NO772604L - PROCEDURES FOR THE PREPARATION OF PHENOXYHYDROXYPROPYLAMIN DERIVATIVES - Google Patents

Description

Method of manufacture of

derivatives of phenoxyhydroxypropylamine.

The invention relates to a process for the production of new derivatives of phenoxy-hydroxypropylamine of the general formula:

where:

R. represents hydrogen, lower alkyl or lower cycloalkyl,

1*2 and R_ each represent lower alkyl, straight chain or

branched, or dimethoxyphenylethyl or phenylisopropyl, R^ may also be hydrogen, R represents hydrogen or halogen, lower alkyl,

lower alkoxy, lower cycloalkyl, nitro, allyl or acetyl,

n is 2 or 3 and

m is 0, 1, 2 or 3.

The term lower alkyl means a radical with 1-4 carbon atoms.

The invention also covers the preparation of pharmaceutically acceptable salts of these derivatives, e.g. chloral hydrate, oxalate, malonate and succinate.

The new compounds produced according to the invention have interesting pharmacological activities and may be useful in therapy as cardioselective ?-adrenergic blocking agents.

The compounds of particular interest are those with the following formulas:

where:

represents hydrogen or methyl or cyclopropyl, R2 represents isopropyl or tert-butyl or dimeth oxyphenylethyl or phenylisopropyl, R^ is hydrogen, R represents hydrogen or halogen or n-propyl,

alkyl or methoxy, and

n is 2 or 3.

The process according to the invention for the preparation of compounds of formula I comprises the following steps:

(a) reaction of a phenol of formula:

with an epihalohydrin to form a compound of formula: where Y is the group or where X represents a halogen atom, (b) reacting the compound of formula II with an amine HNI^R^ at a temperature between 20 and 150°C to form of the desired compound of formula I which is isolated and optionally converted into a non-toxic acid addition salt.

Step (b) can be carried out in a common organic solvent, in particular an alcohol, or without a solvent.

in the usual way, the compounds of formula II can be obtained by reacting a phenol of formula III with an epihalohydrin, e.g. epichlorohydrin or epibromohydrin.

The compounds can be isolated or obtained in a reaction mixture, and in the latter case they are used in the crude state without any purification.

The compounds of formula II where Y is the group

can be prepared by the action of epichlorohydrin or epibromohydrin on a phenol of formula III, previously metallized by means of common metallizing agents, e.g. sodium carbonate, potassium carbonate, methylates, ethylates, etc., in a hydroalcoholic environment, at a temperature between 20 and 150°C.

The compounds of formula II where Y is the group -CH-OH-CH^X can be prepared by the action of epichlorohydrin or epibromohydrin in excess on a phenol of formula III in the presence of a few drops of amine catalyst, e.g. piperidine, e.g. at a temperature between 20 and 150°C, optimally 95-lOO°C.

The phenols of formula III can be prepared by the action of a reducing agent, e.g. the double hydride of aluminum and lithium,, in an organic solvent, e.g. tetrahydrofuran or ether, on a butyrolactone of formula IV or on a ketoester of

fnrtnpl TV ' •

The phenols of formula III can likewise be prepared by the action of a dehydrating agent, e.g. paratoluenesulfonic acid in an organic solvent, benzene, toluene, xylene, etc.,

on diols of formula:

The butyrolactones of formula IV can be prepared by reduction, using et. reducing agent such as borohydride of sodium or potassium, in basic hydroalcoholic medium, of ketbic acids of the formulas VI and VI':

The diols of formula v can be prepared by reduction, using a reducing agent such as e.g. the double aluminium/lithium hydride, in an organic solvent, e.g. tetrahydrofuran or ether, of keto acids of formulas VI and VI1 or their esters or diacids of formula VII or their diesters:

The ketonic acid derivatives of formula VI can be prepared by demethylation with the aid of hydrobromic acid or pyridine chlorohydrate of derivatives of formula:

which itself is produced by the classical Friedel-Crafts reaction between a suitably substituted phenyl nucleus and succinic anhydride (n 2) or glutaric anhydride (n = 3).

The ketonic acid derivatives of formula VI■ or the diacids of formula VII where n = 2 can be obtained by hydrolysis of nitriles of formula : which are themselves obtained by addition of alkali cyanide to the ethylenic derivatives of formula:

Liberation of phenol can take place, in certain cases, by debenzylation using a catalytic hydrogenation of benzyl phenol.

The phenols of formula III can likewise be prepared by catalytic hydrogenation of phenols of formula XI or benzyl phenols of formula XII:

The phenols of formula XI are prepared by reduction in a basic environment, with sodium or potassium borohydride, of ketone phenols of formula:

The benzylphenols of formula XII are produced by a classic condensation reaction between an aldehyde and an acetophenone, which is often substituted, in a basic environment.

The ketone phenols of formula XIII are prepared, e.g. in the demethylation of compounds of formula XIV with the help of the hydrohydrate of pyridine: e.g. by the classic Fries reaction on an ester of formula:

In formulas XIII, XIV and XV, m is at least equal to 1. The compounds of formula XIV are themselves prepared by a Friedel-Crafts reaction on a methoxybenzene which is often substituted.

Introduction of a substitution R = allyl can take place by

a classical Claisen rearrangement on the phenol of formula III, where R = H which has been previously allylated with an allyl halide in a basic environment.

Introduction of a substitution R = COCH^ can take place by a Fries rearrangement on the phenol of formula III where R = H is previously acetylated.

When the phenol starting from formula III does not contain any halogen (R = H), the introduction of a halogen can be carried out by the action of ethhalogen or N-halogenosuccinimide on the same phenol.

In the following, the invention will be illustrated by means of non-limiting examples.

EXAMPLE 1

4- hydroxy- 3- chlorobenzoyl- 3- propionic acid

Formula VI: R = Cl, n = 2

A solution of 515 g of 4-methoxy-3-cl<p>rbenzoyl-3-propionic acid, prepared by the Friedel-Crafts reaction between succinic anhydride and orthochloranxsol, 850 cm 3 of hydrobromic acid of 66% concentration in. 850 cm 3 of acetic acid is brought to reflux for 12 hours.

The reaction mixture is cooled immediately, and they crystallize

that has formed is suctioned off, washed carefully with water and dried.

350 g of 4-hydroxyT3-chlorobenzoyl-3-propionic acid is thus obtained, in the form of crystals with a melting point of 159°C

EXAMPLE 2.

4- hydroxy- 3- chlorophenyl- 5- butyrolactone

FORMULA IV:- R = H, R = Cl , n = 2 , ra = .0

To a solution of 100 g of 4-hydroxyl-3-chlorobenzoyl-3-pyridionic acid, obtained as indicated in Example 1, and 50 g of sodium... ' ' 3 3

carbonate in lozenge form in 200 cm of distilled water and .500 cm of meta-. noi, 50 g of potassium borohydride are added. After everything has been added, it is boiled under reflux cooling. 2 hours.

The cooled reaction mixture is then poured onto ice and hydrochloric acid. After a night's rest, the crystals that have formed are suctioned off, washed carefully with water and dried. 85 g of the aviittel compound are thus obtained, in the form of crystals with a melting point of 142-145°C.

EXAMPLE 3

4- hydroxy- 3- chlorophenyl- 2- tetrahydrofuran

FORMULA III: R-^ = H , R = Cl, n = 2, m = 0

42.5 g of 4-hydroxy-3-chlorophenyl-5-butyrolactone, obtained

.. 3

according to example 2, in solution in 200 cm 3 of tetrahydrofuran, is added dropwise to a suspension of 7.6 g of the double aluminium/lithium hydride in 200 cm 3 tetrahydrofuran.

The reaction mixture is then agitated for 4 hours at ambient temperature. After cooling the reaction mixture, an aqueous, saturated solution of sodium sulfate is carefully added dropwise. When the double hydride no longer reacts, the reaction mixture is poured onto ice and hydrochloric acid, the organic products are extracted with ether, the extract is washed with water and dries. After evaporation of the ether, the obtained residue, weighing 36 g, is filtered over silica gel. By elution with dichloromethane, 26 g of

o the title compound in the form of white crystals with a melting point of 65 C.

EXAMPLE 4

.[ o- chloro- p-( 2 '- tetrahydrofuranyl)]- 1- phenoxy- 3- chloro- propanol- 2 FORMULA II: R^ = H, R = Cl, Y = CH0H-CH2-Cl, n = 2 , m =0 A mixture of 10 g of (4-hydroxy-3-chlorophenyl)-2-tetrahydrofuran, obtained according to Example 3, 30 cm 3 of epichlorohydrin and 6 drops of piperidine is brought to 95-100°C in the course of 6 hours. The reaction mixture is then concentrated under vacuum, and

the obtained oily residue containing the desired product is used crudely for the following operations.

EXAMPLE 5

[o-chloro-p-(2'-tetrahydrofuranyl)}-l-phenoxy-isopropylamino-3-propanol-2

FORMULA I: R^= H, R = Cl, R2= isopropyl, R3 = H,

n = 2, m = 0

A solution of 13.9 g of [o-chloro-p-(2'-tetrahydrofuranyl)]-1-phenoxy-chloro-3-propanol-2 (obtained according to example 4) and 30 cm<3>isopropylamine in 30 cm methanol to 20°C.

