FI61869B - PROFESSIONAL FORM OF THERAPEUTIC ACTIVATION 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) PHENOXY) -2-PROPANOL SAMT DESS SYRA ADDITIONAL SALT - Google Patents

Description

R3S71 [(1 (11.icuuLurusjuKKAisu, 1Λ, 0 ffir · (, 1> UTLAGGNINOSSKMFT 61 007 C £ f) exam issued on 11 10 1982

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(Tl) AB Hassle, Fack, S-l * 3 210 Mölndal, Sweden-Sverige (SE) (72) Soini Kanerva Huhta, Kempele, Lasse Antero Koskenniska, Oulu,

Suomi-Finland (FI) (7 * 0 Berggren Oy Ab (5 * 0 Process for the preparation of therapeutically active 1-isopropylamino-3- [k- (2-methoxyethyl) phenoxy] -2-propanol and its acid addition salts - Förfarande för framställning av therapeutically active 1-isopropylamino-3-N- (2-methoxyethyl) phenoxy] -2-propanol

The invention relates to a new process for the preparation of 1-isopropylamino-3- (4- (2-methoxyethyl) phenoxy] -2-propanol, i.e. metoprolol, of the formula and its acid addition salts.

Metoprolol is a so-called (5-receptor blocker. The disadvantage of most (i-blockers) is that they block not only O-receptors in the heart but also O-receptors in blood vessels and lungs. Metoprolol, on the other hand, is a heart-specific and thus an important drug in the treatment of heart disease.

The preparation of metoprolol is known, for example, from Swedish Patent No. 354,851, which describes 12 analogous methods for its preparation. What these methods have in common is that they are all directed to the preparation of the propanol side chain.

2 61 869

The process according to the invention is characterized in that a propanolamine derivative of the formula

OK 0H

C% O-CH2-Clk / () Vo-CH2-CH-CH2-NH-CH (CH3) 2 is reduced with sodium borohydride to metoprolol. Amine derivative III is a previously known substance (Acta Pharmacol. & Toxicol., 1975, suppl. V, 125).

Finnish applications Nos. 773,391 and 781,001 relate to a process in which the corresponding keto derivative of the formula ch3o-ch2-co - ^^^^ - o-ch2-1h-ch2-nh-ch (ch3) 2

V

reduced to metoprolol with sodium borohydride under strongly acidic conditions. The acids used in the FI application are 773,391 trifluoroacetic acid and in the FI application 781,001 methanesulfonic acid or p-toluenesulfonic acid. It has now surprisingly been found that it is even more advantageous to use alcohol intermediate III as starting material.

It is known from G W Gribble, R M Leese, Synthesis 1977, 172 that keto and alcohol groups can be reduced with sodium borohydride in trifluoroacetic acid to a methylene group. However, the reduction is satisfactory only with benzhydrol derivatives and not, for example, with OC-methylbenzyl alcohol.

Thus, compared to the prior art, it is surprising that intermediate III, which is a substituted N-methoxymethylbenzyl alcohol, can be reduced in good yield under similar conditions.

Methanesulfonic acid and p-toluenesulfonic acid have not been used as lower reagents in sodium borohydride reduction.

3 61869

The process according to the invention is thus characterized in that the alcohol group -CHOH- of the 4-position substituent of the phenyl ring of phenoxypropanolamine III is reduced with sodium borohydride under strongly acidic conditions via carbocation IV to the methylene group. As acidic reagents, methanesulfonic acid or p-toluenesulfonic acid are used.

The reaction can be schematically described by the following reaction equation:

/ \ NaBH4 j) H / V

ch3o-ch2-co / fj Voh? ch3o-ch2-ch- / Voh

1) NaOCH3 ^ OH pH

^ 0 ^ CH30-CH2-Ch / Vo-CH2 “CH-CH2C1 2) C1-CH2-CH -XCH2 \ _ /

Ila

And

OH / T ~ \ A

CH30-CH2-Cft / () Vo-ch2-ch- ch2

Hb

H2N-CH (CH3) 2 <j> H <j> H

- ^ ch3o-ch2-ch / f) \ o-CH2-CH-CH2-NH-CH (CH3) 2

III

61 869

A

NaBHA / CH3SO3H @ ^ CH30-CH2-CH - <^ (J) Vo-CH2-CH-CH2-NH-CH (CH3) 2 or CH2On inert solvent -y CH3O-CH2-CH2 E-CH2-CH2-NH-CH (CH

Compared to the reduction of the keto compound V with sodium borohydride in the presence of methane or p-toluenesulfonic acid, the process according to the invention has the following advantages: yields are considerably higher in the final step. from methoxyacetonophenone by reduction with a small amount of sodium borohydride in ethanol solution to the corresponding alcohol (I), which does not need to be isolated. It is reacted with sodium methoxide and epichlorohydrin to give, in quantitative yield, 1-chloro-3- [4- (1-hydroxy-2-methoxyethyl) phenoxy] -2-propanol and 1,2-epoxy-3- [4- A mixture of (1-hydroxy-2-methoxyethyl) phenoxy] -propane (IIa and 11b). The mixture is reacted with isopropylamine to 1-isopropylamino-3- [4- (1-hydroxy-2-methoxyethyl) phenoxy] -2-propanol (III) by a conventional method in 78% yield. Substance III is obtained as a slowly crystallizing oil, m.p. 65-67 ° C.

5,61869

The reduction of substance III with sodium borohydride is carried out at a temperature of about 0 ° C in an inert solvent such as methylene chloride to which methanesulfonic acid or p-toluenesulfonic acid is added.

The invention is illustrated by the following examples:

Example 1 26.5 g of 1-isopropylamino-3-14- (1-hydroxy-2-methoxyethyl) phenoxy] -2-propanol (III), 100 ml of methylene chloride and 6.0 g of sodium borohydride are placed in a reaction flask and cooled to n.

0 ° C. 50.0 g of methanesulfonic acid are added to the mixture in small portions and the mixture is stirred at 0 [deg.] C. for 2 hours and allowed to warm to room temperature. Add 300 ml of water and adjust the pH to more than 10 with sodium hydroxide. Separate the methylene chloride layer, wash with water and evaporate to dryness. The residue is crystallized from heptane to give 22.1 g of metoprolol base (90.3%), m.p. 41-42 ° C.

Example 2 26.5 g of starting material III, 200 ml of methylene chloride, 10.0 g of NaBH 4 and 70.0 g of p-toluenesulfonic acid are treated as in Example 1. Yield 18.5 g of metoprolol (79.5%), m.p. 42-43 ° C.