NO751238L - - Google Patents

Description

PROCESS FOR THE MANUFACTURE OF A PROPANOLAMINE DERIVATIVE

The present invention relates to the production of propanolamine derivatives and in particular relates to this process for the production of propanolamine derivatives of the type described in British patent no. 1,245,148.

According to the present invention, the method provided for the production of the propanolamine derivative is of the general formula:

in which R is hydrogen, halogen, lower alkyl or lower alkoxy group, and where the benzene ring A may be replaced by a naphthalene ring, as well as pharmaceutically acceptable acid addition salts thereof, where the method comprises hydrolysis of an oxazolidine derivative with the general formula:

wherein R is as above, with an acid or a base.

The term "ISvere" is intended to include any jalkyl and alkoxy group containing up to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl..., or a butyl group or any of the corresponding alkoxy groups.

The present invention also provides an oxazolidine derivative of the formula (II), as indicated above. The compound of formula (II) can be prepared by reacting an epoxy compound of the formula: ;,

with methyl carbamate, ethyl carbamate or urea to give an oxazolidine compound of the formula: and reacting the obtained compound of formula (IV) or an alkali metal derivative thereof, with a benzamide derivative of the formula:

in which R and A are as previously indicated and X is a suitable leaving group, for example a p-toluene sulphonyloxy group or a halogen atom, preferably chlorine.

The epoxy compound of formula (III) can be prepared by reacting a phenol or naphthol of the formula:

with 1-chloro-2,3-epoxypropane in the presence of sodium hydroxide.

The entire synthesis from phenol or naphthol can be represented by the following reaction core:

The compound of formula (I), produced by the method according to the present invention, exhibits useful therapeutic properties and is particularly useful in the curative or prophylactic treatment of heart conditions, such as angina pectoris and arrhythmia cordis, as well as in the treatment of hypertension tion. Suitable administration methods are described in British patent no. 1,245,148 and the compound of formula (I) and pharmaceutical compositions containing these are claimed in the patent.

British patent 1,245,148 describes and claims the method

in the production of the relevant compounds, but the method according to the present invention offers advantages over the previously known methods, especially with regard to an easier purification of the end product. This advantage follows from the fact that the oxazolidinone ring present in the new intermediate of formula (II) acts as a blocking group in the coupling reaction which leads to the formation of the intermediate and thus prevents dialkylation which causes problems in purification according to the known methods.

Preferred examples of compounds of formula (II) are those in which A is a benzene ring, R is a hydrogen atom or a chlorine atom

in the ortho position, a methyl group in the ortho or meta position or a methoxy group in the ortho position, i.e. o-Cl, o-CH^/m-CH3 or o-CH3O. A particularly preferred compound is that in which A is a benzene ring and R is o-CH 2 , i.e. 4-[2-(2-oxo-5-(2-tolyloxymethyl)-3-oxazolidinyl)ethoxy]benzamide.

The latter compound is the starting material used in the method according to the invention for the preparation of the preferred compound of formula (I): 4-[2-(2-hydroxy-3-(2-tolyloxy)propylamino)ethoxy]benzamide. Other compounds of formula (i) which can be prepared by the process according to the compound are those in which R is a hydrogen atom,

o-Cl, m-CH3 or o-CH3O.

Preparation of the compound of formula (I) by hydrolysis of

a compound of formula (II) according to the method

according to the invention can be carried out under basic or acidic conditions in a suitable solvent and the obtained free base can be converted into a pharmaceutically acceptable acid addition salt by treatment with a suitable acid. Suitable bases for use in the hydrolysis are sodium, potassium or barium hydroxide, alternatively the hydrolysis can be carried out using an acid such as hydrochloric acid. Suitable solvents are water or a lower aliphatic alcohol or dimethylformamide containing a sufficient amount of water to provide hydrolysis of the oxazolidine. A preferred solvent for the hydrolysis is technical alcohol (methanol denatured), which contains approx. 4% water.

The hydrolysis can. is carried out at a temperature from 20°C up to the reflux temperature of the solvent for a sufficient time to ensure complete hydrolysis of the oxazolidine. It has been found that the reaction is usually complete after 2-24 hours, depending on the temperature used.

