# US 11,078,163 B2 · Processes for the synthesis of substituted urea compounds

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

- Number: US 11,078,163 B2
- Document ID: US11078163B2
- Status: Granted
- Kind: B2
- Application number: 16/512,872
- Filed: 2019-07-16
- Published: 2020-05-07
- Granted: 2021-08-03
- Earliest claimed: 2014-01-24
- Assignees: Bial - Portela & Ca, S.A.
- Applicants: BIAL-PORTELA & Ca, S.A.
- Inventors: Domenico Russo; Jorge Bruno Reis Wahnon; William Maton; Tibor Eszenyi
- Web page: https://patentgrep.com/patent/US11078163B2

## CPC

- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07C 209/68: from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07D 233/61: with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07C 2601/08: the ring being saturated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention concerns a process for preparing a compound having the Formula A; or a pharmaceutically acceptable salt or derivative thereof, or for preparing a substituted urea compound of Formula IIa, or a pharmaceutically acceptable salt or ester thereof, the process comprising the reaction of an imidazolyl intermediate of Formula IIa′ with a carbamoyl halide of the formula: R1R2NC(═O)Hal, wherein Hal represents Cl, F, I or Br, wherein the intermediate of Formula IIa′ is prepared by oxidation of the derivative of R5 and R6, R6-C(═O)CH2R5 to form a glyoxal intermediate R6-C(═O)(C═O)R5, which is subjected to treatment with ammonium hydroxide and an aldehyde R8CHO to provide the intermediate of Formula IIa′ and wherein the compound substituents are as defined herein.

## Claims

### Claim 1

A process for preparing a compound having the Formula A:
or a pharmaceutically acceptable salt or derivative thereof, the process comprising:
(a) oxidation of
to form a glyoxal intermediate
wherein R6 is NH2CONH-phenyl, a nitrophenyl, aminophenyl, or amino-protected aminophenyl precursor thereof;
b) subjecting the glyoxal intermediate to treatment with ammonium hydroxide and an aldehyde, CH2O, to provide an imidazolyl intermediate of Formula IIa′:
and
(c) reacting the imidazolyl intermediate of Formula IIa′ with a carbamoyl halide of the formula NH2C(═O)Hal, wherein Hal represents Cl, F, I, or Br, thereby forming the compound having Formula A.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the oxidation of
employs an inorganic acid.

### Claim 3 (depends on 2)

The process according to claim 2, wherein the inorganic acid is HX, where X is a halogen atom.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the inorganic acid is HCl or HBr.

### Claim 5 (depends on 1)

The process according to claim 1, wherein DMSO is used as a solvent and oxidising agent in the oxidation of

### Claim 6

A process for preparing an imidazolyl intermediate of Formula IIa′:
or a pharmaceutically acceptable salt thereof, the process comprising the oxidation of
to form a glyoxal
which is subjected to treatment with ammonium hydroxide and an aldehyde CH2O to provide the intermediate of Formula IIa′,
wherein R6 is NH2CONH-phenyl, a nitrophenyl, aminophenyl, or amino-protected aminophenyl precursor thereof.

### Claim 7 (depends on 6)

The process according to claim 6, wherein the intermediate of Formula IIa′ is extracted from the reaction mixture using a solvent comprising butanol.

### Claim 8 (depends on 1)

A process for preparing the compound of Formula A as defined in claim 1, or a pharmaceutically acceptable salt or derivative thereof, the process comprising the reaction of an intermediate of Formula IIa′ as defined in claim 1, with a carbamoyl halide of the formula: R1R2NC(═O)Hal, in a solvent consisting essentially of pyridine, wherein R6 is NH2CONH-phenyl, or a nitrophenyl, aminophenyl or an amino-protected aminophenyl precursor of this moiety which can be subjected to conversion to the NH2CONH-phenyl group after urea formation, and R1 is methyl and R2 is cyclopentyl, and wherein Hal represents Cl, F, I or Br.

### Claim 9 (depends on 8)

The process according to claim 8, further comprising treating the product mixture after urea formation with water.

### Claim 10 (depends on 8)

The process according to claim 8, further comprising treating the product mixture after urea formation with a C5-10 alkane or mixtures thereof.

### Claim 11 (depends on 10)

The process according to claim 10, wherein the C5-10 alkane comprises heptane.

### Claim 12 (depends on 8)

The process according to claim 8, wherein the carbamoyl halide is a carbamoyl chloride.