The reaction mixture is then concentrated under vacuum,<p>g it is then taken up with 10% hydrochloric acid.

The neutral products are extracted 3 times with ether. The water phase is then cooled to 0°C and alkalized with a 10% aqueous sodium carbonate solution. The amino alcohol is extracted with chloroform, the extract is washed with water, dried over sodium carbonate and decolorized with activated charcoal.

After filtering and evaporating the solvent, the obtained residue which crystallizes is suctioned off, after which recrystallization is carried out in isopropyl ether.

6 g of the title compound are thus obtained in the form of white crystals which melt at 68-69°C.

EXAMPLE 6

2 - ( p- benzyloxyphenyl)- butanediol- 1, 4

Benzyl derivative of the compound V where R^ = R H, n = 2

178 g of 2-(p-benzyloxyphenyl)-succinic acid is added in small portions with a spatula to a suspension of 40 g of double aluminium/lithium hydride in one liter of tetrahydrofuran, with good stirring.

After the addition is finished, you continue to agitate

6 hours at ambient temperature. It is then cooled to 0°C and a saturated,. aqueous solution of sodium sulfate.

When the double aluminium/lithium hydride no longer reacts, suction is applied. The filtrate is concentrated under vacuum, and the residue is taken up with petroleum ether. The crystals that have formed are suctioned off. 96 g of the title compound is thus obtained in the form of white crystals, with a melting point of 96-98°C.

EXAMPLE 7

3-(p-benzyloxyphenyl)-tetrahydrofuran

Benzyl derivative of the compound of formula III, wherein

R-j_ = H, n = 2, m = 0

A solution of 95 g of 2-(p-benzyloxyphenyl)-butanediol-1,4, obtained according to example 6, and 20 g of paratoluenesulfonic acid in 300 cm of toluene is refluxed for 2 hours with a water separator.

The reaction mixture is cooled, washed with water, a 5% solution of sodium carbonate and again with water. After drying over

sodium sulfate frees the organic phase from the solvent by evaporation, the evaporation residue with. weight 75 g is filtered over silica gel with benzene as eluent. 59 g of the title compound are thus obtained in the form of white crystals with a melting point below 50°C.

EXAMPLE 8

(p-hydroxyphenyl)-3-tetrahydrofuran

FORMULA III: R-L=R = H,n = 2,m = 0.

A solution of 59 g of (p-benzyloxyphenyl)-3-tetrahydrofuran, obtained as stated in example 7, is hydrogenated at ordinary pressure and ambient temperature in 300 cm^ of methylcellosolve containing 4 g of 5% Pd/C.

After absorption of the theoretical amount of hydrogen, the catalyst is separated by filtration, and the mother liquid is evaporated under vacuum. The crystals obtained are recrystallized in toluene. 22.4 g of the title compound are thus isolated in the form of white crystals with a melting point of 97-99°C.

EXAMPLE 9

[p-(tetrahydrofuranyl-3')]-phenoxy-3-epoxy-1,2-propane

FORMULA II: R1= R = H, Y =

n = 2, m = 0

A solution of 9 g of (p-r-hydroxyphenyl)-3-tetrahydrofuran, obtained as indicated in example 8, 3.7 g of potassium carbonate dissolved in 40 cm 3 of water and 10 cm<3> is stirred for 24 hours at ambient temperature

3

epichlorohydrin in 250 cm ethanol.

The reaction mixture is then concentrated under vacuum, taken up in chloroform, washed with water, with a 5% solution of sodium carbonate and then with water. After the chloroform phase is dried, the solvent is evaporated and 11.9 g of the title compound are obtained in the form of an oil which is used in the following step in the crude state. EXAMPLE 10

[ p-( tetrahydrofurahyl- 3']- 1- phenoxy- isbpropylamino- 3- propanol- 2

FORMULA I: R^= R = H, R2 = isopropyl , R^= H, n = 2,.

m - 0 in the course of 7 hours a solution of 11.9 g of [(p-tetrahydrofuranyl-3')]-phenoxy-3-epoxy-1, 2-

propane, obtained as stated in example 9, and 30 cm 3 isopropylamine in 40 cm 3 isopropanol to 120-130 C. The reaction mixture is then concentrated under vacuum and taken up with 10% hydrochloric acid. The neutral products are extracted three times with ether i.

The water phase is then cooled to 0°C and made alkaline in the cold with an aqueous 10% solution of sodium carbonate. The amino alcohol is extracted with chloroform, the extract is washed with water, dried over sodium carbonate and decolorized with activated charcoal. After filtration and evaporation of the solvent, the obtained oily residue is crystallized by trituration in a pentane/ether mixture. By recrystallization of the obtained crystals in cyclohexane, 7 g of the title compound are isolated in the form of white crystals with a melting point of 48-49°C. EXAMPLE 11

[ o- chloro- p-( tetrahydrofuranyl- 2')]- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: . R± = H, R = Cl, Y =

n = 2, m = 0

One uses the method according to example 9, but uses 29 g of (4'-hydroxy-3'-chlorophenyl)-2-tetrahydrofuran, . obtained as stated in example 3. 35 g of the title compound is recovered in the form of an oil which is used in the crude state for the following step.

EXAMPLE 12

[ o- chloro- p-( tetrahydrofuranyl- 2')]- 1- phenoxy- tert.- butylamino- 3- propanol- 2- chlorohydrate

FORMULA L.: R-j^ .= H, R = Cl , R2 tert.-butyl, R3 = H,

n = 2, m = 0

In the course of 7 hours, a solution of 12 g of [o-chloro-p-(tetrahydrofuranyl-2')]-3-phenoxy-epoxy-1,2-propane obtained as stated in example 11 is brought into the remelted tube, and 30 cm 3 of tert-butylamine in 40 cm"<3>isopropanol to 120-130°C.

The reaction mixture is then concentrated under vacuum, taken. up with 10% hydrochloric acid, to achieve an acidic pH value, and the neutral products are extracted 3 times with ether. The hydrochloride is then extracted for the mother liquor by three extractions in chloroform.

The chloroform phase is dried over sodium sulfate, and the chloroform is evaporated under vacuum. The obtained evaporation residue is taken up with ether, and the crystals that have formed are suctioned off. After recrystallization in acetone, 6.5 g of the title compound are obtained in the form of white crystals with a melting point of 147-148°C.

EXAMPLE 13

[o-chloro-p-(tetrahydrofuranyl-2'.)]-1-phenoxy-(3",4"-dimethoxyphenyl)-3-ethylamino-propanol-2

FORMULA I: R1 - H, R = Cl,

n = 2, m = 0

One works according to the procedure according to example 12, but starting from 12 g of [o-chloro-p-(tetrahydrofuranyl-2')]-3-phenoxy-epoxy-1,2-propane , obtained as indicated in Example 11, and log homoveratrylamine. 8 g of the title compound are obtained in the form of white crystals with a melting point of 130-133°C.

EXAMPLE 14.

(p-hydroxyphenyl)-2- tetrahydrofuran

FORMULA III: R^ = R = H, n = 2, m = 0

A solution of 216 g of the ethyl ester of p-hydroxybenzoyl-3-propionic acid in 1 liter of tetrahydrofuran is added dropwise to a suspension of 55 g of the double aluminum/lithium hydride in 1 liter of tetrahydrofuran, allowing the exothermic reaction to develop and monitoring the dropwise per drop. The addition lasts 1 hour and 30 minutes. The reaction mixture is then allowed to stand under stirring

3 hours and then rest overnight.

After cooling the reaction mixture, a little ethyl acetate is added and then, carefully, a saturated aqueous solution of sodium sulphate. When the hydride no longer reacts, the mixture is emptied on ice and hydrochloric acid, the organic products are extracted with methylene chloride, the extract is dried and evaporated.

After recrystallization of the obtained residue in toluene, 120 g of the title compound are recovered in the form of white crystals with a melting point of 110°C.

EXAMPLE 15

[p-(tetrahydrofuranyl-21)]- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: R1 = R = H,

Proceed as indicated in example 9, but by using 12 g of (p-hydroxyphenyl)-2-tetrahydrofuran obtained as indicated in example. 14. 16 g of the title compound are recovered in the form of an oil which is used in the crude state in the following step.

■ EXAMPLE 16

[ p-(tetrahydrofuranyl- 2')]- 1- phenoxy- isopropylamino- 3- propariol- 2

FORMULA I, Rj^ .= R = H ,■ R2= isopropyl, R3 = H,n = 2,

m = 0

One proceeds as indicated in example 5, but using 14 g of [p-tetrahydrofuranyl-2')]-3-phenoxy-epoxy-1,2-propane obtained as indicated in example 15. One recovers, after recrystallization ..in petroleum ether, gave the title compound in the form of white crystals with a melting point of 57-58°C. To make the hydrochloride of this base, it is dissolved in acetone and neutralized by the addition of hydrochloric acid ether. The crystals that form are filtered off and washed with ether. The chloral hydrate is thus recovered in the form of white crystals with a melting point of 112-115°c.