Preparation of an oxazolidine derivative of the formula (II). the reaction of a compound of formula (IV) with a compound of formula (V) is preferably carried out in the presence of a base, for example sodium hydroxide, and a solvent such as dimethylformamide at a temperature between 20°C and the reflux temperature of the solvent, for a time sufficient to ensure a complete reaction. It has been found that the reaction is essentially complete within 2-24

hours depending on the temperature used. Dimethylacetamide is an alternative solvent. Alternative bases are potassium hydroxide and barium hydroxide. As a further variant of this method, an alkali metal derivative of oxazolidinone of formula (IV) can first be prepared, for example by reacting sodium hydride or sodium amide in the specified solvent or in an inert aromatic hydrocarbon solvent such as xylene or toluene, or by reacting with sodium metal in one of the aromatic hydrocarbon solvents. The alkali metal derivative is then allowed to react with the compound of formula (v) as indicated earlier.

The compound of formula (II) is normally obtained as colorless crystals after purification by recrystallization. The structure of each compound can be determined by IR and NMR spectra and C,

H and N analysis.

It is of course not necessary to isolate the oxazolidine compound of formula (II) in a pure state, as the crude product from the reaction can be used directly without further purification, as starting material for the preparation of the compound of formula (I.).

The invention will be described in more detail with reference to

the following examples which show the preparation of the new compounds of formula (II), as well as the procedure for the preparation of compounds of formula (I).

Example I

Preparation of 4-[2-(2-oxo-5-(2-tolyloxymethyl)-3-oxazolidinyl)ethoxy]benazamide (formula (II) :R=o-CHj)

A mixture of 5-(2-tolyloxymethyl)-2oxazolidinone (20.7 g,

0.1 M), 4-(2-chloroethoxy)benzamide (20 g, 0.1 M) and sodium hydroxide (4 g, 0.1 M) in dimethylacetamide (200 ml) were refluxed overnight after which the solvent was removed and ethanol added. The mixture was heated under reflux, filtered to remove insolubles and then cooled to 0°C and the resulting solid collected to give 27.5 g, 74% of the desired pro-

duct, m.p. 151-153°C.

Example II

Preparation of 4-[2-(2-oxo-5-(2-tolyloxymethyl)-3-oxazolidinyl)ethoxy]benzamide (formula (II):R =<o-CH^) 5-(2-tolyloxymethylj-2-oxazolidinone (27.5 g, 0.133 M) and 4-I (2-chloroethoxy)benzamide (26.5 g, 0.133 M) were suspended in dimethylformamide (132 mL) and heated to 120° C. Solid sodium hydroxide (6.65 g , 0.166 M) was added and the reaction mixture heated to 130°C for 2 h. Then most of the solvent was removed by evaporation under reduced pressure. The residue was diluted with technical ethanol, heated under reflux, filtered to remove insolubles and then cooled to 0°C and the resulting solid collected to give 34 g, 69.1% of the desired product, mp 151-153°C.

Example III

Preparation of 4-[2-(2-oxo-5(2-methoxyphenoxy)methyl-3-oxazolidinyl)ethoxy]benzamide (formula (II): R = o-CH30)

A mixture of 5-(2-methoxyphenoxy)methyl-2-oxazolidinone (13.38 g; 0.06M) and 4-(2-chloroethoxy)benzamide (12.0 g; 0.06M) was dissolved in N,N -Dimethylacetamide (110 mL) and sodium hydroxide (3.0 g, 0.075 M) were added and the reaction mixture heated with stirring to reflux temperature. The mixture was refluxed for 21 hours, after which the reaction mixture was filtered and the solvent removed under vacuum, leaving a brown liquid. Addition of hot methanol (100 mL) caused precipitation of a cream-colored compound (16.74 g, crude yield 72.33%). The product was purified by recrystallization from methanol (18 ml/g) to give a colorless crystalline compound (11.29 g, 58.69% yield), m.p. 171-174°C.

An analytical sample was prepared by a second recrystallization from methanol.

Analytical data.

m.p. 170° to 173°C.

Found C, 61.89; H, 5.78; N, 7.10;

<C>20<H>22<N>2°6

|Theoretical C, 62.16; H, 5.74; N, 7.25

r

^ Example IV

Preparation of 4-[2-(2-oxo-5-(3-tolyloxy)methyl-3-oxazolidinyl)ethoxy]benzamide (formula (II): R = m - CH3)

The procedure of Example III was followed using 5-(3-tolyloxy)methyl-2-oxazolidinone as starting compound. Analytical data

mp..143°.- 146°C.

