Preparation method of high-purity tamoxifen citrate

A technology of tamoxifen and citric acid, applied in the field of preparation of high-purity tamoxifen citrate, can solve the problems of high cost, difficulty in obtaining high-purity tamoxifen citrate, etc. Yield, mild reaction conditions, and the effect of saving operating time

Inactive Publication Date: 2013-12-18
ASYMCHEM LAB TIANJIN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process adopts the method of continuous injection and only needs one step of purification, which solves the difficulties of high cost and difficulty in obtaining high-purity tamoxifen citrate in the pharmaceutical industry

Method used

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  • Preparation method of high-purity tamoxifen citrate
  • Preparation method of high-purity tamoxifen citrate
  • Preparation method of high-purity tamoxifen citrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: a kind of preparation method of high-purity tamoxifen citrate is characterized in that the specific preparation steps are as follows:

[0038] (1) Coupling reaction: Add 60L tetrahydrofuran (15mL / g) into a 200L reactor, add 6.55kg zinc powder (5 equivalents) under stirring, cool down to -10°C, add dropwise 7.66kg titanium tetrachloride (2 equivalents) ), the temperature was raised to 63-68°C for 1 hour after dropping, and then dropped to 20-25°C after 2 hours of heat preservation. Add dropwise a solution of 20L tetrahydrofuran (5mL / g) dissolved with 4kg 4-hydroxybenzophenone (1.0 equivalent) and 2.71kg propiophenone (1 equivalent). After complete conversion of -hydroxybenzophenone, cool down to 20-25°C, add 60L of 20% potassium carbonate aqueous solution (15mL / g) to the system, separate the organic phase, extract the aqueous phase with 40L of methyl tert-butyl ether, combine the organic phase, concentrated to obtain 7.5kg of crude product 4-(1,2-diphenyl-...

Embodiment 2

[0042] Embodiment 2: a kind of preparation method of high-purity tamoxifen citrate is characterized in that the specific preparation steps are as follows:

[0043] (1) Coupling reaction: Add 60L of ethylene glycol dimethyl ether (15mL / g) to a 200L reactor, add 7.87kg of zinc powder (6 equivalents) under stirring, drop the temperature to -10°C and add 11.48kg of tetrachloride Titanium chloride (3 equivalents), after dropping and keeping warm for 1 hour, the temperature of the system was raised to 60-70°C, and after keeping warm for 2 hours, it was lowered to 20-25°C, and then 4kg of 4-hydroxybenzophenone (1.0 equivalent) and 2.84 kg propiophenone (1.05 equivalent) in 20L ethylene glycol dimethyl ether (5mL / g) solution, after the dripping, the system is heated to 60 ~ 65 ° C, kept warm until the conversion of 4-hydroxybenzophenone is complete, then cooled to 20 ~25°C, add 60L 20% potassium carbonate aqueous solution (15mL / g) to the system, separate the organic phase, extract the...

Embodiment 3

[0047] Embodiment 3: a kind of preparation method of high-purity tamoxifen citrate is characterized in that the specific preparation steps are as follows:

[0048] (1) Coupling reaction: Add 60L 2-methyltetrahydrofuran (15mL / g) to a 200L reactor, add 6.6kg zinc powder (5 equivalents) under stirring, cool down to -10°C, and dropwise add 15.4kg tetrachloride Titanium (4 equivalents), the temperature of the system was raised to 60-70°C after the drop and kept for 1 hour, and the temperature was lowered to 20-25°C after 2 hours of heat preservation, and then 4kg of 4-hydroxybenzophenone (1.0 equivalent) and 4.06kg of 20L of 2-methyltetrahydrofuran (5mL / g) of propiophenone (1.5 equivalents), after the dripping is completed, the temperature of the system is raised to 65-70°C, and the temperature is maintained until the conversion of 4-hydroxybenzophenone is complete. Cool down to 20-25°C, add 60L of 20% potassium carbonate aqueous solution (15mL / g) to the system, separate the organi...

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Abstract

The invention discloses a preparation method of high-purity tamoxifen citrate. By improving the problems in the existing route, the invention discloses a novel synthesis method of high-purity low-E-isomer-content tamoxifen citrate. The method comprises the following steps: by using simple and accessible 4-hydroxybenzophenone as a raw material, carrying out coupling reaction and alkylation reaction to obtain a crude product 2-[4-(1,2-diphenyl1-butenyl)-phenoxy]-N,N-dimethylethylamine; directly carrying out isomerization reaction on the crude product, carrying out simple purification, and salifying with citric acid to conveniently obtain the high-purity tamoxifen citrate of which the E isomer content does not exceed 0.05%. The technique adopts a continuous feed mode, and only needs one-step purification, thereby solving the problems of high cost and difficulty in preparing high-purity tamoxifen citrate in pharmaceutical industry. The technique has the advantages of mild reaction conditions, high stability, high purity and high yield, is simple to operate, and provides an option for large-scale production.

Description

(1) Technical field: [0001] The invention relates to the field of organic synthesis and preparative chemistry, in particular to a method for preparing high-purity tamoxifen citrate. (2) Background technology: [0002] The chemical name of tamoxifen citrate is (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine citrate Citrate (compound I), the structural formula is as follows, it belongs to non-steroidal anti-estrogen drugs, there are two isomers of Z type and E type, but only Z type has therapeutic effect. Tamoxifen citrate was developed by Imperial Chemical Industries (ICI). It was first used clinically in 1971, and was approved by the US FDA in 1978 for the treatment of breast cancer at various stages before and after menopause. [0003] [0004] The preparation method of reported tamoxifen citrate has following several kinds at present: [0005] 1. Using the McMurry coupling method (see figure 1 , J.Chem.Soc., Perkin.Trans(I), 1986,475), the reaction h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/18C07C213/08C07C59/285C07C51/41
Inventor 洪浩马建国李九远张成勋张磊
Owner ASYMCHEM LAB TIANJIN
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