MXPA99004570A - New manufacturing process of metoprolol - Google Patents

Abstract

A method for the manufacture of metoprolol wherein the process is performed in water as solvent.

Description

NEW METOPROLOL MANUFACTURING PROCESS FIELD OF THE INVENTION The present invention relates to an improved method for the manufacture of metoprolol base ", 1- (isopropylamino) -3- [p- (2-methoxyethyl) -phenoxy] -2-propanol) via the route of reacting p- ( 2- ethoxyethyl) -phenol (A) and epichlorohydrin (B) and then reacting 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) -benzene (AB) obtained with isopropylamine (C). crude base is then purified.

PREVIOUS TECHNIQUE Chemical Abstracts, volume 112 (1990) extract no. 197820 describes the reaction of p- (2-methoxyethyl) -phenol and epichlorohydrin in the two-phase system of water and organic solvent. Swedish patents 354 851 and 368 004 describe the reaction of p- (2-methoxyethyl) -phenol and epichlorohydrin wherein epichlorohydrin is used not only as a building block in the reaction but also as a solvent.

REF .: 30078 DESCRIPTION OF THE INVENTION It has now been found that metoprolol can be prepared in a manner that is easy, environmentally safe and gives a good yield and high purity using reagents that are known per se. The difference of the prior art is that the new method does not use other solvents other than water for the reaction of A and B. From an environmental point of view as well as an occupational risk point it is a great advantage to replace a dangerous organic solvent with a non-harmful solvent such as water. The method of the invention is illustrated by the following reaction scheme: Stage 2 I r H? .N? leopropylamine (C) 1 - . 1-lsopropylamino-3- [p-. { 2- methoxy (il) -phenoxy] -2-propanol, metoprolol base GENERAL EXAMPLE P- (2-methoxyethyl) phenol (A) and epichlorohydrin (B, 1.4-2.0 equivalents) were reacted in water, at least 1.5 kg, preferably approximately 2 kg of water per kg of phenol, during the addition of the solution of sodium hydroxide (or potassium), (1.3-1.7 equivalents) to form 1- (2,3-epoxypropoxy) -4- (2-methoxyethyl) benzene; (p-methoxyethyl-epoxypropoxybenzene). The reaction is preferably carried out at a temperature of 50-70 ° C. The two phases were separated, and the p-methoxyethylepoxy-propoxybenzene was isolated by distillation under reduced pressure. More particularly, the excess epichlorohydrin was evaporated, and the epoxide was distilled under reduced pressure to obtain a product with a purity of about 96-98%. If desired, before distilling the main fraction of the epoxide, a preliminary fraction / preliminary cut (2-8%, preferably 4-6%) thereof could be distilled. The isolation by distillation of the epoxide under reduced pressure is an important part of the process and essential for the quality of the final product. The epoxide was reacted with isopropylamine preferably in isopropyl alcohol to form metoprolol base. The amount of isopropylamine in relation to the epoxide is at least 1 equivalent, preferably 3-6 equivalents. The reaction mixture was then treated to remove excess isopropylamine.

Alternatively, the amination with isopropylamine is carried out in a pressurized system without isopropyl alcohol at 70 ± 10 ° C at pressures of 2.8-3.2 kg / cm2 (275-515 kPa). The resulting metoprolol was dissolved in toluene, isobutylmethylketone or butyl acetate and extracted with dilute hydrochloric acid or dilute sulfuric acid, preferably at pH 4-6. The phases were separated and the selected solvent with sodium or potassium hydroxide solution to adjust the pH to 11-13 was added to the aqueous phase. The two phases were separated, and the organic phase was evaporated In va c uo to give an oily residue of metoprolol base, which was dissolved in acetone. The purified metoprolol base was then obtained by conventional means.

Work Example 1- (2,3-epoxypropoxy) -4- (2-methoxyethyl) benzene p- (2-methoxyethyl) phenol (A, -6.6 moles), epichlorohydrin (B, 1.45 equivalents) and water were combined (~ 2 kg) and the mixture was heated to ~ 50 ° C. Sodium hydroxide solution was added (50%; 1.4 equivalents) for '3 hours and the temperature was raised to reach approximately 60 ° C during the addition. The formation of the title compound occurred during this period. The batch was stirred for another hour at about 60 ° C, then cooled to about 50 ° C and the phases were separated and the product was washed with water. The residue was distilled < 190 ° C a pressure of < 0.027 kg / cm2 (< _ 20 mm Hg) and the distillate was collected. The yield of the title compound was 80% of the theory and the purity was 98% according to the CG analysis.

Metoprolol base 1- (2,3-epoxypropoxy) -4- (2-methoxyethyl) benzene (1 kg, 4.8 moles), isopropyl alcohol (~ 0.9 kg) and isopropylamine (0.8-1.7 kg, 3-6 equivalents) were mixed and they were reacted for 2-5 hours at reflux. The formation of metoprolol base occurred during this period. The reaction mixture was then concentrated at atmospheric pressure until the internal temperature reached ~ 100 ° C. Water was added to the batch and then distilled in vacuo until the internal temperature reached ~ 100 ° C to form a concentrate.

The resulting concentrate was diluted with isobutyl ethyl ketone (~ 0.6 kg) and water (~ 2.2 kg) and concentrated sulfuric acid were added to adjust the pH to 4-6. After separation, isobutylmethyl ketone (~ 1 kg) was added to the water layer, and concentrated sodium hydroxide solution was added to adjust the pH to 13. The organic layer was concentrated as soon as < 80 ° C, until the distillation was stopped, and the concentrated batch was redissolved in acetone (~ 1.6 kg) and filtered, to provide a solution of metoprolol base. The metoprolol base assay in the solution was determined by titration. Performance: ~ 1.2 kg of metoprolol base (100%), ~ 95% theory. The purity of the metoprolol base was 96%. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A method for the manufacture of metoprolol, characterized in that it is reacted in a first step of p- (2-methoxyethyl) phenol and epichlorohydrin in water as solvent and at a temperature of 50 to 70 ° C, evaporating the excess of epichlorohydrin and then distilling the l- (2,3-epoxypropoxy) -4- (2-methoxyethyl) -benzene obtained under reduced pressure, and in a second step the 1- (2,3-epoxypropoxy) -4- (2-methoxyethyl) is reacted ) -benzene obtained and isopropylamine in the presence of isopropyl alcohol to form metoprolol base.

2. A method according to claim 1, characterized in that the first step is carried out in the presence of sodium hydroxide.

3. A method according to claim 1, characterized in that the first step is carried out in the presence of potassium hydroxide.

4. A method according to any of the preceding claims, characterized in that the resulting metoprolol base is purified by dissolving the metoprolol base in a solvent selected from toluene, isobutylmethyl ketone and butyl acetate and extracted with any solution of hydrochloric acid or sulfuric acid.

5. Metoprolol characterized in that it is prepared by the process according to any of claims 1-4.

6. A method according to any of claims 1 to 4, characterized in that the resulting metoprolol is converted to metoprolol tartrate.

7. A method according to any of claims 1 to 4, characterized in that the resulting metoprolol is converted to metoprolol succinate.

8. A method for the manufacture of a pharmaceutical preparation, characterized in that the metoprolol is produced by the method according to any of claims 1 to 4 or 6 to 7, and the metoprolol is thereafter formulated with a pharmaceutically acceptable diluent or carrier.

9. A method according to claim 8, characterized in that a diuretic is included in the ingredients for the pharmaceutical preparation.

10. A method according to claim 9, characterized in that the diuretic is hydrochlorothiazide.