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US 12,084,454 B2Granted
Process for preparing BTK inhibitors
AssigneeHoffmann-La Roche Inc.
InventorsStephan Bachmann, Lukas Chytil, Serena Maria Fantasia, Alec Fettes, Ursula Hoffmann
Life of this patent
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Abstract
Methods for preparing the Bruton's Tyrosine Kinase (“BTK”) inhibitor compound 2-{3′-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided.
Claims23
A method of preparing compound 190, or a salt thereof, the method comprising:
- (a) forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, and a solvent system comprising a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is from about 0.001:1 to less than 0.005:1;
- and
- (b) reacting the reaction mixture to form a reaction product mixture comprising compound 190 according to the following scheme:
- wherein the palladium catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond,
- wherein:
- (i) the fragment giving rise to the palladium-carbon bond is an allyl derivative of the formula
- wherein each of R6 to R10 is independently selected from the group consisting of H, optionally substituted C1-6 alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl;
- and R6 and R10 may optionally come together to form a fused bicycle comprising an aromatic ring;
- wherein the yield of compound 190, or salt thereof, is at least 50% based on compound 170.
6 more elements
A method of reducing byproduct formation in a Suzuki coupling reaction, the method comprising:
- (a) forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is from about 0.001:1 to less than 0.005:1;
- and
- (b) reacting the reaction mixture to form a reaction product mixture comprising compound 190, or salt thereof, according to the following scheme:
- wherein the palladium catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond,
- wherein:
- (i) the fragment giving rise to the palladium-carbon bond is an allyl derivative of the formula
- wherein each of R6 to R10 is independently selected from the group consisting of H, optionally substituted C1-6 alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl;
- and R6 and R10 may optionally come together to form a fused bicycle comprising an aromatic ring;
- wherein:
- (a) the content of a dimer impurity is less than 0.1 area % based on compound 190, or salt thereof, wherein the dimer impurity is of the structure
- and
- (b) the combined content of an alcohol and a ketone impurity is less than 0.25 area % based on compound 190, or salt thereof, wherein the alcohol and ketone impurities are of the structures
9 more elements
Dependencies are inferred from the claim text.