CA1041546A - Propanol derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to novel propanol derivatives of the formula:

(I) wherein R1 represents a hydrogen or halogen atom, a hydroxy or trifluoro-methyl group or an alkyl or alkoxy group with I to 4 carbon atoms; and R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or a benzyl group or a pharmaceutically acceptable acid addition salt thereof, and to processes for their preparation. The novel compounds possess sympathicomimetic properties and are potentially useful as cardiac and circulation agents. In particular the novel compounds possess a blood pressure increasing activity. The novel compounds, may, moreover serve as intermediates in the preparation of other physiologically active compounds.
Processes for the production of the novel compounds are described and examples of certain of the novel compounds are given. Pharmaceutical compositions containing the novel compounds are described and exemplified.

Description

1041S~6 The present invention relates to propanol derivatives and their acid addition salts, as well as to processes for the production thereof.
The novel compounds possess interesting physiological properties.
According to one feature of the present invention there are provided compounds of the formula:-OH

~ CH2-fH-CH20H (I) R NH-R
1' ,'.

(wherein R1 represents a hydrogen or halogen atom, a hydroxy or trifluoro-methyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms; and R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or a benzyl group) and pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I as hereinbefore defined contain an asymmetric carbon atom and thus ~ay exist not only in racemic form but also in the form of optically active isomers ile~L the D and the L-isomers.
It ~ill he appreoi~ted that sll such fOr~J of the compo~ndY of lor ul-'''~ ' '' ' : ' ; " ~ ' ~3~ ''`~ ' ' ~ -2- ~ ~

.. ~, :. ...
. :. . . . . :

~041546 I (and acid addition salts thereof) are within the scope of the present invention.
The acid addition salts useful for incorporation in pharmaceutical compositions are physiologically compatible acid addition salts. Other acid addition salts may however be useful in the preparation of compounds of formula I and physiologically compatible acid addition salts thereof.
The compounds of general formula I according to the invention and the physiologically compatible acid ~ ~ -addition salts thereof possess interesting physiological -i ;
properties. In particular compounds according to the invention in general possess sympathicomimetic properties and are potentially useful as cardiac and circulation `;
agents. Moreover the compounds of formula I according to the invention and the physiologically compatible acid addition salts are potentially useful as agents for increasing blood pressure, the effect of these compounds . . ~ , , ~
being maintained for a relatively long period of time. -Compounds of the present invention which have been tested have been found capable of maintaining their physiological activity for a longer period than commercial preparations at present on the market and possessing a similar physiological activity. In particular the half-life time of activity of 2-amino-3-(3,5-dihydroxyphenyl)-1-propanol (which is a compound of the present invention) has been found to be about 3 times as long as the half-life time of activity of 1-(3-hydroxyphenyl)-2-ethyl-amino-ethanol. -`
Furthermore compounds according to the invention may serve as intermediates in the preparation of other physiologically active compounds.
Preferred compounds according to the present invention, by virtue of their especially favourable physiological activity include compounds of formula I ~-as hereinbefore defined (wherein Rl represents a hydrogen, fluorine, chlorine or bromine atom or a lS hydroxy, methyl, methoxy or trifluoromethyl group and R2 represents a hydrogen atom, or a methyl, ethyl or `
benzyl group and the acid addition salts thereof, `
Particularly preferred compounds of the present invention, by virtue of their particularly favourable physiological activity, include those preferred compounds, in which Rl represents a chlorine atom, or a 5-hydroxy, methyl, methoxy or trifluoromethyl group e.g. 2-amino-3-(3,5-- 4 - ;

.

-dihydroxyphenyl)-1-propanol and the pharmaceutically acceptable acid addition salts thereof. According to a further feature of this invention there is provided a process for the preparation of a compound of the formula:
OH

~ CH2-~CH-CH20H (I) ' ' wherein R1 represents a hydrogen or halogen atom~ a hydroxy or trifluoro-methyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms; and :
R2 represents a hydrogen atom~ an alkylggroup with 1 to 4 carbon atoms or a benzyl group or a pharmaceutically acceptable acid addition salt thereof~ . :
which comprises either:~reducing a compound of the formula~

OH

~H-R ' (II) ",,- :. . ~ .:
wherein R1 is as defined above~ R21 represents the radical R2 or an acyl group with 1 to 4 carbon atoms or a benizo~l group, and R3 represents an optionally substituted alkoxy group and where R21 is an acyl group as - : -hereinbefore defined, deacylating the product so obtained;~orsubjecting a compound of the formula:-~ CH2 _ IH _ CH20H (I ) wherein R4 represents a hydrogen atom or a group removab~e by ether splitting~ hydrolysis or by hydrogenolysis~ R5 represents the radical R1 ~ :
as defined above or the g~oup - OR7 in which R7 represents a group ~. -.
b: . . -.
~, _S_ ,''" ' '' .-104154~;
removable by ether splitting, hydrolysis or hydrogenolysis, and R6 represents the radical R2 or a group removable by hydrogenolysis, with the proviso that at least one of R4, R6 and R7 represent a removable protecting group;(~or reducing a compound of the formula:- -OH

~ CH2 _ ICH _ CH20H (IV) Rl 2 wherein Rl is as defined above;~4-~ for the preparation of a compound of formula I in which R2 represents an alkyl group with 1 to 4 carbon atoms or a benzyl group, by alkylating or benzylating a compound of the formula:-OH .

~ CH2-- ICH--CH20H (V) Rl 2 wherein Rl is as defined above, either directly or by reaction with the ;~
appropriate aldehyde with 1 to 4 carbon atoms or benzaldehyde followed by reductionS(~rfor the preparation of a compound of formula I in which R2 represents an alkyl group of 1 to 4 carbon atoms or a benzyl~group, reducing a compound of the formula:-OH

~ CH2 _ ICH _ CH20H (VII) Rl ~ NH - COR

wherein Rl is as defined above and R8 represents a hydrogen atom~ an alkyl group with 1 to 3 carbon atoms or a phenyl group, and wherein any of steps (a) to (e) may be followed by the additional step of converting a base of formula I obtained into a corresponding pharmaceutically acceptable acid addition salt.

~ -Sa-~' .

10415~6 Thus, the compounds of formula I (as hereinbefore definedl are, for example, prepared by one of the following processes (a) to (e), which processes constitute further features of the present invention a) reducing a compound of the formula:

OI H

~ CH2-CH-CQR3 (II) Rl NH-R2~

(wherein Rl is as hereinbefore defined~ R2~ represen~s the radical R2 or an acyl group with 1 to 4 carbon atoms or a benzoyl group, and R3 represents an optionall~ substituted alkoxy group) with a complex hydride and, where a compound is obtained~ wherein R21 represents an acyl group deacylating said compound whereby a compound of formula I is obtained.
The reduction is preferably effected by the use of a strongly effective hydride e.g. lithium aluminium hydride or sodium di(methoxyethoxy)aluminium-hydride (SDMA). The reduction may also be effected by the use of a weaker reducing complex hydride, e.g. lithium borohydride, c~lGium borohydride or sodium borohydride.
.. .
,', ' '' ~'''' ', , ~

.',' ' ' ' .' .

