CZ294649B6 - Process for preparing 4-chloro-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing 4-chloro-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine of the general formula I by reacting 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)aminopyrimidine of the general formula II in methanol and in the presence of alkali metal carbonates.

Description

4-Chloro-N- (4,5-dihydro-1 H -imidazol-2-yl) -6-methoxy-2-methyl-5-pyrimidinamine

Technical field

The present invention relates to a novel process for the preparation of 4-chloro-N- (4,5-dihydro-1-77-imidazol-2-yl) -6-methoxy-2-methyl-5-pyrimidinamine of formula (I),

(AND).

which is known as moxonidine and is used in the form of a base, hydrochloride or hydrochloride hydrate as an antihypertensive and a centrally active presynaptic and ₂ -adrenoreceptome agonist.

BACKGROUND OF THE INVENTION

A single method of preparing moxonidine base of formula I has been described so far. It is disclosed in German patent DE 28 49 537 and in US patent 4,323,570, which describes a method of preparing moxonidine base using sodium methoxide in methanol.

A disadvantage of this process is that 4,6-dimethoxy-2-methyl-5- (2-imidazolin-2-yl) aminopyrimidine is a by-product which is a major impurity and exceeds several percent. Another disadvantage of this procedure is the work with hazardous sodium methoxide and the resulting safety precautions.

SUMMARY OF THE INVENTION

These disadvantages are overcome by the process of the present invention, which is a process for the preparation of 4-chloro-N (4,5-dihydro-1 H -imidazol-2-yl) -6-methoxy-2-methyl-5-pyrimidinamine (moxonidine base) of formula I

(AND).

It is an object of the invention to carry out the reaction of 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) aminopyrimidine of formula II

- 1 GB 294649 B6

COCH ₃ in methanol in the presence of alkali metal carbonates.

The starting compound II is readily available and its preparation is well described in the chemical literature.

Another is that the reaction is carried out in the presence of potassium carbonate, optionally in a two-fold excess, that the reaction is carried out at temperatures of 20 to 65 ° C and that the reaction is carried out for 3 to 5 hours.

The advantages of the proposed method according to the present invention are as follows:

- directly from the reaction mixture, a product of high purity (above 99.4%) is obtained which does not require multiple crystallizations to achieve purity;

- the alkali metal carbonates used, such as potassium carbonate, sodium carbonate or sodium bicarbonate, are readily available, inexpensive, the wastes after their use are easily disposed of;

the reaction temperature does not require any extreme values, the reaction at moderate temperatures of 20 to 65 ° C, more preferably 47 to 52 ° C;

the reaction is carried out within a preferred reaction time range of 3 to 5 hours;

said reaction temperature and the time required for the reaction prevent the formation of by-products.

DETAILED DESCRIPTION OF THE INVENTION

The principles of the process according to the invention are illustrated in more detail in the following examples. These examples are illustrative only and in no way limit the scope of the invention.

Example 1

To a suspension of 50 g (0.1735 mol) of 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) aminopyrimidine in 400 ml of methanol is added 48 g (0.3471 mol) of carbonate potassium.

The temperature of the resulting reaction mixture was adjusted to 47-52 ° C and stirred at this temperature for 4.5-5 hours. After cooling, 50 ml of acetic acid was added to the reaction mixture, and the reaction mixture was dissolved in 350 ml of water. Concentration and alkalinization with 50 ml of ammonium hydroxide gave 38.8 g of product (92.5% th.) Containing 99.5% moxonidine base.

Example 2

0.5 g (0.0017 mol) of 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) aminopyrimidine was stirred in 40 ml of methanol and 0.29 g ( 0.003 5mol) sodium bicarbonate. The reaction mixture was heated to reflux (65 ° C) and stirred for 5 hours. 1.2 ml of acetic acid are then added and the mixture is dissolved in 20 ml of distilled water. The solution is filtered with activated carbon and, after concentration on a vacuum evaporator, the mixture is basified with 2.5 ml of ammonium hydroxide to pH 8. 0.36 g (86.1% of th.) Of the product is obtained with a content of 99.5% moxonidine-base.

Industrial applicability

The process for the preparation of 4-chloro-N- (4,5-dihydro-1-77-imidazol-2-yl) -6-methoxy-2-methyl-5-pyrimidinamine of the formula I according to the invention can be used in the preferred technical-economic under very high yields under moderate reaction conditions.

PATENT CLAIMS

Claims (5)

A process for the preparation of 4-chloro-N- (4,5-dihydro-1 H -imidazol-2-yl) -6-methoxy-2-methyl-5- (Ϊ) reaction of 4,6-dichloro-2 methyl-5- (lacetyl-2-imidazolin-2-yl) aminopyrimidine of formula II COCH ₃ in methanol, characterized in that the reaction is carried out in the presence of alkali metal carbonates. Process according to claim 1, characterized in that the reaction is carried out in the presence of potassium carbonate. -3GB 294649 B6 Process according to either of Claims 1 and 2, characterized by a two-molar excess of alkali metal carbonates. Method according to any one of claims 1 to 3, characterized in that it is at a temperature of 20 to 65 ° C. Method according to one of Claims 1 to 4, characterized for a period of 3 to 5 hours.