EXAMPLE 17

[ p-(tetrahydrofuranyl- 2')]- 1- phenoxy- tert.- butylamino- 3- propanol- 2

FORMULA I: R-^ '= R = H, R2 = tert-butyl, R3 = H, n = 2,

m - 0 Proceed as indicated in example 5, but use 16 g of [p-(tetrahydrofuranyl-21)]-3-phenoxy-epoxy-1,2-propane, obtained as

■ .. 3 .

indicated in example 15, and 30 cm tert.-butylamm. After recrystallization in a mixture of ether and petroleum ether, 12 g of the title compound are recovered in the form of white crystals with a melting point of 69-71°C. EXAMPLE 18

( 4- hydroxy- 3- allylphenyl)- 2- tetrahydrofuran

FORMULA III: R- L = H, R = allyl, n = 2, m = 0

49.2 g of (p-hydroxyphenyl)-2-tetrahydrofuran, obtained as indicated in example 14, is methylated with sodium methylate obtained from 7.6 g of sodium in 300 cm 3 of methanol. 43.5 g of allyl bromide is then added to this solution, after which the whole is boiled under reflux for 3 hours. The reaction mixture is then concentrated under vacuum, water is added and extracted with ether. The extract is washed with a 5% sodium carbonate solution, then with water and dried over sodium sulphate. After evaporation of the solvent, the obtained residue (57 g) is dissolved in 300 cm 3 diphenyl oxide, and the solution is refluxed for 1 hour and 30 minutes. The reaction mixture is then cooled, and the phenol is extracted. with a 10% potassium carbonate solution. The alkaline phase is extracted with ether, acidified cold using 10% hydrochloric acid. The phenol is then extracted with chloroform, the extract is washed with water and

dried over sodium sulfate. After evaporation of the solvent, the obtained residue (46 g) is filtered over a little silica gel

the eluent is benzene. 36 g of the title compound is thus recovered in the form of a colorless oil.

EXAMPLE 19

[ o- allyl- p-( tetrahydrofuranyl- 2')]- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II, Rx = H, R = allyl,

n = 2.,

m = 0

Proceed as indicated in example 9, but use 24 g of (4-hydroxyallyl-3-phenyl)-2-tetrahydrofuran, obtained as in example 18. 28 g of the title compound is recovered in the form of an oil which is used in the crude state for following steps: EXAMPLE 20

[- o- allyl- p-( tetrahydrofuranyl- 2')]- 1- phenoxy- isopropylamino- 3- propanol- 2- chlorohydrate

FORMULA I: R1 H, R = allyl, R2= isopropyl, R3= H,

n - 2, m = 0

Proceed as indicated in example 12, but use 14 g of [o-allyl-p-(tetrahydrofuranyl-21)]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 19, and 30 cm of isopropylamm . After recrystallization in ethyl acetate, 9.1 g of the title compound is obtained in the form of white crystals with a melting point of 102-104°c. EXAMPLE 21

[o-allyl-p-(tetrahydrofuranyl-2')]-lr-phenoxytated. - butylamino-2-propanol-2-chlorohydrate

FORMULA I: R1= H, R = allyl, R2= tert-butyl, R3 = H,

n = 2, m = 0

Proceed as indicated in example 12, but use 14 g of [o-allyl-p-(tetrahydrofuranyl-2<1>)]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 19, and 30 cm 3-tert.-butylamine. After recrystallization in an acetone/ether mixture, 10.8 g of the title compound is obtained in the form of white crystals with a melting point of 103-105°C.

EXAMPLE 22

(Hydroxy-4-bromo-3-phenyl)-2- tetrahydrofuran

FORMULA III: R± = H, R = Br, n = 2, m =0

To a solution of 31 g of (p-hydroxyphenyl)-2-tetrahydrofuran o 3 , . obtained as indicated in example 14, in 100 cm dimethylformamide, is added dropwise, while cooling with a mixture of water <p>g ice, a solution of 33 g N-bromosuccinimide 1 100 cm 3 dimethylformamide. The product is allowed to adjust to ambient temperature and .

then stir for 5 hours.

After standing overnight, water is added to the reaction mixture, and the organic products are extracted with ether. The phenol is extracted from the ether base with a 10% aqueous sodium carbonate solution. The alkaline phase is acidified in the cold with 10% hydrochloric acid, and the phenol is extracted with ether. The extract is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is crystallized in pentane. After recrystallization in a heptane/ether mixture, 3.5 g of the title compound are recovered in the form of white crystals with melting point 67-69°C.

EXAMPLE 23

[ o- bromo- p-( tetrahydrofuranyl- 2')]- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: R1= H, R = Br,

One proceeds as indicated in example 9, but uses 12 g of (hydroxy-4-bromo-3-phenyl)-2-tetrahydrofuran, obtained as indicated in example 22. One recovers. 14.5 g of the title compound in the form of an oil which is used in the crude state in the following step.

EXAMPLE 24

[o-bromo-p-(tetrahydrofuranyl-2')]-1-f enoxy-isopropyl. lamino-3-propanol-2

FORMULA I , . R^ = H, R = Br, R2= isopropyl , R^ = H,

n = 2, m = 0'

Proceed as indicated in example 5, but use 8 g of [o-bromo-p-(tetrahydrofuranyl-2')]-3-phenoxy-3-epoxy-1,2-propane, obtained as indicated in example 23, and 20 cm 3 of isopropylamine. After recrystallization in isopropyl ether, 5.3 g of the title compound are recovered in the form of white crystals with a melting point of 75-77°V. EXAMPLE 25

[ o- bromo- p-^ tetrahydrofuranyl- 2')]- 1- phenoxy- tert.- butylamino- 3-propanol- 2- chlorohydrate

FORMULA I: R^= H, R = Br, R2= tert-butyl, R3= H,

Proceed as indicated in example 12, but use 14.5 g of [o-bromo-p-(tetrahydrofuranyl-2<1>)]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 23, and 30 cm 3 tert.-butylamine. After recrystallization in an acetone/ether mixture, 12 g of the title compound are obtained in the form of white crystals with a melting point of 142-144°C.

EXAMPLE 26

[ o- bromo- p-( tetrahydrofuranyl- 2')]- 1- phenoxy- 3", 4"-( dimethoxyphenyl)- ethylamino- 3- propanol- 2- chlorohydrate

FORMULA I : R^= H, R = Br , n = 2 , m = 0

Proceed as indicated in example 12, but use 14 g of [o-bromo-p-(tetrahydrofuranyl-2<1>)]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 23, and 10 g homoveratrylamine. After recrystallization in acetone/ether, 6.2 g of the title compound is obtained in the form of white crystals with a melting point of 116-120°C. EXAMPLE 27

[o-bromo-p-(tetrahydrofuranyl-2')]-1-phenoxy-(ff-phenyl)-isopropylamino-3-propanol-2-chlorohydrate

FORMULA ,I:R1=H, R = Br, n = 2, m = 0

Proceed as indicated in example 12, but use 13 g of [o-brpm-p-(tetrahydrofuranyl-2')]-3-phenoxy-epoxy-1,2-propane. obtained as indicated in Example 23, and 6.5 g of desamfetamine. After recrystallization in an acetone/ether mixture, 2.9 g of the title compound is obtained in the form of white crystals with a melting point of 132-138°C.

EXAMPLE 28

(4-hydroxy-3-allylphenyl)-3-tetrahydrofuran

FORMULA III: Rx = H, R = allyl, n = 2, m = 0

One proceeds as indicated in example 18, but uses 11.4 g of (p-hydroxyphenyl)-3-tetrahydrofuran, obtained as indicated in example 8. One obtains 8 g of the title compound in the form of white crystals with a melting point of 50-52°C .

EXAMPLE 29

[ o- allyl- p-( tetrahydrofuranyl- 3')]- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: R^ = H, R = allyl,

m = 0

n = 2,

Proceed as indicated in example 9, but use: 8 g of (4-hydroxy-3-allylphenyl)-3-tetrahydrofuran, obtained as indicated in example 28. 9 g of the title compound is recovered in the form of oil

which is used in the raw state for the following steps:

EXAMPLE 30

[ o- allyl- p- tetrahydrofuranyl- 3')]- 1- phenoxy- isopropylamineb- 3- propanol- 2- chlorohydrate

FORMULA I: R1 = H, R = allyl, R2 = isopropyl, R^ = H,

n = 2, m = 0

Proceed as indicated in example 12, but use 9 g of [o-allyl-p-(tetrahydrofuranyl-3<1>)]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 29, and 30 cm 3isopropylamine. After recrystallization in ethyl acetate, 4.5 g of the title compound is obtained in the form of white crystals with a melting point of 91-93°C. EXAMPLE 31

( 4- benzyloxy- 3- methoxyphenyl)- 2- butanediol- 1, 4.

Benzyl derivative. of the compound of formula V where R^ = H,

R = 0CH3, n = 2

Proceed as indicated in example 6, but use 144 g.

(4-Benzyloxy-3-methoxyphenyl)-2-succinic acid. 105 g of the title compound is obtained in the form of a thick oil which is used in the crude state for the following operations.

