BE856055A - 4-HYDROXYPHENYLALCANOLAMINE DERIVATIVES AND THEIR PREPARATION - Google Patents

Description

       

  Derivatives of 4-hydroxyphenylalkanolamine and their preparation.

  
.

  
The present invention relates to derivatives of 4-hydroxyphenylalkanolamine and in particular to derivatives of α- (aminoalkyl) 4-hydroxy-3- (alkylthio, alkylsulfinyl or alkylsulfonyl) -benzenemethanols and of 2- [4-hydroxy-3- ( alkylthio, alkylsulfinyl or alkyl-

  
  <EMI ID = 1.1>

  
appropriate intermediaries.

  
British Patent N [deg.] 1,321,701 describes a group of compounds represented by the general formula:

  

  <EMI ID = 2.1>


  
in which, among other things:

  
  <EMI ID = 3.1>

  
R4 is a hydrogen atom or a C1-C4 alkyl group; and

  
  <EMI ID = 4.1>

  
  <EMI ID = 5.1>

  
phenyl or substituted phenyl group. The compounds are reported to exhibit O-adrenergic blocking activity, peripheral vasodilator activity, antiarrhythmic activity and hypotensive activity.

  
The U.S. patent N [deg.] 3.917.704 describes a group of α-aminoalkyl-4-hydroxy-3-alkylsulfonylmethylbenzyl alcohols of formula

  

  <EMI ID = 6.1>


  
in which, among other things:

  
R represents a lower alkyl group of 1 to 5 carbon atoms, straight chain or branched; <EMI ID = 7.1>

  
  <EMI ID = 8.1>

  

  <EMI ID = 9.1>


  
  <EMI ID = 10.1>

  
methyl or ethyl;

  
R3 and R4 represent a hydrogen atom or a hydroxy or methoxy group; and

  
R5 represents a hydrogen atom or a methyl group. The compounds are reported to have utility as p-adrenergic stimulants with relatively greater activity on respiratory smooth muscle than on heart muscle.

  
Kaiser, et al. J. Med. Chem. 18, 674-683 (1975) primarily describe the work done in the U.S. patent. N [deg.] 3.917.704 mentioned above and further describe the compound of formula

  

  <EMI ID = 11.1>


  
which is indicated to be weakly active as a padrenergic agonist and which exhibits p-adrenergic antagonist activity. The work described in Kaiser's publication has been described

  
  <EMI ID = 12.1>

  
nale of the American Chemical Society. A summary of the oral presentation appeared in Abstracts of Papers, ACS Meeting 169; Medi 54
(April 1975).

  
Lutz et al., J. Med. Chem. 15, 795-802 (1972) describe the test for the preparation of 4-hydroxy-3-mercaptophenylethanolamine,

  
  <EMI ID = 13.1>

  

  <EMI ID = 14.1>


  
The compound however has not been isolated as a single entity nor characterized.

  
British Patent N [deg.] 1,154,193 describes as an agent

  
  <EMI ID = 15.1>

  
benzenemethanol, that is to say:

  

  <EMI ID = 16.1>


  
In the field of anti-hypertension therapy, the use of peripheral vasodilator agents to lower blood pressure has often presented a serious drawback, namely reflex tachycardia due to hypotension induced by systemic vasodilation. Recent efforts have been made to overcome this problem by using hypotensive vasodilators in combination with O-adrenergic blockers, the role of the latter being to reduce reflex tachycardia due to hypotension induced by the vasodilator. This mode of treatment obviously has the drawback of requiring two separate drugs and furthermore of requiring different dose regulation as well as increased risks of error by the patient in not taking one or the other of the drugs.

  
The present provides new therapeutically useful compounds which have both hypotensive vasodilator activity and P-adrenergic blocking activity and therefore suitable for use as anti-hypertension agents free from side effects. tachycardia adverse reactions associated with commonly used vasodilator agents.

  
  <EMI ID = 17.1>

  
4-YO-3- (lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl) benzenemethanols which can be used as <EMI ID = 18.1> anti-hypertension agents, of formula 1 below:

  

  <EMI ID = 19.1>


  
in which :

  
  <EMI ID = 20.1>

  
or lower alkyl groups;

  
n is an integer of 1 to 3;

  
Ar is a phenyl or phenyl group having one to three halogen, lower alkyl, hydroxy or lower alkoxy substituents;

  
Q is a lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group;

  
Y is a hydrogen atom or a lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl group;

  
and their acid addition salts. As described more fully below, some of these compounds are also useful as antiarrhythmic agents.

  
Another aspect of the invention relates to [(arylalkyl) amino] alkyl-4-YO-3- (lower alkylthio, lower alkylsulfinyl

  
or lower alkylsulfonyl) phenyl ketones of formula II below:

  

  <EMI ID = 21.1>


  
  <EMI ID = 22.1>

  
data above; and their acid addition salts.

  
These compounds are useful as intermediates in the

  
  <EMI ID = 23.1>

  
above. As described more fully below, some of the ketones are also useful as antihypertensive or antiarrhythmic agents.

  
The particular embodiments reside in the

  
  <EMI ID = 24.1>

  
have the meanings indicated above and Ar is a <EMI ID = 25.1>

  
a phenyl or phenyl group bearing one or two lower alkyl, hydroxy or lower alkoxy substituents.

  
The invention also relates to N- (arylalkyl) -2- [4YO-3- (lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl]) phenyl] ethylamines of formula III below:

  

  <EMI ID = 26.1>


  
  <EMI ID = 27.1>

  
previously indicated; and their acid addition salts.

  
These compounds are useful as antihypertension agents and as better described below some of them are also useful as antiarrhythmic agents.

  
The invention also relates to N- (arylalkyl) -2chloro, bromo or iodo-2- [4-YO-3- (lower alkylthio, lower alkylsulfinyl or lower alkylsulphonyl) phenyl] ethylamines of formula IV below:

  

  <EMI ID = 28.1>


  
  <EMI ID = 29.1>

  
previously indicated; X is a chlorine, bromine or iodine atom; and their acid addition salts.

  
These compounds are useful as intermediates in the preparation of the compounds of formula III above.

  
The benzenemethanols of formula I above can be prepared by reducing the aminoalkyl phenyl ketones of formula II above. Aminoalkyl phenyl ketones of formula II can be prepared by reacting a haloketone of formula V below:

  

  <EMI ID = 30.1>
 

  
  <EMI ID = 31.1>

  
and X is a chlorine, bromine or iodine atom, with a
(arylalkyl) amine of formula VI below.

  

  <EMI ID = 32.1>


  
in which R2, R3, n and Ar have the meanings indicated above.

  
3- (lower alkylsulfinyl) benzene can be prepared.

  
  <EMI ID = 33.1>

  
and Y have the meanings given above and Q is a lower alkylsulfinyl group, oxidizing 3- (alkylthio

  
  <EMI ID = 34.1>

  
n, Ar and Y have the meanings given above and Q is a lower alkylthio group.

  
The 2-phenylethylamines of formula III above can be prepared by reducing the 2-chloro, bromo or iodo-2-phenylethylamines of formula IV above.

  
You can prepare 2- [3- (lower alkylsulfinyl) -

  
  <EMI ID = 35.1>

  
R3, n, Ar and Y have the meanings indicated above and

  
Q is a lower alkylsulfinyl group, oxidizing 2- [3-

  
  <EMI ID = 36.1>

  
ment and Q is a lower alkylthio group.

  
The 2-chloro, bromo or iodo-2-phenylethylamines of formula IV can be prepared by reacting a benzenemethanol of formula I above with a hydracid HX or a mineral acid chloride or bromide.

  
Blood pressure can be reduced in mammals by administering to such mammals a blood pressure lowering effective amount of a benzenemethanol of formula I above. Vasodilation can be produced in mammals by administration to them in an amount effective to produce vasodila-

  
  <EMI ID = 37.1>

  
blood pressure in mammals by administering to them an effective blood pressure lowering amount of a compound

  
  <EMI ID = 38.1>

  
In the expressions lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl, "lower" denotes an alkyl part having from 1 to 4 carbon atoms which can be straight chain or branched. They include methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, etc., with methyl and ethyl groups being preferred.

  
The term “lower alkanoyl” denotes straight or branched chain alkanoyl radicals having from 1 to 6 carbon atoms, as illustrated by the formyl, acetyl, propionyl, butyryl, .isobutyryl, pivalyl, caproyl, etc. groups.

