NO130312B - - Google Patents

Description

Method of manufacture of

phenylaminoethanol derivatives.

This invention relates to a method for manufacturing

of certain phenylaminoethanol derivs.

We have found that phenylaminoethanol derivatives of the formula I below can be prepared from compounds of the formula II below by treatment with formaldehyde in the presence of a strong base and an alkali metal borate.

According to the invention, a method for the production of phenylaminoethanol derivatives of formula I is thus provided:

where means a hydrogen atom or a benzyl group, bg 1*2 means a hydrogen atom or a linear or branched alkyl group containing from 1 to 6 carbon atoms or an aryl-alkyl group. The method is characterized by the fact that a compound of formula II: where R-, and R ? has the meanings given above, is treated with formaldehyde or a formaldehyde-releasing compound in the presence of a strong base and an alkali metal borate, after which, if desired, a phenylaminoethanol derivative obtained, in which R<1> is a benzyl group, is debenzylated. ;Presence of an alkali metal borate unexpectedly leads to selective monohydroxymethylation at the 3-position rather than hydroxymethylation at both the 3- and 5-position. When carrying out the conversion, formaldehyde itself or any suitable source of formaldehyde such as paraformaldehyde can be used. An aqueous solution of formaldehyde, e.g. 40% formalin is preferred. The reaction is carried out in the presence of a strong base, preferably an alkali metal hydroxide such as sodium hydroxide, and an alkali metal borate, particularly sodium borate. The reaction is preferably carried out at ambient temperature in aqueous solution. The compounds of formula I are described in our Norwegian patent 126,014 as intermediates in the production of phenylaminoethanols of formula III which are 8-adrenergic stimulants and useful as bronchodilators. The catalytic hydrogenolysis of compounds of formula (I) (Rj, benzyl, R2 tert.butyl or benzyl) to form compounds of formula (III) (R^ = tert.butyl or H) and the reductive alkylation of the latter with aldehydes or ketones to products of formula (III) where R^ can have a number of different meanings, e.g. p-methoxy~a-methylphenethyl is described in the aforementioned patent. The method according to the invention has the advantage compared to the known methods for producing these compounds (see example 8 in Norwegian patent 126,014) that the introduction of the hydroxymethyl group takes place in a single step. ;Example 1 ;1 13 a - (benzyl-tert-butylaminomethyl)-4-hydroxy-m-xylene-g, a - diol ;a-(benzyl-tert-butylaminomethyl)-4-hydroxy-benzyl alcohol hydrochloride (1, 0 g) was added to a solution of sodium hydroxide (0.24 g) in water (50 ml) and dioxane (20 ml) and the mixture was stirred until a clear solution was obtained. A solution of sodium borate (2.3 g) in water (50 mL) and 36% formaldehyde (5 mL) was added and the solution was kept at room temperature until all starting material had reacted (7-25 days). The reaction mixture was acidified by the addition of 2N hydrochloric acid and then basified with an excess of 8% sodium bicarbonate. The product was extracted into ethyl acetate, washed with brine and dried (Na 2 SO 4 ). Concentration gave a clear oil which crystallized slowly. Recrystallization from ethyl acetate-petroleum ether (b.p. 60-80°C) gave α-benzyl-tert-butylaminomethyl-4-hydroxy-m-xylene-α 1 , α 3-diol (0.35 g; 35%) sm .p. 118-119°c. The melting point was not lowered by mixing with an authentic sample isolated from the method described in example 8 of Norwegian patent 126,014. Example 2 ;a ^-- (dibenzylaminomethyl)-4-hydroxy-m-xylene-g"*", q^-diol

Sodium hydroxide (1N) (2 mL) and dioxane (15 mL) were added to a suspension of α-(dibenzylaminomethyl)-4-hydroxybenzyl alcohol (0.666 g) in water (15 mL) and the mixture was stirred until a clear resolution. A solution of sodium borate (0.76 g) in water (10 mL) and 36% formaldehyde (5 mL) was added and the solution was kept at room temperature until all starting material had reacted

(7-25 days). The reaction mixture was acidified by the addition of 2N hydrochloric acid and then basified with an excess of 8% sodium bicarbonate. After dilution with an equal volume of water, the white precipitate was filtered off and air-dried. The solid material became

dissolved in ethyl acetate, filtered through a short column of silicic acid, and the filtrate and washings combined; and dried (Na2S0^) . Concentration of the solution afforded a white solid which was crystallized from ethyl acetate-cyclohexane' to give α^-dibenzylaminomethyl-4-hydroxy-m-xylene-α! 1 , a 3-diol (0.3 g) m.p. 108-110°C. The melting point was not lowered by mixture with an authentic sample, prepared according to example 22 in Norwegian patent 126,014. This can then be debenzylated by the method described in example 12 in the aforementioned Norwegian patent to give α-aminomethyl-4-hydroxy-m-xylene-α 1 , α 3-diol (R.j=R2=H). This compound can then be reductively alkylated by the method described in examples 17, 18, 19, 20 and 21 of the aforementioned Norwegian patent.

Claims (1)

Process for the preparation of phenylaminoethanol derivatives of formula I: where R-^ means a hydrogen atom or a benzyl group, and R2 means a hydrogen atom or a linear or branched alkyl group containing from 1 to 6 carbon atoms or an aralkyl group, characterized in that a compound of formula II: where R^ and R have the meanings given above, is reacted with formaldehyde or a formaldehyde-releasing compound in presence of a strong base and an alkali metal borate, after which, if desired, a compound obtained of formula I where R 1 is benzyl is debenzylated.