Processes for preparing pyrazolyl-substituted pyrrolo[2,3-d]pyrimidines
The present invention is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines of Formula III, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
1. A process for preparing a compound of Formula XII:
wherein:
P 1 and P 2 are each independently selected from the group of benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsily)ethoxcarbonyl, 2-(4-trifluoromethyl phenylsulfonyl)ethoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, dipheny-4-pyridylmethyl, N′,N′-dimethylhydrazinyl, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-(trimethylsily)ethoxymethyl, N-pivaloyloxymethyl, 1-(ethoxy)ethyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl,hydroxymethyl, diethoxymethyl, tert-butyldimethylsily and tert-butoxycarbonyl;
comprising:
reacting a compound of Formula X:
wherein:
P 1 is selected from the group consisting of benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethyl phenylsufony)ethoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-phenysulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N′,N′-dimethylhydrazinyl, methoxymethyl, tert-butoxymethyl, benxyloxymethyl, 2-tetrahydropyranyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, 1-(ethoxy)ethyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, hydroxymethyl, diethoxymethyl, tert-butyldimethylsilylmethyl and tert-butoxycarbonyl; and
X 2 is tosylate, triflate, iodo, chloro or bromo;
with a compound of Formula XIII:
wherein:
P 2 is selected from the group consisting of benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethyl phenylsulfonyl)ethoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantylcarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N′,N′-dimethylhydrazinyl, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, 1-(ethoxy)ethyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, hydroxymethyl, diethoxymethyl, tert-butyldimethylsilylmethyl and tert-butoxycarbonyl; and
R c and R d are each independently H or C 1-6 alkyl; or
R c and R d , together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3 or 4 C 1-4 alkyl groups;
in the presence of a palladium catalyst, base and a solvent, to form a compound of Formula XII.
2. The process according to claim 1 , wherein P 1 is selected from the group consisting of N-pivaloyloxymethyl and 2-(trimethylsilyl)ethoxymethyl.
3. The process according to claim 1 , wherein the compound of Formula XIII has the formula:
4. A process for preparing a compound of Formula XII:
wherein:
P 1 is —CH 2 OC(=O)C(CH 3 ) 3 ; and
P 2 is selected from the group consisting of 1-(ethoxy)ethyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, hydroxymethyl, methoxymethyl, diethoxymethyl, tert-butyldimethylsilylmethyl and tert-butoxycarbonyl;
comprising:
reacting a compound of Formula X:
wherein:
P 1 is —CH 2 OC(=0)C(CH 3 ) 3 ; and
X 2 is tosylate, triflate, iodo, chloro or bromo;
with a compound of Formula XIII:
wherein:
P 2 is selected from the group consisting of 1-(ethoxy)ethyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, hydroxymethyl, methoxymethyl, diethoxymethyl, tert-butyldimethylsilylmethyl and tert-butoxycarbonyl; and
R c and R d are each independently H or C 1-6 alkyl; or
R c and R d , together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3 or 4 C 1-4 alkyl groups;
in the presence of a palladium catalyst, base and a solvent, to form a compound of Formula XII.
5. The process according to claim 4 , wherein P 2 is selected from the group consisting of 1-(ethoxy)ethyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, hydroxymethyl, methoxymethyl, diethoxymethyl and tert-butyldimethylsilylmethyl.
6. The process according to claim 4 , wherein the compound of Formula X has the formula:
7. The process according to claim 4 , wherein the compound of Formula XIII has the formula:
8. A compound which is: