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-oxopyrroldin-1-yl)cyclohexyl)acetamide

Patent metadata

Field	Value
Publication number	US-11254679-B2
Application number	US-201816631915-A
Country	US
Kind code	B2
Filing date	Jul 19, 2018
Priority date	Jul 20, 2017
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

Abstract

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.

First claim

We claim:

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.

Assignees

• Bristol Myers Squibb Co

Inventors

• Aytar Burcu Selin
• Borovika Alina
• Chan Collin
• Deerberg Joerg
• Domagalski Nathan R
• Eastgate Martin D
• Fan Yu
• Fenster Michael David Bengt
• Forest Robert V
• Gonzalez-Bobes Francisco
• Green Rebecca A
• Hickey Matthew R
• Kopp Nathaniel David
• La Cruz Thomas E
• Lauser Kathleen
• Lee Hong Geun
• Leahy David K
• Luo Helen Y
• Razler Thomas M
• Savage Scott A
• Sfouggatakis Chris
• Soumeillant Maxime C D
• Zaretsky Serge
• Zheng Bin
• Zhu Ye

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D235/06

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2 · CPC title

• C07D207/273

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C327/22

  having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title