~, .
-5b- -, , ' , ~, .,-~041546 Where, however, a compound of formula II is used as starting material inwhich R2' represents an acyl group and a weaker reducing complex hydride is employed the amide grouping in the c0mpound of formula II undergoes virtually no reaction. In this case the acyl grouping is removed sub-sequently by conventional methods e.g. by treatment with hydrochloric acid to form a compound of formula I as hereinbefore defined (in which R2 represents a hydrogen atom). Where, however, a compound of formula II is used in which R2' represents an acyl group and a strongly effective com-plex hydride is employed the acyl grouping is reduced to the corresponding 10 hydrocarbon group i.e. a compound of formula I is obtained in which R2 represents an alkyl group with 1-4 ~arbon atoms or a benzyl group.
b) subjecting a compound of formula:-OR
L~ '. . .
CH2-CH-CH20H (III) ;
NH-R

~ ' q~ ' : . . ~

~' , ' , : -~
, ' , - ' ; --wherein R4 represents a hydrogen atom or a group removHble by ethersplitting, hydrolysis or hydrogenolysis~ R5 represents the radical R1 as hereinbefore defin~d or the group -OR7 (in which R7 represents a group removable by ether splitting, hydrolysis or hydrogenolysis and R6 represents the radical R2 or a group removable by hydrogenolysis , with the proviso that at least one of R4, R6 and R7 represen~ a removable protecting group as defined above, to ether splitting,~hydrolysis or hydrogenolysis~ whereby the said compound of formula III is converted into a compound of formula I.
10The -OH protecting groups may, for example, be groups removable by hydrolysis, hydrogenation, ether cleavage or deacylation. Hydroxyl protecting groups which may be removed by ether cleavage or deacylation include, for example, alkyl groups such as methyl or benzyl groups or acyl . . . .
groups. Removal of the -OH protecting grDups may be effected in a manner known per se. Thus hydrogenation may~ for example~ be effected by the use `
o~ hydrogen and conventional hydrogenation catalysts~ e.g. platinum, palladium or Raney-nickel and ether cleavage and deacylation may, for example, be cffected by the use of hydrobromic acid, hydrochloric !~- - .

S, ~ ~ , '`' .

~.,,,, . ~ ,,, ~ - . . .
. ' ' .

.,; , ' .
,~ ' . . ...
~7~

rr~

,, , ~ , ~ ", ,~ , ,, ",, ,",, ," ~ ,"

~04154f~
acid, boron trifluoride etherate, boron tribromide or aluminium chloride.
c) reducing a compound of the formula:-OH

CH2-CH-CH20H (IV) Rl N02 (wherein Rl is as hereinbefore defined) whereby a compound of formula I is obtained.
The reduction may, for example, be effected catalytically with hydrogen and a conventional hydrogenation catalyst, e.g. platinum, palladium or Raney nickel. d) for the preparation of compounds of formula I
as hereinbefore defined (wherein R2 represents an alkyl group with 1-4 ~
carbon atoms or a benzyl group), the Al~ylation of a compound of the for- ~ -mula--~H

,~ CH2-CH-CH20H (V) either directly or by reaction with the appropriate aldehyde with 1-4 carbon atoms or benzaldehyde followed by reduction, ~.,,. i , . ~ .

- . "

~ ', ,, ..

(wherein Rl is as hereinbefore defined) whereby a compound of formula I (wherein R2 represents an alkyl group with 1 to 4 carbon atoms or a benzyl group) is obtained.
e) for the prFparation of compounds of formula I
as hereinbefore defined (wherein R2 represents an ~ -alkyl group with 1-4 carbon atoms or a benzyl group), the reduction of a compound of the formula:-OH

~ CH2-CH-CH20H (VII) Rl NH-COR8 (wherein Rl is as hereinbefore defined and R8 represents a hydrogen atom, an alkyl group with 1-3 ~ -carbon atoms or a phenyl group) whereby a compound of -formula I (wherein R2 represents an alkyl group with 1-4 carbon atoms or a benzyl group) is obtained.
The reduction is preferably effected by the use of a complex hydride e.g. lithium aluminium hydride or S.D.M.A. --The compounds of formula VII are preferably first ~
'.''. ' ' '' _ g ,. . .
~ . .

- . ~- ,, . . . . :

:; . - . ~" - . : . ., ., .
.. . . . . , , - -. , ,.-, .~ ` ' .,,. ~ ''' ' ; ~'.

... . ,.. . ,, . :

prepared by acylating a compound of the formula:-OH

~ CH2-CH-CH2OH
Rl NH2 (V) (wherein Rl is as hereinbefore defined) whereby a compound of formula VII (as hereinbefore defined) is obtained.
If desired, the bases of formula I may be converted according to conventional methods into their acid addition salts e.g. their physiologically compatible acid addition salts, or where the compounds -are obtained in the form of salts, these salts may, if desired, be converted into salts with other acids or into the corresponding free bases.
Compounds of general formula I as hereinbefore defined may occur in the form of racemates. Any racemates present may, if desired, be resolved into their optically active isomers by conventional methods e.g, by means of optically active acids. Thus, for example, the optically active isomers may be prepared either by starting from optically active starting compounds in the ,~ ~

~041546 processes of the present invention or by resolving the racemates obtained as reaction products into their ,: '- . . . .
optical isomers in conventional manner.
The starting materials for the processes of the present invention may be prepared by processes known per se. The a-amino acid esters required for processes (a) and (b) may be obtained, for example, via the corresponding azalactones or by reaction of the correspondingly substituted benzyl halide wLth acetamido-cyano-acetates or -malonic esters.
", :-' .' The starting materials for process (c) may, ~ ;
for example, be obtained by reacting a correspondingly substituted l-phenyl-2-nitroethane with paraformaldehyde. - -According to a still further feature of the present i . ,, invention there are provided pharmaceutical compositions ` -comprising as active ingredient at least one compound -of formula I as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutlcal carrier or excipient. The compositions ' may be presented in a form suitable for oral, rectal or parenteral administration. Thus, for example, compositions _11- ~'"

.: ' ., , . . . .. , ~.

, ' ~ . ,' ' ' - ' ' ,'` ' , . .

104~546 for oral administration may be solid or liquid and may take the form of granules, tablets, coated tablets, capsules, tinctures, syrups, pills, emulsions, suspensions, powders, or drops, such compositions comprising carriers or excipients conventionally used in the pharmaceutical art. Thus, for example, suitable tabletting excipients include lactose, potato and soluble starches and magnesium stearate.
For parenteral administration, the carrier may be a sterile, parenterally acceptable liquid such as sterile water, or a parenterally acceptable oil e.g.
arachis oil, contained in ampoules. Compositions for rectal administration may take the form of suppositories, the carrier comprising a suppository base.
Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 1 to 100 mg and especially 5 to 20 mg, of active ingredient. -- 12 - ~

:

:',, ' The following examples illustrate the preparation of compounds according to the invention, and also :
phanmaceutical compositions containing such compounds ~.
as active ingredients~
, - 13 - .
:.
.
: . .

.- . - - . ,. , . , .. .. :
.:, ,: , .. , .. ~,: . . . . .
~ . - . . . :
. : - : . . . ,, .

- . . . .

10~1546 Example 1

2-Amino-3-(3,5-dihydroxvphen~l)-1-propanol-hydrobromide a) 2-Amino-3-(3,5-dimethoxyphenyl)-l-propanol-hydr _______________________ ___ _____ __ ______ ___ chloride ________ 6 8 g (28 mmol) of 3,5-dimethoxyphenylalanine-methyl ester are dissolved in 35 ml of absolute tetrahydrofuran and, at 20 to 30C, added dropwise to a stirred suspension of 3.2 g (89 mmol) of lithium aluminium hydride in 35 ml of absolute tetrahydrofuran. The mixture is refluxed for 2 hours, cooled and decomposed cautiously with water. Subsequently, the mixture thus obtained is extracted with ethyl acetate, the organic `
phase is dried over sodium sulfate and the solvent distilled ~-off in vacuo. The residue is converted into the hydrochloride with ethereal hydrochloric acid. ~
Yield: 6.5 g (65% of theory); ~ ;
M.p. 165C.
b) 2-Amino-3-(3,5-dihydroxyphenyl)-l-pro~anol-hydr __________________ ------------ , bromide _______ .: . .
4.5 g (18.5 mmol) of 2-amino-3-(3,5-dimethoxyphenyl)-l-propanol hydrochloride are refluxed together with 45 ml of hydrobromide for one hour. The excess hydrobromic ~ ~-:

acid is then distilled off in vacuo and the residue is dehydrated azeotropically. The crystalline residue is recrystallized from isopropanol/ether.
Yield: 1.8 g (37% of theory);
M.p. 118-120C.
Example 2 2-Benzylamino-3-(3-hvdroxy-4-methylphenvl)-1-propanol-hydrobromide a) 2-Benzylamino-3-(3-methoxy-4-methylphenyl) ______ __________________ _______ _ ___ _____ proPanol hydrochloride 55.5 g (0.16 mol) of N-benzcy1-3-(3-methoxy-4-methylphenyl)-alanine-ethyl ester (m.p. 133C) are dissolved in 550 ml of absolute tetrahydrofuran and slowly added dropwise to a stirred suspension of 37 g (0.98 mol) of lithium aluminium hydride in 1850 ml of absolute tetra-hydrofuran under a nitrogen atmosphere. When the addition has been completed, the mixture is refluxed for 5 hours, allowed to stand overnight and decomposed slowly with water. The inorganic precipitate is filtered off with suction and washed with tetrahydrofuran. The solvent is distilled off in vacuo, the residue is taken up in ether and treated with water. The ether phase is dried over : , . - ~.

~04~S46 sodium sulfate and distilled off. The residue is recrystallized from petroleum ether. Yield: 45.0 g (97.5%
of theory). The base is dissolved in ethyl acetate and ,~
on the addition of ethereal hydrochloric acid converted S into the hydrochloride.
Yield: 49.5 g (95% of theory); m.p. 191C.
b) 2-Benzylamino-3-(3-hydroxy-4-methyl~?henyl)~
______ _____________ ____ _______ _ ___ ____ .
propanol __ ____ :

20 g (62 mmol) of 2-benzylamino-3-(3-methoxy-4-methylphenyl)-l-propanol hydrochloride in 200 ml of 48%
hydrobromic acid are refluxed for 1 hour. The mixture --is cooled, the precipitated crystals are filtered off .~ -with suction and recrystallized from water. Yield: 21.5 g (98.5% of theory), m.p. 199C.
Example 3 ,,~'.` ~ ".. ~ .
2-Amino-3-(3-hydroxy-4-methylphenvl)-1-propanol-hydrobromide 21.5 g (61 mmol) of 2-benzylamino-3-(3-hydroxy-4-methylphenyl)-l-propanol hydrobromide (see Example 2) are dissolved in 250 ml of methanol and after the addition of ~-6 g of palladium/charcoal (5%) debenzylated catalytically at 60C and 5 atmospheres. When the hydrogenation is '~

- :
', ' - .. - .. :... , ~ . . . . ... . . ..

104~S46 completed, the mixture is filtered off, the methanol is distilled off in vacuo and the residue is dissolved hot _ ~ .
in acetonitrile. On cooling, the title compound crystallizes out and is filtered off with suction and dried.
Yield: 13 g (81.5Z of theory).
M.p. 115-117C.
Example 4 2-Amino-3-(3-hydroxv-5-methvlphenyl)-1-Propanol hvdrobromide ~-a~ 3-(3-Methoxy-5-methylphenyl)-alanine-ethyl ester -___________ _______ _ ___ _____________ _______ 56 g (0.33 mol) of 3-methoxy-5-methyl-benzylchloride are added dropwise to a solution of 56 g (0.33 mol) of acetamidocyanoethyl acetate and 7.8 g of sodium in 330 ml of ethanol. The mixture is refluxed for 4 hours, filtered off with suction to remove the precipitated sodium chloride and the alcohol is then distilled off in vacuo. The residue is saponified by boiling with 117 g of potassium ~ . .
hydroxide in 920 ml of water for 20 hours. The resulting product is acidified with concentrated hydrochloric acid and evaporated to dryness.
The amino acid is extracted by treating the amino acid containing mixture twice each time with 1 ltr. of 104~46 ethanol. The alcohol is distilled off and the hydrochloride of the amino acid obtained as residue is recrystallized from acetonitrile.
Yield: 46 g (57% of theory), m.p. 248C.
The ethyl acetate is obtained in 65% yield by azeotropic esterification. The hydrochloride melts at 184-185C. -b) 2-Amino-3-(3-methoxy-5-methylphen~l )-l-propanol _________-------- : , hydrochloride ___________ 33 g of 2-amino-3-(3-methoxy-5-methylphenyl)-alanine ester hydrochloride are suspended in ether and converted into the base on the addition of dilute ammonia. The -.. . .
base is dried over sodium sulfate and the ether is distilled off in vacuo. The resulting product is then diss~olved again -in 330 ml of absolute ether and added dropwise to the stirred suspension of 13.7 g of lithium aluminium hydride in 700 ml of absolute ether. The resulting product is re- -~
fluxed for 5 hours, decomposed with water, filtered off with suction and evaporated in vacuo. The residue is dissolved in acetonitrile and mixed with the calculated quarltity of ethereal hydrochloric acid. The precipitated - -hydrochloride is filtered off with suction and dried. : -... . ..
,, ; . -. ~
- . - . . . , - . . .
., ~ . , - . .- : .. . .

