# US 8,785,642 B2 · Process for preparing 6-substituted-1-(2H)-isoquinolinones and intermediate compound

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- Number: US 8,785,642 B2
- Document ID: US8785642B2
- Status: Granted
- Kind: B2
- Application number: 13/534,698
- Filed: 2012-06-27
- Published: 2013-01-10
- Granted: 2014-07-22
- Earliest claimed: 2011-07-08
- Assignees: Sanofi
- Applicants: Simon Gessler; Theo Wollmann
- Inventors: Simon Gessler; Theo Wollmann
- Web page: https://patentgrep.com/patent/US8785642B2

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61P 9/12: Antihypertensives
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention relates to novel substituted phenyl compounds of the formula and to a process for making them. The compounds can be used as intermediates for making 6-substituted-1-(2H)-isoquinolinone derivatives.

## Claims

### Claim 1

A process for the preparation of a compound of the formula
wherein
n is 1, 2, 3 or 4; and
R1 is H or a protecting group,
comprising
(B) reacting a compound of formula (IV)
wherein R1 is a protecting group
with a mixture of a reagent of the formula (R2O)2HC—N(CH3)2 (V), wherein R2 is (C1-C6)alkyl, and pyrrolidine,
wherein reagent (V) is used in a molar excess of 1.5 or more equivalents and the pyrrolidine is used in a molar excess of 4.0 or more equivalents over a compound of formula (IV); and
optionally removing the protection group in a compound of formula (VI) to give a compound of formula ((VI) wherein R1 is H.

### Claim 2 (depends on 1)

The process according to claim 1, wherein 2.0 to 7.0 equivalents of reagent (V) relative to a compound of formula (IV) are used.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the reagent (V) is N,N Dimethylformamid-dimethylacetal.

### Claim 4 (depends on 1)

The process according to claim 1, wherein 4.0 to 9.0 equivalents pyrrolidine relative to a compound of formula (IV) are used.

### Claim 5 (depends on 1)

The process according to claim 1, wherein DMF is added.

### Claim 6 (depends on 1)

A process for the preparation of a compound of formula (I)
or a salt thereof, wherein
n is 1, 2, 3 or 4; and
R1 is H or a protecting group,
comprising the steps of
(B) preparing a compound of formula (VI)
wherein R1 is a protecting group and
n is 1, 2, 3 or 4;
according to claim 1,
(C) cyclising a compound of formula (VI) in the presence of a hydrohalic acid in a suitable solvent and whereby the protecting group is optionally removed
to give a compound of formula (I), wherein R1 is H or a protecting group;
(D) optionally removing the protecting group from a compound of formula (I), if R1 is a protecting group, to give compound a formula (I) wherein R1 is H, and
(E) optionally converting a compound of formula (I) into a salt thereof.

### Claim 7 (depends on 6)

The process according to claim 6, wherein the hydrohalic acid used in the cyclisation step is HCl.

### Claim 8 (depends on 1)

The process according to claim 1, wherein n is 2 or 3.

### Claim 9 (depends on 1)

The process according to claim 1, wherein the protecting group is acid-labile.

### Claim 10 (depends on 1)

The process according to claim 1, wherein the protecting group in R1 is tert-butoxycarbonyl.

### Claim 11 (depends on 1)

The process according to claim 1, wherein the compound of formula (IV) is prepared by reacting a compound of formula (II)
wherein X is halogen,
in a suitable solvent and in the presence of a base selected from an alkali metal alkoxide, alkali metal hydride or alkali metal with a compound of formula (III)
wherein
R1 is H or a protecting group and
n is 1, 2, 3 or 4,
and, if R1 is H, the amino group in a compound of formula (IV) is protected to give a compound of formula (IV), wherein R1 is a protecting group.

### Claim 12

A compound of formula (VI)
wherein R1 is H or a protecting group and
n is 1, 2, 3 or 4.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein the protecting group is an acid-labile protecting group.

### Claim 14 (depends on 13)

The compound according to claim 13, wherein the acid-labile protecting group is tert-butyloxycarbonyl.

### Claim 15 (depends on 12)

The compound according to claim 12, wherein n is 2 or 3.

### Claim 16 (depends on 12)

The compound according to claim 12, which is 4-[4-Cyano-3-((E)-2-pyrrolidin-1-yl-vinyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester.