Preparation method of tamoxifen

A technology of tamoxifen and catalyst, which is applied in the field of preparation of tamoxifen, can solve the problems of low yield and long working hours, and achieve the effects of high yield, good selectivity and simple process flow

Active Publication Date: 2017-07-18
NINGBO TEAM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The above method is to dehydrate the tertiary alcohol to obtain a mixture of tamoxifen and its E-isomer, and also needs to obtain tamoxifen by refining and splitting, which also has the problems of long working hours and low yield.

Method used

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  • Preparation method of tamoxifen
  • Preparation method of tamoxifen
  • Preparation method of tamoxifen

Examples

Experimental program
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Effect test

Embodiment 1

[0028] In a 1L hydrogenation reactor, add 40g toremifene, 400g methanol, 8.3g potassium hydroxide, 4g 10% palladium carbon, replace with 0.2MPa nitrogen for 3 times, then replace with 0.2MPa hydrogen for 3 times, keep the hydrogen The pressure is 0.3-0.5MPa, the reaction temperature is 70°C, and the reaction is stirred for 14 hours. Cool down to room temperature, filter with suction, distill off methanol under reduced pressure, add 250mL ethyl acetate and 100mL water to wash, stand to separate layers, wash the ethyl acetate layer with 100mL water again, stand to separate, and wash the organic phase with anhydrous sulfuric acid Dry over sodium, filter and distill off ethyl acetate under reduced pressure, add 120mL of acetone to heat and dissolve, then place it at 0°C for crystallization overnight, filter it with suction, and dry it with air at 60°C to obtain 31.5g of white needle-like solid tamoxifen, the yield 86%.Mp:96.5~98℃, 1 H NMR (400MHz, CDCl 3 ): δ0.93(t, J=7.6Hz, 3H,...

Embodiment 2

[0030] Into a 1L hydrogenation reactor, add 40g toremifene, 400g ethanol, 7.1g sodium hydroxide, 4g 10% platinum carbon, replace with 0.2MPa nitrogen for 3 times, then replace with 0.2MPa hydrogen for 3 times, keep the hydrogen The pressure is 0.3-0.5MPa, the reaction temperature is 90°C, and the reaction is stirred for 12 hours. Cool down to room temperature, filter with suction, distill ethanol off under reduced pressure, add 250mL ethyl acetate and 100mL water to wash, stand to separate layers, wash the ethyl acetate layer with 100mL water again, stand to separate, and wash the organic phase with anhydrous sulfuric acid Dry over sodium, filter and distill off ethyl acetate under reduced pressure, add 120mL of acetone to heat and dissolve, place it at 0°C for crystallization overnight, filter it with suction, and dry it with air at 60°C to obtain 31.1g of white needle-like solid tamoxifen, yield 84.9%. Mp: 96.3-97.8°C.

Embodiment 3

[0032] In a 1L hydrogenation reactor, add 40g toremifene, 400g ethanol, 8.3g potassium carbonate, 3g 10% palladium carbon, replace 3 times with 0.2MPa nitrogen gas, then replace 3 times with 0.2MPa hydrogen gas to keep the hydrogen pressure 0.5-0.7MPa, reaction temperature 90°C, stirring for 12 hours. Cool down to room temperature, filter with suction, distill ethanol off under reduced pressure, add 250mL ethyl acetate and 100mL water to wash, stand to separate layers, wash the ethyl acetate layer with 100mL water again, stand to separate, and wash the organic phase with anhydrous sulfuric acid Dry over sodium, filter and distill off ethyl acetate under reduced pressure, add 120mL of acetone to heat and dissolve, place it at 0°C for crystallization overnight, filter it with suction, and dry it with air at 60°C to obtain 32g of white needle-shaped solid tamoxifen, yield 87.5 %. Mp: 96-97.5°C.

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Abstract

The invention relates to a preparation method of tamoxifen. The preparation method is characterized by comprising the following steps of adding toremifene, a catalyst and an alkali compound into an alcohols solvent, and stirring for reacting for 10 to 24 hours at a hydrogen atmosphere at 0.1 to 1.0MPa and 20 to 150 DEG C; then cooling a reaction system to the room temperature, carrying out suction filtration, and vaporizing and eliminating the solvent at normal pressure or reduced pressure; adding ethyl acetate and water for washing, standing for layering, drying an upper-layer organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, vaporizing and eliminating the ethyl acetate at reduced pressure, obtaining a pulp, and adding acetone into the pulp, wherein the ratio of the volume of the acetone to the weight of the pulp is 2 to 5ml / g; then heating to 50 to 56 DEG C for dissolving, and cooling to 0 DEG C for separating crystals out; drying the crystals to obtain the white needle-like solid tamoxifen.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of tamoxifen. Background technique [0002] Tamoxifen (tamoxifen) is a triphenylethylene compound, an anti-estrogen drug developed from diethylstilbestrol estrogen as a precursor. [0003] There are many synthetic methods of tamoxifen. In 2012, Haroutounian et al. made a detailed review of the synthetic methods of tamoxifen, summarizing 8 synthetic strategies of tamoxifen (K.M.Kasiotis and S.A.Haroutounian.Tamoxifen: a synthetic overview.Curr.Org. Chem. 2012, 16, 335-352). Most of these methods involve reactions involving organometallic catalysts or organometallic reagents. The synthetic routes are relatively long, the stereoselectivity is not high, and the operation is cumbersome. Especially in the process of using organometallic reagents with higher activity, there are many potential safety hazards. Wherein, the method that is suitable for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C217/18
CPCC07C213/08C07C217/14C07C217/18
Inventor 徐骥王毅斌王陈杨汪伟
Owner NINGBO TEAM PHARMA
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