- . .

.. .. ..

Yield: 23 g (83% of theory), m.p. 204 - 205C.
c) 2-Amino-3-(3-hydro ~-5-methylphenyl2-l-propanol .-,-hydrobromide ____________ .
23 g (0.1 mol) of 2-amino-3-(3-methoxy-5-methyl-phenyl)-l-propanol hydrochloride are refluxed for one hour after the addition of 230 ml of 48% hydrobromic acid. A part of the hydrobromic acid is distilled off, cooled and filtered off with suction. The product thus obtained is recrystallized from aqueous acetonitrile.
Yield: 20 g (76% of theory), m.p. 160C.
Example 5 2-Amino-3-(3-hydroxy-4-methoxyphenyl)-1-propanol ~ --ydrochloride 6 g (18.6 mmol) of 2-benzylamino-3-(3-hydroxy-4-methoxyphenyl)-l-propanol hydrochloride are dissolved in 60 ml of methanol. After the addition of palladium/char-coal (5%) the mixture is debenzylated catalytically. After uptake of the calculated quantity of hydrogen, the catalyst is filtered off, the solvent is distilled off in vacuo and the residue recrystallized from acetonitrile.
Yield: 4g (92% of theory), m.p. 181-182C.

; :
' , '' ' - ~ '.', .- .

Example 6 2-Amino-3-(3-hydroxyphenyl)-1-propanol-hydrobromide ~ -a) 2-Amino-3-(3-methoxyehenyl2-1 proeanol hydrochloride 29 g (0.139 mol~ of 3-(3-methoxyphenyl)-alaninemethyl ester are dissolved in 170 ml of absolute tetrahydrofuran and added dropwise to a stirred suspension of 10.6 g (0.278 mol~ of lithium aluminium hydride in 170 ml of absolute tetrahydrofuran. After 2-hours' boiling, ~
the reaction mixture is further processed as described ~ v in the preceding Examples. The hydrochloride of 2-amino-

3-(3-methoxyphenyl)-1-propanol is obtained in a yie~t of 26.5% of theory with a melting point of 145~. -b) 2-Amino-3 (3 hydroxyehenyl2 1 propanol hydrobromide 8 g of 2-amino-3-(3-methoxyphenyl)-1-propanol hydrochloride are refluxed in 80 ml of 48% hydrobromic acid for 1 hour. Subsequently, the reaction mixture is evaporated to dryness in vacuo, the water is removed by ~-distillation after the addition of xylene and the residue is recrystallized from glacial acetic acid.
Yield: 6 g (66% of theory), m.p. 150-152C.

., '~

. .

- : . . .. , ~ , . . . .

Example 7 2-Amino-3-(3,5-dihydroxyphenyl)-1-propanol-hydrobromide a) l-(3,5-Dimethoxy~henyl)-2-nitroethane _______________ ___ ________________ 27 g (0.129 mol) of 3,5-dimethoxy-~-nitro-styrol are dissolved in 540 ml of benzene. Nitrogen is passed through the solution in the presence of 1.3 g of tris-(triphenylphosphine)-rhodium-I-chloride as catalyst. Then, at 60C and 5 atmospheres pressure the calculated quantity of hydrogen is introduced. When the hydrogenation is completed, the benzene is distilled off and the residue triturated with ether. This processing causes the catalyst to precipitate. The catalyst is filtered off with suction, the ether is distilled off and the product remaining is recrystallized from methanol.
Yield: 21.3 g (78.S% of theory), m.p. 51-53C.
b) 3-~3~5-Dimethoxyehenyl)-2-nitro-1-eroeanol __ _ __________ ___ _____________ __ _____ 10 g (47.4 mmol) of 1-(3,5-dimethoxyphenyl)-2-nitro-ethane are dissolved in 100 ml of ethanol. 1 ml of conc.
sodium hydroxide solution is then added to the solution.
5 g (50 mmol) of a 30% formalin solution is then added dropwise slowly, the temperature being kept below 20C.

- :: . . . .
, 104~546 The reaction mixture is allowed to stand for 70 hours at room temperature; it should be observed that the solution maintains an alkaline reaction during this time. The solution is acidified with 2 N acetic acid and the solvent is distilled off in vacuo. The resultant product is distributed between ethyl acetate/water, the organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. The residue is triturated with warm toluene, whereby crystallization takes place. -~
Yield: 8.9 g (78% of theory), m.p. 81-83C.
c) 2-Amino-3-(3,5-dimethoxyphenyl2-l-~ro~anol hydro-chloride ________ ~ ~ . .
8.5 g of 3-(3,5-dimethoxyphenyl)-2-nitro-1-propanol are dissolved in 100 ml of methanol and after addition of platinum dioxide it is hydrogenated under nonmal conditions. After uptake of the calculated quantity of -.. . .. .
hydrogen, the catalyst is filtered off a~d the solution evaporated to dryness in vacuo. The residue is dissolved in acetonitrile; on the addition of the calculated quantity of ethereal hydrochloric acid the hydrochloride of melting point 165C is obtained.

- ~ . ... - :, - . : -.. . ..
.- .
. . .

.

Yield: 5.3 g (71% of theory).
In order to produce 2-amino-3-(3,5-dihydroxyphenyl)-l-propanol-hydrobromide, the resultant product is further processed as described in Example 1.
Example 8 2-Amino-3-(3-hydroxy-5-trifluoromethyl-phenyl)-1-propsnol-hydrobromide a) 3-Methoxy-5-trifluoromethyl-benzaldehyde ________ ________________ ___________ __ 125 g of 3-methoxy-5-trifluoromethyl-aniline are diazotized and reacted according to the method of BEECH
(J. Chem.Soc. 1 _ , 1297) to give 3-methoxy-5-trifluoro-methyl-benzaldehyde. (B~p~o 1 58 - 60C, n20 = 1.4833).
b) N-Benzoyl-3-methoxy-5-trifluoro-methylphenyl-alanine- --_______ __________ _________________ _ ___ _________ methylester ____ ______ .
3-methoxy-5-trifluoromethylbenzaldehyde is reacted with hippuric acid to give the azalactone (m.p. 149 - 150C).
By means of boiling in methanol in the presence of catalytic quantities of potassium carbonate the a-benzamido-3-methoxy-5-trifluoromethyl-methyl-cinnamate is obtained (m.p. 143C), which is hydrogenated catalytically to give the N-benzoyl-3-methoxy-5-trifluoromethylphenyl-alanine-methyl ester (m.p. 133C).

