FR2487336A1 - Prepn. of 4-methoxyethyl phenol - from a 4-alkoxyphenyl bromide and a 2-methoxyethyl halide - Google Patents

Abstract

phenol of formula (I) is prepd. by treating a 4-alkoxyphenyl bromide (II) with Mg to form the corresponding magnesium bromide (III) (where R is a gp. that can be eliminated by mineral or organic acid below 70 deg.C); reacting (III) with 2-methoxyethyl chloride, bromide, or iodide to give (IV) and treating this with acid to give (I). Process in which R is tetrahydropyranyl, methoxymethyl, ethoxymethyl or alpha alkyl ethoxymethyl, is pref. The prepn. of the magnesium bromide (III) is pref. effected in a mixed ether solvent, esp. diethyl ether and (THF). Reaction of (III) with the 2-methoxyethyl halide is effected in THF, and elimination of the gp. R is effected with an acid in an alcoholic medium. (I) are intermediates for the cardiovascular agent metoprolol.

Description

New process for the preparation of (2-methoxy-ethyl) -4 phenol "
The present invention relates to a new process for the preparation of (2-methoxy-ethyl) -4 phenol, a product known for example as a starting product for the preparation of metoprolol, a cardiovascular agent described in French Patent No. 2,081,523.

According to R. BAIRD and S. WINSTEIN in Journal of American Chemical Society,
Flight. 85, p. 575 (1963), (2-methoxyethyl) -4 phenol is prepared by reacting (2-bromo-ethyl) -4 phenol with a mixture of anhydrous methanol and silver nitrate, then with methylate sodium. The crude product obtained is then esterified with 3,5-dinitrobenzoyl chloride and then saponified to give the (2-methoxy-ethyl) -4 phenol.

the process according to the inversion is completely different and consists in reacting 2-methoxyethyl bromide with a parabromophenol ether according to the synthetic route described below 1) 4-alkyloxyphenylmagnesium bromide is prepared (3) by doing rea
gir of 4-alkyloxyphenyl bromide with magnesium (2)

This reaction is carried out in the solvents generally used for the preparation of organo-magnesians, or in mixtures of such solvents, for example the ethers-oxides, in particular diethyl ether and tetrahydrofuran.

All the ethers-oxides of parabromophenol (1) whose group R can be eliminated at a temperature below 7O0C and in general at room temperature with a mineral acid (hydrochloric or sulfuric) or better an organic acid (acetic or formic) are suitable for this reaction.

Among the values of R possessing these properties, we retain, for example, the values tetrahydropyrannyl (7), methoxymethyl (8), ethoxymethyl (9) or ethoxymethyl a-substituted by an allyl radical, in particular methyl or ethyl.

2) On prépare un éther du (méthoxy-2 éthyl)-4 phénol (5) en faisant réa-
' , dans le tétrahydrofuranne, le bromure de méthoxy-2 éthyle (4) sur
le bromure d'alkyloxy-4 phénylmagnésium (3) pour donner un alkyloxy-1
(méthoxy-2 éthyl)-4 benzène (5)

It is more particularly the α -methylethoxymethyl radical (10) which was used:

2) A (2-methoxy-ethyl) -4-phenol (5) ether is prepared by reacting
', in tetrahydrofuran, 2-methoxyethyl bromide (4) on
4-alkyloxyphenylmagnesium bromide (3) to give a 1-alkyloxy
(2-methoxy ethyl) -4 benzene (5)

Methyl "ry-2 ethyl bromide (4) is easily obtained by the action of
phosphorus tribromide on 2-methoxy ethanol (which is an alcohol
industrial), or better by preparing 2-methoxy benzenesulfonate
ethyl (by action of benzenesulfonyl chloride on 2-methoxy
ethanol in the presence of soda) and subjecting it to the action of the bro
sodium mure.

Instead of 2-methoxyethyl bromide (4), chlo can be used
or the corresponding iodide, which can be prepared for
from a 2-methoxyethyl arylsulfonate.

3) Ether-oxide of (2-methoxy-ethyl) -4 phenol (5) is split by an acid
mineral or organic, in a generally alcoholic medium, to give
(2-methoxyethyl) -4 phenol (6)

The reaction medium must be a homogeneous liquid dissolving at the
times the ether oxide (5) and the acid used.