EXAMPLE 32

(4-behzyloxy-3-methoxyphenyl)-3-tetrahydrofuran

Benzyl derivative of compound III where R^= H, R = 0CH3, n = 2, m = 0

Proceed as indicated in example 7, but use 105 g of (4-benzyloxy-3-methoxyphenyl)-2-butanediol-1,4, obtained as indicated in example 31. 83 g of the title compound is recovered in the form of an oil which used in the raw state for the following operations. EXAMPLE 33

( 4- hydroxy- 3- methoxyphenyl)- 3- tetrahydrofuran

FORMULA III: R1H, R = 0CH3 , n = 2, m = 0

Proceed as indicated in example 8, but use 83 g of (4-benzyloxy-3-methoxyphenyl)-3-tetrahydrofuran, obtained as indicated in example 32. After filtering over silica gel, the eluent being methylene chloride, 31 g of the title compound is recovered in the form of white crystals with a melting point of 65-68°C..

EXAMPLE 34

[o-methoxy-p-(tetrahydrofuranyl-3')]-3-phenoxy-epoxy-1,2-propane.

FORMULA II: R1= H, R = 0CH3,

n = 2, m = 0

Proceed as indicated in example 9, but use 19.7 g

(4-hydroxy-3-methoxyphenyl)-3-tetrahydrofuran, obtained as indicated in example 33. 25 g of the title compound is recovered in the form of an oil which is used in the crude state for the following operations. EXAMPLE 35

[ o- methoxy- p-( tetrahydrofuranyl- 3')]- 1- phenoxy- isopropylamino- 3-propanol- 2

Proceed as indicated in example 5, but use 10 g of [o-methoxy-p-(tetrahydrofuranyl-3')]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 34, and 30 cm 3 of isopropylamine. After recrystallization in isopropyl ether, 3.5 g of the title compound is recovered in the form of white crystals with a melting point of 53-54°C. EXAMPLE 36

[ o- methoxy- p-( tetrahydrofuranyl- 3')]- 1- phenoxy- tert.- butylamino-3- propanol- 2- chlorohydrate

FORMULA I: R1 = H, R = 0CH3 , R2 = tert-butyl, R^ = H,

n=2, m=0

Proceed as indicated in example 12, but use 10 g of [o-methoxy-p-(tetrahydrofuranyl-3')]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 34, and 30 cm <3>tert-butylamine. After recrystallization in ethyl acetate, 4.3 g of the title compound is recovered in the form of white crystals with a melting point of 99-100°C. EXAMPLE 37

( p- benzyloxyphenyl)- 3- cyano- 3- cyclopropyl- l- propanone- l

FORMULA IX: R= H, R-^ = cyclopropyl 97.5 g of (p-benzyloxyphenyl)-3-cyclopropyl-1-propen-2-one-1 is dissolved, while heating near reflux, obtained by Claisen condensation of p-benzyloxybenzaldehyde and methylcyclopropyl ketone, in 1.2 liters of methanol and 120 cm 3 of ethyl acetate. A solution of 60 g • is quickly added dropwise to this solution. 3'. sodium cyanide in 120 cm of water.

After the addition is complete, reflux cooling is carried out for 5 hours, the reaction mixture is then concentrated to half, it is cooled and slowly, with good stirring, 500 cm 3 of water is added. The crystals obtained are filtered off, washed carefully with water and dried. One thus recovers 90 g of the title compound in the form of manage,

beige crystals with melting point -85-86°C.

EXAMPLE 38

( p- benzyloxyphenyl)- 3- carboxy- 3- cyclopropyl- l- propanone- l

FORMULA VI': R = H, R-j^ = cyclopropyl

Reflux cooling is carried out for 24 hours on a solution of 85 g of (p-benzyloxyphenyl)-3-cyano-3-cyclopropyl-1-propanone-1, obtained as indicated in example 37, 40 g of sodium carbonate in 75 cm

3

water and 750 cm ethanol.

The reaction mixture is then cooled and poured into 2 liters of water and ice, after which it is extracted three times with ether. The mother liquor is acidified in the cold with 10% hydrochloric acid, and the acid is extracted three times with ether. The extract is washed with water and dried over sodium sulphate. After evaporation of the ether, mari recovers 75.4 g of the title compound in the form of white crystals with a melting point of 96°C. EXAMPLE 39

( p- benzyloxyphenyl)- 3- cyclopropyl- l- butanediol- l, 4

Benzyl derivative of the compound of formula V where R = H,

R^ = cyclopropyl, n = 2

Proceed as indicated in example 6, but start from 48.6 g of (p-benzyloxyphenyl)-3-carboxy-3-cyclopropyl-1-propanol-1, obtained as indicated in example 38. 38 g of the title compound is obtained in the form of white crystals with a melting point of 125°C. EXAMPLE 40

(p-benzyloxyphenyl)-4-cyclopropyl-2-tetrahydrofuran

Benzyl derivative of the compound of formula III where R = cyclopropyl, R = H, n = 2, m = 0

Proceed as indicated in example 7, but use 38 g of (p-benzyloxyphenyl)-3-cyclopropyl-1-butanediol-1,4, obtained as indicated in example 39. After filtering over silica gel, the eluent being benzene, 29 g of the title compound in the form of an oil. EXAMPLE 41'

( p- hydroxyphenyl)- 4- cyclopropyl- 2- tetrahydrofuran

FORMULA III: R^=cyclopropyl>R=H,n=2, m=0

Proceed as indicated in example 8, but use 29 g of (p-benzyloxyphenyl)-4-cyclopropyl-2-tetrahydrofuran, obtained as indicated in example 40. 19 g of the title compound is recovered in the form of white crystals with a melting point of 79-80 °C.

EXAMPLE 42 p-(cyclopropyl-2'-tetrahydrofuranyl-4')-1-phenoxy-1-chloro-3-propanol-2

FORMULA II: Rx = cyclopropyl, R = H, Y = CH0HCH2Cl, n = 2, m = 0

A mixture of 16.2 g of (p-hydroxyphenyl)-4-cyclopropyl-2-tetrahydrofuran, obtained as indicated in example 41, is brought

75 cm 3 of epichlorohydrin and 6 drops of piperidine at 95-100°Ci for 7 hours. The reaction mixture is then concentrated under vacuum, and the residue is collected

up with ether. The ether solution is washed in the cold with 5.0 cm 3 of 5% hydrochloric acid, and then three times with 50 cm<3> of water. It is then dried and then the ether is evaporated under vacuum. 22 g of the title compound are thus isolated in the form of an oily residue which is used in the crude state for the following operations.

EXAMPLE 43 p-(2'-cyclopropyl-tetrahydrofuranyl-4')-1-phenoxy-isopropylamino-3-propanol-2-chlorohydrate

FORMULA I: R^= cyclopropyl, R = H, R2= isopropyl, R=H,n = 2,m =0

3

Proceed as indicated in example 12, but use 11 g of p-(2'-.cyclopropyl-tetrahydrofuranyl-4')-1-phenoxy-1-chloro-3-propanol-2, obtained as indicated in example 42 , and 40 em 3 isopropylamine. After recrystallization in an acetone/ether mixture, 8.3 g of the title compound is obtained in the form of white crystals with a melting point of 100°C.

EXAMPLE 44. p-(2'-cyclopropyl-tetrahydrofuranyl-4')-1-phenoxy-t. ert. - butylamino-3-propanol-2-chlorohydrate

FORMULA I: R^ = Cyclopropyl, R = H, R^ = tert.-butyl,

R3 = H, n = 2, m = 0

Proceed as indicated in example 12, but use where 11 g p-(2'-cyclopropyl-tetrahydrofuranyl-4')-1-phenoxy-3-chloro-propanol-2, ■

obtained as stated in example 42, and 40 cm 3 of tert-butylamine. After recrystallization in an acetone/ether mixture, 9.7 g of the title compound are obtained in the form of white crystals with a melting point of 135°C. EXAMPLE 45

( 4- hydroxy- 3- bromophenyl)- 3- tetrahydrofuran

FORMULA III: R^= H, R = Br, n = 2, m = 0

Proceed as indicated in example 22, but use 18.3 g of (p-hydroxyphenyl)-3-tetrahydrofuran, obtained as indicated in example

8. After filtration over silica gel, the eluent being methylene chloride, 18 g of the title compound is obtained in the form of a colorless oil. EXAMPLE 46

[ o- bromo- p-( tetrahydrofuranyl- 3')]- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: R-^ = H, R = Br,

n = 2, m = 0

Proceed as indicated in example 9, but use 18 g of (4-hydroxy-3-bromophenyl)-3-tetrahydrofuran, obtained as indicated in example 45. 21.5 g of the title compound is recovered in the form of an oil which is used in raw state for the following step: EXAMPLE 47

[ o- bromo- p-( tetrahydrofuranyl- 3')]- 1- phenoxy- isopropylamino- 3- propanol- 2- chlorohydrate

FORMULA I: ;R'1= H, R = Br, R2= isopropyl, R' = H,

n = 2, m = 0

Proceed as indicated in example 5, but use 11 g of [o-bromo-p-(tetrahydrofuranyl-3')]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 46, and 30 cm 3 of isopropylamine. [o-bromo-p-tetrahydrofuranyl-3')]-1-phenoxy-isopropylamino-3-propanol-2 is recovered. To make the hydrochloride of this base, it is dissolved in acetone and neutralized by adding hydrochloric acid ether. The crystals that form are filtered off and washed with ether. 7.2 g of the chloral hydrate are thus recovered in the form of white crystals with a melting point of 147-149°C. EXAMPLE 48

[.

