Intermediate for preparing fulvestrant and preparation method therefor
OwnerFuyao ZHANG, Xianjie CHENinventors
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Abstract
The invention relates to a fulvestrant intermediate and a preparation method thereof. Specifically, the invention relates to a compound shown as a formula V and a preparation method thereof, and R1 is hydrogen or a hydroxyl protecting group. The invention also relates to a preparation method for the synthesis of fulvestrant from the compound as shown in the formula V. The method has the advantages of short reaction steps, mild and safe reaction conditions, high selectivity, simplicity and convenience in operation and purification, high synthesis efficiency and the like, and is suitable for large-scale production.
Claims26
A compound as shown in formula V,
- wherein:
- R1 is hydrogen or hydroxyl protecting groups.
A compound as shown in formula VII,
- wherein M is MgCl, MgBr, MgI, Mg1/2, ZnCl, ZnBr, ZnI, Zn1/2, MnCl, Li or Na.
A method for preparing a compound as shown in formula VII, wherein it is prepared by reaction with metal or exchange reaction with metal from compound as described in formula VIII,
- wherein X is Cl, Br or I, M is MgCl, MgBr, MgI, Mg1/2, ZnCl, ZnBr, ZnI, Zn1/2, MnCl, Li or Na.
A method for preparing a compound as shown in formula VIIA, wherein it is prepared by Grignard reaction from the compound as shown in formula VIII with magnesium metal, or with Grignard reagents through Grignard exchange reaction,
- wherein X is Cl, Br or I.
A compound as shown in formula III,
- wherein R1 is hydrogen or hydroxyl protecting groups;
- R2 is hydroxyl protecting groups.
A preparation method for a compound as shown in formula III, wherein it is prepared by aromatization reaction and phenolic hydroxyl protection reaction of the compound shown in formula V,
- wherein R1 is hydrogen or hydroxyl protecting groups;
- R1 is hydroxyl protecting groups.
A method for preparing fulvestrant as shown in formula I, wherein it comprises the following steps,
- 1) The compound shown in formula VI and the compound shown in formula VII undergo addition reaction to obtain the compound shown in formula V;
- 2) The compound shown in formula V undergoes aromatization reaction and phenolic hydroxyl protection reaction to obtain the compound shown in formula III;
- 3) The compound shown in formula III and the compound shown in formula IV undergo substitution reaction to obtain the compound as shown in formula II;
- 4) The compound shown in formula II undergoes oxidation reaction to obtain the compound shown in formula I;
- wherein R1 is hydrogen or hydroxyl protecting groups;
- R2 is hydroxyl protecting groups;
- M is MgCl, MgBr, MgI, Mg1/2, ZnCl, ZnBr, ZnI, Zn1/2, MnCl, Li or Na.
A method for preparing fulvestrant as shown in formula I, wherein it comprises the following steps,
- 1) The compound shown in formula VIa and the compound shown in formula VIIa undergo addition reaction to obtain the compound shown in formula Va;
- 2) The compound shown in formula Va undergoes aromatization reaction and phenolic hydroxyl protection reaction to obtain the compound shown in formula IIIa;
- 3) The compound shown in formula IIIa and the compound shown in formula IVa undergo substitution reaction to obtain the compound as shown in formula II;
- 4) The compound shown in formula II undergoes oxidation reaction to obtain the compound shown in formula I.
A method for preparing fulvestrant, wherein it comprises steps for preparing fulvestrant by 1,9-dichlorononane, 1-chloro-9-bromononane or 1-chloro-9-iodononane.
Dependencies are inferred from the claim text.