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Preparation method of fulvestrant related substance E

A compound and reaction technology, applied in the field of preparation of fulvestrant related substance E, can solve the problems of easy generation of epoxy related substances, difficult reuse of resin, unstable double bond, etc., and achieves reasonable process route design and low cost. , the effect of easy operation

Inactive Publication Date: 2020-07-10
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The double bond formed after the dehydration of this route is unstable in the reaction of oxidizing thioether, and it is easy to produce epoxy-related substances.

Method used

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  • Preparation method of fulvestrant related substance E
  • Preparation method of fulvestrant related substance E
  • Preparation method of fulvestrant related substance E

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of compound of formula V

[0033]

[0034] The compound of formula VI (10 g, 16.5 mmol), pyridine (40 mL), and acetic anhydride (16.9 g, 165 mmol) were added into the reaction flask, and refluxed for 1 hour. The reaction solution was lowered to room temperature, added 100ml of water, 100ml of ethyl acetate, stirred and separated, the organic layer was washed successively with 100ml of saturated sodium dihydrogen phosphate, and 100ml of saturated brine, and the organic layer was dried over anhydrous sodium sulfate for 1 hour, filtered and concentrated to dryness , to obtain 11.2 g of the compound of formula V (16.3 mmol, molar yield: 98.8%).

Embodiment 2

[0036] Preparation of Formula IV Compounds

[0037]

[0038] The compound of formula V (11.2g, 16.3mmol) was added into 60mL of methanol, the temperature was lowered to -5-5°C, sodium borohydride (1.8g, 49mmol) was added in batches, and the reaction was kept for 1 hour. Pour the reaction solution into 2M hydrochloric acid aqueous solution (60ml), add 100ml of dichloromethane, stir and separate the layers, wash the organic layer with 100ml of saturated sodium bicarbonate and 100ml of saturated brine, dry the organic layer with anhydrous sodium sulfate for 1 hour, and filter After concentrating to dryness, 11.1 g (16.1 mmol, molar yield: 98.7%) of the compound of formula IV was obtained.

Embodiment 3

[0040] Preparation of the compound of formula III

[0041]

[0042] Compound of formula IV (11g, 15.9mmol), acetic anhydride (5.7g, 95.4mmol) and ethyl acetate (60ml) were added in the reaction flask, 15% hydrogen peroxide (7ml) was added dropwise, and the reaction was stirred for 20 hours after the dripping was completed. Add 7.5% sodium sulfite solution (50ml) and saturated sodium bicarbonate solution (100ml) to the reaction solution, stir for 20 minutes, separate layers, wash the organic layer with 100ml saturated brine, dry the organic layer with anhydrous sodium sulfate for 1 hour, filter and concentrate to dryness , to obtain 10.4 g (14.7 mmol, molar yield: 92.5%) of the compound of formula III.

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PUM

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Abstract

The invention relates to a preparation method of a fulvestrant related substance E. The invention relates to a preparation method of a fulvestrant related substance E shown as a formula I (See the specification for reference), namely, 7-[9-(4, 4, 5, 5, 5-pentafluoropentylsulfinyl) nonyl] estra-1, 3, 5(10), 6-tetraene-3, 17 beta-diol. The fulvestrant related substance E is obtained by taking (7S, 8R, 9S, 13S, 14S, 17S)-3, 17-dihydroxy-13-methyl-7-(9-((4, 4, 5, 5, 5-pentafluoropentyl) sulfo) nonyl)-7, 8, 9, 11, 12, 13, 14, 15, 16, 17-decahydro-6H-cyclopentadiene-6-ketone as a starting material through the reaction steps of protection, reduction, oxidation, dehydration and deprotection. The method has the advantages of few side reactions, high product yield, good purity, reasonable process design, simple operation and low cost.

Description

technical field [0001] The application field of the present invention relates to the field of chemical synthesis, in particular to a preparation method of fulvestrant related substance E. Background technique [0002] Fulvestrant, chemical name: 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene- 3,17β-diol, English name: Fulvestrant, was developed by AstraZeneca, approved by FDA in April 2002, approved by EMA in March 2004; and listed in the United States in May 2002 and March 2004 Launched in Europe in May. The structural formula is as follows: [0003] [0004] Fulvestrant, an estrogen receptor (ER) down-regulator, is indicated as a second-line treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC) whose disease has progressed on anti-estrogen therapy. [0005] At present, the main synthetic route of fulvestrant is the route disclosed in the patent CN01820270, and the specific route is as follows: [00...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0066
Inventor 于海洲曹莹张小兵余俊
Owner JIANGSU HANSOH PHARMA CO LTD
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