Processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines
AssigneeCelgene Corporation
InventorsGeorge Muller, Roger Chen, Manohar Saindane, Chuansheng Ge
Life of this patent
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Abstract
The present invention concerns new processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines which are useful for preventing or treating diseases or conditions related to an abnormally high level or activity of TNFα. The invention provides processes for the commercial production of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines including, but not limited to, the therapeutically active 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
Claims72
A process for preparing a compound of Formula 1:
- or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein:
- each of R1′, R2′, R3′, and R4′ is at each occurrence independently hydrogen, halo, alkyl, alkoxy, —CF3, —CN, —NO2, —NHProtG2, or —NR5R6;
- each of R5 and R6 is at each occurrence independently hydrogen or alkyl;
- R7 is hydrogen, halo, alkyl, or benzyl;
- and
- ProtG2 is a suitable N-protecting group,
- which comprises the alternative sequences of steps of:
- (1)(a) coupling a glutamine ester or a salt thereof with an optionally substituted 2-haloalklylbenzoate;
- (b) cyclizing the coupled product;
- and
- (c) optionally transforming one or more benzo substituents of the cyclized product into other substituent(s) in one or more steps,
- or:
- (2)(a) coupling a glutamine ester or a salt thereof with an optionally substituted 2-haloalkylbenzoate;
- (b) transforming one or more benzo substituents of the coupled product into other substituent(s) in one or more steps;
- and
- (c) cyclizing the transformed product.
A process for preparing a compound of Formula 1:
- or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein:
- each of R1′, R2′, R3′, and R4′ is at each occurrence independently hydrogen, halo, alkyl, alkoxy, —CF3, —CN, —NO2, —NHProtG2, or —NR5R6;
- each of R5 and R6 is at each occurrence independently hydrogen or alkyl;
- R7 is hydrogen, halo, alkyl, or benzyl;
- and
- ProtG2 is a suitable N-protecting group,
- which comprises the alternative sequences of steps of:
- (1)(a) cyclizing a compound of Formula 2:
- and
- (b) optionally transforming one or more of the R1, R2, R3, and/or R4 substituents of the cyclized product of Formula 3:
- into one or more of the corresponding R1′, R2′, R3′, and/or R4′ substituents, respectively, of the compound of Formula 1 in one or more steps,
- or:
- (2)(a) transforming one or more of the R1, R2, R3, and/or R4 substituents of a compound of Formula 2:
- into one or more of the corresponding R1′, R2′, R3′, and/or R4′ substituents, respectively, of a compound of Formula 4:
- in one or more steps, and
- (b) cyclizing the transformed product of Formula 4,
- wherein, for both sequences of steps unless noted otherwise:
- each of R1, R2, R3, R4, R1′, R2′, R3′, and R4′ is at each occurrence independently hydrogen, halo, alkyl, alkoxy, —CF3, —CN, —NO2, —NHProtG2, or —NR5R6;
- each of R5 and R6 is at each occurrence independently hydrogen or alkyl;
- R7 is hydrogen, halo, alkyl, or benzyl;
- R8 is alkyl or benzyl for sequence (1) and is hydrogen, alkyl, or benzyl for sequence (2);
- and
- ProtG2 is a suitable N-protecting group.
A process for preparing a compound of Formula 11:
- or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, which comprises the alternative sequences of steps of:
- (1)(a) cyclizing a compound of Formula 12:
- and
- (b) reducing the —NO2 group of the cyclized product of Formula 13:
- to an —NH2 group,
- or:
- (2)(a) reducing the —NO2 group of a compound of Formula 12:
- to an —NH2 group, and
- (b) cyclizing the reduced product of Formula 14:
Dependencies are inferred from the claim text.