# US 8,785,644 B2 · Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds

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- Number: US 8,785,644 B2
- Document ID: US8785644B2
- Status: Granted
- Kind: B2
- Application number: 13/117,196
- Filed: 2011-05-27
- Published: 2011-09-15
- Granted: 2014-07-22
- Earliest claimed: 2005-06-30
- Assignees: Celgene Corporation
- Applicants: Chuansheng Ge; George W. Muller; Roger Chen; Manohar Tukaram Saindane
- Inventors: Chuansheng Ge; George W. Muller; Roger Chen; Manohar Tukaram Saindane
- Web page: https://patentgrep.com/patent/US8785644B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/10: for osteoporosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides new processes for the preparation of unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds which are useful, for example, for preventing or treating diseases or conditions related to an abnormally high level or activity of TNF-α. The invention can provide improved and/or efficient processes for the commercial production of unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds, including, but not limited to, unsubstituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

## Claims

### Claim 1

A process for preparing a compound of Formula (I):
free amine comprising the step of cyclizing a compound of Formula (II) or (IIA):
with a cyclizing agent of Formula (V):
wherein R1 is H, F, benzyl, (C1-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl; and each of X and Y is independently an unsubstituted or substituted imidazolyl, benzimidazolyl or benzotriazolyl, in an organic solvent, at temperature from about 20° C.-100° C.

### Claim 2 (depends on 1)

The process of claim 1, wherein the compound of Formula (II) is cyclized.

### Claim 3 (depends on 1)

The process of claim 1, wherein the compound of Formula (IIA) is cyclized.

### Claim 4 (depends on 1)

The process of claim 1, wherein the compound of Formula (I) is a racemic mixture, the (+)-enantiomer or the (−)-enantiomer.

### Claim 5 (depends on 1)

The process of claim 1, wherein the cyclizing agent is 1,1′-carbonyldiimidazole.

### Claim 6 (depends on 5)

The process of claim 5, wherein the ratio of the compound of Formula (II) or (IIA) to 1,1′-carbonyldiimidazole is from about 1:1 to about 1:2.

### Claim 7 (depends on 5)

The process of claim 5, wherein the cyclizing step occurs in a solvent selected from the group consisting of acetonitrile, THF, ethylacetate, DMF, N-methyl pyrrolidinone, toluene and mixtures thereof.

### Claim 8 (depends on 7)

The process of claim 7, wherein the solvent is acetonitrile or N-methyl pyrrolidinone.

### Claim 9 (depends on 8)

The process of claim 8, wherein the solvent is acetonitrile, and the reaction temperature is from about 80° C. to about 87° C. and the reaction time is from about 1 hour to about 5 hours.

### Claim 10 (depends on 1)

The process of claim 1, wherein R1 is H.

### Claim 11 (depends on 1)

The process of claim 1, wherein the compound of formula I is optionally converted to a pharmaceutically acceptable salt in 1:1 ratio with a pharmaceutically acceptable acid.