  
The term "halo" as used herein refers to fluorine, chlorine, bromine or iodine.

  
  <EMI ID = 39.1>

  
3,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2,5-dimethylbenzoyl, m-isopropylbenzoyl, [pound] -t-butylbenzoyl, etc ...

  
We will see that Y in formulas I and II can represent! acyl residues other than the preceding groups since it is known that such esters undergo hydrolytic cleavage under physiological conditions, giving in situ the parent phenols which obviously have the biological activity indicated above.

  
When used herein, the term "toluenesulfonyl" includes ortho, meta, and para-toluenesulfonyl.

  
The benzenemethanols represented by formula I above are obtained by reducing the aminoalkyl phenyl ketones of formula II with a suitable reducing agent in a suitable solvent, for example sodium borohydride or lithium borohydride in water or a lower alkanol; lithium aluminum double hydride in ether, tetrahydrofuran or dioxane; diborane in tetrahydrofuran or diethylene glycol dimethyl ether; aluminum isopropylate in 2-propanol; or by hydrogenation in the presence of a noble metal as a catalyst, for example palladium or platinum.

  
When the aminoalkyl phenyl ketone contains a carboxylic ester group (formula II in which Y is a lower alkanoyl or aroyl group), and it is desired to keep the ester group in the reduction product (formula I in which Y is a group lower alkanoyl or aroyl), the use of reducing means leading to the reduction of the carboxylic ester groups should obviously be avoided. Accordingly, in this case, the reduction is preferably carried out with an alkali metal borohydride or by catalytic hydrogenation, which results in a selective reduction of the ketone function. When the ultimately desired product is free phenol
(formula I where Y is a hydrogen atom), the preceding reduction reaction can be followed by the hydrolysis of the ester group,

  
  <EMI ID = 40.1>

  
with a reagent capable of reducing both the ketone and carboxylic ester functions, for example lithium aluminum double hydride. by treating

  
The borohydride reduction process is conveniently carried out / aminoalkyl phenyl ketone by sodium borohydride in the

  
  <EMI ID = 41.1>

  
about 15 minutes to 2.5 hours or until reduction is essentially complete as indicated by thin layer chromatography. If the starting material contains an ester group (formula II in which Y is a lower alkanoyl or aroyl group) and it is desired to keep the latter in the final product, the reaction of the mixture with acid is stopped and The esterified benzenemethanol (formula I wherein Y is a lower alkanoyl or aroyl group) is isolated in a conventional manner. If, on the other hand, free phenol is desired
(formula I in which Y is a hydrogen atom), the reaction mixture is treated with one equivalent of sodium or potassium hydroxide in water and the mixture is stirred at about 20 [deg.] C-65 [deg. ] C for about 30 minutes to 15 hours. The resulting phenol is isolated in a conventional manner.

  
The catalytic hydrogenation process is conveniently carried out in a suitable solvent, for example N, N-dimethylformamide, at 20 [deg.] C-50 [deg.] C under a hydrogen pressure of 1.4 to 3, 5 kg / cm <2> in the presence of a noble metal as a catalyst, for example palladium. The hydrogenation is continued until the theoretical amount of hydrogen has been absorbed. After removal of the catalyst, the reduction product is isolated in a conventional manner.

  
Although 3- (lower alkylsulfinyl) benzenemethanols of formula I wherein Q is lower alkylsulfinyl can be obtained by reducing ketones <EMI ID = 42.1>

  
corresponding to formula II in which Q is a lower alkylsulfinyl group According to the preceding procedures, it is usually preferred to prepare the sulfinyl derivatives by oxidizing the corresponding 3- (lower alkylthio) benzenemethanols of formula I in which Q is a lower alkylthio group, to using a suitable oxidizing agent such as a peracid, hydrogen peroxide or sodium metaperiodate.

  
The oxidation is preferably carried out by treating the 3-
(lower alkylthio) benzenemethanol with peracetic acid

  
50% in methanol, which is available commercially, at a

  
  <EMI ID = 43.1>

  
hour and a half or until oxidation is essentially complete as indicated by thin layer chromatography.

  
Alternatively, the oxidation is carried out with 30% hydrogen peroxide in methanol at about 20 [deg.] C-65 [deg.] C for
24 to 72 hours or until oxidation is essentially complete as indicated by thin layer chromatography.

  
The oxidation product is isolated according to conventional methods.

  
The aminoalkyl phenyl ketones of formula II above can be obtained by reacting a haloketone of formula V with an excess of an (arylalkyl) amine of formula VI in a suitable solvent such as acetonitrile, dimethylsulfoxide or N, N -dimethylformamide, at a temperature of about -65 [deg.] C to + 25 [deg.] C for

  
1 to 4 hours or until reaction is essentially complete as indicated by thin layer chromatography.

  
In the case where Y in formula V is a lower alkanoyl or aroyl group, reaction with an (arylalkyl) amine may result in partial cleavage of the ester function, or the ester of formula II (i.e. when Y is as defined above) can be hydrolyzed to free phenol in a separate step. When desired, the partially deacylated or hydrolyzed product can be esterified again according to known procedures, for example with an acyl halide in the presence of a strong acid such as trifluoroacetic acid. Likewise, a free phenol of formula I or III can be converted into the corresponding ester by such esterification.

  
Although 3- (lower alkylsulfinyl) phenyl ketones of formula II in which Q is a lower alkylsulfinyl group can be obtained by reacting a haloketone of formula V in which Q is an alkylsulfinyl group <EMI ID = 44.1>

  
generally prefers to prepare 3- (lower alkylsulfinyl) phenyl ketones of formula II by oxidation of the corresponding sulfides (formula II, Q is a lower alkylthio group) as described above for the preparation of 3- (lower alkylsulfinyl) benzenemethanols of formula I where Q is a lower alkylsulfinyl group.

  
The (arylalkyl) amines of formula VI are generally known or, if they are new, they are obtained according to procedures described for the preparation of the known compounds.

  
Thus, the tertiary carbinamines, i.e. the (arylalkyl) amines of formula VI in which R2 and R3 are both a lower alkyl group, can be obtained from the corresponding generally known tertiary alcohols, by the reaction well known to Ritter [Organic Reactions 17, 213 (1969)] followed by hydrolysis of the resulting tertiary carbinamides.

  
The (arylalkyl) amines of formula VI in which one of R2 and R3 or both are hydrogen atoms can be obtained by reacting an aldehyde or a ketone having the appropriate number of carbons with the 'ammonia or a derivative of ammonia

  
  <EMI ID = 45.1>

  
(1948) and Organic Reactions 5, 301 (1949).

  
The haloketones of formula V are obtained by halogenating with chlorine or bromine the appropriate phenyl ketone of formula VII below:

  

  <EMI ID = 46.1>


  
  <EMI ID = 47.1>

  
and Y is a methyl, lower alkanoyl or aroyl group. The reaction is conveniently carried out by treating with bromine the ketone of formula VII in an inert solvent such as chloroform, at about 25 [deg.] C, and optionally in the presence of an inorganic base,

  
  <EMI ID = 48.1>

  
an induction period and in some cases it may be advantageous to initiate the reaction by exposing the mixture to a <EMI ID = 49.1>

  
ultraviolet radiation until bromination has started, as evidenced by the simultaneous discoloration and evolution of hydrobromic gas. If desired, the Y substituent can be removed from the resulting haloketone according to well known procedures, for example by hydrolysis of the ester when Y is a group.

  
  <EMI ID = 50.1>

  
a Lewis acid such as aluminum chloride, hydrobromic gas or boron tribromide when Y is a methyl group.

  
The corresponding iodoketenes (formula V in which X is iodine) can be obtained by reacting the chloro- or

  
  <EMI ID = 51.1>

  
tone, under the conditions of the well-known Finkelstein reaction

  
The above phenyl ketones of formula VII can be obtained by various procedures which are generally known in the art.

