Crystal form of fulvestrant and preparation method thereof
A fulvestrant and crystal form technology, which is applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, steroids, etc., can solve the problem of no mention of crystal form spectral characteristics, no literature mention of fulvestrant Problems such as crystal form and preparation method have been solved to achieve the effect of good bulk density, stable crystal form and no decrease in content
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Embodiment 1
[0034] The preparation of embodiment 1 fulvestrant intermediate II
[0035] Add 10g bromide (Br-(CH 2 ) 9 -S-(CH 2 ) 3 -CF 2 CF 3 , see scheme 2), 0.7g metal magnesium and 100ml dry tetrahydrofuran, the mixture was heated to 77°C for 3h, cooled to room temperature, and used under the protection of nitrogen. This makes the Grignard reagent.
[0036] In another reaction flask, add 5g of 6-dehydronandrolone acetate, 50ml of dry tetrahydrofuran, and 0.5g of anhydrous ketone acetate, cool the reaction mixture to -45°C ~ -50°C, and slowly add the above Grignard reagent, add dropwise within 3.5h, react at -45°C for 4h after addition, end the mixture with 5ml of concentrated hydrochloric acid, keep the temperature below 10°C, keep the mixture below 10°C for 30 minutes, during about 20 minutes , add 50ml of water, add 100ml of dichloromethane, separate the water layer, wash the dichloromethane layer with 10ml of 25% ammonia water, and finally wash the dichloromethane with water ...
Embodiment 2
[0037] The preparation of embodiment 2 fulvestrant intermediate III
[0038]Add 4g of Intermediate II, 50ml of anhydrous methanol and 1g of potassium hydroxide to the reaction flask, stir and react at 20°C to 30°C for 24h, evaporate the methanol to dryness in a water bath below 30°C, add 10ml of water and 100ml of acetic acid to the residue Ethyl was mixed, then 1ml of acetic acid was added to adjust the pH to 6, the aqueous layer was separated, the ethyl acetate layer was washed with water until neutral, dried over anhydrous sodium sulfate, and the ethyl acetate was evaporated to dryness to obtain 3.1g of an oil (intermediate III), which was directly used in the next step.
Embodiment 3
[0039] Embodiment 3 Preparation of Fulvestrant Intermediate IV
[0040] Add 6g of intermediate III, 80ml of dry acetonitrile, 5.3g of copper bromide, and 1.1g of lithium bromide into the reaction flask, and heat the mixture to reflux for 3h. After the reaction is completed, the mixture is cooled to room temperature, and stirred by adding 6g of 25% ammonia water and 50ml of dichloromethane After 12 hours, the water layer was separated, the dichloromethane layer was washed with water until neutral, and the dichloromethane was evaporated to dryness to obtain 5.8 g of an oil (intermediate IV).
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