Process for producing bicycloaniline derivatives
The present invention relates to a process for producing a hydrate of 3-(2,6-dichlorophenyl)-4-imino-7-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-yl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (Compound A) or of a pharmaceutically acceptable salt of Compound A and a crystalline form of Compound A or of a pharmaceutically acceptable salt of Compound A, which are useful in the field of treatment of various cancers as a kinase inhibitor, especially as a Weel kinase inhibitor.
1. A crystalline form of a 3.5 hydrate of Compound A dihydrochloride:
having an X-ray powder diffraction pattern, obtained using Cu K alpha radiation, containing the following angle 2 theta values: 8.4° , 22.3° and 24.9° , and at least one angle 2 theta value selected from the group consisting of: 12.7° , 15.3° , 16.3° , 24.4° , 26.5° , and 28.6° .
2. A process for preparing a crystalline form of a 3.5 hydrate of Compound A dihydrochloride, which comprises the steps of:
(a) concentrating a solution of Compound A in an organic solvent to form a slurry;
(b) treating the slurry of step (a) with hydrogen chloride in a solvent on heating;
(c) cooling the slurry of step (b) to room temperature;
(d) collecting crystals from the resulting slurry of step (c);
(e) drying the crystals of step (d); and
(f) treating the dried crystals of step (e) with wet inert gas to stabilize water content in the desired crystalline form.
3. A pharmaceutical composition comprising a therapeutically-effective amount of the crystalline hydrate compound of claim 1 , and a pharmaceutically acceptable carrier or diluent.
4. A process for preparing a compound of formula (6):
or a salt thereof, which comprises the steps of:
(a) reacting a compound of formula (1):
with a compound of formula (2):
X 1 —CH 2 CH 2 —X 2 (2)
wherein X 1 and X 2 each independently is a leaving group, to obtain a compound of formula (3):
(b) nitrating a compound of formula (3) to obtain a compound of formula (4):
(c) reducing oxo groups of the compound of formula (4) to obtain a compound of formula (5):
or a salt thereof;
(d) reducing a nitro group of the compound of formula (5) or a salt thereof to obtain a compound of formula (6) or a salt thereof; and optionally converting said compound of formula (6) into a salt thereof.
5. The hydrate of claim 1 , having an X-ray powder diffraction pattern, obtained using Cu K alpha radiation, containing the following angle 2 theta values: 8.4° , 22.3° , 24.9° and 12.7° .
6. The process of claim 2 , wherein the crystalline form has an X-ray powder diffraction pattern, obtained using Cu K alpha radiation, containing the following angle 2 theta values: 8.4° , 22.3° and 24.9° , and at least one angle 2 theta value selected from the group consisting of: 12.7° , 15.3° , 16.3° , 24.4° , 26.5° , and 28.6° .
7. The process of claim 2 , wherein the organic solvent of step (a) is an alcohol-containing solvent or a mixture thereof.
8. The process of claim 7 , wherein the alcohol-containing solvent is selected from the group consisting of methanol, ethanol, propanol, and isopropanol.
9. The process of claim 7 , wherein the organic solvent of step (a) optionally contains organic or inorganic solvents other than alcohol.
10. The process of claim 9 , wherein the organic or inorganic solvents are selected from the group consisting of chloroform, dichloromethane, N, N-dimethylformamide, and water.