# US 2013/0158256 A1 · Process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid

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

- Number: US 2013/0158256 A1
- Document ID: US20130158256A1
- Status: Published application
- Kind: A1
- Application number: 13/673,145
- Filed: 2012-11-09
- Published: 2013-06-20
- Earliest claimed: 2011-12-20
- Assignees: Les Laboratoires Servier
- Inventors: Jean-Luc RENAUD; Nicolas Pannetier; Jean-Pierre Lecouve; Lucile Vaysse-Ludot; Solenne Moulin
- Web page: https://patentgrep.com/patent/US20130158256A1

## CPC

- A61P 9/00: Drugs for disorders of the cardiovascular system
- B01J 31/2295: {Cyclic compounds, e.g. cyclopentadienyls}
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- B01J 2235/05: Nuclear magnetic resonance [NMR]
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Process for the synthesis of ivabradine of formula (I): addition salts thereof with a pharmaceutically acceptable acid, and hydrates thereof.

## Claims

### Claim 1

A process for the synthesis of ivabradine of formula (I):
wherein a compound of formula (V):
is subjected to a reductive amination reaction with an amine of formula (VI):
in the presence of an iron-based catalyst,
optionally in the presence of trimethylamine N-oxide,
under dihydrogen pressure of from 1 to 20 bars,
in an organic solvent or mixture of organic solvents,
at a temperature from 25 to 100° C.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the iron-based catalyst has the following general formula:
wherein R1, R2, R3 and R4 independently represent:
a hydrogen atom,
an —SiR5R6R7 group, wherein R5, R6 and R7 independently represent an optionally substituted, linear or branched (C1-C6)alkyl group or an optionally substituted aromatic or heteroaromatic group,
an optionally substituted aromatic or heteroaromatic group,
an optionally substituted, linear or branched (C1-C6)alkyl group,
an electron-attracting group,
an amine group that is aliphatic, aromatic, heteroaromatic or carrying an electron-attracting group, or
an aliphatic, aromatic or heteroaromatic ether group,
or the pairs R1 and R2, or R2 and R3, or R3 and R4, together with the carbon atoms to which they are attached, form a 3- to 7-membered carbocycle or heterocycle,
X represents:
an oxygen atom,
an —NH group or a nitrogen atom substituted by an aliphatic, aromatic, heteroaromatic or electron-attracting group,
a —PH group or a phosphorus atom substituted by one or more aliphatic, aromatic or electron-attracting groups, or
a sulphur atom,
L1, L2 and L3 independently represent a carbonyl, nitrile, isonitrile, heteroaromatic, phosphine, phosphite, phosphonite, phosphoramidite, phosphinite, phospholane, phospholene, aliphatic amine, aromatic amine, heteroaromatic amine, electron-attracting-group-carrying amine, aliphatic ether, aromatic ether, heteroaromatic ether, sulphone, sulphoxide or sulphoximine group or an N-heterocyclic carbene group having one of the two following formulae:
wherein Y and Z independently represent a sulphur or oxygen atom or an NR8 group wherein
R8 represents an optionally substituted alkyl group or an optionally substituted aromatic or heteroaromatic group,
K represents a carbon or nitrogen atom,
R9 and R10 independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aromatic or heteroaromatic group, a halogen atom, an aliphatic, aromatic or heteroaromatic ether group, an aliphatic, aromatic or heteroaromatic amine group, or the pair R9 and R10, together with the atoms to which they are attached, form a 3- to 7-membered carbocycle or heterocycle,
or
wherein R11 and R12 independently represent an optionally substituted alkyl group or an optionally substituted aromatic or heteroaromatic group and n is 1 or 2.

### Claim 3 (depends on 2)

The process according to claim 2, wherein the iron-based catalyst has the following general formula:
wherein R2 and R3 each represent a hydrogen atom or, together with the carbon atoms to which they are attached, form a 3- to 7-membered carbocycle or heterocycle,
and R1 and R4 independently represent:
an —SiR5R6R7 group, wherein R5, R6 and R7 independently represent an optionally substituted, linear or branched (C1-C6)alkyl group or an optionally substituted aryl group,
an optionally substituted aromatic or heteroaromatic group, or
an optionally substituted, linear or branched (C1-C6)alkyl group.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the iron-based catalyst is selected from:

### Claim 5 (depends on 2)

The process according to claim 2, wherein the iron-based catalyst has the following general formula:
wherein R2 and R3 each represent a hydrogen atom or, together with the carbon atoms to which they are attached, form a 3- to 7-membered carbocycle or heterocycle,
and R1 and R4 independently represent:
an —SiR5R6R7 group, wherein R5, R6 and R7 independently represent an optionally substituted, linear or branched (C1-C6)alkyl group or an optionally substituted aromatic or heteroaromatic group,
an optionally substituted aromatic or heteroaromatic group, or
an optionally substituted, linear or branched (C1-C6)alkyl group.

### Claim 6 (depends on 5)

The process according to claim 5, wherein the iron-based catalyst is selected from:

### Claim 7 (depends on 2)

The process according to claim 2, wherein the iron-based catalyst has the following formula:

### Claim 8 (depends on 2)

The process according to claim 2, wherein the iron-based catalyst has the following formula:

### Claim 9 (depends on 1)

The process according to claim 1, wherein the amount of catalyst used in the reductive amination reaction is from 1 mol % to 10 mol % relative to the aldehyde.

### Claim 10 (depends on 1)

The process according to claim 1, wherein the amount of trimethylamine N-oxide used in the reductive amination reaction is from 0 to 3 equivalents relative to the catalyst.

### Claim 11 (depends on 10)

The process according to claim 10, wherein the amount of trimethylamine N-oxide used in the reductive amination reaction is from 0.5 to 1.5 equivalents relative to the catalyst.

### Claim 12 (depends on 1)

The process according to claim 1, wherein the dihydrogen pressure in the reductive amination reaction is from 1 to 10 bars.

### Claim 13 (depends on 1)

The process according to claim 1, wherein the solvent in the reductive amination reaction is an alcohol.

### Claim 14 (depends on 13)

The process according to claim 13, wherein the solvent in the reductive amination reaction is ethanol.

### Claim 15 (depends on 1)

The process according to claim 1, wherein the temperature of the reductive amination reaction is from 50 to 100° C.