Methods of preparing heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators
Inventors
Dener, Jeffrey Mark • HUNT, Hazel Joan • Lemons, Travis • Reid, Gary • GARREC, Kilian • Stephens, Thomas C. • GAMMACK YAMAGATA, Adam Daisuke • LU, Yunguo
Assignees
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Publication Number
US-12152028-B2
Publication Date
2024-11-26
Expiration Date
Abstract
The present invention provides methods of preparing heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators, and compositions having low impurity levels.
Core Innovation
The invention provides multistep methods of preparing a compound of Formula J, a compound of Formula I, and a compound of Formula Ia, or pharmaceutically acceptable salts thereof. The preparation is built around forming defined reaction mixtures from intermediates such as Formula IIb, Formula IIa, and Formula IIb-2, together with sulfonyl chlorides, to obtain the target formulas with specified yield and purity.
The invention further describes upstream preparation of Formula IIa using a Grignard reagent route, including a reaction mixture comprising tetrahydrofuran, toluene, iPrMgCl, a compound of Formula III, and 2-bromo-4-(trifluoromethyl)pyridine. The process includes adding acetic acid and water to form a workup mixture, distilling to form an intermediate mixture comprising Formula IIa, and converting that intermediate with acetonitrile and methanesulfonic acid to form Formula IIb-2.
The patent also describes purification of a compound of Formula I, or a pharmaceutically acceptable salt thereof, by eluting through a High Pressure Liquid Chromatography C18 column using three specified mobile-phase mixtures. The purification is followed by extraction, vacuum mixing, filtration, precipitation in heptane, dissolution in methanol, and precipitation into water to obtain a purified compound of Formula I with at least 99% purity and controlled named impurities. In addition, the document defines compositions containing Formula I or Formula Ia at at least 99% (w/w) with one or more impurity in an amount of from 0.01 to 1% (w/w), and a crystalline tris-methanesulfonic acid salt form characterized by an XRPD peak pattern.
Claims Coverage
The independent claims cover multistep methods of preparing Formula J, Formula I, and Formula Ia; a method of purifying Formula I with controlled impurity limits; compositions containing Formula I or Formula Ia at high weight percentage with limited impurities; and a crystalline form characterized by XRPD peaks. Across the claims, the inventive features center on defined reaction-mixture routes, sulfonyl chloride-based conversion from specific intermediates, high-yield and high-purity isolation, impurity thresholds, and solid-form characterization.
Sulfonylation of Formula IIb with specified solvate and purity/yield targets
Forming a first reaction mixture comprising a compound of Formula IIb and a sulfonyl chloride to prepare the compound of Formula J in a yield of at least 60% and a purity of at least 98%, wherein X1 is −CH3 or −N3, HX is an acid solvate of HBr, R1 is C1-6 alkyl, and subscript n is from 1 to 4.
HBr conversion of Formula IIa to Formula IIb-1
Preparing the compound of Formula IIb-1 by forming a second reaction mixture comprising the compound of Formula IIa, and reacting it with gaseous HBr to form the compound of Formula IIb-1.
Grignard-based preparation of Formula IIa with defined pyridine and Grignard ratios
Preparing the compound of Formula IIa by forming a third reaction mixture containing a Grignard reagent and a compound of Formula III, using 2-bromo-4-(trifluoromethyl)pyridine in a molar ratio of 1.0 to 1.5 and the Grignard reagent in a molar ratio of 1.5 to 1.7 relative to the compound of Formula III.
High-purity purification of Formula I using C18 HPLC with three mobile-phase mixtures and controlled impurities
Eluting the compound of Formula I through a High Pressure Liquid Chromatography C18 column using a first mobile mixture, a second mobile mixture, and a third mobile phase to form an eluted mixture comprising the compound of Formula I having a purity of at least 98% and the compound of Formula X-5 in an amount of less than 0.75% (w/w), followed by extracting into ethyl acetate, vacuum mixing with methyl t-butyl ether, filtering, precipitation in heptane, dissolving in methanol, and adding to water to precipitate a purified compound of Formula I having a purity of at least 99% and comprising impurities with specified maximum levels including 1,4-dibromopentane in an amount of less than 6 ppm and methyl-1-methyl-1H-pyrazole-4-sulfonate in an amount of less than 6 ppm.