FORMULA I: R = H, R = .Br, R2 = tert.-butyl , R^ = H,

Proceed as indicated in example 12, but use 10 g of [o-bromo-p-(tetrahydrofuranyl-3 1 )]-3-phenoxy-epoxy-1, 2-propane, obtained as indicated in example 46 , and 30 cm3 of tert-butylamine. After recrystallization in isopropanol, 8 g of the title compound are recovered in the form of white crystals with a melting point of 144-147°C.

EXAMPLE 49

( p- hydroxybenzoyl)- 4- butyric acid

FORMULA VI: R = H, n =.3 . Proceed as indicated in example 1, but start from 85 g of (p-methoxybenzoyl)-4-butyric acid, produced by Friedel-Crafts reaction between glutaric anhydride and anisole. 31 g of the title compound are obtained in the form of crystals with a melting point of 190-195°C.

EXAMPLE 50

(p-hydroxybenzoyl)-4-butyric acid ethyl ester

FORMULA IV': R = H,.n 3

A solution of 31 g is boiled under reflux for 6 hours

(p-hydroxybenzoyl)-4-butyric acid., obtained as indicated in Example 4.9,

3. 3

in 250 cm of ethanol containing 2 cm of concentrated sulfuric acid.

The solution is then concentrated under vacuum, the residue is taken up in methylene chloride, washed with water and dried over sodium sulphate. After evaporation of the solvent, the residue crystallizes, and the crystals are washed with it. pentane. One thus isolates 30 g of the title compound in the form of white crystals with a melting point of 75-78°C. EXAMPLE 51

(p-hydroxyphenyl)-2- tetrahydropyran

FORMULA III: R;L=R= H,n=3,m = 0

One proceeds as indicated in example 14, but starts from

30 g of the ethyl ester of (p-hydroxybenzoyl)-4-butyric acid, obtained

as stated in example 50. After filtration over silica gel, the eluent being a methylene chloride/ether mixture 9:1, 12 g of the title compound in the form of white crystals with a melting point of 81-83°C are recovered. ,

EXAMPLE 52

[p-(tetrahydropyranyl-2')]- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: R-^= R = H,

n = 3, m = 0

One proceeds as indicated in example 9, but uses 11.5 g of (p-hydroxyphenyl)-2-tetrahydropyran, obtained as indicated in example 51. One recovers 14 g of the title compound in the form of an oil which is used in the crude state in following steps.

EXAMPLE 53

[p-(tetrahydropyranyl-2')]- 1- phenoxy- isopropylamino- 3- propanol- 2

FORMULA I^R^ = R = H, R2= isopropyl, R^ = H, n = 3,

m = 0

You go forward. as indicated in Example 5, but using 14 g of [p-(tetrahydropyranyl-21)]-3-phenoxy-epoxy-1,2-propane, obtained

as indicated in Example 52, and 30 cm 3 of isopropylamine. After recrystallization in pentane, 10.7 g of the title compound is recovered in the form of white crystals with a melting point of 67-68°C.

EXAMPLE 54

(2-p-hydroxyphenyl)-4-methyltetrahydrofuran

FORMULA III: R H, R^ = CH3, n = 2, m = 0

A solution of 26.5 g of the ethyl ester of p-hydroxybenzoyl-3-methyl-2-propionic acid in 110 cm 3 tetrahydrofuran is added dropwise to a suspension of 6.3 g of the double aluminium/lithium hydride in 110 cm 3 tetrahydrofuran , allowing the exothermic reaction to develop and controlling it by the dropwise addition. The addition lasts for 1 1/2 hours, the mixture is then allowed to stir for 3 hours and then rests overnight.

After cooling the reaction mixture, a little ethyl acetate is added and then, carefully, a saturated, aqueous solution of sodium sulfate. When the hydride no longer reacts, the mixture is poured onto ice and hydrochloric acid, the organic products are extracted with methylene chloride, the extract is dried and the solvent is evaporated. The obtained residue (19 g) is filtered over silica gel, the eluent being dichloromethane. 9 g of the title compound are thus recovered in the form of white crystals with a melting point of 118°C. EXAMPLE 55

p-(4'- methyl- 2- tetrahydrofuranyl)- 3- phenoxy- epoxy- 1, 2-propane

FORMULA II: R= H, R1= CH3, h = 2, m = 0,

A solution of 9 g of (p-hydroxyphenyl)-2-methyl-4-tetrahydrofuran, obtained as stated in example 43, 3.2 g of potassium carbonate dissolved in 20 cm"^ 3 is stirred for 24 hours at ambient temperature. .3

water and 10 cm epichlorohydrin in 150 cm ethanol.

The reaction mixture is then concentrated under vacuum, taken up with chloroform, washed with water, with a solution of 5% sodium carbonate and then with water. After the chloroform phase has been dried, the solvent is evaporated and 10 g of the title compound is obtained in the form of an oil which is used in the crude state for the following step.

EXAMPLE 56

p-(4'- methyl- tetrahydrofuranyl- 2')- 1- phenoxy- isopropylamino- 3-propanol 2

FORMULA I: R^= R = H, R^= CH3, n 2, m = 0, R2=

isopropyl

A mixture of 10 g of p-(4'-methyl-tetrahydrofuranyl-2')-3-phenoxy-epoxy-1,2-propane, obtained as stated in example 55, and 20 cm 3 of isopropylamine is left for 48 hours in a stoppered flask.

The reaction mixture is then concentrated under vacuum, the residue obtained is taken up with ether, and the basic products are extracted with a 10% aqueous solution of hydrochloric acid.

The acidic phase is made alkaline in the cold, and the organic products are extracted with ether, the extract is dried and evaporated.

The residue obtained crystallizes in pentane. After recrystallization in pentane, 4.2 g of the title compound is recovered in the form of white crystals with a melting point of 59-62°c.

EXAMPLE 57

(p-benzyloxyphenyl)-1-3-propen-2-one-1

FORMULA III: . R .= R, = H, n = 2

3

Mari dissolves 60 g of p-benzyloxy-acetophenone and 24 g of furfural in 150 cm3 of ethanol in heat. The solution is then cooled and 1.3 g of potassium carbonate dissolved in 15 cm 3 of 95% ethanol is added. The reaction mixture is stirred at ambient temperature for 3 hours and then 150 g of ice is added. The crystals that have formed are suctioned off, washed with water. and dried.. 78 g of the title compound are thus recovered

in the form of crystals with a melting point of 114°C.

EXAMPLE 5 8

(p-hydroxyphenyl)-1-(tetrahydrofuranyl:-2')-3-propane

FORMULA III: ^ = R = H, n = 2, m = 3

A solution of 78 gjp-(benzyloxyphenyl)-1-furyl-3-propene-2-. on-1, obtained as indicated in Example 57, in 400 cm^ of methanol is subjected to hydrogenation for 7 hours with 70 kg of hydrogen and at 120°C, in the presence of Ni-Raney previously washed with a 10% solution of hydrochloric acid and then twice with water.

The reaction mixture is then filtered, concentrated under vacuum, and the residue taken up with chlorodimethylmethane. The organic phase is extracted with a 10% solution of potassium carbonate. The alkaline water phase is acidified in the cold with hydrochloric acid, and the organic products are extracted with ether. The ether phase is washed with water, dried, and the ether is evaporated under vacuum. One thus recovers 13 g of the title compound in the form of a thick oil which is used as it is for the following operations.

EXAMPLE 59

| p-[(tetrahydrofuranyl-2')-3-propyl]phenoxy-3-epoxy-1,2-propane

FORMULA II: R = Rx = H, n = 2, m = 3,

Proceed as indicated in example 55, but use 11.5 g of (p-hydroxyphenyl)-1-(tetrahydrofuranyl-2')-3-propane, obtained as indicated in example 58. 14 g of the title compound are recovered in the form of an oil which is used in the crude state for subsequent steps. EXAMPLE 60

| p— I (tetrahydrofuranyl-2')-3-propyl]-phenoxyl-1-isopropylamino-3-propanol-2

FORMULA I: R' = R^= R^ = H, n = 2, m = 3, R2 = isopropyl, Over the course of 7 hours, in a remelted tube, a

solution of 14 g of β-[(tetrahydrofuranyl-2■)-3-propyl]-phenoxyj-3-epoxy-1,2-propane, obtained as indicated in Example 59, and 30 cm'<3>isopropylamine in 30 cm^ isopropanol to 120-130°C.

The reaction mixture is then concentrated under vacuum and

taken up with 10% hydrochloric acid. The neutral products are extracted three times with ether.