  
Thus, for example, we obtain 3- (lower alkylthio) phenyl ketones of formula VII where Q is a lower alkylthio group and Y is a lower alkanoyl or aroyl group, by alkylation of 3-mercapto-4-hydroxyphenyl ketones of formula VII wherein Q is a mercapto group and Y is a hydrogen atom, with a suitable lower alkyl halide in a suitable solvent such as a lower alkanone in the presence of an acid acceptor, for example an alkali metal carbonate, followed by esterification of the resulting 3- (alkylthio) -4-hydroxyphenyl ketones (formula VII in which Q is a lower alkylthio group and Y is a hydrogen atom) with a suitable acylating agent such as a halide or anhydride lower alkanoyl or aroyl, in an inert solvent such as methylene chloride, chloroform,

   benzene or toluene, in the presence of an acid acceptor such as triethylamine or pyridine. The 3-mercapto-4-hydroxyphenyl ketones are in turn obtained by chlorosulfonation of the generally known 4-hydroxyphenyl ketones of formula VII in which Q and Y are atoms

  
  <EMI ID = 52.1>

  
25 [deg.] C, preferably in the absence of a solvent, followed by reduction of the resulting 3-chlorosulfonyl-4-hydroxyphenyl ketones with a suitable reducing agent such as stannous chloride and hydrochloric acid, or zinc and sulfuric acid.

  
Alternatively, the 3- (lower alkylthio) phenyl ketones of formula VII where Q is a lower alkylthio group and Y is a lower alkanoyl group can be obtained by acylating the generally known o- (lower alkylthio) phenols with a

  
  <EMI ID = 53.1>

  
Friedel-Crafts conditions, then esterifying the resulting 3- (alkylthio) -4-hydroxyphenyl ketones, as previously described.

  
It will be seen that although the 3- (lower alkylsulfinyl) phenyl ketones of formula III can be obtained by oxidizing the corresponding sulfides of formula V in which Q is a lower alkylthic group, it is generally preferred to use the latter as a starting material and to carry out any desired oxidation of the sulfide to sulfoxide at the last stage of the synthesis, as previously described.

  
The 3- (lower alkylsulfonyl) phenyl ketones of formula VII in which Q is a lower alkylsulfonyl group and Y is a methyl group are obtained, by oxidizing the 3- (lower alkylsulfonyl) anisoles of formula VIII below:

  

  <EMI ID = 54.1>


  
in which R1 has the meaning given above and Q is a lower alkylsulfonyl group, with a suitable oxidizing reagent, such as ammonium persulfate, in the presence of silver nitrate in aqueous medium, at an approximate temperature range of 20 [deg .] C to 70 [deg.] C, for about 2 to 3 hours. 3- (lower alkylsulfonyl) anisoles are obtained by sulfonating the generally known anisoles of formula 8 in which Q is hydrogen, with a suitable lower alkylsulfonic anhydride in an inert solvent, for example the symbol. tetrachloroethane at about 130 [deg.] C-180 [deg.] C.

  
The 2-phenylethylamines of formula III above can be obtained by reducing a 2-halo-2-phenylethylamine of formula IV with a suitable reducing agent, such as lithium aluminum hydride in ether, tetrahydrofuran or dioxane, sodium borohydride in a lower alkanol or N, N-dimethylformamide; or by catalytic hydrogenation.

  
  <EMI ID = 55.1>

  
The reduction is conveniently carried out using sodium borohydride in N, N-dimethylformamide, at a temperature of -10 [deg.] C to + 25 [deg.] C, for about a quarter of an hour to

  
2 hours or until reaction is essentially complete, as indicated by thin layer chromatography.

  
Obviously, when the 2-halo-2-phenylethylamine contains another reducible function, such as an ester group (for example formula IV in which Y is a lower alkanoyl or aroyl group) and it is desired to retain this function in the product of reduction, the precautions described above must be taken for the reduction of the aminoalkyl phenyl ketone of formula II. Likewise, if the free phenol of formula III where Y is a hydrogen atom is desired, the esterified product obtained is hydrolyzed with a base (formula III where Y is a lower alkanoyl or aroyl group).

  
The 2-halo-2-phenylethylamines of formula IV above are obtained by reacting a suitable benzenemethanol of formula I with a hydracid or a mineral acid halide in a suitable solvent, for example hydrochloric gas in tetrahydrofuran or dioxane, hydrobromic gas in acetic acid, sodium or potassium iodide in phosphoric acid, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus oxybromide, trichloride of phosphorus or phosphorus tribromide in benzene, toluene, chloroform or pyridine.

  
Although 2-phenylethylamines of formula III where Q is a lower alkylsulfinyl group can be obtained by the previously described series of halogenation of the appropriate benzenemethanol of formula I where Q is a lower alkylsulfinyl group followed by reduction of the resulting halogen derivative of formula IV where Q is a lower alkylsulfinyl group, it is usually preferred to carry out the successive halogenation and reduction in

  
  <EMI ID = 56.1>

  
(formula I where Q is a lower alkylthio group) followed by oxidizing in the last step to obtain the desired lower alkylsulfinyl derivative. The oxidation is carried out according to the processes described above for the preparation of benzene-

  
  <EMI ID = 57.1>

  
laughing.

  
Due to the presence of the basic amino group, the free bases of the final products represented by the formulas

  
  <EMI ID = 58.1>

  
formulas II and IV, react with organic and mineral acids forming acid addition salts. The compounds of the invention can be used both in the form of the free base and in the form of acid addition salts, and both forms are within the scope of the invention. Acid addition salts are simply a more convenient form of use, and in practice use of the salt form corresponds to use of the base form.

  
Acid addition salts are prepared from any organic or inorganic acid. They are obtained in a conventional manner, for example by directly mixing the base with the acid, or when this is not appropriate by dissolving one or the other of the base or the acid or both, separately in water or an organic solvent, and mixing the two solutions, or dissolving the base and the acid together in a solvent. The resulting acid addition salt is isolated by filtration, if it is insoluble in the reaction medium, or by evaporation of the reaction medium to leave the acid addition salt as a residue. Acid parts or anions

  
of these salt forms in themselves are neither new nor critical and therefore can be any acid anion or acid-like substance capable of forming salts with a base.

  
Typical acids for the formation of acid addition salts include formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tannic acid, glutamic acid, tartaric acid, dibenzoyltartaric acid, oxalic acid, pyromucic acid, citric acid, acid lactic acid, mandelic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, 3, 5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridine- acid

  
  <EMI ID = 59.1>

  
picric acid, quinic acid, tropic acid, 3indole-acetic acid, barbituric acid, cyclohexylsulfamic acid, isethionic acid, methanesulfonic acid, benzene-

  
  <EMI ID = 60.1> <EMI ID = 61.1>

  
acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, sulfamic acid, glutaric acid, l phosphoric acid, arsenic acid, etc.

  
All the acid addition salts can be used as sources of the free base form, by reaction with an inorganic base. It will therefore be seen that if one or more of the characteristics of a given base or of an acid addition salt, such as solubility, crystallinity, molecular weight, physical appearance, toxicity, etc. ., make this shape unsuitable for final needs, they can easily be made into a more suitable shape according to procedures well known in the art.

  
When the compounds of the invention are to be used for pharmaceutical purposes, the acids used to prepare the acid addition salts preferably include those which give, when combined with the free base, pharmaceutically acceptable salts. medical, that is to say salts whose anions are relatively harmless to the animal organism at the medical doses of the salts, so that the beneficial properties inherent in the free base are not impaired by side effects attributable to anions. Suitable medically acceptable salts within the scope of the invention are those derived from acids such as hydrochloric acid, acetic acid, lactic acid, tartaric acid, cyclohexylsulfamic acid, methanesulfonic acid, phosphoric acid, etc.

  
The compounds of the invention represented by the formulas

  
  <EMI ID = 62.1>

  
amphoteric, because they have both an acidic phenol group and a basic amino group, and therefore they form salts with bases and with acids.

  
Due to the presence of at least one asymmetric center of up to four, in the compounds of the invention represented by formula I (i.e. the carbon atom of

  
  <EMI ID = 63.1>

  
lower alkyl group, the carbon atom to which R2 and R3 are attached when they are different and the sulfur atom when Q is a lower alkylsulfinyl group), these compounds can exist in as many stereoisomeric forms as sixteen, forms which are all individually or in form

  
mixture of two or more compounds considered to be within the scope of this invention. If desired, the separation or production of a particular stereochemical form or of a mixture of two or more stereochemical forms can be effected, applying the general principles known in

  
the technique.

