Process for the preparation of N-((1R,2S,5R)-5-(
The invention generally relates to an improved process for the preparation of N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, as well as novel intermediates employed in the process, which may be useful for the treatment of cancer.
1. A process for the preparation of a compound of formula (I):
wherein the process comprises the following steps:
a) reacting Compound 1 of the formula:
with a Compound 2 of the formula:
wherein:
R 1 is halogen or OC(O)CH 3 ;
in the presence of an acid and a solvent, to afford Compound 3 of the formula:
b) reacting Compound 3 above with a compound of the formula:
wherein:
R 2 is H or C 1 -C 6 alkyl; and
R 3 is H or C 1 -C 6 alkyl;
in the presence of a Lewis acid, followed by (a) sodium borohydride, (b) Pt/Al in the presence of hydrogen gas, or (c) Pd/C in the presence of hydrogen gas, to afford Compound 4 of the formula:
wherein:
X is halogen, sulfate, tartrate, or citrate;
c) reacting Compound 4 above with (a) sodium hydroxide, followed by methanesulfonic acid, in the presence of dichloromethane, or (b) sulfuric acid in the presence of isopropyl alcohol, to afford Compound 5 of the formula:
wherein:
X is halogen, sulfate, tartrate, or citrate;
d) reacting Compound 5 above with Compound 6 of the formula:
in the presence of triacetoxyborohydride and a solvent, to afford Compound 7 of the formula:
e) reacting Compound 7 above with an acid, in the presence of hydroxylamine, or a salt thereof, and a solvent, to afford Compound 8 of the formula:
f) reacting Compound 8 above with an acid or a base, followed by heating the reaction mixture to a temperature in the range of 45° C.-70° C., in the presence of a solvent or solvent mixture, to afford Compound 9 of the formula:
g) reacting Compound 9 above with Pd/C in the presence of hydrogen gas, followed by an acid, to afford Compound 10 of the formula:
wherein:
X is halogen; and
h) reacting Compound 10 above with Compound 11a of the formula:
wherein:
X is halogen, 1-methylimidazole, or OR; and
R is alkyl, aryl, a phosphate ester, or a sulfate ester;
in the presence of a solvent or solvent mixture, to afford the compound of formula (I) above.