Methods of preparing heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators
AssigneeCorcept Therapeutics, Inc.
InventorsHazel Joan Hunt, Gary Patrick Reid, Jeffrey Mark Dener, Adam Daisuke Gammack Yamagata, Gareth C. Sheppard
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Abstract
The present invention provides methods of preparing heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators, and compositions having low impurity levels.
Claims41
A method of preparing a compound of Formula I:
- or a pharmaceutically acceptable salt thereof, comprising:
- (a) forming a first reaction mixture comprising a compound of Formula II:
- 4-(trifluoromethyl)benzenesulfonyl chloride:
- to prepare the compound of Formula I in a yield of at least 60% and a purity of at least 98%,
- wherein
- HX is an acid solvate;
- and
- subscript n is 1 to 4.
-4. (canceled)
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A method of preparing a compound of Formula IIa:
- comprising:
- (b) forming a second reaction mixture comprising a compound of Formula IIb:
- and
- a sulfonic acid of the formula:
- to form the compound of Formula IIa,
- wherein
- R1 is C1-6 alkyl, C1-10 haloalkyl, phenyl, or 4-methylphenyl;
- and
- subscript n is 1 to 4.
-41. (canceled)
A method of preparing a compound of Formula I:
- or a pharmaceutically acceptable salt thereof, comprising:
- (c) forming a third reaction mixture comprising tetrahydrofuran, toluene, iPrMgCl, a compound of Formula III:
- 2-bromo-pyridine:
- wherein the pyridine is present in a molar ratio of about 3.0 to the compound of Formula III, and wherein the Grignard reagent is present in a molar ratio of about 3.0 to the compound of Formula III;
- (c1) adding acetic acid and water to the third reaction mixture to form a workup mixture;
- (c2) distilling the workup mixture to form an intermediate mixture comprising a compound of Formula IIb:
- (b) forming a second reaction mixture comprising the intermediate mixture, acetonitrile, and methanesulfonic acid, to form a compound of Formula IIa having the structure:
- (a) forming a first reaction mixture comprising the compound of Formula IIa, triethylamine, ethyl acetate, and 4-(trifluoromethyl)benzenesulfonyl chloride:
- wherein the sulfonyl chloride is present in a molar ratio of about 1.0 to the compound of Formula IIa;
- (a1) adding N-methylpiperazine to the first reaction mixture to remove unreacted 4-(trifluoromethyl)benzenesulfonyl chloride;
- (a2) adding HCl and water to the first reaction mixture to partition the first reaction mixture into a first water mixture and a first organic mixture;
- (a3) separating the first water mixture from the first organic mixture;
- (a4) concentrating the first organic mixture;
- (a5) adding ethanol to the concentrated first organic mixture;
- and
- (a6) adding water to the concentrated first organic mixture to precipitate the compound of Formula I in a yield of at least 75% and a purity of at least 98%.
A method of preparing a compound of Formula IIb:
- comprising the steps of:
- (c) forming a third reaction mixture comprising a Grignard reagent, a compound of Formula III:
- and
- 2-bromo-pyridine:
- wherein the pyridine is present in a molar ratio of 2.8 to 3.2 to the compound of Formula III, and wherein the Grignard reagent is present in a molar ratio of 2.8 to 3.3 to the compound of Formula III, to prepare the compound of Formula IIb.
-50. (canceled)
A composition comprising:
- a compound of Formula I in an amount of at least 99%:
- and
- one or more impurity in an amount of from 0.01 to 1%.
-55. (canceled)
A crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone that is:
- (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid;
- (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone camphorsulfonic acid;
- (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone dibenzoyl-L-tartaric acid;
- or
- (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone 4-nitrobenzene acid.
A crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone methanesulfonic acid:
- characterized by an X-ray powder diffraction (XRPD pattern having peaks at about 7.8, 14.7, and 15.5° 2-θ±0.2° 2-θ.
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Dependencies are inferred from the claim text.