  
. When preparing a particular stereoisomer or a particular mixture of two or more stereoisomers of any kind, it is advantageous to use intermediates of fixed stereochemical configuration, which limits the number of stereochemically.

  
stereoisomeric forms present in the final product and this simplifies the isolation of the desired components. Accordingly, before

  
reaction with a haloketone of formula V, a
(arylalkyl) amine of formula VI containing an asymmetric center

  
  <EMI ID = 64.1>

  
identical) in its optical antipodes (+) and (-) according to conventional techniques and using conventional resolving agents such as optically active tartaric acid, 0,0- dibenzoyl tartaric acid, mandelic acid, malic acid, etc. If desired, the (+) or (-) - (arylalkyl) amine can be reacted with a haloketone according to the procedure described above to obtain an aminoalkyl phenyl ketone of formula II having a stereochemical configuration fixed on carbon

  
  <EMI ID = 65.1>

  
When haloketone also contains an asymmetric center

  
  <EMI ID = 66.1>

  
is a lower alkylthio or lower alkylsulfonyl group), reaction with the (+) or (-) - (arylalkyl) amine produces two diastereomeric aminoalkyl phenyl ketones of formula II (R- is a lower alkyl group, Q is an alkylthio group lower or lower alkylsulfonyl) which can be separated by conventional methods, for example by fractional crystallization of a suitable addition salt.

  
Obviously, when haloketone does not contain a center

  
  <EMI ID = 67.1>

  
lower alkylthio or lower alkylsulfonyl), reaction with (+) or (-) - (arylalkyl) amine directly produces a single stereoisomer (+) or (-) of the aminoalkyl phenyl ketone

  
  <EMI ID = 68.1> lower alkylthio or lower alkylsulfonyl).

  
The reduction of the stereochemically fixed aminoalkyl phenyl ketone as described previously creates a new asymmetric center (i.e. the carbon atom of the alcohol) and therefore produces two 3- (lower alkylthio or lower alkylsulfonyl ) diastereomeric benzenemethanols of formula I. If desired, the diastereomers can be separated according to known methods, for example by fractional crystallization of

  
addition salt of an optically active acid such as (+) or (-) - mandelic acid, tartaric acid, O, O-dibenzoyltartaric acid, malic acid, etc., or by transforming the diastereomeric mixture into a suitable ester derivative (i.e. Y

  
in formula I is a lower alkanoyl, aroyl, benzenesulfonyl or p-toluensulfonyl group), for example the acetate,

  
benzoate, E-toluenesulfonate, and separating the esters by chromatography or by fractional crystallization of one of their appropriate acid addition salts.

  
Each of the diastereomers of 3- (lower alkylthio) benzenemethanol (formula I where Q is a lower alkylthio group) obtained previously can be oxidized as described above, which again gives rise to a new center of asymmetry
(i.e. the sulfur atom) thereby producing two diastereoisomeric sulfoxides (formula I, Q is a lower alkylsulfinyl group) which can also be separated according to the conventional procedures described above.

  
Alternatively, the two diastereomeric 3- (lower alkylthio) benzenemethanols can be oxidized directly to obtain a mixture of the four diastereomeric sulfoxides which, if desired, can also be separated according to the procedures described above, for example by fractional crystallization of a suitable acid addition salt such as hydrochloride or cyclohexylsulfamate.

  
The 2-phenylethylamine of formula III, having three potential centers of asymmetry, can therefore exist in stereoisomeric forms of up to 8. All these forms, either separately or in the form of two or more, are obviously considered to be part of the scope of the present invention. The production of a particular isomer or a particular mixture of isomers is more conveniently obtained starting from a benzenemethanol of formula I having the desired stereochemistry, obtained according to the procedures described above.

  
  <EMI ID = 69.1>

  
above exhibit anti-hypertension activity,

  
  <EMI ID = 70.1>

  
The combination in a single compound of vasodilator activity and 3-adrenergic blocking activity is particularly advantageous because the reflex tachycardia associated with the reduction in blood pressure by vasodilation is effectively reduced or eliminated by 6-adrenergic blockade. The compounds are therefore effective in lowering blood pressure without causing adverse effects such as tachycardia.

  
Note, however, that although vasodilator activity and O-adrenergic blocking activity both exist in the same compound, the time of onset of each of these actions appears to be different, with vasodilation usually preceding the 6- blockade. adrenergic. This can obviously give rise to a temporary moderate increase in heart rate which may be observed on the first day or both.

  
  <EMI ID = 71.1>

  
adrenergic then takes full effect and continuous medication can be continued with prolonged lowering of blood pressure without any appreciable rise in heart rate.

  
Further, unlike the antihypertensive response which is directly dose related, the increase in heart rate observed at the lower doses tested is not appreciably increased either in magnitude or duration at higher doses. It is therefore possible to increase the dose to achieve a further reduction in blood pressure without causing a corresponding increase in heart rate.

  
A preferred embodiment of this invention is the

  
  <EMI ID = 72.1>

  
hydrogen atoms; R3 is a methyl group; n is 2; Ar is a 4-methoxyphenyl group; and Q is a methylsulfinyl group) which has a high anti-hypertension activity and a particularly efficient distribution of the vasodilating and 3-adrenergic blocking activity and which is therefore particularly effective as an anti-hypertension agent without any side effects unwanted tachycardia.

  
The compound described above contains three centers of asymmetry (that is to say the carbon atom carrying the methyl group, the carbon atom carrying the alcohol group and the sulfur atom) and can therefore exist in the form of a mixture having up to eight stereoisomers. Particularly preferred among these are the four diastereomers derived from (+) - 4'-

  
  <EMI ID = 73.1>

  
  <EMI ID = 74.1>

  
4-methoxyphenyl group; and Q is a methylthio group) by reduction of the carbonyl group followed by oxidation of the methylthio group. These isomers, either individually or as a mixture of any two or more than two compounds, exhibit potent antihypertensive activity with no unwanted side effects of tachycardia. Although each of the four diastereomers can be separated from the mixture as previously described, this is generally not necessary and therefore it is economically advantageous to use

  
the mixture as obtained.

  
When an amount of a compound of formula I is administered to mammals effective to reduce hypertension in such mammals, the compounds may be administered in a suitable pharmaceutical composition, for example orally in the form of pills, tablets. , capsules, for example a mixture with talc, starch, lactose or other inert pharmaceutical carrier, that is to say non-toxic or pharmacologically acceptable, or in the form of aqueous solutions, suspensions, suspensions in capsules, gels, elixirs, aqueous alcoholic solutions, for example in admixture with sugar or other sweetening agents, flavoring agents, colorants, thickeners and other conventional pharmaceutical excipients.

   When injected subcutaneously, intramuscularly or intravenously, they can be administered as a solution or a suspension in water or peanut oil, using excipients and agents. conventional supports for this mode of administration. The best route of administration and the best dose will be evident from the laboratory tests carried out to determine the activity and toxicity of the chosen compound, which tests are conventionally carried out in the development phase of a product. pharmaceutical.

  
The molecular structures of the compounds of this invention were assigned based on their methods of preparation and the study of their IR and NMR spectra, and were confirmed by the correspondence between the values calculated and found for the elemental analysis of compounds. representative.

  
The identity and purity of individual stereoisomers as well as the composition of stereoisomeric mixtures were determined based on optical rotation and high pressure liquid chromatography.

  
The invention is illustrated by the following examples without, however, being limited thereto. Unless otherwise indicated, the rotational powers are determined on a 2% solution of the compound in methanol.

  
EXAMPLE 1

  
A. A 100 g (0.085 mol) of chlorosulfonic acid at 5 [deg.] C, one

  
  <EMI ID = 75.1>

  
The temperature is allowed to rise gradually to 22 ° C. while the reaction mixture is stirred overnight. Then we

  
raise the temperature to 55-60 [deg.] C and stirring is continued for an additional hour. The reaction mixture is poured into ice-water and the precipitated solid is collected and washed with water. The product is dissolved in ethyl acetate and the resulting solution is dried and evaporated to dryness. The residues are recrystallized from benzene to give 12.5 g of 4'-hydroxy-3'-

  
  <EMI ID = 76.1>

  
a second crop of 5.0 g, m.p. 124-136 [deg.] C.

  
B. Hydrogen chloride gas is bubbled through a stirred mixture containing 105 g (0.46 mole) of stannous chloride dihydrate and
400 ml of glacial acetic acid until an almost clear solution is obtained. To the latter solution, 18 g (0.077 mole) of 4'-hydroxy-3 '- (chlorosulfonyl) acetophenone are added in portions over 20 minutes crude by maintaining the temperature at 25-30 [deg.] C. When the addition is complete, stirring is continued for a further half hour. Then the reaction mixture is poured into 400 ml of 12N hydrochloric acid, diluted with 800 ml of water and extracted with chloroform. The extracts are washed with a saturated aqueous solution of sodium chloride and evaporated to dryness. The residue is recrystallized from benzene to give 4 g of 4-hydroxy-3'-mercaptoacetophenone, m.p. 117-120 [deg.] C.

