FR2487338A1 - 4:methoxyethyl phenol prodn. from a 4:alkoxyphenyl bromide - and a methoxy aldehyde, nitrile or ester, used as intermediate for the cardiovascular agent metoprolol - Google Patents

Abstract

In the prepn. of 4-(2-Methoxyethyl) phenol (I) a 4-alkoxyphenyl bromide (II) (where R is a group that can be eliminated easily below 70 deg.C by treatment with an acid) is treated with magnesium to form the corresp. magnesium bromide, and this is condensed with a methoxy acetic derivative (III). CH3O-CH2R1 (III) (where R1=an acetaldehyde, nitrile, or a methyl or ethyl acetate function to form the derivative (IV) or (V). The protecting group R is removed and the ketone group on the phenol form (V) is catalytically hydrogenated to give (VI). Dehydration with acetic anhydride/acetic acid gives the esterified vinyl derivative (VII) and this is hydrogenated and saponified to give (I). The reaction in which R is tetrahydropyranyl, methoxymethyl, ethoxymethyl and alpha alkyl or ethyl ethoxymethyl is preferred.

Description

Improved 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 sciium methylate. 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 invention is completely different and consists in reacting an ether of parabromophenol and a methoxyacetic derivative having a functional group capable of reacting on the magnesium derivative of the ether of parabromophenol to form an ether of (hydroxy-1 methoxy2 ethyl) -4 phenol (1) or an ether of (2-methoxy acetyl) -4 phenol (2)

R represents a group which can be eliminated at a temperature below 70 ° C. and, in general, at ambient temperature by the action of a mineral acid (hydrochloric, sulfuric) or an organic acid (acetic, formic).

The preparation of (2-methoxy-ethyl) -4 phenol from (1) or (2) is carried out according to the diagram below - passage from (2) to (1) by catalytic hydrogenation carried out on the
phenols corresponding to (2) - dehydration of (1) to (2-methoxy-vinyl) -4 phenol or its acetate - saturation by catalytic hydrogenation of (2-methoxy-vinyl) -4 phenol
or its (4-methoxy-ethyl) -4-phenol acetate or its acetate - possible cleavage of (2-nethoxy-ethyl) -4-phenol acetate into (methoxy
2 ethyl) -4 phenol
The process according to the invention can be described in more detail as below 1) A 4-alkyloxyphenylmagnesium bromide (5) is prepared by reacting
gir a 4-alkyloxyphenyl bromide t3) on magnesium (4)

This reaction is carried out in the solvents generally used for the preparation of crgano-magmeses, or mixtures of such solvents, for example the ethers-oxides, in particular diethyl ether and tetraphhydrofuran. These latter solvents make it possible to vary the boiling point of the reaction medium and therefore the reaction temperature, which makes it possible to act on the yield and the quality of the (2-methoxy-ethyl) -4 phenol obtained.

2) On condense le bromure d'alkyloxy-4 phénylmagnésium sur un dérivé
méthoxyacétique de formule générale
CH3OCH2-R1 (10) dans laquelle R1 représente un groupement fonctionnel acétaldéhyde, nitrile ou acétate de méthyle ou éthyle.Among the values of R satisfying the conditions given above, there may be mentioned, for example, the groups tetrahyrannyl t5), methoxymethyl (7), ethoxymethyl (8) and ethoxymethyl a-substituted by an alkyl radical, in particular methyl or ethyl. It is more particularly the group α -methylethoxymethyl (9) yes was used

2) The 4-alkyloxyphenylmagnesium bromide is condensed on a derivative
methoxyacetic of general formula
CH3OCH2-R1 (10) in which R1 represents an acetaldehyde, nitrile or methyl or ethyl acetate functional group.

Condensation takes place in tetrahydrofuran, diethyl ether or a mixture of these two solvents, and by addition of the methoxyacetic derivative (70) to the organomagnesium.

The action of the compound (10), in which R1 represents an acetaldehyde function, on the organomagnesium (5) leads to a secondary alcohol (13):

The action of compound (10), in which R1 represents a nitrile or acetate function, leads to a ketone (14)

(5) 10, R1 = CN (14)
(10, R1 = COOCH3 or COOC2H5) 3) The ethers (13) and (14) are split respectively into (1-hydroxy-methoxy
2 ethyl) -4 phenol (15) and (2-methoxy acetyl) -4 phenol (16). Cleavage
takes place at the time of the hydrolysis of the organomagnesium by an acid
mineral (hydrochloric or sulfuric) or by an organic acid (aceti
that or formic)

These products (15 and 16) are isolated in the raw state and are directly
engaged in the rest of the synthesis.

