a white solid, yield: 87.6%. The obtained solid was placed in a 500ml three-neck flask, 250ml of acetone was added, 20ml of acetic acid was added, heated to 60°C, and reacted for 3h. According to TLC detection, the reaction was completed, cooled, evaporated to remove the solvent and excess acetic acid, washed with pure water (100ml×3), and dried to obtain 20.1g of a white solid with a yield of 87.0%.

[0038] Free base MS (+1): 471.

[0039] HNMR: δ (ppm, CDCl 3 ), 7.46-7.48(d, 2H, Ar-H), 7.15-7.17(d, 2H, Ar-H), 6.95-6.96(d, 2H, Ar...

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a preparation method of bazedoxifene acetate. The method comprises the following steps: carrying out condensation reaction on a compound I and a compound II in an organic solvent under an alkaline condition, so as to obtain an intermediate III; hydrolyzing and salifying the intermediate III, so as to obtain the target compound, namely bazedoxifene acetate (TM). By adopting the method, the productivity and the quality of bazedoxifene acetate can be obviously improved.

Description

technical field [0001] The invention relates to a preparation method and a key intermediate of bazedoxifene acetate. Background technique [0002] Bazedoxifene acetate chemical name: 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl -1 H -Indole-5-ol acetate, a novel selective estrogen receptor modulator, caps spine and hip bone mineral density and significantly reduces vertebral fracture risk in postmenopausal women with osteoporosis. [0003] Its main preparation method is as follows at present: [0004] [0005] The main disadvantage is that the reaction requires high-pressure hydrogenation, which has potential safety hazards in operation and difficulties in industrial scale-up. Contents of the invention [0006] The object of the present invention is to provide a kind of new preparation method of bazedoxifene acetate, this method can obviously improve the productive rate and the quality of bazedoxifene acetate. [0007] (1) In an organic solvent...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 翟富民郭夏翟志瑞
Owner 万全万特制药江苏有限公司
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