Dividend 45.80%

Found C, 65.23; H, 5.96; N, 7.73;<C>20<H>22<N>2°5theoretical c/64.85; H, 5.99; N, 7.56%

Example V

In a similar manner as shown in example III, 4-[2-(2-oxo-5-(2-chlorophenoxy)methyl-3-oxazolidinyl)ethoxy]benzamide mono-hydrate (formula (II) : R = o - Cl) produced.

Analytical data

m.p. 146° - 150°C.

Dividend 26.90%

Found C, 56.27; H, 4.77; N, 7.23; C19H19CIN2°5*H2° theoretical c>55.94; H, 5.18; N, 6.85%

Example VI

Preparation of 4-[2-(2-oxo-5-ferToxymethyl-3-oxazolidinyl)ethoxy]benzamide (formula (II) : R = H)

5-phenoxymethyl-2-oxazolidinine (3.86 g; 0.02M) was dissolved in xylene (50 mL) and the solution heated to reflux with stirring. At the reflux temperature, sodium (0.53 g, 0.023 M) was carefully added and the mixture was refluxed for 1 hour. The reaction mixture was allowed to cool and 4-(2-chloroethoxy)benzamide (4.00 g, 0.02 M) was dissolved in xylene

(50 mL) was added and the reaction heated under reflux for 19 h.

The reaction mixture was cooled and 10 ml of technical alcohol (methanol denatured) and water (100 ml) were added and the resulting mixture was filtered to give a brown residue. Pro-

the product was purified by recrystallization from ethyl acetate (10 ml/g) to give a colorless crystalline compound (1.23 g, 17.25% yield) m.p. 141°-144°C.

Analytical data

Found C, 63.86; H, 5.55; N, 8.12; cigH2o<N>2<05>

Theoretical C, 64.03; H, 5.66; N, 7.86.

Example VII

Preparation of 4-[2-(2-hydroxy-3-(2-tolyloxy)propylamino)ethoxy]benzamide hydrochloride (formula (I); R = o - CH^)

A mixture of 4-[2-(2-oxo-5-(2-tolyloxymethyl)-3-oxazolidinyl)ethoxy]benzamide (18.5 g, 0.05 m) and sodium hydroxide (4 g,

0.1 M) in 100 ml denatured technical alcohol was refluxed overnight and then diluted with water and cooled to 0°C. The resulting solid was filtered off and converted to the hydrochloride salt by treatment, with concentrated hydrochloric acid in boiling aqueous ethanol, the product was isolated by cooling, filtering and drying to give 13 g, 75% yield, m.p. 234°-236°C.

Example VIII

Preparation of 4-[2-(2-hydroxy-3-(2-methoxyphenoxy)propylamino)ethoxy]benzamide (formula I; R = o - OCH^)

4-[2-(2-oxo-5-(2-methoxyphenoxy)methyl-3-oxazolidinyl)ethoxy] benzamide (5.80 g; 0.015 M) was dissolved in 4% (w/v) sodium hydroxide solution in methanol denatured technical ethanol (45 ml, 1.80 g NaOH, 0.045 M) and the solution dissolved

Heated under reflux and stirring for 7.5 hours, after which water (100 ml) was added. The reaction mixture was cooled in an ice bath and then filtered to give a colorless compound (4.36 g, crude yield 80.60%). The product was purified by recrystallization from ethyl acetate (3 ml/g) to give a colorless crystalline compound (3.24 g, 59.88% yield), m.p. 138°-141°C.

The above procedure was used to prepare 4-[2-(2-hydroxy-3-(2-chlorophenoxy)propylamino)ethoxy]benzamide hydrochloride (formula (I); R = o - Cl; m.p. 215°-222° C.)> 4-[2-(2-hydroxy-3-(3-tolyloxy)propylamino)ethoxy]benzamide (formula (I); R = o - Cl; m.p. 130°C);

4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]benzamide (formula (I); R = H, m.p. 138<0->141°C.

In all these cases, the obtained IR spectra were identical

with those of the reference samples.

Claims (2)

1. Starting compound for use in the preparation of a propanolamine derivative of the general formula: in which R is hydrogen or a halogen atom, a lower alkyl or alkoxy group and where the benzene ring A may be replaced by a naphthalene ring, characterized by the general formula: wherein R and A have the meanings given above. 2. Starting compound according to claim 1, characterized in that A is a benzene ring and R is a hydrogen atom, or a chlorine atom in the ortho position or a methyl group in the ortho or meta position or a methoxy group in the ortho position.