Prior art Chemical Abstracts, vol. 112 (1990) abstract no 197820 discloses 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 disclose the reaction of p-(2-methoxyethyl)-phenol and epichlorohydrin where the epichlorohydrin is used not only as a building block in the reaction but also as solvent.

Disclosure of the invention It has now been found that metoprolol can be prepared in a manner that is fast, environmentally sound and gives a good yield and high purity using reactants that are known per se. The difference from the prior art is that the new method uses no other solvents than water for the reaction of A and B. From an environmental as well as an occupational hazard point of view it is a great advantage to be able to replace a hazardous organic solvent with an non-noxious solvent such as water.

The method of the invention is illustrated by the reaction scheme below: OH p-(2-Methoxyethyl)phenol (A) 0 0 CI Epichlorohydrin (B) Step I r > -(2,3- Epoxypropoxy)-4- (2-methoxyethyl (AB) /0 Isopropylamine (C) Step 2 H2N V oy;N 1 -Isopropylamino-3-[p-(2- OH methoxyethyl )-phenoxy 2-propanol, metoprolol base ¼ 0

General example p-(2-Methoxyethyl)phenol (A) and epichlorohydrin (B, 1.4-2.0 eqv.) are reacted in water, at least 1.5 kg, preferably about 2 kg of water per kg of phenol, during the addition of sodium (or potassium) hydroxide solution, (1.3-1.7 eqv.) to form 1-(2,3-epoxypropoxy)-4 (2-methoxyethyl)benzene; (p-methoxyethyl-epoxypropoxybenzene). The reaction is preferably performed at a temperature of 50 - 70 "C.

The two phases are separated, and the p-methoxyethylepoxy-propoxybenzene is isolated by distillation under reduced pressure. More particular, the excess of epichlorohydrin is evaporated, and the epoxide is 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 prefraction/forecut (2-8 %, preferably 4-6 %) thereof could be distilled. The isolation by destillation of the epoxide under reduced pressure is an important part of the process and essential for the quality of the end product.

The epoxide is reacted with isopropylamine preferably in isopropyl alcohol to form metoprolol base. The amount of isopropylamine in relation to epoxide is at least 1 eqvivalent, preferably 3-6 eqvivalents. The reaction mixture is then treated in order to eliminate the excess of isopropylamine.

Alternatively, the amination with isopropylamine is carried out in a pressurized system without isopropyl alcohol at 70 + 100C at pressures of 2.8-3.2 kg / 275-315 kPa.

The resulting metoprolol is dissolved in toluene, isobutyl methyl ketone or butyl acetate and extracted with dilute hydrochloric acid or sulphuric acid, preferably at pH 4-6. The phases are separated and the chosen solvent with sodium or potassium hydroxide solution to adjust the pH to 11 - 13 is added to the aqueous phase. The two phases are separated, and the organic phase is evaporated in vacuo to an oily residue of metoprolol base which is dissolved in acetone. Purified metoprolol base is then obtained by conventional means.

Working example 1-(2,3 -epoxypropoxy)-4-(2-methoxyethyl) benzene p-(2-Methoxyethyl)phenol (A, - 6,6 mol), epichlorohydrin (B, 1.45 eqv.) and water (- 2 kg) were combined and the mixture heated to - 500C.

Sodium hydroxide solution (50%; 1.4 eqv.) was added during 3 hours and the temperature was elevated to reach approximately 60"C during the addition. Formation of the title compound occured during this period.

The batch was stirred for another hour at approximately 60"C, then cooled to approximately 500C and the phases were separated and the product washed with water.

The residue was distilled at 51900C and a pressure of120 mm Hg and the distillate was collected. The yield of the title compound was 80% of theory and the purity was 98% according to GC analysis.

Metoprolol base 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)benzene (1 kg, 4.8 mol), isopropyl alcohol (~0.9 kg) and isopropylamine (0.8-1.7 kg, 3-6 eqv.) were mixed and reacted for 2-5 hours at reflux. Formation of metoprolol base occured during this period.

The reaction mixture was then concentrated at atmospheric pressure until the inner temperature reached -100"C. Water was added to the batch and then distilled off in vacuo until the inner temperature reached ~ 1 000C to form a concentrate.

The resulting concentrate was diluted with isobutyl methyl ketone (-0.6 kg) and water (-2.2 kg), and concentrated sulphuric acid was added, to adjust the pH to 4-6.

After separation, isobutyl methyl 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 in vacuo at <800C, until distillation ceased, and the <BR> <BR> <BR> concentrated batch was redissolved in acetone (-1.6 kg) and filtered, to yield metoprolol base solution. The assay of metoprolol base in the solution was determined by titration.

Yield: -1.2 kg metoprolol base (100 %) 95 % of theory. The purity of the metoprolol base was 96 %.