Process for the preparation of a cyp11a1 inhibitor and intermediates thereof
OwnerOskari Karjalainen, Miika Karjomaainventors
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Abstract
The present invention relates to an improved process for the preparation of 4H-pyranone structured CYP11A1 inhibitors such as 5-((1-(methylsulfonyl)-piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (1A) and key intermediates thereof including 5-(trifluoromethyl)isoindoline (V) and 5-hydroxy-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (III). CYP11A1 inhibitors are useful in the treatment of hormonally regulated cancers, such as prostate cancer and breast cancer.
Claims37
A process for the preparation of a compound of formula (V) or a pharmaceutically acceptable salt thereof
- comprising the steps of either
- a) treating a compound of formula (VI)
- with copper cyanide to obtain a compound of formula (VII)
- b) protecting the compound of formula (VII) to obtain a compound of formula (VIII) wherein Pg is a protecting group
- c) reducing the compound of formula (VIII) to obtain a compound of formula (IX)
- and
- d) deprotecting the compound of formula (IX) to obtain a compound of formula (V);
- and optionally converting it to its pharmaceutically acceptable salt;
- or
- a′) treating a compound of formula (VI)
- with hexacyanoferrate[II] salt in the presence of a catalyst to obtain a compound of formula (X) or a pharmaceutically acceptable salt thereof
- b′) reducing the compound of formula (X) or a pharmaceutically acceptable salt thereof to obtain a compound of formula (XI) or a pharmaceutically acceptable salt thereof
- c′) treating the compound of formula (XI) or a pharmaceutically acceptable salt thereof with thionyl chloride to obtain a compound of formula (V);
- and optionally converting it to its pharmaceutically acceptable salt.
A process for the preparation of a compound of formula (III)
- comprising the steps of
- a″) reacting a compound of formula (XII)
- with hydrochloride salt of 5-(trifluoromethyl)isoindoline (V) in dimethyl sulfoxide in the presence of N,N-diisopropylethylamine;
- b″) adding isopropyl alcohol and water to the mixture;
- and
- c″) isolating the compound of formula (III).
A process for the preparation of a compound of formula (1A) or a pharmaceutically acceptable salt thereof
- comprising the steps of
- i″) reacting a compound of formula (III)
- with a compound of formula (IV);
- wherein LG is a leaving group selected from a mesyl or a tosyl group,
- in dimethyl sulfoxide in the presence of cesium carbonate;
- ii″) adding acetonitrile and water to the mixture;
- and
- iii″) isolating the compound of formula (1A);
- and optionally converting it to its pharmaceutically acceptable salt.
A compound of formula (IXa), or (XI) or a pharmaceutically acceptable salt thereof
Dependencies are inferred from the claim text.