NL7907207A - 1-Isopropyl-amino-3-(4-(2-methoxyethyl)phenoxy)-2-propanol prepn. - by redn. of 1-isopropylamino-3-(4-(1-hydroxy-2-methoxyethyl) phenoxy)-2-propanol with sodium borohydride in e.g. tri:fluoro:acetic acid - Google Patents

Abstract

Therpeutically active 1-isopropylamino-3-(4-(2-methoxyethyl) phenoxy)-2-propanol of formula (I) and the pharmaceutically acceptable acid addn. salts are prepd. by reducing 1-isopropylamino- 3-(4-(1-hydroxy-2-methoxyethenoxy)-2-propanol (II) with sodium borohydride at ca. 0 deg.C. in an inert solvent contg. trifluoroacetic acid, methanesulphonic acid or p- toluenesulphonic acid as reagent. (I) (also known as Metropolol) is useful in heart therapy as a heart-specific beta-adrenerg receptor blocking agent. Redn. of (II) with NaBH4 in place of the keto cpd. CH3OCH2CO-p-C6H4-CH2CH(OH)CH2NHCH(CH3)2 as described in Japanese application 39236/1979, gives considerably higher yields of (I) and uses less NaBH4 and acid, thus giving improved economy.

Description

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Title: Method for the preparation of therapeutically active propanol-amine

The invention relates to a new process for re-grading 1-isopropylamino-3 [b- (2-methoxyethyl) phenoxy] -2-propanol or metropolol of the formula 5 and its acid addition salt and .

Metropolol is a so-called β-adr ener g-ecpt blocker end agent.

Most of the 5-adrenergic receptor blocking agents have the drawback of blocking not only the β receptors of the heart, but also the β receptors of the blood vessels and lungs. Metropolol, on the other hand, is heart-specific and therefore an important drug in cardiac therapy.

The preparation of metropolol is e.g. described in Swedish Patent No. 35 ^ -851, which claims 12 methods of preparation.

These methods have in common that they all concern the preparation of the pro-panol side chain.

A characteristic of the method according to the invention is that a propanolamine derivative of the formula 3 of the formula sheet is reduced with sodium borohydride to metropolol. The amine derivative (3) is a known compound (Acta Pharmacol et Toxicol-1975, 36 Suppl. V, 125).

Japanese patent application 39236/1979 relates to the reduction of the corresponding keto compound of the formula 6 with sodium borohydride to metropolol under strong acid conditions using trifluoroacetic acid, methanesulfonic acid, p-toluene sulfonic acid.

It has now surprisingly been found that it is even more advantageous to use the alcohol intermediate 3 as the starting material.

From the publication G.W. Gribble, R.M. Leese, Synthesis 1977, 172, is known that keto and alcohol groups can be reduced with sodium borohydride in trifluoroacetic acid to a methylene group.

The reduction proceeds satisfactorily only with benzhydrol derivatives, but not with e.g. alpha-methyl alcohol. Thus, compared to the prior art 790 7 2 0 7 '* -2- «, it is surprising that the intermediate compound 3, which is a substituted α-methoxybenzyl alcohol, can be reduced in good yield under similar conditions. Methanesulfonic acid and p-toluenesulfonic acid have not previously been used as reagents in sodium borohydride reductions.

The process according to the invention is therefore characterized in that the alcohol group -CH-CH in the substituent of the phenyl group of the phenoxypropanolamine (3) is reduced with sodium borohydride under strongly acidic conditions via the carbocation k to form a methyl group. reagents are used trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid. -

The reaction can be illustrated with the reaction scheme of the formula sheet.

Compared to the reduction of the keto compound 6 with .....

The sodium borohydride method of the invention has the following advantages.

- are the yields. markedly higher - in the last step, the amounts of both sodium borohydride and acid are smaller - for the above reasons, it is not clearly improved economically.

The starting material (3) is prepared e.g. by reduction of 4-hydroxy-OJ-methoxyacetophenone with a small amount of sodium borohydride in ethanolic solution to the corresponding alcohol (1), which need not be isolated. It is reacted with sodium methoxide and epichlorhydrin to yield a quantitative yield of a mixture of 1-chloro-3 - [^ - (1-hydroxy-2-methoxyethyl) phenoxy] -2-propanol and 1,2-epoxy-3- [ U- (1-hydroxy-2-methoxylethyl) phenoxy] propane (formulas 2a and 2b) is obtained. The mixture is reacted according to conventional methods with isopropylamine to give 1-isopropylamine-3 - [(1-hydroxy-2-methoxyethyl) -phenoxy] -2-propanol (3) in a yield of JQ%. The compound (3) is obtained as an oil which crystallizes slowly (melting point 65-67 ° C).

7907207 -3- V - "/

The reaction of compound (3) with sodium borohydride takes place at a temperature of about 0 ° C in trifluoroacetic acid, which can be diluted with a suitable inert organic solvent e.g. methylene chloride or in an inert solvent to which: methanesulfonic acid or p-toluenesulfonic acid is supplied.

The invention is further illustrated by the examples below.

Example I

26.5 g of 1-isopropylamino-3- [U - (- 1-hydroxy-2-methoxyethyl) phenoxy] -

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2-propanol (3), 100 ml of methylene chloride and 5.0 g of sodium borohydride are placed in a reaction flask and cooled to about 0 ° C. 50 ml of trifluoroacetic acid are added dropwise to the mixture and the mixture is stirred at 0 ° C for 2 hours, after which the temperature is allowed to come to room temperature. 300 cm3 of water are added and the pH value is adjusted above 10 with sodium. hydroxide. The methylene chloride layer is separated, washed with water and evaporated to dryness. The residue is crystallized from heptane to give 23.2 g of metoprolol base (95.3%), mp hh-45 ° C. When this is converted into the hydrochloride, a product is obtained with a melting point of 82-83 ° C.

Example II

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26.5 g of starting material (3), 100 cm of methylene chloride and 6.0 g of sodium borohydride are cooled to 0 ° C. 50.0 g of methanesulfonic acid are added portionwise and continued as in Example 1. The yield of metoprolol base is 22.1 g (90.3%), mp 11-42 ° C.

Example III

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26.3 g of starting material (3), 200 cm of methylene chloride, 10.0 g of sodium borohydride and 70.0 g of p-toluenesulfonic acid are treated as in Example 1. The yield is 18.5 g of metoprolol (T9.5%), melting point t0-1 ° C.

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Claims (1)

2. C 1 -CH 1 -C 1 -CH; 2 2 and 2b OH 0 CH30-CH2-CH - ^^ - 0-CH2-CH - CH2 H2N-CH (CH3) 2 oh oh -CH30-CH2-CH- ^ y0-CH2-CH-CH2-NH-CH (CH3) 2 k NaBH./CF-COOH, CH, SQ, H r \ - _ OH 4 3 3 3 N (+) // \\ i -; -> CH30-CH2-CH- ^ yO-CH2 -CH-CH2-NH-CH (CH3) 2 or ch3 ^ so3h inert solvent JL __ OH -> CH30-CH2-CH2- /--0-CH2-CH-CH2-NH-CH (CH3) 2 i OH CH30 -CH2-C0 - ^ "^^ - Q-CH2-CHrCH2-NH-CH (CH3) 2 790 7 20 7 FARMOS-YHTYMA. OY