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Preparation method of fulvestrant

A technology of fulvestrant and pentafluoropentyl, which is applied in the field of preparation of the anticancer drug fulvestrant, can solve problems such as the difficulty of fulvestrant synthesis, achieve easy post-processing, reduce production costs, and increase yields. rate effect

Inactive Publication Date: 2014-05-14
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis of fulvestrant is relatively difficult, so a variety of synthetic routes have been studied in the prior art

Method used

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  • Preparation method of fulvestrant
  • Preparation method of fulvestrant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The preparation of embodiment 1 formula II-1 compound

[0042]

Embodiment 1-1

[0043] Example 1-1 Preparation of 9-bromononanol tert-butyldimethylsilyl ether

[0044]

[0045] Add 223 grams of 9-bromononanol, 205 grams of imidazole and 1 liter of dichloromethane into a 3-liter three-necked flask, and stir under nitrogen protection. At -15°C, 178 g of tert-butyldimethylsilyl chloride (dissolved in 200 ml of dichloromethane) was added dropwise, and the dropwise addition was completed within 1 hour. The reaction was carried out at temperature for 24 hours, and at room temperature for 24 hours. Wash with water 6 times after the reaction, each 1000 milliliters, then wash 2 times with saturated sodium chloride water. The organic phase was concentrated at 100°C to obtain 302 g of the title compound as a pale yellow viscous liquid.

Embodiment 1-2

[0046] Example 1-2 Preparation of 9-bromononanol tert-butyldimethylsilyl ether Grignard reagent

[0047]

[0048] Add 36 grams of metal magnesium chips and 2 liters of anhydrous tetrahydrofuran to the dried 3-liter three-neck flask under nitrogen protection, add a grain of iodine under stirring, the color of the solution turns yellowish brown, turn on the heating device, and add the above-mentioned Example 1 at 60°C The light yellow viscous liquid of -1 was refluxed while adding dropwise, and continued to reflux for 16 hours after the addition was completed, and then set aside for later use.

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Abstract

The invention relates to a preparation method of fulvestrant. The preparation method comprises a step of implementing reaction on a fulvestrant intermediate body (represented as formula II) and S-(4,4,5,5,5-pentafluoro amyl) isothiourea mesylate to introduce a pentafluoro amyl sulfenyl group, and further comprises a step (ii) of removing a protecting group of hydroxyl and / or a step iii) of oxidizing thioether into sulfoxide according to demand. According to the preparation method disclosed by the invention, raw materials are convenient to prepare and the post-processing is relatively simple, the yield of a target product is increased, the production cost is reduced, and the fulvestrant is applicable to large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of an anticancer drug fulvestrant. Background technique [0002] Fulvestrant (Faslodex, ICI182780, ZD182780, ZD9238, ZM182780) is an estrogen receptor antagonist with the chemical name (7α, 17β)-7-[9-(4,4,5,5,5 -Pentafluoropentasulfinyl)nonyl]-estra-1,3,5(10)-triene-3,17-diol, CAS No. 129453-61-8, has the following structural formula. [0003] Fulvestrant [0004] In 2002, fulvestrant was approved by the US FDA and marketed by AstraZeneca under the trade name of Faslodex, which is used for postmenopausal metastatic advanced breast cancer that is ineffective in the treatment of anti-estrogen therapy, disease progression, and estrogen receptor (ER) positive. Cancer treatment, intramuscular injection once a month, 250mg each time. The study found that high doses of fulvestrant significantly prolonged disease progression compared to the 250 mg do...

Claims

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Application Information

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IPC IPC(8): C07J31/00
CPCY02P20/55
Inventor 姜力勋刘玉先张洪英刘飞张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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