Method for preparing fulvestrant and intermediates

A fulvestrant and intermediate technology, which is applied in the field of pharmaceutical synthesis, can solve the problems of low yield, high route cost and high energy consumption, and achieves the effects of high yield, safe reaction reagents and high low-temperature conversion rate

Active Publication Date: 2020-03-31
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the low polarity and thermal instability of the side chain iodine, it is inconvenient to purify and not suitable for industrialization
Due to the long side chain of side chain iodine, the main side chain condensation yield is low and the route cost is high
[0012] In WO2014064712 (Intas Pharmaceuticals Ltd), triethyl boron and a catalyst are used for the condensation of main and side chains. Triethyl boron is a spontaneously combustible substance with high toxicity, which is not conducive to the personal safety of on-site production personnel
The use of catalyst and high-temperature reaction conditions (toluene reflux up to more than one hundred degrees) not only increase the cost, but also the production is unsafe, and the energy consumption is high. In addition, the yield of the intermediate Full II prepared by it is very low, only 49.2%
[0013] The prior art discloses various methods for preparing fulvestrant, but it is necessary to overcome the problems of expensive raw materials, harsh reactions, high ratio of isomers, unsuitability for industrialization, high cost, high temperature reaction, unsafe production, and high yield in the above methods. Various deficiencies such as low rate

Method used

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  • Method for preparing fulvestrant and intermediates
  • Method for preparing fulvestrant and intermediates
  • Method for preparing fulvestrant and intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] Intermediate 3 (30 g, 66 mmol, 1 eq) and toluene (150 ml, 5V) were added to the reaction flask. Add potassium tert-butoxide (7.4 g, 66 mmol, 1 eq) and stir for 15 minutes. Add 1,9-diiodononane (50.2g, 132mmol, 2eq) and potassium tert-butoxide (11.1g, 99mmol, 1.5eq) to the reaction solution, and stir at a temperature of 25°C until TLC detects that the reaction is complete (about 8- 10 hours). TLC conditions: PE / EA=10:1, color development with phosphomolybdic acid. Add the reaction solution into saturated ammonium chloride solution (1000ml), stir for 30 minutes, let stand to separate layers, extract the aqueous phase with 1000ml of ethyl acetate, combine the organic phases, wash with 1000ml of water, 1000ml of brine successively, anhydrous sodium sulfate 100 g dry. Filter and concentrate under reduced pressure to obtain 90 g of dark red oil.

[0038] Add 1000ml of ethyl acetate to dissolve, 540g of silica gel to make sand, and 3000g of silica gel for colum...

Embodiment 2

[0040]

[0041]Intermediate 3 (30 g, 66 mmol, 1 eq) and toluene (150 ml, 5V) were added to the reaction flask. Add potassium tert-butoxide (7.4 g, 66 mmol, 1 eq) and stir for 15 minutes. Add 1,9-diiodononane (75.3g, 198mmol, 3eq) and potassium tert-butoxide (11.1g, 99mmol, 1.5eq) to the reaction solution, and stir at a temperature of 25°C until TLC detects that the reaction is complete (about 8 to 10 hours). TLC conditions: PE / EA=10:1, color development with phosphomolybdic acid. Add the reaction solution into saturated ammonium chloride solution (1000ml), stir for 30 minutes, let stand to separate layers, extract the aqueous phase with 1000ml of ethyl acetate, combine the organic phases, wash with 1000ml of water, 1000ml of brine successively, anhydrous sodium sulfate 100 g dry. Filter and concentrate under reduced pressure to obtain 120 g of dark red oil.

[0042] Add 1500ml ethyl acetate to dissolve, 600g silica gel to make sand, and 3000g silica gel to pack. It was...

Embodiment 3

[0044]

[0045] Intermediate 3 (30 g, 66 mmol, 1 eq) and toluene (150 ml, 5V) were added to the reaction flask. Add sodium tert-butoxide (6.4 g, 66 mmol, 1 eq) and stir for 15 minutes. Add 1,9-diiodononane (50.2g, 132mmol, 2eq) and sodium tert-butoxide (9.5g, 99mmol, 1.5eq) to the reaction solution, and stir at a temperature of 25°C until TLC detects that the reaction is complete (about 8~ 10 hours). TLC conditions: PE / EA=10:1, color development with phosphomolybdic acid. Add the reaction solution into saturated ammonium chloride solution (1000ml), stir for 30 minutes, let stand to separate layers, extract the aqueous phase with 1000ml of ethyl acetate, combine the organic phases, wash with 1000ml of water, 1000ml of brine successively, anhydrous sodium sulfate 100 g dry. Filter and concentrate under reduced pressure to obtain 85 g of dark red oil.

[0046] Add 1000ml of ethyl acetate to dissolve, 400g of silica gel to make sand, and 3000g of silica gel for column packi...

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Abstract

The invention relates to a method for preparing fulvestrant and intermediates, particularly to a method for preparing a fulvestrant intermediate. According to the method, estradiol is used as a starting raw material, and is linked to a protecting group to obtain an intermediate 1; the benzyl site of the intermediate 1 is hydroxylated to obtain an intermediate 2; the intermediate 2 is oxidized to obtain an intermediate 3; the intermediate 3 and an intermediate 4 (1,9-dibromo nonane is subjected to iodination to obtain an intermediate 4, ie., 1,9-diiodononane) are subjected to a condensation reaction to obtain an intermediate 5 (a compound represented by a formula I); the intermediate 5 and an intermediate 7 (4,4,5,5,5-pentafluoropentanol and p-toluenesulfonyl chloride are condensed, and thecondensed product reacts with thiourea to obtain p-toluenesulfonic acid pentafluorothiourea salt) are subjected to a reaction to obtain an intermediate 8; the intermediate 8 is subjected to deprotection-reduction to obtain an intermediate 9; and the intermediate 9 is oxidized to obtain a target product. The method has the advantages of simple operation process, high yield of fulvestrant and highpurity of fulvestrant, and is suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of fulvestrant. Background technique [0002] Fulvestrant, developed and marketed by AstraZeneca, is an estrogen receptor (ER) down-regulator, used as an anti-estrogen therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC ) of therapeutic drugs. [0003] It was approved by FDA in April 2002 and EMA in March 2004; it was launched in the United States in May 2002 and in Europe in March 2004. [0004] Its structural formula is as follows: [0005] [0006] Breast cancer is a disease in which breast ductal epithelial cells lose their normal characteristics and proliferate abnormally under the action of various internal and external carcinogenic factors, so that they exceed the limit of self-repair and become cancerous. The main clinical manifestation is breast mass. Breast cancer is one of the most common ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J17/00C07J31/00
CPCC07J17/00C07J31/006Y02P20/55
Inventor 余俊武华周曹莹游军辉张小兵
Owner JIANGSU HANSOH PHARMA CO LTD
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