Alcohols, such as methanol, ethanol, propanol or isopropanol,
are particularly suitable for this use.

The example below illustrates, in a nonlimiting manner, the method according to the invention
Preparation of (2-methoxyethyl) -4 phenol a) preparation of (1-ethoxy-ethoxy) -4 phenylmagnesium bromide
2.4 g (0.1 at. G.) Of magnesium in turnings are introduced into a 250 cc flask, 2.5 g (0.01 mole) of (1-ethoxy-ethoxy) -4 bromobenzene and 8 ml of a ethyl ether-tetrahydrofuran mixture 60/40.

Heat slightly while stirring and add an iodine crystal which colors the medium yellow.

At around 35 ° C., the medium discolours and discoloration is followed by an attack on the metal. The exothermicity of the reaction brings the medium to a boil and a solution of 22.1 g (0.09 mole) of (ethoxy1 ethoxy) -4 'bromobenzene in 72 ml of the ethyl ether-tetrah7-drofuran mixture is then slowly added. 60/40. The addition is adjusted so as to maintain the boiling of the medium and lasts from 1:30 to 2 hours. The boiling is then extended for 15 minutes.

b) preparation of (1-ethoxy-ethoxy) -1 (2-methoxy-ethyl) -4 benzene
13.9 g (0.1 mol) of methoxyethyl bromide are added to the organo-magnesian solution prepared above in 30 minutes, the reaction medium being at boiling point, which is maintained for 5 hours.

The medium is then cooled and poured into ice water, then the organic products are extracted 3 times with 200 ml of ethyl ether.

The ethereal solution is then washed once with 100 ml of an aqueous solution of sodium chloride and then dried. After evaporation of the solvent under vacuum, 22.8 g of a yellow oil are recovered.

c) preparation of. (2-methoxy ethyl) -4 phenol
The crude oil obtained above is poured into a methanolic solution containing 1.556 36% hydrochloric acid at 30C and the mixture is stirred for 15 minutes between 50 and 10 C. It is then diluted with 400 ml of water and extracted the phenolic derivative with 3 times 150 ml of ethyl ether.

The ethereal solution is washed with salt water until the washing water is neutral, then dried over anhydrous sodium sulfate. After removal of the solvent by vacuum distillation, 16.4 g of a yellow oil are recovered which are chromatographed on a silica column with a mixture of 80/20 ethyl ether n-heptane as eluent. 4.5 g of a practically colorless oil are obtained which crystallizes.

Yield: 3O ', o' Melting point: 420C.

It is possible, in the above operating mode, to reverse, without modifying the results, the order of implementation of the reagents, either to gradually add the organo-magneslen to a solution of 2-methoxy bromide ethyl in 15 ml of ether and tetrahydrofuran (60/40) brought to the boil, instead of adding the latter solution to the organomagnesium.

Claims (5)

Claims 1. Process for the preparation of (2-methoxy-ethyl) -4 phenol, characterized in  what we  a) reacts a 4-alkyloxyphenyl bromide of general formula

 in which R represents a group which can be eliminated at ambient temperature or below 700C by a mineral or organic acid, with magnesium to form a 4-alkyloxyphenylmagnesium bromide of general formula

 in which R has the same value as above b) reacts the organomagnesium (3) above with a halide  of 2-methoxy ethyl of general formula  X-CR2CH20CH3 (4) in which X represents chlorine, bromine or iodine, to form a (methoxy-2 ethyl) -4 phenol ether of general formula

 in which R has the same meaning as above.

 formula  alcoholic medium, to give the (2-methoxy-ethyl) -4 phenol of c) split the ether (5) above with a mineral or organic acid, in  2. Method according to Claim 1 characterized in that R represents  a tetrahydropyrannyl, methoxymethyl, ethoxymethyl or  ethoxymethyl a-substituted by an alkyl radical. 3. Method according to Claim 1 characterized in that R represents  a cc-methylethoxymethyl group. 4. Method according to Claim 1 characterized in that the reaction (a)  is carried out in a mixture of ethyl ether / tetrahydrofurarme 60/40. 5. Method according to Claim 1 characterized in that X represents  bromine.