4) If we used in the 2nd stage methoxynketonitrile or a metho
alkyl xyacetate, then (1-hydroxy-2-methoxy-ethyl) -4 is prepared
phenol (15) by catalytic hydrogenation of (2-methoxy acetyl) -4
phenol in acetic solution, in the presence of palladium carbon containing
5% palladium.

Hydrogenation can take place at room temperature and pressure
however, it is faster under pressure and at a temperature of 80 C.

The product (15) obtained in acetic solution is used as is for
following the synthesis.

If we used methoxyaldehyde in the 2nd step, we obviously pass
directly from the 3rd stage to the 5th.

5) (2-methoxy-vinyl) -4 phenyl acetate (17) is prepared in dehydra
both (1-hydroxy-2-methoxy-ethyl) -4 phenol (15).

To the acetic solution of (1-hydroxy-2-methoxy-ethyl) -4 phenol is added
an excess of acetic anhydride to acetylate the two hydroxyls, and this
in the presence of molten sodium acetate. The reaction medium is heated
at reflux to form, after deacetylation, 2-methoxy acetate
vinyl) -4 phenyl (17).

The product (17) is not isolated and is used directly in the next step in the form of the acetic solution obtained in the 5th step.

6) (2-Methoxy-ethyl) -4-phenyl (18) acetate is prepared by hydroge-
catalytic nation, in the presence of 5% palladium palladium carbon,
after filtration of the acetic solution (17) obtained in the phase
former

This hydrogenation is faster than that of phase 4 7) The (2-methoxy-ethyl) -4 phenol (19) is prepared by saponifying under
nitrogen atmosphere (2-methoxy-ethyl) -4 phenyl acetate (18)

The following example illustrates, in a nonlimiting manner, the method according to the invention.

Process for the preparation of (2-methoxyethyl) -4 phenol 1) Preparation of (1-ethoxy-ethoxy) -4 phenylmagnesium bromide
2.8 g (0.116 at. G.) Of magnesium in turnings, 2.8 g (0.011 mole) of (1-ethoxy-ethoxy) -4 bromobenzene and 10 ml of a mixture are introduced into a 250 cc reactor. diethyl ether tetrahydrofuran 60 40.

The mixture is heated slightly with stirring and an iodine crystal is added which colors the solution in yellow. A discoloration of the reaction medium is observed after a few minutes, followed by an attack on the metal.

 The exothermicity of the reaction brings the medium to the boil and a solution of 25.7 g (0.1 mol) of (1-ethoxy-ethoxy) -4 bromobenzene in 80 ml of an ether mixture is then added slowly. diethyl / tetrahydrofuran 60/40.

The addition is adjusted so as to maintain the boiling and lasts 1:30 to 2 hours. The boiling is then extended for 15 minutes to obtain a solution of (1-ethoxy-ethoxy) -4 phenylmagnesium bromide.

2) Preparation of I hydroxy-4 / -methoxyacetophenone
The above organo-magnesian solution is cooled to around 5 ° C. and a solution of 7.1 g (0.1 mole) of methoxyacetonitrile in 15 ml of diethyl ether is added slowly, while cooling.
The temperature is maintained between 0 and 59C for the entire duration of the introduction, ie approximately 1 hour.

The reaction medium is kept under stirring for 4 hours between 0 and 5 C and then poured into 400 ml of a 5% methanolic solution of 36% hydrochloric acid previously cooled to 0 C. After 15 minutes of stirring, diluted with 1 liter of water and extracted several times with diethyl ether. The ethereal solution is washed with water several times until it is true, dried over anhydrous sodium sulfate and then concentrated in vacuo. 18 g of a highly colored cloud containing a large quantity of hydroxy-4 # -methoxyacetophenlone are collected, the presence of which is revealed by thin layer chromatography on an HF 254 silica gel plate, with a 90/10 benzene / methanol mixture as solvent. After revelation with iodine or UV rays, an Rf of 0.15 is obtained.

3) Preparation of (1-hydroxy-2-methoxy-ethyl) -4 phenol
The oil obtained above is dissolved in 150 ml of glacial acetic acid 15 0 and the solution obtained is hydrogenated at QOOG under slight pressure (2 to 300 g), in the presence of 1.5 g of palladium on carbon. 5% palladium.

After the end of the absorption of hydrogen, the catalyst is filtered off and the acetic solution of (1-hydroxy-2-methoxy-ethyl) -4 phenol is directly used in the next step.

