# US 10,870,637 B2 · Process for the preparation of a sulfonamide structured kinase inhibitor

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,870,637 B2
- Document ID: US10870637B2
- Status: Granted
- Kind: B2
- Application number: 16/495,865
- Filed: 2018-03-22
- Published: 2020-04-02
- Granted: 2020-12-22
- Earliest claimed: 2017-03-23
- Assignees: Orion Corporation
- Applicants: Orion Corporation
- Inventors: Oskari Karjalainen; Pekka Pietikäinen
- Web page: https://patentgrep.com/patent/US10870637B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present disclosure relates to an improved process for the preparation of a sulfonamide structured kinase inhibitor, namely N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (1A) and pharmaceutically acceptable salts thereof. Compound of formula (1A) is a selective inhibitor of FGFR/VEGFR kinase families and is useful in the treatment of cancer.

## Claims

### Claim 1

A process for the preparation of a compound of formula (1A), or a pharmaceutically acceptable salt thereof:
comprising the steps of:
a) reacting 2′,4′-difluoro-[1,1′-biphenyl]-3,5-diami ne of formula (V)
with 4-bromo-2-fluoronitrobenzene in the presence of an organic base and an organosilane, to obtain a compound of formula (IV)
b) treating the product obtained from step (a) with an organic acid and isolating the formed organic salt;
c) releasing the compound of formula (IV) from its salt form;
d) either (i) reacting the compound of formula (IV) with cyclopropanesulfonyl chloride to obtain a compound of formula (III)
and subsequently reacting the compound of formula (III) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; or
(ii) reacting the compound of formula (IV) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain a compound of formula (IIIb)
and subsequently reacting the compound of formula (IIIb) with cyclopropane-sulfonyl chloride;
to obtain a compound of formula (II);
e) hydrogenating the compound of formula (II) in formic acid in the presence of a catalyst to obtain the compound of formula (1A), which is optionally converted to its pharmaceutically acceptable salt.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the organic base used in step a) is N,N-diisopropylethylamine (DIPEA).

### Claim 3 (depends on 1)

The process according to claim 1, wherein the organosilane used in step a) is ethoxytrimethylsilane.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the organic acid used in step b) is a sulfonic acid.

### Claim 5 (depends on 4)

The process according to claim 4, wherein the organic acid is methanesulfonic acid, p-toluenesulfonic acid, o-toluenesulfonic acid, ethanesulfonic acid or benzenesulfonic acid.

### Claim 6 (depends on 5)

The process according to claim 5, wherein the sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid.

### Claim 7 (depends on 1)

The process according claim 1, wherein step c) is carried out by heating the salt in an organic solvent in the presence of an organic base.

### Claim 8 (depends on 1)

The process according to claim 1, wherein step d) is carried out by reacting the compound of formula (IV) with cyclopropanesulfonyl chloride to obtain the compound of formula (III) and subsequently reacting the compound of formula (III) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the compound of formula (II).

### Claim 9 (depends on 8)

The process according to claim 8, wherein the compound of formula (IV) is reacted with cyclopropanesulfonyl chloride in the presence of a base.

### Claim 10 (depends on 8)

The process according to claim 8, wherein the compound of formula (III) is reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in the presence of a base and a catalyst.

### Claim 11 (depends on 10)

The process according to claim 10, wherein the base is a carbonate.

### Claim 12 (depends on 10)

The process according to claim 10, wherein the catalyst is a palladium catalyst.

### Claim 13 (depends on 1)

The process according to claim 1, wherein step d) is carried out by reacting the compound of formula (IV) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the compound of formula (IIIb), and subsequently reacting the compound of formula (IIIb) with cyclopropanesulfonyl chloride to obtain the compound of formula (II).

### Claim 14 (depends on 13)

The process according to claim 13, wherein the compound of formula (IV) is reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in the presence of a base and a catalyst.

### Claim 15 (depends on 14)

The process according to claim 14, wherein the base is a carbonate.

### Claim 16 (depends on 14)

The process according to claim 14, wherein the catalyst is a palladium catalyst.

### Claim 17 (depends on 13)

The process according to claim 13, wherein the compound of formula (IIIb) is reacted with cyclopropanesulfonyl chloride in the presence of a base.

### Claim 18 (depends on 1)

The process according to claim 1, wherein the catalyst used in step e) is a palladium catalyst.

### Claim 19 (depends on 18)

The process according to claim 18, wherein the palladium catalyst is palladium on charcoal.

### Claim 20 (depends on 9)

The process according to claim 9, wherein the base is pyridine.