..
:. . ..... : .-, . ..

"- :. ., ' ~. ,, .: ,' ' ';;`

104~546 c) 2 Benzylamino-3-(3-methoxy-5-trifluoromethylphen l-propanol hydrochloride __ __ ______ ___________ ~
17 g of the ester mentioned under (b) are reduced -to the amino alcohol according to the method described ~-in Example 2(a). The melting point of the hydrochloride amounts to 161C. - -d) 2-Benzylamino-3-(3-hydroxy-5-trifluoromethylphenyl)-______ _____________ ____ ________________ _ ___ ___ .
l_eropanol hydrobromide 15 g of 2-benzylamino-3-(3-methoxy-5-trifluoro-10 methylphenyl)-l-propanol hydrochloride are demethylated by boiling with 48% hydrobromic acid for one hour. Then, the reaction mixture is cooled, the precipitated crystals -are filtered off with suction and dried. -Yield 11 g; m.p. 206 - 207C.
15 e) 2-Amino-3-(3-hydroxy-5-trifluoromethylphenyl)-1-__________ ___ ____ ___________--___ -- -------------- .~ .
propanol hydrobromide Debenzylation is effected catalytically in methanol.
After uptake of the calculated quantity of hydrogen, the catalyst is filtered off, the solvent is distilled off -in vacuo and the residue recrystallized in acetonitrile. ;
The 2-amino-3-(3-h~droxy-5-trifluoromethylphenyl)-1-propanol hydrobromide melts at 155-156C.

- 24 - ;
.'~
,` ' Example 9 2-Amino-3-(2-chloro-5-hydroxyphenyl)-1-propanol hydrobromide The azalactone is obtained in the manner described in Example 8 starting from 2-chloro-5-methoxy-benzaldehyde by condensation with hippuric acid (m.p. 167C), from which the corresponding hydroxymethyl-cinnamate (m.p.
121-123C) is obtained following which reduction with lithium aluminium hydride yields the hydrochloride of 2-benzylamino-3-(2-chloro-5-methoxyphenyl)-1-propanol (m.p. 167 - 168C). After catalytic debenzylation (m.p. 153 - 155C) and demethylation with 48% hydrobromic acid, the hydrobromide of 2-amino-3-(2-chloro-5-hydroxy-phenyl)-l-propanol of m.p. 174-175C is obtained.
Example 10 ,2-Ethvlamino-3-(3,5-dihydroxyphenvl)-1-propanol hvdro-bromide a) N-Acetyl-3 5-dimethoxyphenyl-alanine-methylester ______ ___~__________ ___ ______________ ______ 3,5-dimethoxy-benzaldehyde is condensed with aceturic acid, yielding 45% of a product having a m.p. 142-143C. By refluxing in methanol in the presence of potassium carbonate and subsequent hydrogenation .. . . :- . ... , . - . . ~; . ., . ............ . , , :

. , .~ ~ . .. . ......

10415~S
the N-acetyl-3,5-dimethoxyphenyl-alanine-methyl ester (m.p. 110 - 111C) is obtained. -~
b) 2~Ethylamino-3-(3~5-dimethoxyehenyl)-i-propan __ ___________ __________ ___ _____ __ ____ ~ .
hydrobromide __________ 42 g of N-acetyl-3,5-dimethoxyphenylalaninemethyl ester are reduced in absolute tetrahydrofuran with lithium aluminium hydride to yield the 2-ethylamino-3-(3,5-dimethoxyphenyl)-1-propanol (m.p. 82 - 83C).
The hydrobromide melts at 175C.
10 c)2-Ethylamino-3-(3,~5-dihydroxy~henyl)-1-~ropanol .,'. -_____ ___________ _____ --_-------------------- .. ~ , :.
hydrobromide -__________ .. .
10 g of 2-ethylamino-3-(3,5-dimethoxyphenyl)-1-propanol hydrobromide are demethylated by boiling with 48% hydrobromic acid. After distilling off the excess hydrobromic acid, the remaining residue is recrystallized from acetonitrile. The 2-ethyl-amino-3-(3,5-dihydroxyphenyl)-1-propanol hydro-bromide melts at 167 - 168c.
Example 11 20 2-Methylamino-3-(3,5-dihydroxvphenyl-1-propanol hYdro .
bromide The hydrobromide of 2- `~-methylamino-3-(3,5-dimethoxyphenyl)-1-propanol, m.p.

-~041546 142C, is obtained by a process similar to that of Example 10 starting from N-formyl-3,5-dimethoxyphenyl-alanine-methyl ester by reduction with lithium aluminium hydride. The demethylation with 48% hydrobromic acid yields 2-methylamino-3-(2,5-dihydroxyphenyl)-1-propanol hydrobromide, m.p. 183 - 186C.
Example 12 2-Amino-3-(3-hydroxv-2-methvlphenyl)-1-propanol hydrobromide a) N-Benzoyl-3-methoxy-2-methylPhenylalanine-methylester 3-methoxy-2-methyl-aniline is reacted according to BEECH (see Example 8) to yield 3-methoxy-2-methyl-benzaldehyde. Reaction of this latter compound with hippuric acid yields the corresponding azalactone (m.p.
166C), which is then reacted by boiling with methanol/
potassium carbonate followed by catalytic hydrogenation to yield the N-benzoyl-3-methoxy-2-methylphenyl-alanine methyl ester (m.p. 143-144C.).
b) 2-Amino-3-(3-hydroxy-2-methylphenyl)-l-eropan ______ _------------ :
hydrobromide N-benzoyl-3-methoxy-2-methylphenyl-alanine-methyl ester reacts with lithium aluminium hydride to yield :; .
.- .

... '~: . -'.

1~4:1546 2-benzylamino-3-(3-methoxy-2-methylphenyl)-1-propanol.
The hydrochloride melts at 174C. By means of boiling with 48~/o hydrobromic scid, the 2-benzylamino-3-(3~
hydroxy-2-methylphenyl)-1-propanol-hydrobromide (m.p. -~ 153C) is obtained. This latter compound is debenzylated catalytically to yield the 2-amino-3-(3-hydroxy-2-methylphenyl)-l-propanol hydrobromide. ;
. .
(m.p. 166C).
Example 13 2-Amino-3-(3-hydroxy-6-methylphenyl)-1-propanol hydro-bromide ~;
a) N-Benzoyl-3-methoxy-6-methylehenyl-alanine-methyl-ester _____ ,, 2,5-cresotic acid is methylated with dimethylsulfate to yield 5-methoxy-o-toluylic acid (m.p. 152-154C).
According to the Rosenmund method, 5-methoxy-o-tolualde-hyde (b.p.o 3 75C) is obtained via the acid chloride (b.p.0 '3 81-83C). As described in Example 12, the :` `
, ~.
azalactone (m.p. 170-171C) as well as the N-benzoyl-3-methoxy-6-methylphenyl-alanine-methyl ester (m.p. 98C) are produced.