  
C. Stir for two and a half hours at room temperature

  
  <EMI ID = 77.1> mercaptoacetophenone, 0.9 g (0.0063 mole) of methyl iodide, 0.83 g (0.006 mole) of potassium carbonate and 12 ml of acetone. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in chloroform and the resulting solution washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate and evaporated to dryness. We dissolve

  
the residue in hot benzene and the solution filtered through a 6.3 mm pad of silica gel to remove a colored impurity. Evaporation of the filtrate gives 0.9 g of 4'-hydroxy-3'-
(methylthio) acetophenone, m.p. 117-120 [deg.] C.

  
D. Alternatively, to a stirred solution containing 61.4 g (0.435 mole) of o- (methylthio) phenol and 35 g (0.45 mole) of acetyl chloride in 170 ml of nitrobenzene is added in portions

  
in 20 minutes 80 g (0.60 mol) of aluminum chloride. The reaction mixture is stirred overnight at room temperature and then for one hour at 65 [deg.] C. The reaction mixture is cooled, diluted with water and ice, and extracted with methylene chloride. The organic extracts are evaporated in vacuo, the residue is diluted with ether and left to stand for two days in the refrigerator. The precipitated product is collected

  
which is dried and 27 g of 4'-hydroxy-3 '- (methylthio) acetophenone are obtained.

  
E. To a cooled and stirred solution containing 24.5 g
(0.134 mol) of 4'-hydroxy-3 '- (methylthio) acetophenone and 21 g
(0.21 mole) of triethylamine in 400 ml of methylene chloride, 16.4 g (0.21 mole) of acetyl chloride are added dropwise over 30 minutes. After stirring overnight at room temperature, the reaction mixture is washed with water, dried over anhydrous sodium sulfate and concentrated to a small volume. The concentrate is diluted with ether and cooled in an ice bath. The resulting precipitate, 23.5 g of 4'-hydroxy-3 '- (methylthio) acetophenone 4'-acetate, was collected.

  
F. To a stirred solution containing 23.2 g (0.108 mol) of

  
  <EMI ID = 78.1>

  
calcium carbonate in 300 ml of chloroform, add drop

  
drop in two hours a solution containing 6 ml (0.108 mol) of -bromine in 30 ml of chloroform. The reaction mixture is filtered, the filtrate washed with a saturated aqueous solution of sodium bicarbonate and evaporated to dryness. The residue is dissolved in ether and the ethereal solution is diluted with cyclohexane and <EMI ID = 79.1>

  
chills it in ice. The resulting precipitate was collected and dried to afford 26.5 g of 2-bromo-4-hydroxy-3 '- (methylthio) acetophenone 4'-acetate.

  
G. To a stirred solution containing 16.5 g (0.10 mol) of

  
  <EMI ID = 80.1>

  
triethylamine in 40 ml of N, N-dimethylformamide at - 65 [deg.] C, 15.5 g (0.051 mol) of 2-bromo-4'-hydroxy-3 4'acetate are added dropwise over two hours '- (methylthio) acetophenone in

  
40 ml of N, N-dimethylformamide. After the addition is complete, stirring is continued at -65 [deg.] C for an additional hour. The reaction mixture is then acidified with 10 ml of 12N hydrochloric acid and diluted with 100 ml of water. By stirring the aqueous solution with 200 ml of a 2: 1 mixture of ether and methylene chloride, the product begins to precipitate in the aqueous phase. The layers are separated and the aqueous part is cooled in ice. The resulting precipitate was collected and dried for 3 hours over phosphorus pentoxide in a vacuum oven at 65 [deg.] C, to give 12.1 g of 4'-acetate hydrochloride.

  
  <EMI ID = 81.1>

  
(methylthio) acetophenone.

  
EXAMPLE 2

  
A stirred solution containing 12.5 g (0.029 mol) of the hydrochloride of water is cooled in an ice-acetone bath.

  
  <EMI ID = 82.1>

  
milking it in portions over 15 minutes with 0.9 g of sodium borohydride. Once the addition is complete, stirring is continued for a further 20 minutes. The reaction mixture is then brought to pH 7 with glacial acetic acid and evaporated to dryness. The residue is diluted with ether and washed thoroughly with a saturated aqueous solution of sodium bicarbonate. The ethereal solution is dried over anhydrous sodium sulfate and concentrated to a small volume. The concentrate is acidified with an ethereal solution of hydrochloric gas and cooled overnight in a refrigerator. The product which has precipitated is collected and recrystallized from a mixture of methanol and isopropyl alcohol, to give 2.1 g of the hydrochloride of 4-.

  
  <EMI ID = 83.1>

  
In addition to its anti-hypertension activity, we have found

  
not <EMI ID = 84.1>

  
adrenergic as shown by its ability to block histamine-induced bronchoconstriction in dogs.

  
EXAMPLE 3

  
To a stirred suspension of 6.9 g (0.016 mol) of 4'-hydroxy-2 - {[2- (4-methoxyphenyl) - 4'-acetate hydrochloride

  
  <EMI ID = 85.1>

  
methanol, 400 mg of sodium borohydride are added. After 5 minutes all of the starting material dissolved. The reaction mixture is treated with 10 ml of water and stirred overnight.

  
at room temperature. Then we add a solution containing
900 mg of potassium hydroxide in 10 ml of water and the mixture is heated under reflux for half an hour. The resulting solution is concentrated to half volume, the concentrate is slightly acidified with 12N hydrochloric acid and evaporated to almost dryness. The residue is diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate, acidified with glacial acetic acid and concentrated until crystallization begins. The product is collected, triturated with chloroform and finally recrystallized from a mixture of methanol and chloroform, which gives 3.9 g of the 4- acetate.

  
  <EMI ID = 86.1>

  
(methylthio) benzenemethanol, m.p. 163-165 [deg.] C.

  
EXAMPLE 4

  
A solution containing 1.5 ml of 30% hydrogen peroxide and the free base obtained from 9 g of 4-acetate hydrochloride is stirred for two days at room temperature and then for an hour and a half at reflux. hydroxy-a- <{[2- (4-methoxy-

  
  <EMI ID = 87.1>

  
in 150 ml of methanol. The reaction mixture is then evaporated to dryness. The residue is dissolved in water and the solution is filtered to remove insoluble impurities. The filtrate is acidified with 12N hydrochloric acid and evaporated to dryness. The residue is triturated with a mixture of ether and iso- acetate.

  
  <EMI ID = 88.1>

  
The resulting filter is filtered to remove insoluble impurities and the filtrate is evaporated to dryness. The residue is triturated with ether and cyclohexane, and the resulting solid is collected and dried over phosphorus pentoxide for 6 hours at 85 [deg.] C, to give 4.6 g of 4- hydrochloride. hydroxy-a- <{[2- (4-methoxy-

  
  <EMI ID = 89.1>

  
methanol as an amorphous yellow-brown solid, m.p. 115 [deg.] C.

  
In addition to its anti-hypertension activity, this compound has also been found to have stimulating activity (3-adrenergic as shown by its ability to block histamine-induced bronchoconstriction in dogs.

  
EXAMPLE 5

  
A. A solution is heated at reflux for 17.5 hours.

  
  <EMI ID = 90.1>

  
with hot water, the reaction mixture is evaporated to dryness in vacuo, leaving 20 g of a dark oil which is combined with the product of two previous runs and distilled under reduced pressure. The fraction boiling at 90-120 [deg.] C / 0.5mm is collected, and it is redistilled on a. short column of Vigreux. The impurities boiling at 45-65 [deg.] C / 0.5 mm are discarded and the residue remaining in the flask is distilled again. The impurities are discarded, boiling at 175-187 [deg.] C / 10 minutes, leaving 30 g of almost pure 4-ethyl-2- (methylsulfonyl) anisole.

  
B. A solution containing 55 g (0.242 mole) of ammonium persulfate, 520 mg of silver nitrate and 26 g (0.121 mole) of 4-ethyl-2- (methylsulfonyl) is stirred at 20 ° C. anisole in 300 ml of water. After one hour the temperature rose to 48 [deg.] C and after 2.5 hours it dropped back to 30 [deg.] C. The product is extracted with chloroform and, after drying over anhydrous sodium sulfate, the chloroform extracts are evaporated to dryness. The residue is adsorbed on a column of deactivated silica gel with 20% water by weight. The impurities are washed from the column with ether and

  
the product is eluted with hot methylene chloride, which

  
  <EMI ID = 91.1>

  
146-148 [deg.] C.

