Amorphous solid form of a BET protein inhibitor
AssigneeIncyte Corporation
InventorsShili Chen, William Frietze, Zhongjiang Jia, Pingli Liu, Jiacheng Zhou
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Abstract
The present invention relates to an amorphous solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one, and processes for its preparation, which is an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and is useful in the treatment of various diseases such as cancer.
Claims19
A method for preparing (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1-(S)), comprising:
- reacting 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 4x) with (3,5-dimethylisoxazol-4-yl)boronic acid in the presence of a palladium complex to afford 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1);
- and
- separating the S enantiomer of Compound 1 using chiral column chromatography to afford Compound 1-(S).
A method for preparing 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1), comprising reacting 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 4x) with (3,5-dimethylisoxazol-4-yl)boronic acid in the presence of a palladium complex.
A method for preparing (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1-(S)), comprising
- 1) reacting 2-bromo-1-pyridin-2-ylethanone hydrobromide with 2-amino-nitrophenol in the presence of a base and an organic solvent to afford 5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-ol (Compound 1x);
- 2) reacting Compound 1x with hydrogen in the presence of palladium on carbon and an organic solvent to afford 3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine (Compound 2x);
- 3) reacting Compound 2x with N,N-carbonyldiimidazole in the presence of an organic solvent to afford 4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 3x);
- 4) reacting Compound 3x with N-iodosuccinimide to afford 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 4x);
- 5) reacting Compound 4x with (3,5-dimethylisoxazol-4-yl)boronic acid in the presence of a palladium complex to afford 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1);
- and
- 6) separating the S enantiomer of Compound 1 using chiral column chromatography to afford Compound 1-(S).
A method for preparing (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1-(S)) in the form of an amorphous powder, comprising
- a) dissolving Compound 1-(S) in a solvent system comprising water and a base to form a basic aqueous solution;
- and
- b) adding an acid to the basic solution to precipitate the Compound 1-(S) as an amorphous powder.
Dependencies are inferred from the claim text.