The aqueous phase is then cooled to 0°C and made alkaline in the cold with a 10% aqueous sodium carbonate solution. The amino alcohol is extracted with chloroform, the extract is washed with water, dried over sodium carbonate, decolorized with activated charcoal. After filtration and evaporation of the solvent, 7.5 g of one oily residue is recovered. The maleate is made from this oily residue by adding maleic acid dissolved in acetone. the salt crystallizes in an acetone/ether mixture. The crystals are suctioned off, washed with an acetone/ether mixture and dried. 8.2 g of the title compound are thus recovered in the form of white crystals of maleate with a melting point of 127-129°C. EXAMPLE 61

( Furyl- 2 ) - ( ip- methoxy enyl) - ketone

FORMULA XIV: R = R = J., n = . 2, m = 1

A mixture of 270 g of furan-2-carboxylic acid, 340 g of anisole and 2 kg of polyphosphoric acid is stirred for 4 hours at 55°C. The reaction mixture is then poured onto ice, and the organic products are extracted with ether, the extract is washed carefully with water, with a 5% sodium carbonate solution and then again with water and dried. After evaporation of the solvent, the obtained oily residue is subjected to distillation under vacuum. 262 g of the title compound are thus recovered in the form of white crystals,

KPo™m Hg = 160-168°C, m.p. = 56-58°C

c2mm Hg

EXAMPLE 62

(Furyl-2)-(p-hydroxyphenyl) ketone

FORMULA XIII, R^ = R = H, n = 2., m 1

A mixture of 30 g of (furyl-2)-(p-methoxyphenyl)ketone, obtained as stated in example 61, and 90 g of pyridine chlorohydrate is brought to 210°C over the course of 1 hour. The reaction mixture is then poured onto ice, and the precipitation product that has formed is sucked off. This precipitation product is then taken up in a 5% potassium carbonate solution. The aqueous, alkaline solution is carefully washed with ether, and acidified in the cold. The crystals obtained are suctioned off and dried. 16.5 g of the title compound are thus recovered in form. of white crystals with melting point 163°C.

EXAMPLE 63

p-furfurylphenol

FORMULA. XI: R^= R = H, n = 2 , m

One brings a solution of 14.5 g (furyl-2) -. (p-hydroxyphenyl)ketone, obtained as indicated in Example 62, in 65 cm 3 of water containing 6 g of potassium carbonate, at 70-80°C.

Carefully add 12 g of potassium borohydride to this solution with a spatula. The reaction mixture is then heated on a boiling water bath for 4 hours.

It is then poured onto ice and acidified at 0°C with 10% hydrochloric acid. The organic products are then extracted with ether, the extract is washed with water and dried. The oily residue of 12 g which is obtained is distilled under vacuum. 9 g of the title compound are thus recovered in the form of white crystals.

Kp„ mm _ _. = 135 - 138°C, m.p. below 50°C.

2 mm Hg

EXAMPLE 64

p-tetrahydrofurfurylphenol

FORMULA III: R1= R = H, n = 2, m = 1 .

A solution of 10 g of p-furfurylphenol, obtained as indicated in Example 63, in 100 cm 3 of water containing 2.6 g of sodium carbonate in the presence of 2 g of Ni-Raney, is hydrogenated for 1 hour and 15 minutes with 50 kg of hydrogen and at 110°C. The reaction mixture is then filtered to separate the catalyst, and the filtrate is extracted with ether. The alkaline water phase is acidified at 0°C with 10% hydrochloric acid. and the organic products are extracted with ether. The ether phase is washed with water and dried. The ether is evaporated under vacuum, and the oily residue (8 g) is distilled under vacuum. 5 g of the title compound are thus recovered in the form of a colorless oil.

Kp0c mm „ = 155-158°C.

^3.5 ram Hg

EXAMPLE 65 p-tetrahydrofurfuryl-3-phenoxy-epoxy-1,2-propane

FORMULA II: R=R1=H, n = 2, m = 1,

Proceed as indicated in example 55, but use 5 g of p-tetrahydrofurfurylphenol, obtained as indicated in example 64. 5.8 g of the title compound is recovered in the form of an oil which is used in the crude state for the following step.

EXAMPLE 66

p- tetrahydrofurfury1- 1- phenoxy- isopropylamino- 3- propanol- 2

FORMULA I: R = R][= R3= H, n = 2, m = 1, R2= isopropyl Proceed as indicated in example 56, but use 2.5 g of p-tetrahydrofufuryl-3-phenoxy-epoxy- 1,2-propane, obtained as stated in example 65. 2.4 g of the title compound is recovered in the form of white crystals with a melting point of 58-60°C.

EXAMPLE 67

o- bromo- p- tetrahydrofurfurylphenol

FORMULA III: R^= H, R = Br, . n = 2, m = 1

To a solution of 8 g of p-tetrahydrofurfurylphenol, obtained as indicated. tt in example 64, 8.5 g of N-bromosuccinimide are added with a spatula in small portions to 100 cm of 3dimethylformamide, cooled by a mixture of water and ice. The mixture is allowed to return to ambient temperature at the end of the addition and then stirred for 6 hours

and leave the mixture overnight. The reaction mixture is then added to ice water, and the organic products are extracted with water. The ether phase is washed with water and dried. After evaporation of the ether, a residue of 10 g is obtained. This residue is taken up with a mixture of ether/acetbn/petroleum ether. The insoluble product that separates (1.2 g), corresponding to o-dibromo-p-tetrahydrofurfurylphenol (m.p. = 143-147°C), is removed by filtration. The filtrate is evaporated under vacuum, and the filter residue crystallizes. After recrystallization of the crystals obtained in isopropyl ether, 4.5 g of the title compound are recovered in the form of white crystals with a melting point of 89-91°C.

EXAMPLE 68

o- bromo- p- tetrahydrofurfuryl- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: Rx = H, R.= Br , n = 2, m = 1,

One proceeds as indicated in example 55, but applies

4.5 g of o-bromo-p-tetrahydrofurfurylphenol, obtained as indicated in example 67. 5 g of the title compound are recovered in the form of an oil used in its crude state for the following step.

EXAMPLE 69

o- bromo- p- tetrahydrofurfury1- 1- phenoxy- tert.- butylamino- 3- propanol- 2

FORMULA I: ^ =..R3= H, R = Br, n = 2, m = 1, R2~tert-butyl

Proceed as indicated in example 56, but use 5 g of b-bromo-p-tetrahydrofurfuryl-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 68, and 10 cm of 3-tert.-butylamm. An oil is extracted which is dissolved in ether and hydrochloric acid ether is added. The hydrochloride that is formed crystallizes and is suctioned off, washed with ether and then recrystallized in isopropanol. One thus extracts. 4 g of the title compound in the form of white crystals of chloral hydrate with a melting point of 164-166°C.

. EXAMPLE 70

( 4- hydroxy- 3- chlorophenyl)- 2- methyl- 4- tetrahydrofuran

FORMULA III : R = Cl , Rj_ = CH3, n 2 , m = 0

15 .8 g of N-chlorosuccinimide in solution in 80 cm 3 of dimethylformamide, in small portions. At the end of the addition, the mixture is allowed to return to ambient temperature and then stirred for 8 hours, after which the mixture is allowed to stand for 24 hours. Water and ice are then added to the reaction mixture, and the organic products are extracted with ether.

The ether phase is washed with water and dried. After evaporation of the ether, a residue of 24.6 g is obtained. This residue is triturated in an ether/peritane mixture and the crystals that form are filtered off and recrystallized in isopropyl ether. 14.4 g of the title compound are thus recovered in the form of white crystals with a melting point of 101-103°C. EXAMPLE 71

[ o- chloro- p-( methyl- 4'- tetrahydrofuranyl- 2')]- 3- phenoxy- epoxy-1, 2- propane

FORMULA II, R =Cl, Rx =C<H>3, n = 2, m =0,

A solution of 4.3 g of (hydroxy-4-chloro-3-phenyl)-2-methyl-4-tetrahydrofuran, obtained as indicated in example 70, 1.5 g of potassium carbonate is stirred for 24 hours at ambient temperature dissolved in 3 3 . 3 10 cm water and 7.5 cm epichlorohydrin in 75 cm ethanol.

The reaction mixture is concentrated under vacuum, taken up with chloroform, washed with water, with a 5% sodium carbonate solution and then with water. After the chloroform phase is dried, the solvent is evaporated and 5.2 g of the title compound are obtained in

form of an oil which is used in its crude state for the following step. EXAMPLE 72

[ O- chloro- p-( methyl- 4'- tetrahydrofuranyl- 2')]- 1- phenoxy- isopropylamino- 3- propanol- 2- chlorohydrate

FORMULA I: R = Cl, Rx C<H>3, R3 = H, n 2, m = 0, R2 isopropyl

In a stoppered flask, a mixture of 6.5 g of [o-chloro-p-(methyl-4<1->tetrahydrofuranyl-2')]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 71, and 15 cm 3 of isopropylamine to stand for 48 hours.

The reaction mixture is then concentrated under vacuum, the residue obtained is taken up with ether and the basic products are extracted with a 10% aqueous hydrochloric acid solution.

The acidic phase is made alkaline in the cold, and the organic products are extracted with ether, the extract is dried and evaporated.

The oily residue (6 g) that is obtained is dissolved in 50 cm 3 of ether, and hydrochloric acid ether is added in the cold to an acidic pH value. The crystals obtained are suctioned off and washed carefully with ether. After drying, 5.7 g of the title compound are recovered in the form of white crystals

down melting point 102-104°C.

EXAMPLE 7 3

[ o- chloro- p-( methyl- 4'- tetrahydrofuranyl- 2')]- 1- phenoxy- tert.- butylamino- 3- propanol- 2- maleate

FORMULA I: R = Cl, Rx = CH3 , R3 = H, n = 2, m = 0,

R 2 = tert-butyl.