..
, , ,; . : - . . ,, , ., . :

~, . . . . . . .

. . .
,, - . , , . - , ~ , .
.

b) 2-Amino-3-(3-hydroxy-6-methylphenyl)-l-ero~anol ______________ ____ _______ _ ___ _____ __ ____ hydrobromide _ _ _ _ _ _ _ _ _ _ The 2-benzylamino-3-(3-methoxy-6-methylphenyl)-1-propanol hydrochloride obtained by reduction with lithium aluminium hydride is first demethylated (m.p. 166-167C) and then catalytically debenzylated to yield 2-amino-3-(3-hydroxy-6-methylphenyl)-1-propanol hydrobromide (m.p. 143C).
Example 14 2-Amino-3-(3,5-dihvdroxvphenyl)-1-propanol hvdrochloride a) 2-Benzamido-3-(3 5-dimethoxyphenyl)-l-propan ________________~__________ ___ _____ __ ____ To 34.3 g of N-benzoyl-3-(3,5-dimethoxyphenyl)-a~nine methylester in 350 ml of tetrahydrofuran are added 4.2 g of sodium borohydride, while stirring at room temperature.
The mixture is first stirred for 30 minutes and it is then refluxed for 5 hours. After cooling, the solvent is ~.
distilled off in vacuo, the residue is suspended in -.
water and acidified with acetic acid. The precipitating - ~
crystals are filtered off with suction, washed with ~ ;
water and dried. By recrystallization from toluene e~zam;O~O
2-bonzamide-3-(3,5-dimethoxyphenyl)-1-propanol of - 2g - ~, "

~ ' . ' - -$: . : , .. , - :

, i. : : ' .: . ~

104~546 m.p. 117-118C is obtained.
b) 2-Amino-3-(3~5-dihydroxy~henyl2-l-eropan hydrochloride _ _ _ _ _ _ _ _ 21 g of 2-benzamido-3-(3,5-dimethoxyphenyl)-1-propanol are refluxed in 200 ml of 6 N hydrochloric acid ~ -for 8 hours. After cooling, the mixture is extracted three times with chloroform and evaporated to dryness in vacuo. The residue is recrystallized from glacial acetic acid. The hydrochloride of the 2-amino-3-(3,5-dihydroxyphenyl)-l-propanol melts at 167C.
Example 15 2-Benzylamino-3-(3-hydroxy-4-methoxyphenyl)-1-propanol , :
hydrochloride 13 g of N-benzoyl-3-(3-hydroxy-4-methoxyphenyl)-alaninemethyl ester (m.p. 11 -116C) are dissolved in 130 ml of absolute tetrahydrofuran and added dropwise to a stirred suspension of 9 g lithium aluminium hydride in 450 ml of absolute tetrahydrofuran. The mixture is -refluxed for 6 hours, allowed to stand overnight and decomposed with water. The precipitate is filtered off with suction, extracted twice with dimethylformamide at - ~ ~
- . , . .
- . . .
.

10~546 and the two organic solutions are evaporated to dryness.
The residue is dissolved in 2 N hydrochloric acid, extr-acted with ethyl acetate and made alkaline again by the addition of potash. After drying over sodium sulfate, the solvent is distilled off in vacuo. The residue is dissolved in acetonitrile, mixed with the calculated quantity of ethereal hydrochloric acid and filtered off with suction.
Yield: 6 g (47% of theory), m.p. 128C.
ExamPle 16 2-Amino-3-(3,5-dihvdroxvphenyl)-1-propanol hvdrochloride a) N-Benzoyl-3,5-dihydroxy-~henylalanine-methylester -~
31 g (0.067 mol) of 2-phenyl-4-(3,5-bisbenzyloxy-benzylidene)-5-oxazolone are suspended in ten times the quantity of methanol and, after the addition of 1 g of anhydrous potash, refluxed for 10 minutes. The solution obtained is filtered warm into a hydrogenation vessel ;
and hydrogenated after the addition of Raney-nickel until the uptake of hydrogen is completed. The catalyst is filtered off with suction and the methanol is distilled .
off in vacuo. The residue is dissolved in a little ... .
methanol _ 31 -. .
- ~. .~. . -. . ~ , - .. .

and brought to crystallization by the addition of water.
The precipitate is filtered off with suction and dried.
Yield: 18 g (85% of theory) f m.p. 168C.
b) 2-Benzamido-3-(3~5-dihydroxy~henyl)-1-~ro~anol ________________ _____ ____ ___ _____ __ ____ 12.7 g (0.144 mol) of calcium chloride are dissolved at room temperature in 360 ml of ethanol.
18 g of (0.057 mol) of N-benzoyl-3,5-dihydroxyphenyl-alanine-methyl ester are then added and the mixture is cooled to -10C. At this temperature 11 g (0.288 mol) ~ -of sodium borohydride are cautiously added. When the ~
addition is completed, the reaction mixture is stirred ~ -for 1 hour at -10C, 1 hour at -5C and two hours more at 0C. The alcohol is distilled off in vacuo (temp-erature of bath 40 to 50C). The residue is mixed with lS water and, while cooling, acidified with 2 N hydrochloric ~-acid. The product thus obtained is extracted 4 to 5 times with hot ethyl acetate, dried over sodium sulfate and the solvent is distilled off in vacuo. The residue is i -dissolved in a little methanol and by adding water slowly precipitated in crystalline form. The precipitate is filtered off with suction and recrystallized several - 32 - ;~

. . .
~ .~¢;.....

, . ~04~546 times from ethyl acetate.
Yield: 12.5 g (76% of theory), m.p. 132-134C.
c) 2-Amino-3-(3,5-dihydroxyphenyl)-l-propan __________________ ____ -------------- :
hydrochloride ___________ .
S 39 g (0.136 mol) of 2-benzamido-3-(3,5-dihydroxy-phenyl)-l-propanol in 390 ml of 2 N hydrochloric acid are refluxed for 18 hours. The reaction mixture is cooled, the benzoic acid is extracted with chloroform and the remainder is distilled to dryness in vacuo.
The residue is triturated with acetonitrile until crystallization is achieved and the crystals are then filtered off with suction. The hydrochloride of the 2-amino-3-(3,5-dihydroxyphenyl)-1-propanol is recry-stallized from lS0 ml of glacial acetic acid in the presence of 5 drops of 40% sodium bisulfite solution and activated charcoal. .
Yield: 25 g (84% of theory), m.p. 166-167C.
Example 17 -. . .
2-Benzvlamino-3-(3,5-dihvdroxyphenyl)-1-propanol hydrobromide 15.7 g (0.05 mol) of N-benzoyl-3-(3,5-dihydroxyphenyl)-.
, .. ... ...... .

