FI61473C - MELLAN PRODUCTS FOR THERAPEUTIC ACTIVATION OF ACTIVE THERAPEUTIC 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) -PHENOXY) -2-PROPANOL - Google Patents

Description

NAHT.

f 14 7 3 Intermediate for the preparation of therapeutically active 1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol - Mellan product in the formulation of therapeutically active 1-isopropylamino-3- [4- (2-metoxietyl) fenoxi] -2-propanol

By division separated from application 801680.

The present invention relates to a novel intermediate for the preparation of therapeutically active 1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol, i.e. metoprolol of the formula

§ OH

CH3OCH2CH2— / ΓΛ V— OCH2CHCH2NHCH (CH3) 2 (x)

Metoprolol is therapeutically valuable in the so-called Β-receptor blocker. It is a heart-specific and therefore important drug in the treatment of heart disease. The preparation of metoprolol has previously been described e.g. in Finnish patent application 801680.

The invention is characterized in that the intermediate is 1-isopropylamino-3- [4- (1-alkoxy-2-methoxyethyl) phenoxy] -2-propanol of the formula

? R / - \? H

CH 3 OCH 2 CH- / ΓΛ-O-CH 2 CHCH 2 NHCH (CH 3) 2 (I) wherein R is a methyl or ethyl group.

61 473 2

In the preparation of the intermediate according to the invention, the known and easily prepared sodium salt of 4- (methoxyethanoyl) phenol (II) is used as starting material.

o * —v ΘΘ CH3OCH2C— / Q \ 0: Na (II)

It is reduced in the first step to 4- (1-hydroxy-2-methoxyethyl) phenol (III).

ch3och2ch - ^ - 0H (III) Heating a mixture of hydroxyphenol (III) and methanol in the presence of an acid catalyst gives 4- (1,2-dimethoxyethyl) phenol (IV). Ethanol under similar conditions gives 4- (1-ethoxy-2-methoxyethyl) phenol (V).

OCH3 / v 9C2H5 / -V

CH 3 OCH 2 CH- / Q V-OH CH 3 OCH 2 (!

IV V

Reaction of hetoxyphenol (IV) and ethoxyphenol (V) under basic conditions with epichlorohydrin gives 1,2-epoxy-3- [4- (1,2-dimethoxyethyl) phenoxy] propane (VI) and 1,2-epoxy-3- [4 - (1-ethoxy-2-methoxyethyl) phenoxy] propane (VII).

fHV-V / \ fC2H5 / -V A

CH-JOCH ^ H- / Q V-OCH2CHCH2 CH3OCH2CH— / Q \ -OCH2CHCH2

VI VII

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Reaction of methoxyepoxide (VI) and ethoxyepoxide (VII) with isopropylamine produces 1-isopropylamino-3- [4- (1,2-dimethoxyethyl) phenoxy] -2-propanol (VIII) and 1-isopropylamino-3- [4 - (1-ethoxy-2-methoxyethyl) phenoxy] -2-propanol (IX).

OCHo, - OH CHo 1 3 / 7n \ 1 /

ch3och2ch - OCH2CHCH2NH2H

(VIII) and (j> c2H5> - <j) H ^ CH3 ch3och2ch— / Q Y- och2chch2nhch '- *' Nnch3 (IX)

The two series of reactions described above, the methoxy and ethoxy lines, are most preferably carried out up to methoxy and ethoxymetoprolol (VIII and IX) without intermediates, which makes the practical execution of the series very easy and simple. In addition, both sets of reactions succeed in high yield. If desired, the reaction series can also be carried out by isolating each intermediate or part of the intermediates. This is, of course, a much more cumbersome way than a series of reactions without intermediate insulation, especially on an industrial scale.

The reduction of the ketophenolate (II) to the hydroxyphenol (III) is best carried out with sodium borohydride in a suitable solvent, e.g. water, but most preferably in an alcohol for further reaction. The reduction is carried out at a temperature of about 30-90 ° C, which also depends on the solvent used. If it is intended to proceed along the methoxy line, it is most convenient to carry out the reduction in methanol. Namely, after reduction, the pH of the reaction mixture is acidified with a suitable acid, e.g. concentrated sulfuric acid, and then the reaction mixture is boiled without isolating hydroxyphenol (III) directly to methoxyphenol (IV) by reacting methanol as solvent with hydroxyphenol (III).