Multistep preparation of Formula I via intermediate Formula IIa and subsequent conversion to Formula IIb-2 and precipitation
Forming a sixth reaction mixture comprising tetrahydrofuran, toluene, iPrMgCl, a compound of Formula III, and 2-bromo-4-(trifluoromethyl)pyridine, wherein the pyridine is present in a molar ratio of about 3.0 to the compound of Formula III and the Grignard reagent is present in a molar ratio of about 3.05 to the compound of Formula III; adding acetic acid and water to form a workup mixture; distilling to form an intermediate mixture comprising a compound of Formula IIa; forming a fifth reaction mixture comprising the intermediate mixture, acetonitrile, and methanesulfonic acid to form a compound of Formula IIb-2; forming a fourth reaction mixture comprising the compound of Formula IIb-2, triethylamine, ethyl acetate, and 1-methyl-1H-pyrazole-4-sulfonyl chloride wherein the sulfonyl chloride is present in a ratio of about 1.0 to the compound of Formula IIb-2; and adding methanol and water to precipitate the compound of Formula I in a yield of at least 75% and a purity of at least 98%.
Composition with at least 99% of Formula I and 0.01 to 1% (w/w) of one or more impurities
A composition comprising a compound of Formula I in an amount of at least 99% (w/w) and one or more impurity in an amount of from 0.01 to 1% (w/w).
Composition with at least 99% of Formula Ia and 0.01 to 1% (w/w) of one or more impurities
A composition comprising a compound of Formula Ia in an amount of at least 99% (w/w) and one or more impurity in an amount of from 0.01 to 1% (w/w).
Crystalline form defined by XRPD peaks for a tris-methanesulfonic acid salt
A crystalline form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoro methyl)pyridin-2-yl)methanone tris-methanesulfonic acid, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at about 5.0°, 9.9°, 14.5°, 16.5°, 17.6°, 17.9°, 18.2°, 18.3°, 19.0°, 19.7°, 20.8°, 22.9°, 23.4°, and 25.3° 2-theta, with 2-theta at about 10.2°.
Across the independent claims, the core coverage lies in multistep preparation of Formula J, Formula I, and Formula Ia through defined reaction mixtures involving Formula IIb, Formula IIb-1, Formula IIa, and Formula IIb-2 intermediates and sulfonyl chlorides, supported by Grignard-based formation of Formula IIa and by final methanol and water precipitation to reach specified yield and purity. The independent claims further cover compositions where Formula I or Formula Ia is present at at least 99% (w/w) with a defined impurity range, and a specific crystalline solid form identified by an XRPD peak list.
Stated Advantages
Preparation of a compound of Formula J in a yield of at least 60%.
Preparation of a compound of Formula J with a purity of at least 98%.
Purification of a compound of Formula I to at least 98% purity in the eluted mixture.
Purification of a compound of Formula I to at least 99% purity as the purified compound.
Purified compound of Formula I with controlled levels of impurities including 1,4-dibromopentane in less than 6 ppm and methyl-1-methyl-1H-pyrazole-4-sulfonate in less than 6 ppm.
Compositions containing at least 99% (w/w) of Formula I or Formula Ia with impurities limited to 0.01 to 1% (w/w).
A crystalline form characterized by a specified XRPD peak pattern.
Produces the compound of Formula I in a yield of at least 75% and a purity of at least 98%.
Produces the compound of Formula Ia in a yield of at least 75% and a purity of at least 98%.
Documented Applications
Pharmaceutical composition including the composition of Formula 33 plus one or more pharmaceutically acceptable excipients.
Method for treating a disorder or condition by administering a therapeutically effective amount of a composition that modulates a glucocorticoid receptor.
Method for treating a disorder or condition by antagonizing a glucocorticoid receptor through administering a therapeutically effective amount of a composition.
Method for treating fatty liver disease by administering a therapeutically effective amount of the composition referenced in the claims.
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