You proceed as indicated in example 72, but use

5.2 g of [o-chloro-p-(methyl-4'-tetrahydrofuranyl-2')]-3-phenoxy-.' epoxy-1,2-propane, obtained as indicated in Example 71, and 15 cm<3>tert-butylamine, recovering 5.7 g of base in the form of an oily residue. The maleate is made from this residue by adding maleic acid to an ether/acetone mixture. After washing with ether and suctioning off the crystals that have formed, 6.1 g of the title compound is recovered in the form of white crystals with a melting point of 91-94°C. EXAMPLE 74

o-chloro-p-tetrahydrofurfurylphenol

FORMULA III, R1=H, R=Cl, n=2, m=1

You proceed as indicated in example 70, but use .

20g of p-tetrahydrofurfurylphenol, obtained as indicated in example 64, and obtains after recrystallization in an isopropyl ether/pentane mixture 17.2 g of the title compound in the form of white crystals with a melting point of 54-57°C.

EXAMPLE 75

o-chloro-p-tetrahydrofurf. uryl- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II, R-,^= H, R = Cl , n = 2, m = 1,

You proceed as indicated in example 71, but use

8.6 g of o-chloro-p-tetrahydrofurfurylphenol, obtained as indicated in example 74. 10 g of the title compound are recovered in the form of a. oil used in its crude state for the following step.

EXAMPLE 76

p- chloro- p- tetrahydrofurfuryl- phenoxy- l- isopropylamino- 3-.

propanol-2-chlorohydrate

FORMULA I: Rx = R3 = H, R = Cl, n = 2, m = 1, R2 =

isopropyl.

You proceed as indicated in example 72, but use

10 g of o-chloro-p-tetrahydrofurfuryl-3-phenoxy-epoxy-1,2-propane,

obtained as indicated in Example 75, and 20 cm 3 of isopropylamine, and recovers the base in the form of an oily residue. This residue is dissolved in 50 cm^ of ether, and hydrochloric acid ether is added in the cold to an acidic pH value. The crystals obtained are suctioned off and washed carefully with ether. After drying, 9.3 g of the title compound are recovered in the form of white crystals with a melting point of 99-102°C.

EXAMPLE 77 o-chloro-p-tetrahydrofurfuryl-l-phenoxy- tert.-butylamino-3-propanol-2-chlorohydrate

FORMULA I: R, = R0= H, R - Cl, n = 2, m = 1, R =

1 3 . , 2 tert.-butyl

One proceeds as indicated in example 72, but using 8 g of o-chloro-p-tetrahydrofurfuryl-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 75, and 15 cm of tert.-butylamine, one recovers the base in the form of an oily residue. This oily residue is dissolved in 50 cm 3 of ether, and cold hydrochloric acid ether is added to an acidic pH value. The crystals obtained are suctioned off and washed carefully with ether. After drying, 5.2 g of the title compound are recovered in the form of white crystals with a melting point of 128-131°C.

EXAMPLE 7 8 p-tetrahydrofurfuryl-1-phenoxy-tert.-butylamino-3-propanol-2-maleate FORMULA I: R^ = R3= R = H, n = 2, m = 1, R2 = tert.-butyl .

One proceeds as indicated in example 72, but uses 12 p-tetrahydrofurfuryl-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 65, and • 20 cm 3 tert.-butylamine, and recovers the base in the form of an oily residue. The maleate is made from this residue by adding maleic acid to an acetone/ether mixture. After suctioning off and washing the crystals that have formed, . with ether, 11 g of the title compound are recovered in the form of white crystals with a melting point of 144-147°C.

EXAMPLE 79

(5-methyl-2-furyl)-(p-methoxyphenyl)-ketone

FORMULA XIV: Rx = CH3, R=H,n=2,m=1

The magnesium salt of 4-bromoanisole is prepared by starting from 150 g of 4-bromoanisole and 20 g of magnesium in 400 cm 3 of anhydrous tetrahydrofuran. To this magnesium-containing solution, a solution of 75 g of 5-methyl-2-furylnitrile in . 100 cm 3 of tetrahydrofuran. After everything has been added, you stir for 1 hour at the temperature in the laboratory and then carry out 4 hours of reflux cooling.

The reaction mixture is then cooled and ice and 300 cm<3>20% sulfuric acid are added. It is then stirred for 1 hour at the temperature in the laboratory and then 2 1/2 hours at 60°C.

After cooling and adding water, extract with ether, wash with water and dry over sodium sulphate. After evaporation of the ether, the obtained residue of 127 g is distilled under vacuum. One thus recovers 96 g of the title compound in the form of

a f heirless .ol je. Kp- __ = 205-215°G.

J ^2mm Hg

EXAMPLE 80

(5-methyl-2-furyl)-(p-hydroxyphenyl)-ketone

FORMULA XIII: R^ = CH^, R = H, n = 2., m = 1

To a solution of 96 g of (5-methyl-2-furyl)-(p-methoxyphenyl)-ketone, obtained as indicated in Example 79, in 150 cm 3 of chlorobenzene, 96 g of aluminum chloride is carefully added with a spatula. After everything has been added, the reaction mixture is heated for 1 hour at 130°C. It is then cooled, water and chloroform are added and the organic phase is separated. This organic phase is then extracted with a 10% potassium carbonate solution. The basic phase is then acidified in the cold, and the precipitate that has formed is suctioned off and washed with water. After drying, 84 g of the title compound are recovered in the form of white crystals with a melting point of 201°C.

EXAMPLE 81

p-(5-methyl-furfuryl)-phenol

FORMULA XI: R1=CH3, R=.H, n=2, m=-1

A solution of 84 g of (5-methyl-2-furyl)-(p-hydroxyphenyl)-ketone, obtained as indicated in Example 80, in 830 cm 3 of water containing 46.5 g of potassium carbonate, is brought to 70-80° C. 45 g of potassium borohydride is carefully added to this solution with a spatula.

The reaction mixture is then heated at boiling water bath i

.1 1/2 hours. It is then cooled, poured onto ice and acidified at 0°C with 10 "^ hydrochloric acid. The organic products are extracted with ether, the extract is washed with water and dried. After evaporation of the solvent, the obtained oily residue (85 g) is distilled under vacuum. 50.7 g of the title compound is thus recovered

in the form of an oil. Bpn__ 130-135°C.

Jc Lmm Hg

EXAMPLE 82

p-(5-methyl-tetrahydrofurfuryl)-phenol

FORMULA III: R-^= CH3, R H,n = 2,m=l A solution of 50.7 g of p-(5-methylfurfuryl)-phenol, obtained

... 3

as indicated in Example 81, in 200 cm of water containing 19.5 g of sodium carbonate in the presence of 10 g of Ni-Raney, is hydrogenated for 1 hour<p>g 15 minutes with 50 kg of hydrogen at 110°C. The reaction mixture is then filtered to separate the catalyst, and the filtrate is extracted with ether; The aqueous, alkaline phase is acidified at 0°C with 10% hydrochloric acid, and the organic products are extracted with ether. The ether phase is washed with water and dried, the ether is evaporated under vacuum and the oily residue is distilled under vacuum. One thus recovers 20 g of the title compound in the form of white crystals

numbers. Kp,, TT = 160-175°C, m.p. = 77°C.

^2mm Hg . r

Eczema PEL 83

p-(5- methyltetrahydrofurfuryl)- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: Rx = CH3, R = H, n = 2, m = 1,

You proceed as indicated in example 71, but use

7 g of p-(5-methyltetrahydrofurfuryl)-phenol, obtained as indicated in

example 82.. 9 g of the title compound are recovered; in the form of a. oil which is used in its raw state for the next step.

EXAMPLE 84 p-(5-methyl-tetrahydrofurfuryl)-1-phenoxy-isopropylamino-3-propanol-2-male' at

FORMULA I : R = H , R^ = CH3 , n = 2 , m = 1 , R3= H,

R 2 = isopropyl

Proceed as indicated in example 72, but use 9 g of p-(5-methyl-tetrahydrofurfuryl)-3-phenoxy-epoxy-1,2-propah,

obtained as indicated in Example 83, and 20 cm 3 of isopropylamine, and recovers the base in the form of an oily residue. Drain the remaining stock

the maleate is obtained by adding maleic acid in an ether/acetone mixture. After recrystallization of the obtained crystals in acetone, 5.8 g of the title compound are recovered in the form of white crystals with a melting point of 102-103°C.

EXAMPLE 85 o-bromo-p-(5-methyl-tetrahydrofurfuryl)-phenol

FORMULA III: Rx = CH3, R = Br, n = 2, m = 1

You proceed as indicated in example 70, but use

7.3 g of p-(5-methyl-tetrahydrofurfuryl)-phenone, obtained as indicated in Example 82, and 6.8 g of N-bromosuccinimide, and after recrystallization in heptane obtain 6.3 g of the title compound in the form of white crystals with melting point 101°C.

EXAMPLE 86 o-bromo-p-(5-methyl-tetrahydrofurfuryl)-3-phenoxy-epoxy-1,2- propane

FORMULA II :' R = CH3 , R = Br , n = 2 , m = 1 ,

You proceed as indicated in example 71, but use

6.3 g of o-bromo-p-(5-methylated rahydrofurfuryl)-phenol, obtained as indicated in example 84. 7.3 g of the title compound are recovered in the form of an oil which is used in raw state for the following .step. EXAMPLE 87

[ o- bromo- p-(5- methyltetrahydrofurfuryl)]- 1- phenoxy- tert.- butylamino- 3- propanol- 2- maleate

FORMULA I: R = Br, R^= CH3, n = 2, m = 1 , R3 = H ,

R2 = tert-butyl Proceed as indicated in example 72, but use

7.3 g of [o-bromo-p-(5-methyltetrahydrofurfuryl)]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in Example 86, and 20 cm 3 of tert-butylamine, recovering 7 g of the base in the form of an oily residue.

