Processes for the preparation of (S)-3-(4- (4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and pharmaceutically acceptable forms thereof

Patent metadata

Field	Value
Publication number	US-9309220-B2
Application number	US-201313962764-A
Country	US
Kind code	B2
Filing date	Aug 8, 2013
Priority date	Aug 9, 2012
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

Provided are processes for the preparation of enantiomerically enriched or enantiomerically pure 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable form thereof.

First claim

What is claimed is:

1. A process for preparing an enantiomerically enriched or enantiomerically pure compound of Formula (I):

or a pharmaceutically acceptable form thereof, comprising
(step_1.1) transforming an enantiomerically enriched or enantiomerically pure compound of Formula (II):

or a salt thereof, wherein
(i) Z 1 is NHY, and Z 2 is OR; or
(ii) Z 1 is OR, and Z 2 is NHY; wherein
R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or a suitable protecting group of a carboxy group; and
Y is hydrogen, or a suitable amino protecting group;

to an enantiomerically enriched or enantiomerically pure compound of Formula (III), or a salt thereof:

wherein
(i) Z 3 is NHY, and Z 4 is OH; or
(ii) Z 3 is OH, and Z 4 is NHY;

under conditions suitable for ester to acid transformation, wherein step 1.1 occurs in the presence of an acid;
(step 1.2) cyclizing the enantiomerically enriched or enantiomerically pure compound of Formula (III) to an enantiomerically enriched or enantiomerically pure compound of Formula (I-a):

under conditions suitable for cyclization;
(step 1.3) where Y is an amino protecting group, deprotecting the enantiomerically enriched or enantiomerically pure compound of Formula (I-a) to an enantiomerically enriched or enantiomerically pure compound of Formula (I) under conditions suitable for deprotection; and
(step 1.4) optionally transforming the enantiomerically enriched or enantiomerically pure compound of Formula (I) to a pharmaceutically acceptable salt thereof under conditions suitable for salt formation.

2. The process of claim 1 , wherein step 1.1 and step 1.2 occur in one-pot.

3. The process of claim 1 , wherein step 1.1 occurs in the presence of R b COOH wherein R b is hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 haloalkyl, or substituted or unsubstituted C 5-14 aryl.

4. The process of claim 3 , wherein step 1.1 occurs in the presence of formic acid, acetic acid, trifluoroacetic acid, or benzoic acid.

5. The process of claim 1 , wherein step 1.1 occurs in the presence of R b SO 3 H wherein R b is hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 haloalkyl, or substituted or unsubstituted C 5-14 aryl.

6. The process of claim 5 , wherein step 1.1 occurs in the presence of sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid.

7. The process of claim 6 , wherein step 1.1 occurs in the presence of benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or methanesulfonic acid.

8. The process of claim 7 , wherein step 1.1 occurs in the presence of benzenesulfonic acid.

9. The process of claim 1 , wherein step 1.2 occurs in the presence of a dehydrating agent.

10. The process of claim 9 , wherein step 1.2 occurs in the presence of 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide (EDCI) or 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU).

11. The process of claim 1 , wherein step 1.2 occurs by azeotropic distillation.

12. The process of claim 1 , wherein step 1.1 and step 1.2, separately or in one-pot, occur in a solvent of, or a combination of solvents containing, diethyl ether, 1,4-dioxane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetonitrile, methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide, glyme, diglyme, dimethylacetamide, or N-methyl-2-pyrrolidone.

13. The process of claim 12 , wherein step 1.1 and step 1.2, separately or in one-pot, occur in a solvent of acetonitrile.

14. The process of claim 1 , wherein the reaction temperature for step 1.1 and step 1.2, separately or in one-pot, is from about −100° C. to about 200° C.

15. The process of claim 14 , wherein the reaction temperature for step 1.1 and step 1.2, separately or in one-pot, is about 90° C.

16. The process of claim 1 , wherein the reaction time for step 1.1 and step 1.2, separately or in one-pot, is from about 1 minute to about 14 days.

17. The process of claim 16 , wherein the reaction time for step 1.1 and step 1.2, separately or in one-pot, is from about 8 hours to about 9 hours.

18. A process for preparing an enantiomerically enriched or enantiomerically pure compound of Formula (I):

or a pharmaceutically acceptable form thereof, comprising
(step_1.i) transforming an enantiomerically enriched or enantiomerically pure compound of Formula (II):

or a salt thereof, wherein
(i) Z 1 is NHY, and Z 2 is OR; or
(ii) Z 1 is OR, and Z 2 is NHY; wherein
R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or a suitable protecting group of a carboxy group; and
Y is hydrogen, or a suitable amino protecting group;

to an enantiomerically enriched or enantiomerically pure compound of Formula (I-a):

under conditions suitable for cyclization, wherein step 1.i occurs in the presence of an acid;
(step 1.3) where Y is an amino protecting group, deprotecting the enantiomerically enriched or enantiomerically pure compound of Formula (I-a) to an enantiomerically enriched or enantiomerically pure compound of Formula (I) under conditions suitable for deprotection; and
(step 1.4) optionally transforming the enantiomerically enriched or enantiomerically pure compound of Formula (I) to a pharmaceutically acceptable salt thereof under conditions suitable for salt formation.

19. A process for preparing an enantiomerically enriched or enantiomerically pure compound of Formula (I):

or a pharmaceutically acceptable form thereof, comprising
(step_1.a) transforming an enantiomerically enriched or enantiomerically pure compound of Formula (II):

or a salt thereof, wherein
(i) Z 1 is NHY, and Z 2 is OR; or
(ii) Z 1 is OR, and Z 2 is NHY; wherein
R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubsti

Assignees

• Celgene Corp

Inventors

• Traverse John F
• Zhang Chengmin
• Feigelson Gregg B
• Cohen Benjamin M
• Leong William W

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title