  
C. To a solution containing 14.5 g (0.063 mol) of 4'methoxy-3 '- (methylsulfonyl) acetophenone in 200 ml of chloroform is added dropwise a solution containing 10.2 g of bromine in 40 ml of chloroform. After an induction period of half an hour, the bromine begins to be consumed. When the addition is almost complete, the product begins to precipitate. The reaction mixture is diluted with methylene chloride and the resulting solution is washed successively with a. saturated aqueous solution of sodium bicarbonate and water and evaporated to dryness. Recrystallization of the residue from a mixture of methylene chloride and carbon tetrachloride gives 17.9 g

  
  <EMI ID = 92.1>

  
170 [deg.] C.

  
D. A vigorously stirred mixture containing 4.5 g of 2-bromo-4'-methoxy-3'- is heated under reflux for two hours.
(methylsulfonyl) acetophenone, 4.5 g of aluminum chloride and
100 ml of chlorobenzene. The reaction mixture is poured into ice-water and extracted with a mixture of ether and ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate and evaporated to dryness. The residue is triturated with ether and the resulting yellow-brown crystallized solid, 3.0 g of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) acetophenone, is collected.

  
E. To a stirred solution containing 10 g (0.06 mol) of 2-

  
  <EMI ID = 93.1>

  
formamide at -30 [deg.] C (carbon dioxide snow-carbon tetrachloride),

  
a solution containing 7 g (0.024 mol) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) acetophenone in 20 ml of N, N-dimethylformamide is added dropwise. Once the addition is complete, the

  
  <EMI ID = 94.1>

  
water and extracted with chloroform. The chloroform extracts are dried over anhydrous sodium sulfate, acidified with ethanolic hydrochloric acid and stored overnight in the refrigerator. The product which crystallizes is collected and recrystallized from chloroform, which

  
  <EMI ID = 95.1>

  
EXAMPLE 6

  
A solution containing 3.7 g of the hydrochloride is hydrogenated.

  
  <EMI ID = 96.1>

  
3 '- (methylsulfonyl) acetophenone in 100 ml of N, N-dimethylformamide, under an initial hydrogen pressure of 3.5 kg / cm <2>

  
in the presence of 1 g of a hydrogenation catalyst which is 10% palladium on carbon. After 15 minutes, one molar equivalent of hydrogen was absorbed. The catalyst is then removed by filtration and the filtrate is evaporated to dryness. The residue is diluted with

  
ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated to

  
100 ml. The concentrate is acidified with glacial acetic acid, concentrated to about 70 ml and cooled. The resulting crystalline precipitate is collected to give 2.9 g of the acetate.

  
  <EMI ID = 97.1>

  
EXAMPLE 7

  
To a stirred solution containing 24 g (0.135 mol) of

  
  <EMI ID = 98.1>

  
dimethylformamide at -50 [deg.] C, a solution containing 15 g (0.05 mol) of 2-bromo-acetate is added dropwise over 15 minutes.

  
  <EMI ID = 99.1>

  
formamide. When the addition is complete, stirring is continued for an additional one-quarter hour. Then the reaction mixture is treated with 4 ml of 12N hydrochloric acid, diluted with 100 ml of water and extracted with a mixture of ether and ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate, acidified with ethanolic hydrochloric acid and evaporated to dryness. The crude product containing the 4'-acetate and 4'-hydroxy derivatives is dissolved in a solution containing 10 ml of acetyl chloride in 120 ml of trifluoroacetic acid and the mixture is stirred for two hours at room temperature. The solution is then evaporated to dryness and the residue is distributed between ether and water. The ethereal layer is dried over anhydrous sodium sulfate and acidified with ethanolic hydrochloric acid.

   The resulting precipitate was collected and triturated with a mixture of acetone and ether to give 6.0 g of 4'-hydroxy-2 - {[3- (4-) 4'-acetate hydrochloride.

  
  <EMI ID = 100.1>

  
m.p. 160-165 [deg.] C.

EXAMPLE 8

  
Has a stirred mixture of 9.0 g (0.021 mole) of the hydrochloride

  
  <EMI ID = 101.1>

  
temperature of -5 to 0 [deg.] C, 0.5 g (0.015 mol) of sodium borohydride is added in portions. After another half hour of stirring, a solution is added containing 1.0 g of potassium hydroxide in 10 ml of water and the resulting mixture is stirred at room temperature under nitrogen overnight and then at reflux for half an hour. The pH was adjusted to 7 with glacial acetic acid and the resulting solution was concentrated to a small volume, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, acidified with glacial acetic acid, concentrated to a small volume and cooled.

   The product which separates is collected and recrystallized from a mixture of ethyl acetate and ethanol to give 7.2 g of 4-hydroxy-a- acetate.

  
  <EMI ID = 102.1>

  
thio) benzenemethanol, m.p. 132-134 [deg.] C.

  
. EXAMPLE 9

  
A. To a stirred solution containing 100 g (0.55 mol) of 4'-hydroxy-3 '- (methylthio) acetophenone in 600 ml of 15- pyridine.
18 [deg.] C, 68 ml (0.58 mol) of benzoyl chloride are added dropwise over one hour. After the addition is complete, stirring is continued at room temperature for one and a half hours. Then the reaction mixture is poured into 1.5 l of water at ice temperature. The solid which precipitates is collected by filtration, washed successively with water and 2-propanol.

  
cold and n-hexane and dried, yielding 146 g of 4'-

  
  <EMI ID = 103.1>

  
benzene at 20 [deg.] C, 15 ml of a solution containing 85 g are added
(0.53 mol) of bromine in 100 ml of benzene. The mixture is irradiated with ultraviolet light for about an hour to initiate the reaction. When the reaction begins (as indicated by the discoloration), a slow stream of nitrogen is bubbled through the reaction mixture and the remainder of the bromine solution is added over 2 hours while maintaining the temperature at 20-24. [deg.] C. The reaction mixture is stirred for an additional half hour and then cooled to 16 [deg.] C. The solid which precipitated was collected by filtration, washed with water and with n-hexane and dried to give 90 g of 2-bromo-4'-hydroxy-3 4'-benzoate. '-

  
  <EMI ID = 104.1>

  
provides an additional 21 g of product, m.p. 126-129 [deg.] C.

  
C. To a stirred solution containing 36 g (0.2 mole) of 3-

  
  <EMI ID = 105.1> <EMI ID = 106.1>

  
extra minutes. Then the reaction mixture is diluted with
200 ml of chloroform, treated with 20 ml of 45% hydrobromic acid and then diluted with 200 ml of cold water. The layers are separated and the aqueous layer is extracted again with chloroform. The organic layers are combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to about 100 ml. The concentrate is diluted with 400 ml of ether and cooled. The resulting precipitate was collected by filtration, washed successively with cold 2-propanol and ether and dried to give 26 g of 4'-benzoate hydrobromide.

  
  <EMI ID = 107.1>

  
thio) acetophenone.

EXAMPLE 10

  
To a stirred solution of 25 g (0.046 mol) of hydrobromide

  
  <EMI ID = 108.1>

  
at 0 [deg.] C, 1.4 g (0.037 mol) of sodium borohydride are added in portions over half an hour. After another 20 minutes of stirring, the reaction mixture is treated with a solution containing 2.5 g of potassium hydroxide in 30 ml of water and the mixture is refluxed for 40 minutes. The reaction mixture is concentrated in vacuo until a cloudy suspension forms. We wear

  
the suspension at pH 3 with 6N hydrochloric acid and then basified with a saturated aqueous solution of sodium bicarbonate. The remaining methanol is removed by evaporation in vacuo.

  
The resulting suspension is diluted with 200 ml of ethyl acetate and the resulting two-phase mixture is allowed to stand overnight. The solid which has precipitated is collected, washed with water then with n-pentane and recrystallized from 2propanol, which gives 6 g of 4-hydroxy-a-. <{[3- (4-methoxyphenyl) -

  
  <EMI ID = 109.1>

  
126-129 [deg.] C.