The maleate is made from this residue by adding maleic acid to an ether/acetone mixture. The crystals obtained are suctioned off and washed

kes with ether. 7.7 g of the title compound are thus recovered in the form of white crystals with a melting point of 85-88°C.

EXAMPLE 88

(2-furyl)-(4-methoxy-3-n-propylphenyl)-ketone

FORMULA XIV: R^ = H, R = n-propyl, n = 2, m = 1.

To a solution of 64 g of 2-n-propyl-1-methoxybenzene

in . 600 cm 3 of dichloromethane, which contains in suspension 60 g of aluminum chloride, is added dropwise by cooling with a water/ice mixture, a solution of 56 g of furan-2-carboxylic acid chloride in 100 cm 3 of dichloromethane .

The reaction mixture is then stirred for 3 hours and. 30 minutes at the temperature in the laboratory. It is then emptied onto a mixture of water and ice acidified with hydrochloric acid. The dichloromethane phase is decanted, washed with water, with a solution of 5% sodium carbonate and then again with water and dried over sodium sulfate. After evaporation of the solvent, the residue is distilled under vacuum. One thus recovers 112.5 g of the title compound in the form of a colorless liquid.

CP? mm n„ = 175-190°C.

2 mm Hg

EXAMPLE 89

( 2- furyl)-( 4- hydroxy- 3- n- propylphenyl)- ketone

FORMULA XIII: R^= H, R = n-propyl, n = 2, m = 1

One proceeds as indicated in Example 80, but uses 112.5 g of (2-furyl)-(4-methoxy-3-n-propylphenyl)-ketone, obtained as indicated in Example 88, and recovers 95.5 g of the title compound in the form of white crystals with a melting point of 102°C..

EXAMPLE 90

o- n- propyl- p- furfurylphenol

FORMULA XI: R1 = H, R = n-propyl, n' = 2, m = 1

You proceed as indicated in example 81, but use

95 g of (2-furyl)-(4-hydroxy-3-n-propylphenyl)-ketone., obtained as

stated in Example 89, and recovered after distillation under vacuum

26 g of the title compound in the form of a colorless oil. Kp~ = .. ^2 mm Hg = 158-160°C

EXAMPLE 91 o-n-propyl-p-tetrahydrofurfurylphenol

FORMULA III: R^ - = H, • R = n-propyl, n = 2, m = 1

A solution of 25.8 g of o-n-propyl-p-furfuryl enol, obtained 3 as indicated in Example 90, in 100 cm of water, containing 8.1 g of potassium carbonate in the presence of Raney nickel, is hydrogenated for 16 hours with 40 kg of hydrogen at ambient temperature.

The reaction mixture is filtered to separate the catalyst, and the filtrate is extracted with ether. The alkaline phase is acidified at 0°C with 10% hydrochloric acid, and the organic products are extracted with ether. The ether phase is washed with water and dried, the ether is evaporated under vacuum, and the oily residue (25 g) is distilled under vacuum. 21 g of the title compound is thus recovered in the form of a colorless oil. Kp„ __ = 185°C.

J. 2 mm Hg

EXAMPLE 9 2

.[ o- n- propyl- p- tetrahydrofurfuryl[- 3- phenoxy- epoxy- 1, 2- propane

FORMULA II: R1= H, R = n-propyl, n = 2, m = 1,

Proceed as indicated in example 71, but use 21 g of o-n-propyl-p-tetrahydrofurfurylphenol, obtained as indicated in example 91. 24.3 g of the title compound is recovered in the form of an oil which is used in the crude state for the following step.

EXAMPLE 9 3

[ o- n- propyl- p- tetrahydrofurfuryl[- 1- phenoxy- tert.- butylamino- 3-propanol- 2- maleate

FORMULA I: R = H, R = n-propyl, n = 2, m = 1, = H,

R2 tert-butyl

Proceed as indicated in example 72, but apply 14.3. g [o-n-propyl-p-tetrahydrofurfuryl[-3-phenoxy-epoxy-1,2-propane, obtained as indicated in Example 92, and 25 cm 3 of tert-butylamine, and recover 9.2 g of base in the form of an oily residue. The maleate is made from this residue by adding maleic acid to an acetone/ether mixture. After suctioning off the crystals that have formed and washing them with ether, 10.9 g of the title compound are recovered in the form of white crystals with a melting point of 106-108°C.

EXAMPLE 94

[ o- n- propyl- p- tetrahydrofurfuryl]- 1- phenoxy- isopropylamino- 3- propanol- 2- chlorohydrate

FORMULA I: R1= H, R = n-propyl, n = 2, m = 1,

: R 1 = H, R 2 - isopropyl

One proceeds as indicated in example 72, but uses 10 g of [o-n-propyl-p-tetrahydrofurfuryl]-3-phenoxy-epoxy-1,2-propane, obtained as indicated in example 92, and 20 cm 3 of isopropylamine-, and 7.4 g of base are recovered in the form of an oily residue. This residue is dissolved in 50 cm 3 of ether, and cold hydrochloric acid is added to an acidic pH value. The crystals obtained are suctioned off and washed carefully with ether. After drying, 7.5 g of the title compound are recovered in the form of white crystals with a melting point of 108-111°C.

The pharmacological properties of the products produced according to the invention are demonstrated in the following experiments.

I - CARDIOVASCULAR HEMODYNAMICS IN DOGS

A) PROPER CONDUCT

Method

Mixed litter dogs, male or female, are anesthetized with sodium mebubarbital (30 mg/kg I.V.) and artificially ventilated with a

Pesty pump RPP. They are supplemented with oxygen. One measures:

The systolic (P.A. syst.) and diastolic (P.A. Diast.)

pressure in the carotid artery;

heart rate (F.C.);

the contractile force of the heart muscle (F.Co.). [The signals are amplified and recorded on the BeckmanDynograph.

Man :calculates:

the mean arterial pressure (P.A. mean) = diastolic pressure + 0.43 (systolic pressure diastolic pressure)..

the products from the examples are injected into the parent vein,

in doses of 0.125, 0.50, 2 and 4 mg/kg, dissolved in a"9 ^oo aqueous solution of sodium chloride.

Results

Table I below shows the average of the results obtained in percent variation in relation to the original value, for the different cardiac parameters that have been studied, for the products from each example.

B) ^- BLOCKING EFFECT

Method

The /3-blocking adrenergic activity of the various examples has been studied in the same dogs, in relation to the effects ( 31 and /3 2 of isoprenaline.

One calculates the percentage inhibition of the effects /?1 (reinforcement of the myocardial contractile force) and the effects

( 32 (reduction of diastolic arterial pressure) for isoprenaline, as a function of doses (mg/kg I.V.) of products from the various examples.

Results

Tables II and III below show the average percentage inhibition of the effects ( 31 and ( 32) of isoprenaline for the different products.

IT - TOXICITY

The lethal dose 50 for rats, of products from the various examples, is between 64 and 256 mg/kg. These products are administered intraperitoneally.

In conclusion, the products of the examples show a/31-blocking activity, and can be administered as a therapeutic for angina pectoris and elevated blood pressure in daily oral doses of 100 to 400 mg, or intravenously at 25 to 100 mg.

These products can be presented as tablets of 25 and 100 mg, or in ampoules with injectable solution in doses of 5 and 25 mg.

Claims (4)

1. Process for the preparation of derivatives of phenoxy-hydroxypropylamine of the general formula: where m is equal to 0.1, 2 or 3, n is equal to 2 or 3, represents a hydrogen atom, a lower alkyl radical or lower cycloalkyl radical, R2 and R^ each represent a lower alkyl radical which is straight-chain or branched, or dimethoxyphenylethyl or phenyl-isopropyl radical, R^ can likewise be a hydrogen atom, R represents a hydrogen atom or halogen atom, or a lower alkyl radical, lower alkoxy radical, lower cycloalkyl radical, allyl radical, or a nitro or acetyl group, the designation lower.alkyl meaning a radical having 1-4 carbon atoms, as well as non-toxic, pharmaceutically acceptable acid addition salts of these derivatives, characterized in that it comprises the following steps: (a) conversion of a phenol of formula: with an epihalohydrin to form a compound of formula: . where Y is the group or where X means a halogen atom, (b) reacting the compound of formula II with an amine HNF^R^ at a temperature between 20 and 150°C to form the desired compound of formula I which is isolated and optionally converted to a non-toxic acid addition salt. 2. Method as stated in claim 1, characterized in that step (b) is carried out in a common organic solvent, especially alcohol, or without solvent. 3. Method as set forth in claim 1, characterized in that step (a) comprises reacting a phenol of formula III which is previously associated with epichlorohydrin or epibromohydrin, in a hydroalcoholic environment at a temperature between 20 and 150°C. 4. Method as stated in claim 1, characterized in that step (a) comprises reacting a phenol of formula III with an excess of epichlorohydrin or epibromohydrin in the presence of an amine catalyst at a temperature between 20 and 150°C.