The above product identification has been carried out as follows
10 ml of the above acetic solution are taken and poured into 100 ml of water. The solution is extracted twice with 50 ml of diethyl ether, the ethereal solution is washed with water until neutral and it is dried over anhydrous sodium sulfate. The solvent is eliminated and 1 g of a brown oil is collected in which gold identifies the (1-hydroxy-2-methyl-ethoxy) -4 phenol by thin layer chromatography under the marly conditions as above: an Rf is obtained 0.10.

Is isolated pure product by column chromatography and a product is obtained whose melting point is 1400C.

4) Preparation of (2-methoxy-vinyl) -4 phenol acetate
15 cm3 of acetic anhydride and 1.5 g of molten sodium acetate are added to the acetic solution obtained in the preceding stage and the reaction medium is heated to reflux for two hours and with stirring, then allowed to cool until at room temperature.

Sodium acetate is removed by filtration and the solution of (2-methoxy-vinyl) -4 phenol acetate is collected in the mixture of acetic acid and acetic anhydride. This solution will be directly engaged in the next step.

(2-Methoxy-vinyl) -4 phenol acetate is identified as follows
A few cm3 of solution are taken and taken up with hot water to hydrolyze the excess acetic anhydride. The hydrolysis products are diluted with water and extracted with ether. The ethereal solution is washed with water until neutral and then dried over anhydrous sodium sulfate. After removal of the ether, an oil is obtained which is chromatographed on a thin layer under the same conditions as above.

An Rf of 0.70 is obtained.

5) Preparation of (2-methoxy-ethyl) -4-benzene acetate
The procedure is carried out from the solution obtained above and according to the same conditions as in the 3rd step.

The collected solution is directly engaged in the next step.

6) Preparation of (2-methoxy-ethyl) -4 phenol
A 10% aqueous sodium hydroxide solution is added to the above solution under a nitrogen atmosphere and until neutral.

300 ml of 10% sodium hydroxide are then added and the mixture is heated under reflux for 1 hour. It is taken up in water and acidified until it turns red
Congo. Extracted 3 times on 70 ml of diethyl ether, the ethereal solution is washed with water until neutral and dried over anhydrous sodium sulfate. The diethyl ether is eliminated and the residual oil is taken up in a petroleum ether / diethyl ether 90/10 mixture.

 Dn purifies the product by chromatography on a silica gel column with a petroleum ether / diethyl ether 80/20 mixture as eluent.

6 g of (2-mehoxy-ethyl) -4 phenol, melting at 420 ° C., are collected.

Yield: 40%.

The product is identified by thin layer chromatography under the same conditions as above. An Rf of 0.50 is obtained.

Claims (3)

Claims 1. Process for the preparation of (2-methoxy-ethyl) -4 phenol, characterized in  what  a) reacting 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, on magnesium to form a 4-alkyloxyphenylmagnesium bromide of general formula

 and when R1 represents a nitrile or acetate function a compound of general formula

 represents an acetaldehyde function, a compound of general formula  nitrile or methyl or ethyl acetate, to form when R1  in which R1 represents an acetaldehyde functional group,  CH3OCH2-R1 (10)  methoxyacetic derivative of general formula  in which R has the above meaning b) the 4-alkyloxy bromide ph.enylmagnesium (5) is condensed on a  in which R has the meaning give above.  (2-methoxy acetyl) -4 phenol (16) catalytic.  (1-hydroxy-2-methoxy-ethyl) -4 phenol (15) by hydrogenation  (2-methoxy acetyl) -4 phenol (16) d) when R1 represents a nitrile or an acetate,  to form (1-hydroxy-2-methoxy-ethyl) -4 phenol (15) or c) the ethers (13 and (14) are split by a mineral or organic acid  form phenyl (2-methoxy-vinyl) -4 acetate (17).  e) the (1-hydroxy-2-methoxy-ethyl) -4 phenol (15) is dehydrated to  catalytic hydrogenation of the compound (17).  f) (2-methoxyethyl) -4-phenyl acetate (18) is prepared by  ethyl) -4 phenyl (18) to form (2-methoxy-ethyl) -4 phenol (19).  g) the acetate of (methoxy-2) is saponified under a nitrogen atmosphere 2. Method according to Claim 1 characterized in that R represents  a tetrahydropyrahnyl, methoxymethyl, ethoxymethyl and  ethoxymethyl α -substituted by a methyl or ethyl radical.  an α -methyl-ethoxymethyl radical. 3. Method according to Claim 1 characterized in that R represents  mixture of these two solvents.  is carried out in ethyl ether, tetrahydrofuran or a r. Process according to Claim 1, characterized in that the reaction (a) 3. Method according to Claim 1 characterized in that the derivative  methoxyacetic (10) is added to the organomagnesium (5).