:. . ~ , ... ', . :. . . ' ~.

-alanine-methyl ester (m.p. 168C) are dissolved in 200 ml of absolute tetrahydrofuran and slowly added dropwise to a stirred suspension'of 15.2 g (0.4 mol) of lithium aluminium hydride in 600 ml of absolute -S tetrahydrofuran. The reaction mixture is refluxed for 3 hours and allowed to stand overnight. The excess lithium aluminium hydride is decomposed, filtered off with suction and the residue extracted with warm dimethylformamide. The organic phase is evaporated in vacuo. The residue is dissolved in dilute hydrobromic acid, filtered over activated charcoal and then evaporated to dryness in vacuo. The hydrobromide of 2-benzylamino-3-(3,5-dihydroxyphenyl)-1-propanol (m.p. 117-119C) thus obtained is recrystallized from acetonitrile.
Example 18 ~ ' ~- - .
2-Amino-3-(3-hYdroxy-6-methYlPhenyl)-l-propanol hydrochloride -~
6 ~ ~n~/ -10 g of 3-(3-hydroxy-S-methy~)-2-nitro-1-propanol, prepared in a manner similar to Example 7, are dissolved in 200 ml of methanol and after the addition of platinum ; :

.
,; , , , ,, , .:, :

.
. .
~ ' ~ . , ;" ~ - .

1041S46 :
oxide hydrogenated under normal conditions at room temperature. After uptake of the calculated quantity of hydrogen, the catalyst is filtered off and evaporated to dryness in vacuo. The residue is dissolved in .
dilute hydrobromic acid and the solution is evaporated ,~
to dryness in vacuo. The residue thus obtained is first -triturated with acetonitrile and then recrystallized from glacial acetic acid. The 2-amino-(3-hydroxy-6-methylphenyl)-l-propanol hydrobromide melts at 141-143C.
Example 19 2-Ethylamino-3-(3,5-dihydroxvphenvl)-1-propanol hydrobromide . . .
13.2 g (0.05 mol) of 2-amino-3-(3,5-dihydroxyphenyl)- -l-propanol hydrochloride are dissolved in 100 ml of methanol and refluxed for 1 hour after the addition of 2.2 g (0.05 mol) of acetaldehyde. Subsequently `
the reaction mixture is cooled and after the addition of 10 g of palladium charcoal (5%) hydrogenated at 5 atmospheres pressure until the uptake of hydrogen is completed. The catalyst is filtered off with suction "" ' ' ~.. - .

and evaporated to dryness in vacuo. The residue i8 taken up in dilute hydrobromic acid, filtered over activated charcoal and the filtrate evaporated to :
dryness in vacuo. By recrystallization from acetonitrile 2-ethylamino-3-(3,5-dihydroxyphenyl)-1-propanol-hydro-bromide is obtained.
Melting point: 167 - 168C. ~ -s .
- ' ..

10~1546 . ' Pharmaceutical Composition Examples Example A ~-Tablets :
Composition: ~ -Active ingredient according to the invention 5 parts by weight stearic acid 6 " " "
glucose 589 " " "
The components are processed in the conventional way to form tablets each weighing 0.600 g. If desired, the active ingredient content may be decreased or increased and the quantity of glucose used increased :
or decreased accordingly. ~.
Example B , :
Suppositories Composition: . --. ... ... ... .
2-Amino-3-(3,5-dihydroxyphenyl)-1- '~ : -propanol hydrobromide20 parts by weight lactose, pulverized S parts by weight cocoa butter 1635 parts by weight :~
'. .

, . . .
., ' ., ~04i546 The components are processed in the conventional way to form suppositories each weighing 1.7 g.
Example C
Capsules Composition: - -Active ingredient according to the invention : -lO parts by weight lactose 90 " " "
corn starch 400 " " "
The capsules are formulated by carefully mixing lOOO mg of the finely pulverized components and filled into hard gelatin capsules.

:' ' ~ , ' . ;
~ - . .
.

Claims (37)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula:

(I) wherein R1 represents a hydrogen or halogen atom, a hydroxy or trifluoro-methyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms; and R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or a benzyl group or a pharmaceutically acceptable acid addition salt thereof, which comprises either: (a) reducing a compound of the formula:

(II) wherein R1 is as defined above, R2' represents the radical R2 or an acyl group with 1 to 4 carbon atoms or a benzoyl group, and R3 represents an optionally substituted alkoxy group and where R2' is an acyl group as hereinbefore defined, deacylating the product so obtained; (b) or subjec-ting a compound of the formula:- (III) wherein R4 represents a hydrogen atom or a group removable by ether splitting, hydrolysis or by hydrogenolysis, R5 represents the radical R1 as defined above or the group -OR7 in which R7 represents a group removable by ether splitting, hydrolysis or hydrogenolysis, and R6 represents the radical R2 or a group removable by hydrogenolysis, with the proviso that at least one of R4, R6 and R7 represents a removable protecting group: (c) or reducing a compound of the formula:- (IV) wherein R1 is as defined above; (d) or for the preparation of a compound of formula I in which R2 represents an alkyl group with 1 to 4 carbon atoms or a benzyl group, by alkylating or benzylating a compound of the formula:- (V) wherein R1 is as defined above, either directly or by reaction with the appropriate aldehyde with 1 to 4 carbon atoms or benzaldehyde followed by reduction, (e) or for the preparation of a compound of formula I in which R2 represents an alkyl group of 1 to 4 carbon atoms or a benzyl group, reducing a compound of the formula:- (VII) wherein R1 is as defined above and R8 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a phenyl group, and wherein any of steps (a) to (e) may be followed by the additional step of converting a base of formula I obtained into a corresponding pharmaceutically acceptable acid addition salt.

2. A compound of the formula:

(I) wherein R1 represents a hydrogen or halogen atom, a hydroxy or trifluoro-methyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms; and R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or a benzyl group or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.

3. A process according to Claim 1 which comprises reducing a compound of the formula:

(II) wherein R1 is as defined in Claim 1, R2' represents the radical R2 or an acyl group with 1 to 4 carbon atoms or a benzoyl group, and R3 represents an optionally substituted alkoxy group with a complex hydride and, where a compound is obtained in which R2' represents an acyl group, deacylating said compound whereby a compound of formula I is obtained.

4. A process as claimed in Claim 3 wherein the deacylation is effected by treatment with hydrochloric acid.

5. A process according to Claim 3 in which the complex hydride is lithium aluminium hydride, sodium di-(methoxyethoxy)aluminium hydride, lithium borohydride, sodium borohydride or calcium borohydride.

