FR2487339A1 - 4-Methoxy-2-ethyl phenol prepn. - from a methoxy ethyl halide, magnesium, 4:bromo phenol ether and acid - Google Patents

Abstract

4-Methoxy-2-ethyl phenol of formula (I) is prepared from a 2-methoxy ethyl halide of formula CH3OCH2CH2X (II) (where X is Cl, Br or I). (II) is treated with Mg to form the corresp, halide. This is treated with a bromophenol ether of formula (III) (where R is a group that is easily removed below 70 deg.C by acid) to give 4-(2-methoxy ethyl)phenol ether offormula (IV) which is treated with an acid to give (I). The reaction in which R is a tetrahydropyranyl, methoxymethyl, ethoxymethyl, and alpha methyl or ethyl ethoxymethyl group is partic. pref. (I) is an intermediate for the prepn. of the cardiovascular agent metoprolol.

Description

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-methoxy-ethyl) -4 phenol is prepared by reacting (2-bromo-ethyl) -4 phenol with a mixture of anhydrous methanol and silver nitrate, then with sodium methylate. The crude product obtained is then esterified with 3,5-dinitrobenzoyl chloride and then saponified to give back the (2-methoxy-ethyl) -4 phenol.

The process according to the invention is completely different and consists in reacting 2-methoxyethyl bromide with a parabromophenol ether according to the synthetic route described below 1)) Methoxy-2-ethylmagnesium bromide (3 ) by reacting
2-methoxy-ethyl bromide (1) 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, such as ethers-oxides, in particular diethyl ether and tetrahydrofuran.

2-methoxyethyl bromide (1) is easily obtained by the action of phosphorus tribromide on 2-methoxy ethanol (which is an industrial alcohol) or better, by preparing 2-methoxyethyl benzene sulfonate (by the action of chloride benzenesulfonyl on 2-methoxy
ethanol in the presence of soda) and subjecting it to the action of bromide
sodium.

Instead of 2-methoxyethyl bromide, chloride can be used
or the corresponding iodide, which can be prepared from a
2-methoxyethyl arylsulfonate.

2) A (2-methoxy-ethyl) -4 phenol (5) ether is prepared by reacting
in tetrahydrofuran, 2-methoxy-ethylmagnesium bromide (3)
on a bromophenol ether (4)

All the ethers-oxides of parabromophenol (4), the group R of which can be eliminated at ambient temperature or below 700C by a mineral acid (hydrochloric or sulfuric) or better an organic acid (acetic or formic) are suitable for this reaction.

Among the values of R exhibiting these properties, there are, for example, 1 the values tetrahydropyrannyl (7), methoxymethyl (3), ethoxymethyl (9) or ethoxymethyl a-substituted by an aikyl radical, in particular methyl or ethyl.

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

3) L'éther-oxyde du (méthoxy-2 éthyl)-4 phénol (5) est scindé par un
acide minéral ou organique, en milieu généralement alcoolique, pour don
ner le (méthoxy-2 éthyl)-4 phénol (6)

CH30CH2- i C2H5OCH2-
(8) (9)

3) The ether-oxide of (2-methoxy-ethyl) -4 phenol (5) is split by a
mineral or organic acid, in generally alcoholic medium, for donation
ner (2-methoxy-ethyl) -4 phenol (6)

The reaction medium must be a homogeneous liquid dissolving both the ether-oxide (5) and the acid used. Alcohols, such as
methanol, ethanol, propanol or isopropanol, are suitable party
especially for this purpose.

The formation of the organomagnesium is initiated by adding bromide
of 2-methyl methoxy on magnesium in tetrahydrofuran. Once
the reaction initiated, the reaction medium is added simultaneously
two tetrahydrofuran solutions (1) and (4), this gives better
result that spi is added (4) on the organo-magnesian (3) already formed.

The example below illustrates in a nonlimiting manner the method according to the invention
Preparation of (2-methoxy-ethyl) -4 phenol 1) Raw materials
Mixture 1: magnesium turnings: 2.4 g (0.1 at. G.)
mercuric chloride: 0.2 g
anhydrous tetrahydrofuran: 12 ml
Mixture 2: methoxyethyl bromide: 14 g (0.1 mole)
anhydrous tetrahydrofuran: 28 mi
Mixture 3: (ethoxy-1 ethoxy) -4 bromobenzene: 18.5 g (0.075 mole)
anhydrous tetrahydrofuran: 20 ml 2) Procedure
In a 3-necked 250 cc flask equipped with mechanical stirring and two isobaric ampoules, mixture 1 is introduced and then 5 ml of mixture 2.

The mixture is heated slightly with stirring, which causes an attack on the metal and a release of heat which brings the temperature of the reaction medium to 600C.

The medium is then cooled to 0 ° C. and mixtures 2 and 3 are added simultaneously, so that the additions last approximately 3 hours and end at approximately the same time. During this time, the temperature is maintained at OOC.

The reaction medium is then allowed to return to ambient temperature while maintaining stirring.

The reaction medium is then poured into 250 ml of a 5% methanolic solution of 36% hydrochloric acid previously cooled to 0 C.

It is diluted with water and the medium is extracted several times with ether. The ethereal solution is finally washed with water until neutral and then dried over anhydrous sodium sulfate.

After removal of the solvent by vacuum distillation, 8 g of an oil are recovered which, according to thin layer chromatography, contains
50, ó of phenol
10% (2-methoxyethyl) -4 phenol
40% 4,4 'dihydroxy diphenyl
The (2-methoxy-ethyl) -4 phenol is then separated by chromatography on a silloagel column, with a mixture of petroleum ether (Eb. 450 - 600C) and 80/20 - 60/40 sulfuric ether as solvent. as an eluent for petroleum ether.

Phenol (2-methoxy-ethoxy) -4 is obtained with a yield of 10%.

Melting point: 420C.

Claims (6)

Claims 1. Process for the preparation of (2-methoxy-ethyl) -4 phenol, characterized in that  than  a) reacting a 2-methoxyethyl halide of formula  general  CH OCH CH X (1)  3 22  in which X represents chlorine, bromine or iodine, with  magnesium (2) to form the 2-methoxy-ethylmagnesium halide of  formula  CH3OCH2CH2MgX (3)  b) the 2-methoxyethylmagnesium halide (3) is reacted on a  bromophenol ether of general formula

 in which R represents a group which can be eliminated at room temperature or below 700C by a mineral or organic acid to form a (2-methoxy-ethyl) -4 phenol ether of general formula

 in which R has the above meaning c) the ether-oxide of (2-methoxy-ethyl) -4 phenol (5) is split by a  mineral or organic acid, in alcoholic medium, to form the  (2-methoxy ethyl) -4 phenol of formula

 2. Method according to Claim 1 characterized in that the reaction (a)  is carried out in diethyl ether or tetrahydrofuran. 3. Method according to Claim 1 characterized in that X represents  bromine. 4. Method according to Claim 1 characterized in that R represents a  tetrahydropyrannyl, methoxymethyl, ethoxymethyl, ethoxy group  methyl substituted by a methyl or ethyl radical. 5. Method according to Claim 1 characterized in that R represents  an a-methyl-ethoxymethyl group.  organo-magnesian (3).  and (b) are carried out simultaneously after starting the training  6. Method according to Claim 1 characterized in that steps (a)