# US 9,040,697 B2 · Process for the production of moxonidine

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- Number: US 9,040,697 B2
- Document ID: US9040697B2
- Status: Granted
- Kind: B2
- Application number: 14/173,688
- Filed: 2014-02-05
- Published: 2014-08-14
- Granted: 2015-05-26
- Earliest claimed: 2013-02-08
- Assignees: Arevipharma GmbH
- Applicants: Arevipharma GmbH
- Inventors: Harald Hofmeier; Michael Limmert; Heike Heydemüller; Helge Hartenhauer
- Web page: https://patentgrep.com/patent/US9040697B2

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61K 31/506: not condensed and containing further heterocyclic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

4,6-dichloro-2-methyl-5-(1-acyl-2-imidazolin-2-yl)-aminopyrimidine is reacted with methanol in the presence of a non-ionic organic base, and moxonidine is obtained directly from the reaction mixture.

## Claims

### Claim 1

A process for the synthesis of moxonidine of formula I
or a pharmaceutically acceptable salt thereof, the process comprising the steps of:
reacting a 4,6-dichloro-2-methyl-5-(1-acyl-2-imidazolin-2-yl)-aminopyrimidine derivative of formula II
wherein R denotes an acyl group;
with methanol in the presence of a non-ionic organic base; and
obtaining moxonidine (I) from the reaction mixture.

### Claim 2 (depends on 1)

The process according to claim 1, wherein methanol alone is used as the reaction medium, without adding water during or after the completion of the reaction.

### Claim 3 (depends on 1)

The process according to claim 1, wherein R is acetyl, i.e. 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (IIa, R=COCH3) is provided and reacted with methanol.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the organic base is selected from organic nitrogen bases.

### Claim 5 (depends on 4)

The process according to claim 4, wherein the organic nitrogen base is selected from the group consisting of guanidine group compounds, amidine group compounds and amine group compounds.

### Claim 6 (depends on 5)

The process according to claim 5, wherein the organic base is selected from 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

### Claim 7 (depends on 1)

The process according to claim 1, wherein 1.0-2.0 molar equivalents of organic base, relative to the provided starting compound 4,6-dichloro-2-methyl-5-(1-acyl-2-imidazolin-2-yl)-aminopyrimidine (II) is used.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the ratio of methanol to the provided starting compound is adjusted to 20-40 ml of methanol per g of 4,6-dichloro-2-methyl-5-(1-acyl-2-imidazolin-2-yl)-aminopyrimidine (II).

### Claim 9 (depends on 1)

The process according to claim 1, wherein the reaction is carried out in the presence of activated charcoal.

### Claim 10 (depends on 1)

The process according to claim 1, wherein prior to obtaining moxonidine from the reaction mixture, organic acid is added.

### Claim 11 (depends on 1)

The process according to claim 1, wherein moxonidine is obtained from the reaction mixture by precipitation or crystallization.

### Claim 12 (depends on 1)

The process according to claim 1, wherein prior to obtaining moxonidine from the reaction mixture the reaction mixture is concentrated, optionally after an initial crystallization period, and finally moxonidine is isolated.

### Claim 13 (depends on 1)

A process for preparing a pharmaceutical composition comprising moxonidine of formula I or a pharmaceutically acceptable salt thereof,
the process comprising:
carrying out a process according to claim 1 for preparing said moxonidine of formula I or a pharmaceutically acceptable salt thereof, and
mixing the prepared moxonidine compound of Formula I or a pharmaceutically acceptable salt thereof with at least one pharmaceutically active ingredient to obtain a pharmaceutical composition.

### Claim 14 (depends on 10)

The process according to claim 10, wherein the organic acid is acetic acid.