Synthesis and use of kinase inhibitors
AssigneePoniard Pharmaceuticals, Inc.
InventorsYixiong Lei, Carl Henry Behrens, Hui-Yin Li, Connie L. Sun
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Abstract
An improved synthesis of a class of inhibitor of Focal Adhesion Kinase (FAK) is provided, wherein use of an expensive palladium-based catalyst is reduced and reaction yields and product purities are improved. Two key reactions of coupling of aryl halides with anilines are optimized with the surprising discovery that the palladium-based catalyst can be dispensed with entirely in one of the reactions. The invention also provides the use of the FAK-inhibitory compounds in the treatment of inflammatory and immune disorders and of arthritis.
Claims43
A method of synthesizing a compound of formula (I)
- wherein
- R1 is independently at each occurrence alkyl, aryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- R2, R3 and R4 are independently at each occurrence alkyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, or fluoro;
- R5 is hydrogen, alkyl, aryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- w is 0 to 8;
- x is 0 to 3;
- y is 0 to 2;
- and
- z is 0 to 4;
- including any stereoisomer thereof;
- comprising contacting a compound of formula (II)
- and a compound of formula (III)
- under conditions comprising:
- (a) a solution of compounds (II) and (III) in a liquid hydroxylic solvent of boiling point higher than about 115 degrees C.;
- (b) the compound of formula (II) being present at a concentration of no less than about 0.4 M;
- (c) the compound of formula (III) being present at a concentration about 10% higher than the concentration of the compound of formula (II);
- (d) a temperature in excess of about 100° C.;
- (e) a duration of time of at least about 48 hours;
- (f) an absence of added bases;
- (g) an absence of transition metal catalysts;
- followed by precipitation of the compound of formula (I) by addition of a hydrocarbon to the hydroxylic solvent following cooling of the solvent to ambient temperature, then collection of the precipitated compound.
A method of preparing a compound of formula (II)
- wherein R3 and R4 are independently at each occurrence alkyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, or fluoro;
- R5 is hydrogen, alkyl, aryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- y is 0 to 2;
- and
- z is 0 to 4;
- comprising:
- (a) contacting a compound of formula (IV)
- and a compound of formula (V)
- in an ethereal solvent at about 80° C.,
- under conditions comprising:
- (a) no more than about 0.5 wt % Pd2(dba)3;
- (b) no more than about 1.5 wt % xantphos;
- (c) no more than about 1.1 molar equivalents of Cs2CO3;
- (d) a concentration of the compound of formula (IV) of no less than about 0.5 M;
- (e) a concentration of the compound of formula (V) of no less than about 0.5 M;
- (f) for a duration of about 2-3 days.
Dependencies are inferred from the claim text.