# US 9,434,689 B2 · Processes for the preparation of isoindole compounds and isotopologues thereof

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- Number: US 9,434,689 B2
- Document ID: US9434689B2
- Status: Granted
- Kind: B2
- Application number: 14/642,511
- Filed: 2015-03-09
- Published: 2015-07-02
- Granted: 2016-09-06
- Earliest claimed: 2012-09-14
- Assignees: Celgene Corporation
- Applicants: Celgene Corporation
- Inventors: Terrence J. Connolly; Alexander L. Ruchelman; Kelvin H. Y. Yong; Chengmin Zhang
- Web page: https://patentgrep.com/patent/US9434689B2

## CPC

- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07C 315/04: by reactions not involving the formation of sulfone or sulfoxide groups
- C07D 209/46: with an oxygen atom in position 1
- C07D 209/49: and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Processes for the preparation of certain isoindole compounds, and isotopologues thereof, are provided. In some embodiments, the processes comprise catalytic asymmetrical hydrogenation with hydrogen gas or deuterium gas in a solvent containing exchangeable proton or deuterium for proton-deuterium exchange.

## Claims

### Claim 1

A process for the preparation of an enantiomerically enriched or enantiomerically pure aminosulfone compound of Formula (III):
or a salt stereoisomer, or isotopologue thereof, wherein:
R1 and R2 are each independently hydrogen, halogen, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1-C6)alkoxy, (C3-C18)cycloalkyl, (C3-C6)cycloalkoxy, cyano, —CF3, (C3-C18)cycloalkyl-(C1-C6)alkoxy, or an isotopologue thereof;
R3 is (C1-C6)alkyl, or an isotopologue thereof;
Y1 is hydrogen or deuterium; and
Y2 and Y3 are both hydrogen or both deuterium;
wherein not all of Y1, Y2, and Y3 are hydrogen;
comprising the step of
(a) reducing an enamine of Formula (II):
or a salt or isotopologue thereof, via hydrogenation with hydrogen gas or deuterium gas, in a solvent, and in the presence of (1) a metal catalyst and a chiral ligand or (2) a chiral metal catalyst/ligand complex to form an enantiomerically enriched or enantiomerically pure aminosulfone of Formula (III), or a salt or isotopologue thereof, wherein deuterium gas or a solvent containing exchangeable deuterium for proton-deuterium exchange or both is used.

### Claim 2 (depends on 1)

The process of claim 1, wherein the enamine of Formula (II), or a salt or isotopologue thereof, is synthesized by reacting a nitrile of Formula (IV):
or an isotopologue thereof, with LiCH2SO2R3, or an isotopologue thereof.

### Claim 3 (depends on 1)

The process of claim 1, wherein R1 and R2 are substituted or unsubstituted (C1-C6)alkoxy, or an isotopologue thereof.

### Claim 4 (depends on 3)

The process of claim 3, wherein R1 is OMe enriched with 0, 1, 2, or 3 deuterium, and R2 is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium.

### Claim 5 (depends on 4)

The process of claim 4, wherein R1 is OCD3, and R2 is OEt.

### Claim 6 (depends on 4)

The process of claim 4, wherein R1 is OCD3, and R2 is OCD2CD3.

### Claim 7 (depends on 1)

The process of claim 1, wherein R3 is Me enriched with 0, 1, 2, or 3 deuterium.

### Claim 8 (depends on 1)

The process of claim 1, wherein the enamine of Formula (II), or a salt or isotopologue thereof, is an enamine of Formula (II-a):
or a salt or isotopologue thereof, wherein the enamine of Formula (II-a), or a salt or isotopologue thereof, is synthesized by reacting a nitrile of Formula (IV):
or an isotopologue thereof, with CH3SO2CH3 and n-BuLi.

### Claim 9 (depends on 1)

The process of claim 1, wherein the enamine of Formula (II), or a salt or isotopologue thereof, is an enamine of Formula (II-b):
or a salt or isotopologue thereof, wherein the enamine of Formula (II-b), or a salt or isotopologue thereof, is synthesized by reacting a nitrile of Formula (IV):
or an isotopologue thereof, with CD3SO2CD3 and n-BuLi.

### Claim 10 (depends on 1)

The process of claim 1, wherein the hydrogenation in step (a) occurs with hydrogen gas.

### Claim 11 (depends on 1)

The process of claim 1, wherein the hydrogenation in step (a) occurs with deuterium gas.

### Claim 12 (depends on 1)

The process of claim 1, wherein the hydrogenation in step (a) occurs in a solvent containing exchangeable proton for proton-deuterium exchange.

### Claim 13 (depends on 12)

The process of claim 12, wherein the solvent containing exchangeable proton for proton-deuterium exchange is 2,2,2-trifluoroethanol.

### Claim 14 (depends on 1)

The process of claim 1, wherein the hydrogenation in step (a) occurs in a solvent containing exchangeable deuterium for proton-deuterium exchange.

### Claim 15 (depends on 14)

The process of claim 14, wherein the solvent containing exchangeable deuterium for proton-deuterium exchange is 2,2,2-trifluoroethanol-d1.

### Claim 16 (depends on 1)

The process of claim 1, wherein the hydrogenation in step (a) occurs in a solvent containing neither exchangeable proton nor exchangeable deuterium for proton-deuterium exchange.

### Claim 17 (depends on 1)

The process of claim 1, wherein the metal catalyst is Rh(cod)2OTf.

### Claim 18 (depends on 1)

The process of claim 1, wherein the chiral ligand is (S,R)-t-Bu Josiphos.