  
The ethyl acetate layer is separated from the filtrate, washed successively with dilute aqueous sodium bicarbonate solution and with water and dried over anhydrous magnesium sulfate. The resulting solution is diluted with 120 ml of isopropyl acetate, treated with 3 ml of glacial acetic acid, seeded and cooled. The resulting precipitate is collected, <EMI ID = 110.1>

  
washed with isopropyl acetate and dried at 65.degree. C. in vacuo to give 7 g of product in acetate form, m.p.
132-134 [deg.] C.

  
EXAMPLE 11

  
A. To a stirred solution containing 3.5 g (0.0083 mol)

  
  <EMI ID = 111.1>

  
at - 5 [deg.] C, a solution containing 630 mg (0.0083 mol) of 40% peracetic acid of commerce in 10 ml of methanol is added dropwise over half an hour. When the addition is complete, the reaction mixture is evaporated to dryness. The resulting oil is diluted with ethyl acetate and the gum which separates is allowed to stand for two days in a refrigerator under a mixture of ethyl acetate and ethanol. The resulting dirty white amorphous solid was collected to give 3.2 g of the acetate of

  
  <EMI ID = 112.1>

  
3- (methylsulfinyl) benzenemethanol, which softens at 95 [deg.] C and melts at 100-105 [deg.] C.

  
B. To a stirred solution containing 50 g (0.119 mol) of ac-

  
  <EMI ID = 113.1>

  
20.2 ml (0.119 mol) of commercial 40% peracetic acid are added dropwise over 70 minutes. When the addition is complete, the reaction mixture is evaporated to dryness in vacuo. The residual oil is taken up in 50 ml of ethyl acetate and evaporated again to dryness in vacuo. The remaining oil was dissolved in 350 ml of tetrahydrofuran and the resulting clear solution stirred and made slightly cloudy by gradual addition of ether. After seeding, the mixture was stirred for two days at room temperature, after which a fine white solid began to precipitate. The mixture is treated dropwise by
50 ml of ether and stirred for 5 hours, then an additional 50 ml of ether is added dropwise and stirred for an additional 4 hours.

   After stirring overnight in a refrigerator, the mixture is cooled to 0 [deg.] C while adding dropwise over three hours 300 ml of ether. Stirring is continued at 0 [deg.] C for an additional 3 hours. The product which has precipitated is then collected and dissolved in 1250 ml of tetrahydrofuran. The resulting solution is filtered to remove a small amount of insoluble material and concentrated to a volume of 250 ml.

  
The concentrate is cooled in a refrigerator overnight. The resulting white crystalline precipitate was collected, washed with tetrahydrofuran and ether, and dried to give

  
  <EMI ID = 114.1>

  
131-133 [deg.] C.

EXAMPLE 12

  
To a stirred solution containing 19 g (0.123 mol) of 3-

  
  <EMI ID = 115.1>

  
dimethylformamide at -65 [deg.] C, a solution containing 12 g (0.042'mole) of 2-bromo-4'-hydroxy3 '- (methylsulfonyl) acetophenone 4'-acetate is added dropwise in approximately 70 ml of N, N-dimethylformamide. When the addition is complete, stirring is continued for an additional 1.5 hours. The reaction mixture was then acidified with 8 ml of 48% hydrobromic acid and extracted with chloroform. The chloroform extracts are cooled to - 65 ° C. and diluted with ether. The supernatant liquor is decanted from the gum which has precipitated and this gum is then dissolved in a minimum volume of chloroform and is dissolved. let stand for two days in the refrigerator.

   The resulting 3 g of hydrobromide was dissolved in a saturated aqueous solution of sodium bicarbonate and the resulting solution was extracted with a mixture of n-butanol and ethyl acetate. The organic extracts were acidified with glacial acetic acid and evaporated to dryness to give 2.2 g of 4'-hydroxy acetate.

  
  <EMI ID = 116.1>

  
acetophenone as a yellow oil.

EXAMPLE 13

  
A solution containing 2.2 g of the acetate is hydrogenated

  
  <EMI ID = 117.1>

  
(methylsulfonyl) acetophenone in 100 ml of N, N-dimethylformamide, under an initial pressure of hydrogen of about 3.5 kg / cm <2> in the presence of 0.5 g of a hydrogenation catalyst which is 10% palladium on carbon. After 2 hours, one molar equivalent of hydrogen was absorbed. The catalyst is removed by filtration

  
  <EMI ID = 118.1>

  
column of silica gel which is first eluted with a mixture
95: 5 of ethyl acetate and methanol and then with a 90:10 mixture of ethyl acetate and methanol, which gives 1.4 g of crystalline product. After trituration with acetone and filtration,

  
Vils <EMI ID = 119.1>

  
m.p. 151-153 [deg.] C.

  
EXAMPLE 14

  
A. To a stirred solution containing 376 g (1.0 mole) of (-) - dibenzoyltartaric acid in a mixture of 5 L of methanol and
550 ml of water at 42 [deg.] C, 179 g (1.0 mol) of (+) - 3- (4-

  
  <EMI ID = 120.1>

  
at 40 [deg.] C then 20 hours at room temperature. The resulting precipitate was collected and dried to give a first crop of 176.5 g of (-) - (-) - 3- (4-methoxy-) (-) - dibenzoyltartrate.

  
  <EMI ID = 121.1>

  
to use them in Part B below. The first crop is recrystallized from 90% methanol to give 145.3 g of

  
  <EMI ID = 122.1>

  
aqueous sodium hydroxide and the liberated amine is extracted into chloroform. The chloroform extracts are dried over anhydrous potassium carbonate and evaporated to dryness. The residual oil is dissolved in 2-propano ™, the resulting solution is acidified with 25 ml of 12N hydrochloric acid and evaporated to dryness. The solid residue was dried, recrystallized from 2propanol and dried again to give 52.0 g of the hydrochloride.

  
  <EMI ID = 123.1>

  
B. The mother liquors remaining after isolation of (-) - 3- (4methoxyphenyl) -1-methylpropylamine (-) - dibenzoyltartrate were concentrated to a volume of 500 ml and cooled to 0 [deg.] C for 2 hours. . The resulting precipitate is collected and dried.

  
  <EMI ID = 124.1>

  
methylpropylamine, m.p. 159-162 [deg.] C (decomposition). This salt is treated with aqueous sodium hydroxide and the liberated amine is extracted into chloroform. Evaporation of the chloroform leaves 80 g of an oil which is then added to a solution containing 168 g of (+) - dibenzoyltartaric acid in 1860 ml of 90% methanol. After 20 hours of stirring at room temperature, the salt which has precipitated is collected and dried to give 173.5 g of the salt.

  
  <EMI ID = 125.1> <EMI ID = 126.1>

  
described in part A, the amine is freed from (+) - dibenzoyltartrate and converted into the hydrochloride, and 55.0 g of

  
  <EMI ID = 127.1>

  
indicates contamination with about 10 to 15% of the levorotatory isomer.

  
C. 8781 g of (-) - are recrystallized from aqueous methanol

  
  <EMI ID = 128.1>

  
prepared according to the previous part B, and 7690 g of product are obtained, m.p. 163-165 [deg.] C. A 700 g sample is recrystallized twice from aqueous methanol to give 558 g of the salt which is then converted into the free amine and distilled off under reduced pressure, to obtain 180.5 g of (+ ) -3- (4-methoxyphenyl) -

  
  <EMI ID = 129.1>

  
> 97% optical purity.

  
D. We also obtain as follows (+) - 3- (4-methoxy-

  
  <EMI ID = 130.1>

  
95%, to a hot stirred solution (40-45 [deg.] C) of 250 g (1.67 mol) of d-tartaric acid in 2.6 1 of water and 4.2 1 of ethanol at 95%. The clear solution is seeded at about 38 ° C. and then allowed to come to room temperature overnight with stirring. We filter

  
the solid crystallized and pressed carefully with a rubber pad; it is washed twice with enough 8% aqueous ethanol at ice temperature to cover the cake and pressed carefully until dry. The product is dried at 60 ° C. under vacuum for 5 hours to give 276 g.

  
crude d-amine bitartrate, m.p. 181-182 [deg.] C. Five recrystallizations from aqueous ethanol afforded 125 g of the bitartrate, m.p.

  
  <EMI ID = 131.1>

  
methylpropylamine released is greater than or equal to 97%.

