Processes for preparing 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

Patent metadata

Field	Value
Publication number	US-11312699-B2
Application number	US-202017112802-A
Country	US
Kind code	B2
Filing date	Dec 4, 2020
Priority date	Dec 6, 2019
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

Provided herein are processes for preparing 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide.

First claim

What is claimed:

1. A process for preparing 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide comprising contacting Compound M with 2-(4-chlorophenyl)-2,2-difluoroacetic acid in the presence of a base and 1-propylphosphonic anhydride in a solvent, under conditions suitable to provide 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, wherein Compound M is selected from methanesulfonate, hydrochloride, sulfate, phosphate and acetate salt of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

2. The process of claim 1 , wherein the process comprises contacting Compound L

with 2-(4-chlorophenyl)-2,2-difluoroacetic acid in the presence of a base and 1-propylphosphonic anhydride in a solvent, under conditions suitable to provide 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide.

3. The process of claim 1 , wherein the base is N-methyl morpholine.

4. The process of claim 1 , wherein the solvent is dimethylformamide.

5. The process of claim 1 further comprising contacting Compound G

with a reducing agent in a solvent followed by contacting with an acid selected from methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, under conditions suitable to provide Compound M.

6. The process of claim 5 , wherein the reducing agent is 5% or 10% palladium on carbon.

7. The process of claim 5 , wherein the solvent comprises one or more of N-methyl pyrrolidone, 1 propanol, isopropyl alcohol, ethanol and tetrahydrofuran.

8. The process of claim 1 further comprising contacting Compound G

with a reducing agent in a solvent followed by contacting with an methanesulfonic acid, under conditions suitable to provide Compound L.

9. The process of claim 8 , wherein the reducing agent comprises 10% palladium on carbon.

10. The process of claim 8 , wherein the solvent comprises water and 1-propanol.

11. The process of claim 8 , wherein the solvent comprises water and isopropanol.

12. The process of claim 8 further comprising contacting Compound X

wherein L 1 is a leaving group;
with 3-aminopiperidine-2,6-dione hydrochloride in the presence of a salt, followed by a solvent and a base, under conditions suitable to provide Compound G.

13. The process of claim 12 , wherein L 1 is halogen or methanesulfonate.

14. The process of claim 8 further comprising contacting Compound D

with 3-aminopiperidine-2,6-dione hydrochloride in the presence of a salt, followed by a solvent and a base, under conditions suitable to provide Compound G.

15. The process of claim 12 , wherein the salt is potassium bromide or potassium iodide.

16. The process of claim 12 , wherein the base is N,N-diisopropylethylamine.

17. The process of claim 12 , wherein the solvent comprises acetonitrile.

18. The process of claim 12 , wherein the solvent comprises acetonitrile and water.

19. The process of claim 12 further comprising contacting Compound A

with 1) dimethyl sulfate in a solvent; 2) a base; 2) methanesulfonyl chloride; and 4) lithium chloride, under conditions suitable to provide Compound D.

20. The process of claim 14 , wherein the base is N-methyl morpholine.

21. The process of claim 14 , wherein the solvent is dimethylacetamide.

22. The process of claim 19 further comprising contacting 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile

with a base in a solvent under conditions suitable to provide Compound A.

23. The process of claim 22 , wherein the base is potassium hydroxide.

24. The process of claim 22 , wherein the solvent is isopropyl alcohol.

Assignees

• Celgene Corp

Inventors

• Beauchamps Marie G
• Feigelson Gregg
• Han Jianxin
• Hansen Joshua
• Kothare Mohit A
• Williams Michael James
• Zacuto Michael J
• Zhang Weihong

Classifications

• C07D401/04 Primary

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

• C07C255/55

  containing cyano groups and esterified hydroxy groups bound to the carbon skeleton · CPC title

• C07C253/16

  by reaction of cyanides with lactones or compounds containing hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C253/04

  by reaction of cyanogen halides, e.g. ClCN, with organic compounds · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title