Processes for preparing 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide
AssigneeCelgene Corporation
InventorsMarie G. Beauchamps, Gregg B. Feigelson, Jianxin Han, Joshua Hansen, Mohit A. Kothare, Michael James Williams, Michael J. Zacuto, Weihong Zhang
Life of this patent
Estimating the term…
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.
Claims22
A process for preparing 2-(4-chlorophenyl)-N-((2-( 2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide
- comprising
- a) contacting 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile
- with potassium hydroxide in isopropyl alcohol, under conditions suitable to provide Compound A
- b) contacting Compound A with 1) dimethyl sulfate in dimethylacetamide, 2) N-methyl morpholine, 3) methanesulfonyl chloride, and 4) lithium chloride, under conditions suitable to provide Compound D
- c) contacting Compound D with i) 3-aminopiperidine-2,6-dione hydrochloride in the presence of potassium bromide, followed by ii) a solvent comprising acetonitrile and water, and iii) N,N-diisopropylethylamine, under conditions suitable to provide Compound G,
- d) contacting Compound G with 10% wt Pd/C, methanesulfonic acid, and a solvent comprising water and 1-propanol, under conditions suitable to provide Compound L
- and
- e) contacting Compound L with 2-(4-chlorophenyl)-2,2-difluoroacetic acid in the presence of dimethylformamide, N-methyl morpholine and T3P, under conditions suitable to provide 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide.
A process for preparing polymorph Form C of 2-(4-chlorophenyl)-N-((2-( 2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2, 2-difluoroacetamide comprising
- a) contacting 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile
- with potassium hydroxide in isopropyl alcohol, under conditions suitable to provide Compound A
- b) contacting Compound A with 1) dimethyl sulfate in dimethylacetamide, 2) N-methyl morpholine, 3) methanesulfonyl chloride, and 4) lithium chloride, under conditions suitable to provide Compound D
- c) contacting Compound D with i) 3-aminopiperidine-2,6-dione hydrochloride in the presence of potassium bromide, followed by ii) a solvent comprising acetonitrile and water, and iii) N,N-diisopropylethylamine, under conditions suitable to provide Compound G,
- d) contacting Compound G with 10% wt Pd/C, methanesulfonic acid, and a solvent comprising water and 1-propanol, under conditions suitable to provide Compound L
- and
- e) contacting Compound L with 2-(4-chlorophenyl)-2,2-difluoroacetic acid in the presence of dimethylformamide, N-methyl morpholine and T3P, under conditions suitable to provide 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide, and
- f) contacting 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide with formic acid and water at 60° C. to obtain polymorph Form C of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide.
A process for preparing Compound A
- comprising contacting 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile
- with potassium hydroxide and isopropyl alcohol, under conditions suitable to provide Compound A.
A process for preparing Compound D
- comprising contacting Compound A
- with 1) dimethyl sulfate in a solvent;
- 2) a base;
- 3) methanesulfonyl chloride;
- and 4) lithium chloride, under conditions suitable to provide Compound D.
A process for preparing Compound G
- comprising contacting Compound X
- where L1 is a leaving group;
- with i) 3-aminopiperidine-2,6-dione hydrochloride in the presence of potassium bromide, followed by ii) a solvent comprising acetonitrile and water, and iii) N,N-diisopropylethylamine, under conditions suitable to provide Compound G.
A process for preparing Compound L
- comprising contacting Compound G
- with 10% dry palladium on carbon, methanesulfonic acid, water and 1-propanol, under conditions suitable to provide Compound L.
A process for preparing polymorph Form C of 2-(4-chlorophenyl)-N-((2-( 2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide comprising contacting 2-(4-chlorophenyl)-N-((2-( 2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2, 2-difluoroacetamide with formic acid and water at 60° C. to obtain polymorph Form C of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide.
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 L
- with 2-(4-chlorophenyl)-2,2-difluoroacetic acid in the presence of N-methyl-2-pyrrolidone and thionyl chloride, under conditions suitable to provide 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide.
A process for preparing Form C of 2-(4-chlorophenyl)-N-((2-( 2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2, 2-difluoroacetamide comprising contacting 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide with acetone to obtain a mixture, and heating the mixture under nitrogen to about 70-75° C. with agitation.
Dependencies are inferred from the claim text.