Methods of making protein deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-2016355486-A1
Application number	US-201615176826-A
Country	US
Kind code	A1
Filing date	Jun 8, 2016
Priority date	Jun 8, 2015
Publication date	Dec 8, 2016
Grant date	—

Abstract

The present invention relates to methods and intermediates useful for the synthesis of protein deacetylase inhibitors.

First claim

1 . A method of making compound (Ia):

comprising the steps of:
converting compound 11a into compound 3a:

wherein X is selected from fluorine, chlorine, bromine and iodine;
Z is selected from the group consisting of —CN and —CO 2 R; and
R is C 1 -C 6 alkyl; and

converting compound 3a into compound (Ia).

2 . The method of claim 1 , wherein compound 11a is prepared by a method comprising the step of:
converting compound 1a into compound 11a:

wherein X is selected from fluorine, chlorine, bromine and iodine;
Z is selected from the group consisting of —CN and —CO 2 R; and
R is C 1 -C 6 alkyl.

3 . The method of claim 1 , wherein the step of converting compound 3a into compound (Ia) comprises the steps of:
converting compound 3a into compound 4a:

 and
converting compound 4a into compound (Ia).

4 . The method of claim 3 , wherein the step of converting compound 4a into compound (Ia) comprises the steps of:
converting compound 4a into compound 5a:

wherein X is selected from fluorine, chlorine, bromine and iodine; and
R′ is C 1 -C 6 alkyl; and

converting compound 5a into compound (Ia):

wherein X is selected from fluorine, chlorine, bromine and iodine.

5 . The method of claim 1 , wherein X is chlorine.

6 . The method of claim 1 , wherein Z is CO 2 Et.

7 . The method of claim 4 , wherein R′ is methyl.

8 . A method of making compound (I):

comprising the steps of:
converting compound 11b into compound 3b:

wherein Z is selected from the group consisting of —CN and —CO 2 R;
wherein R is C 1 -C 6 alkyl; and
converting compound 3b into compound (I).

9 . The method of claim 8 , wherein compound 11b is prepared by a method comprising the step of:
converting compound 1b into compound 11b:

10 . The method of claim 8 , wherein the step of converting compound 3b into compound (I) comprises:
converting compound 3b into compound 4:

 and
converting compound 4 into compound (I).

11 . The method of claim 10 , wherein the step of converting compound 4 into compound (I) comprises:
converting compound 4 into compound 5b:

wherein R′ is C 1 -C 6 alkyl; and
converting compound 5b into compound (I).

12 . The method of claim 8 , wherein Z is CO 2 Et.

13 . The method of claim 11 , wherein R′ is methyl.

14 . The method of claim 9 , wherein the step of converting compound 1b into compound 11b comprises reacting compound 1 with 2-chloroaniline to obtain compound 11:

15 . The method of claim 8 , wherein the step of converting compound 11b into compound 3b comprises reacting compound 11 with iodobenzene to obtain compound 3:

16 . The method of claim 10 , wherein the step of converting compound 3b into compound 4 comprises hydrolyzing the ester of compound 3:

17 . The method of claim 16 , wherein the step of converting compound 4 into compound 5b comprises reacting compound 4 with methyl 7-aminoheptanoate to obtain compound 5:

18 . The method of claim 11 , wherein the step of converting compound 5b into compound (I) comprises reacting compound 5 with hydroxylamine, or a salt thereof, to obtain compound (I), or a salt thereof.

19 . A method of making compound (I) comprising the following steps:
(1) reacting ethyl 2-chloropyrimidine-5-carboxylate with 2-chloroaniline to obtain compound 11:

(2) reacting compound 11 with iodobenzene to obtain compound 3:

(3) reacting compound 3 with aqueous base, followed by reacting with acid, to obtain compound 4:

(4) reacting compound 4 with methyl 7-aminoheptanoate to obtain compound 5:

 and
(5) reacting compound 5 with hydroxylamine, or a salt thereof, to obtain compound (I), or a salt thereof:

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Assignees

• Acetylon Pharmaceuticals Inc

Inventors

• Seyedi Farzaneh
• Van Duzer John H

Classifications

• C07D239/42 Primary

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D239/30

  Halogen atoms or nitro radicals · CPC title