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If, on the other hand, it is intended to proceed along the ethoxy line, it is most preferable to carry out the reduction in ethanol and then carry out a digestion similar to that for methanol above, in which case the ethoxyphenol (V) is obtained directly. The reaction mixtures are then filtered. The methanol solution is neutralized with, for example, sodium methoxide and the ethanol solution with sodium ethoxide, respectively.

In the next step, methoxyphenol (IV) is reacted with epichlorohydrin under basic conditions, most conveniently in the presence of potassium carbonate in methanol solution, whereby the methoxyphenol (IV) obtained above does not need to be isolated. The reaction is carried out either at or below the boiling point of the mixture. Ethoxyphenol (V) is reacted similarly in ethanol solution.

It is most convenient to react the methoxy epoxide (VI) in methanol solution and the ethoxy epoxide (VII) in ethanol solution without changing the solvent either at or below the boiling point of the mixtures to give methoxymethoprolol (VIII) and ethoxymetoprolol (IX), which are useful in this step. .

Intermediates VIII and IX are prepared by reduction of metoprolol, mainly by catalytic hydrogenation. The hydrogenation is preferably carried out with a palladium-carbon catalyst in acetic acid in the presence of an acid catalyst, which can be used e.g. hydrochloric acid.

The reaction proceeds at a sufficient rate already at room temperature, and even at a temperature of 100 ° C the reaction is successful. · The great ease of the reaction at elevated temperature was a great surprise, let alone that the reaction already proceeds at room temperature. Finally, the product is made into, for example, a tartrate salt.

The invention is described in more detail in the following Examples 1 and 2. Examples 3 and 4 describe the preparation of a compound of formula X, i.e. metoprolol, from intermediates VIII and XI.

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Example 1 5-Isopropylamino-3- [4- (1,2-dimethoxyethyl) phenoxy] -2-propanol.

Dissolve 18.8 g (100 mmol) of the Na salt of 4- (methoxyethanoyl) phenol in 120 ml of hot methanol. While stirring the mixture and maintaining the temperature at 50 ° C, 1.9 g (50 mmol) of sodium borohydride are added in small portions. After complete addition of sodium borohydride, the mixture is stirred for a further 1 h at 50 ° C, after which the mixture is cooled. While stirring the reaction mixture and maintaining the temperature at 20 ° C, 4 g of concentrated sulfuric acid are added dropwise, followed by a 50% solution of sulfuric acid-methanol until the pH reaches 3 on the basis of pH paper. [The intermediate is 4- (1-hydroxy-2-methoxyethyl) phenol, m.p. at 102-4 ° C]

The mixture is then refluxed for 1 h. After cooling, the mixture is filtered and neutralized with methanolic sodium methoxide solution. [The intermediate is 4- (1,2-dimethoxyethyl) phenol, m.p. is 58-60 ° C]. 17.3 g (125 mmol) of anhydrous potassium carbonate are added. While stirring the reaction mixture and maintaining the temperature at 10 ° C, 20.8 g (225 mmol) of epichlorohydrin are added dropwise. Continuing to stir, the mixture is refluxed for 30 minutes. [The intermediate is 1,2-epoxy-3- [4- (1,2-dimethoxyethyl) phenoxy] -propane, an oil having a b.p. at 145-9 ° C / 0.3 mmHg] The mixture is cooled and 31.3 g (530 mmol) of isopropylamine are added. The mixture is then refluxed for 1 h. Activated carbon is added and refluxing is continued for another 5 minutes. The cooled mixture is filtered, after which the solvent is evaporated off on a rotary evaporator. The evaporation residue is a colorless, oily 1-isopropylamino-3- [4- (1,2-dimethoxyethyl) phenoxy] -2-propanol, the 1 H-NMR spectrum of which is shown in Figure 1 (FIG. 1). The yield is 24.4 g (82%). Tartrate sp. is 134-136 ° C.

