US 8,076,479 B2 · Process and intermediates for the synthesis of (3-alkyl-5-piperidin-1-yl-3,3a-dihydro-pyrazolo[1,5-a]pyrimidin-7-yl)-amino derivatives and intermediates

Abstract

Disclosed is a process for the synthesis of compounds of Formula I by sequentially aminating, first with a primary amine and then with a secondary amine, an intermediate compound of the structure of Formula E1, wherein R1 is a linear, branched, or cyclic alkyloxy functional group of the structure (—R2a—OH), R2a is a linear, branched or cyclic alkyl group, R2 is a linear, branched or cyclic alkyl group, and R3 is an alkylene-heterocycle, said process comprising forming intermediate compound of Formula E1 by reacting, in a refluxing reaction solvent selected from alcohols having 5 or less carbon atoms and mixtures of two or more thereof, a methanol solution of a salt of a 4-alkyl-3-amino-pyrazole compound of Formula C1, with a diamidization reagent selected from dimethylmalonate, monomethylmalonyl-chloride, and malonyl dichloride in the presence of a Lewis base having sufficient proton affinity to abstract a proton from the 1-position nitrogen on the pyrazole ring.

Claims41

Dependent claims

A process for the synthesis of CDK inhibitor compounds having the structure of Formula I

from an intermediate compound of the structure of Formula E1,
wherein R1 is a linear, branched, or cyclic alkyloxy functional group of the structure (—R2a—OH), R2a is a linear, branched or cyclic alkyl group, R2 is a linear, branched or cyclic alkyl group, and R3 is an alkylene-heterocycle, said process comprising:
(a) forming intermediate compound of Formula E1 by reacting, in a refluxing reaction solvent selected from the group consisting of alcohols having 5 or less carbon atoms and mixtures of two or more thereof, a methanol solution of a salt of a 4-alkyl-3-amino-pyrazole compound of Formula C1,
with a diamidization reagent selected from the group consisting of dimethylmalonate, monomethylmalonylchloride, and malonyl dichloride in the presence of a Lewis base having sufficient proton affinity to abstract a proton from the 1-position nitrogen on the pyrazole ring;
(b) derivatizing the intermediate E1 prepared in Step (a) to provide the compound of Formula F1,
wherein “X” is selected from the group consisting of chloride, bromide, iodide, fluoride, and a sulfonyl group;
and (c) sequentially aminating the compound of Formula F1 with a primary amine, and then with a secondary amine, to form the compound of Formula 1.

4 more elements

A process for making the compound of Formula II,

the process comprising:
a) forming a compound having the structure of Formula E,
by reacting, in a refluxing reaction solvent selected from the group consisting of alcohols having 5 or less carbon atoms and mixtures of two or more thereof, a methanol solution of a salt of a 4-alkyl-3-amino-pyrazole compound of Formula C
with a diamidization reagent selected from the group consisting of dimethylmalonate, monomethylmalonylchloride, and malonyl dichloride in the presence of a metal alkoxide base comprising an alkoxide moiety having 5 carbon atoms or less;
b) forming a compound having the structure of Formula F;
by reacting the compound of Formula E prepared in Step “a” with phosphorous oxychloride in the presence of a Lewis Base selected from the group consisting of N,N-dimethylaniline, pyridine, diisopropylethylamine, and triethyl amine;
(c) refluxing the reaction mixture from Step “b” containing the compound of Formula F in the presence of a dihydrochloride salt of N-oxide-pyridin-3-yl-amine, K3PO4, and water to form the compound of Formula G,
d) refluxing the isolated compound of Formula G prepared in Step “c” in N-methylpyrollidine in the presence of sodium carbonate, a sufficient water to maintain a refluxing temperature of from about 140° C. to about 160° C., and the amino alcohol compound having the structure of Formula G1a,
to yield forming the compound of Formula II;
and
e) optionally, isolating the compound of Formula II prepared in refluxing Step “d” from the reaction product and recrystalling it from ethanol by adding tert-methyl butyl ether.

8 more elements

Dependencies are inferred from the claim text.

Process and intermediates for the synthesis of (3-alkyl-5-piperidin-1-yl-3,3a-dihydro-pyrazolo[1,5-a]pyrimidin-7-yl)-amino derivatives and intermediates

Life of this patent

Process and intermediates for the synthesis of (3-alkyl-5-piperidin-1-yl-3,3a-dihydro-pyrazolo[1,5-a]pyrimidin-7-yl)-amino derivatives and intermediates

Life of this patent

Abstract

Claims41