6. A process as claimed in Claim 3 wherein the complex hydride comprises lithium aluminium hydride.

7. A process as claimed in Claim 3 wherein the complex hydride comprises sodium di(methoxyethoxy)aluminium hydride.

8. A process as claimed in Claim 3 wherein the complex hydride comprises lithium borohydride, sodium borohydride or calcium borohydride.

9. A process according to Claim 1 which comprises subjecting a compound of the formula:- (III) wherein R4 represents a hydrogen atom or a group removable by ether splitting, hydrolysis or hydrogenolysis, R5 and R6 are as defined in Claim 1 with the proviso that at least one of R4, R6 and R7 represents a remo-vable protecting group as defined above, to ether splitting, hydrolysis or hydrogenolysis whereby the said compound of formula III is converted into a compound of formula I.

10. A process as claimed in Claim 9 wherein a compound of formula III is used in which R4 and/or R7, where present, represents an alkyl, benzyl, or acyl group, said compound being subjected to ether cleavage, hydrogenolysis or hydrolysis.

11. A process as claimed in Claim 9 wherein a compound of formula III is used in which R4 and/or R7 represents a methyl or benzyl group, said compound being subjected to ether cleavage or hydrogenolysis.

12. A process as claimed in Claim 9 wherein the hydrolysis is effected by the use of an aqueous acid or base.

13. A process as claimed in Claim 9 wherein the hydrogenolysis is effected in the presence of platinum, palladium or Raney nickel as hydrogenation catalyst.

14. A process as claimed in Claim 9 wherein the ether splitting or hydrolysis is effected by the use of hydrobromic acid, hydrochloric acid, boron trifluoride etherate, boron tribromide or aluminium chloride.

15. A process according to Claim 1 which comprises reducing a compound of the formula:- (IV) (wherein R1 is as defined in Claim 1) whereby a compound of formula I is obtained.

16. A process as claimed in Claim 15 wherein the reduction is effected by catalytic hydrogenation.

17. A process as claimed in Claim 16 wherein the catalytic hydro-genation is effected in the presence of platinum,palladium or Raney nickel as hydrogenation catalyst.

18. A process according to Claim 1, wherein R2 represents an alkyl group with 1 - 4 carbon atoms or a benzyl group, which comprises alkylating a compound of the formula:- (V) either directly or by reaction with the appropriate aldehyde with 1 - 4 carbon atoms or benzaldehyde followed by reduction, wherein R1 is as defined in Claim 1 whereby a compound of formula I, wherein R2 represents an alkyl group with 1 to 4 carbon atoms or a benzyl group, is obtained.

19. A process according to Claim 1, wherein R? represents an alkyl group with 1 - 4 carbon atoms or a benzyl group, which comprises reducing a compound of the formula:- (VII) wherein R1 is as defined in Claim 1 and R8 represents a hydrogen atom, an alkyl group with 1 - 3 carbon atoms or a phenyl group whereby a compound of formula I, wherein R2 represents an alkyl group with 1 - 4 carbon atoms or a benzyl group, is obtained.

20. A process as claimed in Claim 19 wherein the reduction is effected by the use of a complex hydride.

21. A process as claimed in Claim 20 wherein the complex hydride comprises lithium aluminium hydride or sodium di-(methoxyethoxy)aluminium hydride.

22. A process as claimed in any of Claims 19 to 21 wherein the compound of formula VII is first prepared by acylating a compound to the formula:- V

wherein R1 is as defined in Claim 19, whereby a compound of formula VII as defined in Claim 19 is obtained.

23. A process according to Claim 1 in which R1 (or R5) represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxy, methyl, methoxy or trifluoromethyl group and R2 (or R6) represents a hydrogen atom or a methyl, ethyl or benzyl group.

24. A compound as claimed in Claim 2 wherein R1 represents a hydro-gen, fluorine, chlorine or bromine atom or a hydroxy, methyl, methoxy or trifluoromethyl group; and R2 represents a hydrogen atom or a methyl, ethyl or benzyl group, whenever prepared by the process of Claim 23 or by an obvious chemical equivalent thereof.

25. A process according to Claim 1 in which R1 (or R5) represents a 5-methoxy, 5-trifluoromethyl, 5-hydroxy or 2-, 4-, 5- or 6-methyl group or a hydrogen atom or a chlorine atom in the 2-position.

26. A compound as claimed in Claim 2 wherein R1 is as defined in Claim 25 whenever prepared by the process according to Claim 25 or by an obvious chemical equivalent thereof.

27. A process according to Claim 25 in which R2 is a hydrogen atom, a benzyl group, an ethyl group or a methyl group, R2' or R6 is a hydrogen atom, a benzyl group, an ethyl group, a methyl group or a benzyl group, R8 is phenyl, and R4 is a methyl group or a hydrogen atom.

28. A process according to Claim 1 in which R1(or R5) is 5-hydroxy, R2' is benzyl, R3 is methoxy, R4 is methyl or hydrogen and R6 is hydrogen.

29. A process according to Claim 1(b) in which 2-amino-3-(3,5-di-hydroxyphenyl)-1-propanol hydrobromide is prepared by demethylating 2-amino-3-(3,5-dimethoxyphenyl)-1-propanol or an acid addition salt thereof by reaction with hydrogen bromide.

30. A process according to Claim 29 in which the starting material is prepared by reducing 3,5-dimethoxyphenylalanine methyl ester by reaction with lithium aluminium hydride.

31. A process according to Claim 29 in which the starting material is prepared by catalytically hydrogenating 1-(3,5-dimethoxyphenyl)-2-nitroethane.

32. A process according to Claim 1(b) in which 2-amino-3-(3,5-dihydroxyphenyl)-1-propanol hydrobromide is prepared by demethylating and hydrolyzing 2-benzamido-3-(3,5-dimethoxyphenyl)-1-propanol.

33. A process according to Claim 32 in which the demethylation and hydro b sis is effected by reaction with 6N hydrochloric acid.

34. A process according to Claim 32 in which the starting material is prepared by reducing N-benzoyl-3-(3,5-dimethoxyphenyl)alanine methyl ester by reaction with sodium borohydride.

35. A process according to Claim 1(a) in which 2-amino-3-(3,5-dihydroxyphenyl)-1-propanol hydrochloride is prepared by reducing N-benzoyl-3,5-dihydroxyphenylalanine methyl ester by reaction with sodium borohydride and hydrolyzing the 2-benzamido compound so obtained by reaction with hydrochloric acid.

36. 2-amino-3-(3,5-dihydroxyphenyl)-1-propanol hydrobromide whenever prepared by the process of Claim 29 or 32 or by an obvious chemical equivalent thereof.

37. 2-amino-3-(3,5-dihydroxyphenyl)-1-propanol hydrochloride when-ever prepared by the process of Claim 35 or by an obvious chemical equivalent thereof.