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Example 2 61473 1-Isopropylamino-3- [4- (1-ethoxy-2-methoxyethyl) phenoxy] -2-propanol

Dissolve 18.8 g (100 mmol) of the Na salt of 4- (methoxyethanoyl) phenol in 150 ml of hot ethanol (abs.). While stirring the mixture and maintaining the temperature at 70 ° C, 1.9 g (50 mmol) of sodium borohydride are added in small portions. After complete addition of sodium borohydride, the mixture is stirred for a further 1 h at 70 ° C, after which the mixture is cooled. While stirring the reaction mixture and maintaining the temperature at 20 ° C, 4 g of concentrated sulfuric acid are added dropwise, followed by a 50% sulfuric acid-ethanol solution until the pH reaches 3 on the basis of pH paper. [The intermediate is 4- (1-hydroxy-2-methoxyethyl) phenol, cf. e.g. 1.] The mixture is then refluxed for 1 h. After cooling, the mixture is filtered and neutralized with ethanolic sodium ethoxide solution. [The intermediate is 4- (1-ethoxy-2-methoxyethyl) -phenol, m.p. 66-8 ° C] 17.3 g (125 mmol) of anhydrous potassium carbonate are added. While stirring the reaction mixture and maintaining the temperature at 10 ° C, 20.8 g (225 mmol) of epichlorohydrin are then added dropwise. Continuing to stir, the mixture is refluxed for 30 min. [Intermediate is 1,2-epoxy-3- [4- (1-ethoxy-2-methoxyethyl) phenoxy] propane, oil * having a b.p. is 148-50 ° C / 0.3 mmHg]. The mixture is cooled and 31.3 g (530 mmol) of isopropylamine are added. The mixture is then refluxed for 30 minutes. Add activated carbon and continue refluxing for another 5 minutes. The cooled mixture is filtered, after which the solvent is evaporated off on a rotary evaporator. The evaporation residue is dissolved in toluene and washed with water. The evaporation residue is a colorless, oily 1-isopropylamino-3- [4- (1-ethoxy-2-methoxyethyl) phenoxy] -2-propanol, the 1 H-NMR spectrum of which is shown in Figure 2 (FIG. 2). The yield is 27.1 g (87%). Tartra-tin sp. is 135-137 ° C.

Example 3 7 61473 1-Isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol

24.4 g (82 mmol) of the 1-isopropylamino-3-14 (1,2-deraethoxyethyl) phenoxy] -2-propanol obtained in Example 1 are dissolved in 125 ml of acetic acid. 12.7 g (123 mmol HCl) of concentrated hydrochloric acid and 2.44 g of 10% palladium on carbon are added. The mixture is hydrogenated at 20 ° C until the reaction is complete (about 5 h). The catalyst is removed by filtration, followed by the addition of 19.6 g (185 mmol) of solid sodium carbonate. The solvent is evaporated off on a rotary evaporator. The evaporation residue is dissolved in water. The aqueous solution is then washed with toluene, after which the pH is adjusted to about 9 with solid ^ 2 ^ 3. The product is then extracted into toluene. The toluene solution is washed with water, after which the solvent is evaporated off. The evaporation residue weighing 19.0 g (87%) is 1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol. The product is recrystallized from hexane to give a melting point of 45 ° C. The melting point of tartrate prepared from tartaric acid in acetone is approx.

120 ° C.

Example 4 1-Isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol

27.1 g (87 mmol) of the 1-isopropylamino-3- [4- (1-ethoxy-2-methoxyethyl) phenoxy] -2-propanol obtained in Example 2 are dissolved in 130 ml of acetic acid. 13.5 g (131 mmol HCl) of concentrated hydrochloric acid and 2.71 g of 10% palladium on carbon are added.

The mixture is hydrogenated at 20 ° C until the reaction is complete (about 5 h). The catalyst is removed by filtration, followed by the addition of 20.8 g (196 mmol) of solid sodium carbonate. The solvent is evaporated off on a rotary evaporator.

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The evaporation residue is dissolved in water. The aqueous solution is then washed with toluene, after which the pH is adjusted to about 9 with solid ^ 2 ^ 03 ^ 118. The product is then extracted into toluene. The toluene solution is washed with water, after which the solvent is evaporated off. The evaporation residue weighing 19.6 g (85%) is 1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol. The product is recrystallized from hexane to give a melting point of 45 ° C. The tartrate prepared from the product in tartaric acetone has a melting point of about 120 ° C.