SK155898A3 - Method for the synthesis of (r)- or (s)-metipranolol - Google Patents

Abstract

Disclosed is a synthesis of (R)- or (S)-metipranolol, in which 4-O-acetyl-2,3,5-trimethylhydroquinolone reacts with (R)- or (S)-epichlorhydrine in the solvent or without a solvent in the presence of non-aqueous alkali metal carbonate. When the reaction finishes the inorganic salts are removed, the organic layer is thickened, the residual is re-crystallised in the organic solvent. The prepared (R)- or (S)-1-(4-acetoxy-2,3,5- trimethylphenoxy)-2,3-epoxypropane reacts with isopropylamine in the solvent or without the solvent. When the reaction finishes the mixture is thickened to dry and the resulting product (R)- or (S)-metipranolol is re-crystallised in the suitable solvent.

Description

Method for the synthesis of (R) - or (S) -Metipranolol

Technical field

The present invention is in the field of the synthesis of optically active forms of Metipranolol, which is used as an active ingredient in the field of oral and parenteral adrenolytics with high specific beta-lytic activity.

BACKGROUND OF THE INVENTION

The optically active forms of Metipranolol, which are believed to have a more pronounced pharmacodynamic effect, are according to U.S. Pat. No. 152096 are prepared by resolution of the racemate in an alkanol environment by treatment with an optically active acid. The separated salt of one enantiomer is separated and purified by fractional crystallization; the second enantiomer of Metipranolol is crystallized from the crystallization liquors. Separation of racemic metipranolol into individual enantiomers via diastereomeric salts is also the subject of Japanese patent JP 58126845.

SUMMARY OF THE INVENTION

The invention provides a process for the synthesis of optically active forms of Metipranolol, i. (R) - or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) -3-isopropylamino-2-propanol of formula (S) -Ia (R) -1.

(R) -I

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According to the present invention, (R) - or (S) -Metipranolol is synthesized such that

4-O-Acetyl-2,3,5-trimethylhydroquinone is reacted with (R) - or (S) epichlorohydrin in a solvent, preferably acetone, or without a solvent, in the presence of anhydrous alkali metal carbonate. Upon completion of the reaction, the inorganic salts are removed e.g. filtration or multiple extraction with water. The organic layer is then concentrated and purified by crystallization from an organic solvent, preferably ethanol. The (R) - or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) -2,3-epoxypropane (R) -II or (S) -II thus prepared is reacted with isopropylamine in a solvent, preferably in ethanol or without solvent at a temperature of 30 to 85 ° C. After completion of the reaction, the reaction mixture is concentrated to dryness and the resulting product is crystallized

(R) -II (S) -II from an organic solvent, preferably toluene, or an aliphatic alcohol having a carbon number of C-1 to C-3.

DETAILED DESCRIPTION OF THE INVENTION

The synthetic process of the invention is further illustrated by the following non-limiting examples.

Example 1

20 ml of (R) - or (S) -epichlorohydrin, 5 g of 4-O-acetyl-2,3,5-trimethylhydroquinone, 5 g of anhydrous K 2 CO 3 are added and the mixture is heated under reflux for 5 hours. The reaction mixture is cooled, extracted with 2 x 50 ml of water, the organic layer is concentrated to dryness, the residue is dissolved in 20 ml of toluene, the solution is extracted with 2 x 20 ml of water, the toluene layer is separated and the solvent is distilled off. 20 ml of ethanol and 10 ml of isopropylamine are added to the residue, the mixture is heated at reflux for 2 hours, then concentrated to dryness and the residue is crystallized from toluene. After separating the crystals and drying them, 1.7g of (R) or (S) -metipranolol of high optical purity (ee = 99.0%, determined by capillary zone electrophoresis under the conditions of a capillary of 40 µm x 0.05 mm, mM triethanolamine / acetate buffer pH 5.70.20 mM carboxymethyl-β-cyclodextrin, 17 ° C, 20 kV).

Example 2

A mixture of 20 ml of (R) - or (S) -epichlorohydrin, 11 g of 4-O-acetoxy-2,3,5-trimethylhydroquinone, 12 g of anhydrous K 2 CO 3 in 100 ml of acetone is heated at the boiling point of the solvent for 6 hours. After completion of the reaction, the solid is filtered off, the filtrate is concentrated to dryness, 14 ml of ethanol and 14 ml of isopropylamine are added to the residue, and the mixture is refluxed for 2 hours. The solution was concentrated and the residue was crystallized from toluene. 5.6 g wet are obtained, after drying to constant weight 3.9 g of (R) - or (S) -Metipranolol of high optical purity (ee = 99.0%, determined by the procedure of Example 1).

- * τ [a] 20, D = + 5.8, resp. -5.8 ° (c = 1, methanol).

Example 3

A mixture of 20 ml of (R) - or (S) -epichlorohydrin, 11 g of 4-O-acetoxy-2,3,5-trimethylhydroquinone, 12 g of anhydrous K 2 CO 3 in 100 ml of acetone is heated for 6 hours at the boiling point of the solvent. thicken to dryness. The residue was crystallized from ethanol (12ml). To the wet (R) - or (S) -1- (4acetoxy-5S-trimethylphenoxy-4-epoxypropane) was added 12 ml of ethanol and 12 ml of isopropylamine, the mixture was refluxed for 2 h, the solvents were distilled off and the residue was crystallized from toluene.

4g of (R) - or (S) -metipranolol is obtained.

Industrial usability

The invention is useful in the manufacture of pharmaceutical substances.

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Claims (7)

Process for the synthesis of (R) - or (S) -Metipranolol of formula (R) -I or (S) -I (R) -I (S) -I, characterized in that 4-O-acetoxy-2,3 , 5-trimethylhydroquinone, alkali metal carbonate and (R) - or (S) -epichlorohydrin react in the presence or absence of an organic solvent at the boiling point of the reaction mixture for 3 to 6 hours, removing the inorganic salts from the reaction mixture, concentrated, crystallized from ethanol, crystallized (R) or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) -2,3-epoxypropane in an organic solvent or without an organic solvent with isopropylamine at temperature 30-85 ° C, the reaction mixture is concentrated and the residue is recrystallized from an organic solvent. Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that potassium carbonate is used as the alkali metal carbonate. I » Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that, as a solvent for the reaction of 4-O-acetoxy-2,3,5-trimethylhydroquinone, anhydrous alkali metal carbonate and (R) - or (S). -epichlorohydrin is used an aliphatic ketone having a carbon number of C-3 to C-6. Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that the inorganic salts are removed from the reaction mixture by extraction with water, The organic layer is concentrated to dryness, the residue is dissolved in toluene, the solution is extracted with water. Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that the inorganic salts are removed from the reaction mixture by filtration. Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that (R) - or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) - Of 2,3-epoxypropane and isopropylamine, an aliphatic alcohol having a carbon number of C1 to C-3 is used. Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that (R) - or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) - 3-isopropylamino-2-propanol used is toluene, an aliphatic alcohol having a carbon number of C1 to C-3, or a mixture thereof.