Process for making phosphoramidate protected nucleoside compounds

Patent metadata

Field	Value
Publication number	US-10618926-B2
Application number	US-201615562973-A
Country	US
Kind code	B2
Filing date	Mar 28, 2016
Priority date	Apr 2, 2015
Publication date	Apr 14, 2020
Grant date	Apr 14, 2020

Abstract

The present invention is directed to process for making Compounds of Formula (II): (II), and salts thereof, wherein B, X, R 2 , R 3 , R 4 R 7 , R 8 and R 9 are defined herein.

First claim

What is claimed is:

1. A process for making a compound of formula (II):

wherein said process comprising the step of contacting a compound of formula (I):

with a compound of formula (III):

in the presence of an aluminum complex having the formula the formula (C 1 -C 6 alkyl) 2 AlCl or Al(—O—(C 1 -C 6 alkyl)) 3 , and base 2,6-lutidine, in an organic solvent A for a time and at a temperature sufficient to form the compound of formula (II),
wherein:
X is O, S or CH 2 ;
B is a natural or non-natural purine or pyrimidine base, or B is selected from one of the following groups:

R 1 is selected from the group consisting of pentafluorophenyl, and 3-chloropyridyl;
R 2 is selected from the group consisting of C 6 -C 10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10 aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with one or more R 5 groups;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or benzyl, wherein said C 3 -C 7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R 5 groups;
R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 14 cycloalkyl) and —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl);
each occurrence of R 5 is independently selected from the group consisting of —C 1 -C 6 alkyl, halo, —OR 6 , —C(O)R 6 , —CO 2 R 6 , —SR 6 , —C 1 -C 6 hydroxyalkyl, —C 1 -C 6 haloalkyl, —N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —CN and —NO 2 ;
each occurrence of R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl);
R 7 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, F, —CN, —N 3 , —N(R 9 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 3 -C 7 cycloalkyl;
R 8 is selected from the group consisting of H and —C(O)R 13 ;
each occurrence of R 9 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 6 -C 10 aryl and C 3 -C 7 cycloalkyl;
R 10 , R 11 and R 12 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, halo, —OR 14 , —SR 14 , —S(O)R 14 , —S(O) 2 R 14 , —S(O) 2 N(R 14 ) 2 , —NHC(O)OR 14 , —NHC(O)N(R 14 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 14 ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), —C(O)R 14 , —C(O)OR 14 , —C(O)N(R 14 ) 2 and —NHC(O)R 14 ;
each occurrence of R 13 is independently H or C 1 -C 6 alkyl;
each occurrence of R 14 is independently selected from the group consisting of H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) and —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl); and
each occurrence of m is independently 0 or 1.

2. The process of claim 1 , wherein the aluminum complex is (CH 3 ) 2 AlCl or Al(t-BuO) 3 .

3. The process of claim 1 , wherein the compound of formula (I) is:

wherein:
R 1 is pentafluorophenyl or 3-chloropyridyl;
R 3 is —C 1 -C 6 alkyl; and
R 4 is —C 1 -C 6 alkyl.

4. The process of claim 3 , wherein R 1 is pentafluorophenyl.

5. The process of claim 3 , wherein the compound of formula (I) is:

6. The process of claim 1 , wherein organic solvent A is THF.

7. The process of claim 1 , wherein the compound of formula (III) has the formula (IIIa):

wherein R 7 is selected from the group consisting of F, —CN, C 2 -C 6 alkynyl, —NH 2 and —N 3 ; and R 8 is H or —C(O)CH(CH 3 ) 2 .

8. The process of claim 7 , wherein R 7 is F, —C≡CH, —N 3 or —NH 2 ; and R 8 is H.

9. The process of claim 7 , wherein R 7 —CN and R 8 is —C(O)CH(CH 3 ) 2 .

10. The process of claim 1 , wherein the compound of formula (II) that is made is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Assignees

• Silverman Steven M
• Simmons Bryon Ladd
• Liu Zhuqing
• Liao Jing
• Klapars Artis
• Campos Kevin R
• Bellomo Peraza Ana Ines
• Merck Sharp & Dohme

Inventors

• Silverman Steven M
• Simmons Bryon Ladd
• Liu Zhuqing
• Liao Jing
• Klapars Artis
• Campos Kevin R
• Bellomo Peraza Ana Inés

Classifications

• C07F9/58

  Pyridine rings · CPC title

• C07H1/02 Primary

  Phosphorylation · CPC title

• C07F9/65586

  at least one of the hetero rings does not contain nitrogen as ring hetero atom · CPC title

• C07F9/242

  of hydroxyaryl compounds · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title