EXAMPLE 15

  
To a stirred solution containing 35.7 g (0.172 mol) of <EMI ID = 132.1>

  
incompletely split, [a] 25 = -6.0 [deg.] (2% in water), in
125 ml of N, N-dimethylformamide, 25 ml of triethylamine are added, which causes the immediate precipitation of triethylamine hydrochloride. The mixture was stirred for 20 minutes then cooled to -50 [deg.] C. The remainder of the preparation is carried out by following a similar procedure to that of Example 7, but using 20 g (0.66 mol) of 2-bromo-4'-hydroxy3 '- 4'-acetate (methylthio ) acetophenone and 8 ml of acetyl chloride, for

  
  <EMI ID = 133.1>

  
EXAMPLE 16

  
To a stirred solution containing 12 g (0.027 g) of (-) - 4'-hydroxy-2 - {[3- (4-methoxy-) 4'-acetate hydrochloride

  
  <EMI ID = 134.1>

  
methanol at 0 [deg.] C, 0.8 g (0.020 mol) of sodium borohydride is added in portions. After another 15 minutes of stirring, a solution containing 1.6 g of potassium hydroxide is added in
25 ml of water and the resulting mixture is heated to reflux under

  
nitrogen for half an hour. Concentrate the reaction mixture

  
to a small volume, it is acidified with 3N hydrochloric acid and then made alkaline with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the ethyl acetate solution is evaporated to dryness, which leaves 11 g of a pale yellow oil. This oil is dissolved in 200 ml of ethyl acetate and a 40 ml aliquot is adsorbed on a silica gel column and the product is eluted with a 92: 8 mixture of ethyl acetate and methanol. , which gives 1.7 g of an oil which is converted to acetate, which gives 1.22 g of 4-hydroxy-a- acetate <{[3-

  
  <EMI ID = 135.1>

  
EXAMPLE 17

  
Following a procedure similar to that described in Example 11 but using 1.2 g (0.0028 mole) of the ac-

  
  <EMI ID = 136.1>

  
[a] 25 = -6.4 [deg.]) and 216 mg of commercial 40% peracetic acid, <EMI ID = 137.1>

  
EXAMPLE 18

  
A. Following a procedure similar to that described in Example 15 but using 43 g (0.20 mol) of the hydrochloride

  
  <EMI ID = 138.1>

  
+ 10.2 [deg.].

  
B. By following a procedure similar to the previous one but by acidifying the reaction mixture with 48% hydrochloric acid instead of 12N hydrochloric acid and by omitting the reacylation step then after two recrystallizations from a mixture of chloroform and isopropyl acetate and recrystallization from a mixture of chloroform and acetone, one obtains

  
  <EMI ID = 139.1>

  
EXAMPLE 19

  
A. Following a procedure similar to that described in Example 16 but using 17.1 g (0.039 mole) of hydrochloride

  
  <EMI ID = 140.1>

  
= + 10.2 [deg.]), 1.0 g (0.025 mole) of sodium borohydride and 2.0 g of potassium hydroxide, 15 g of 4-hydroxy-a- are obtained. <{[3- (4-

  
  <EMI ID = 141.1>

  
methanol, as a dextrorotatory pair of diastereomeric benzenemethanols. A 3.0 g sample was dissolved in isopropyl acetate and the resulting solution acidified with glacial acetic acid. The mixture is allowed to crystallize slowly over two days, which gives 2.75 g of crystalline acetate,

  
  <EMI ID = 142.1>

  
B. When using a procedure similar to the previous one using (+) - 4'-hydroxy- 4'-acetate hydrobromide

  
  <EMI ID = 143.1> <EMI ID = 144.1>

  
C. Following a similar procedure to that described in Example 10 but using 40 g (0.0758 mol) of (+) - 4'-hydroxy-2 - {[3- 4'-benzoate hydrobromide. (4-methoxy-

  
  <EMI ID = 145.1>

  
Example 23B below, 1.5 g of sodium borohydride and 4.5 g of potassium hydroxide, 25.1 g of 4-hydroxy acetate are obtained.

  
  <EMI ID = 146.1>

  
of a dextrorotatory pair of diastereoisomeric benzenemethanols. Another similar trial provides a product with m.p. from 129-

  
  <EMI ID = 147.1>

  
153-155 [deg.] C.

  
The pair of diastereoisomeric benzenemethanols of this example corresponds to the products of Examples 21C and 28.

  
EXAMPLE 20

  
A. Following a similar procedure to that described in Example 11 but using 2.5 g (0.0049 mole) of acetate

  
  <EMI ID = 148.1>

  
a mixture of 4 diastereoisomeric sulfoxides. In addition to its anti-hypertension activity, this product has been found to be as active as procaine as a local anesthetic agent when tested according to the method of Bulbring and Wadja, J. Pharm. Exp. Therap.
85, 78 (1945).

  
B. When performing the previous oxidation on the acetate

  
  <EMI ID = 149.1> methanol, prepared by a procedure similar to that described in part B above, is transformed by a procedure

  
  <EMI ID = 150.1>

  
0.0 [deg.] C.

  
D .. A sample of 4-hydroxy-a- acetate <{[3- (4-methoxy-

  
  <EMI ID = 151.1>

  
methanol prepared by a procedure similar to that described in part B above, is converted by a conventional procedure into the corresponding methanesulfonate, m.p. 142-148 [deg.] C,

  
  <EMI ID = 152.1>

  
methanol, prepared by a procedure similar to that described in part B above, is converted by a conventional procedure into the corresponding hydrochloride, m.p. 172-175 [deg.] C, [a] 25 =
- 8.1 [deg.].

  
F. The hydrochloride can also be prepared directly as follows:

  
To a stirred solution containing 844 g (2 moles) of acetate

  
  <EMI ID = 153.1>

  
> -3- (methylthio) benzenemethanol in 7 1 of methanol at 0 [deg.] C, is added in portions of 25 ml over about 40 minutes, 308 ml of 40% peracetic acid of commerce. Stirring is continued at 0-3 [deg.] C for an additional 45 minutes. The reaction mixture is then evaporated under reduced pressure while maintaining the temperature below 35 [deg.] C. The residue is diluted with one liter of 2-propanol and the solution evaporated to dryness in vacuo. This is repeated once more and then the residue is dissolved in 6 L of 2-propanol, and the resulting solution is treated with a solution containing 2.14 moles of hydrogen chloride in 2-propanol. The resulting pale yellow solution was cooled in ice. The precipitated product is collected, washed with a mixture of 2-propanol and ether and dried to give 705 g of 4- hydrochloride.

  
  <EMI ID = 154.1>

  
The four diastereomeric sulfoxides obtained according to the preceding examples correspond to the sulfoxides of the Examples
30, 31, 32 and 33.

  
The products of several preparations made according to

  
  <EMI ID = 155.1> <EMI ID = 156.1>

  
sodium hydroxide, and analyzed by high pressure liquid chromatography on microparticle silica gel using an 85: 15: 0.4 mixture of n-hexane, 2-propanol and 2propylamine as eluent at a flow rate of 0 , 54 ml / minute and a pressure of about 84 kg / cm <2> and we find that they have the following composition:

  

  <EMI ID = 157.1>


  
When tested in one or more of the conventional biological assays described below, the product obtained according to part E or F above is found to have usable cardiotonic activity. The effectiveness of this compound is judged,

  
in vitro, based on the percentage increase in contractile force of the isolated atrium and papillary muscle from cats and, in vitro, based on the percentage increase in cardiac contractile force in an intact anesthetized dog.

  
The in vivo test procedures used are described below:

  
Cardiotonic Test Procedure I - Male cats weighing 0.8 to 1.5 kg are anesthetized with α-chloralose (80 mg / kg intraperitoneally i.p.). We open the chest, excise the heart and cut the two atria. A silk suture is made on each of the two opposite sides of the right atrium. One side of the atrium is attached to a glass rod and then mounted in a 50 ml organ bath filled with Tyrode's solution. The second suture is attached to a displacement transducer and the tension on the atrium is set at 1.5 + 0.5 g. The transducer is then connected to a Grass polygraph and the force and speed of the contraction is continuously recorded. the headset. The left atrium is treated the same way using silver thread instead of silk thread.

   The silver wire also serves as a stimulating electrode. The two atria are mounted in the same bath. The right atrium beats spontaneously due to the presence of the sinoatrial node, <EMI ID = 158.1> as the left atrium is electrically stimulated at a rate of three beats per second, by rectangular pulses above the threshold with a duration of 5 milliseconds. Tyrode's solution bathing the atria has the following composition (in mmoles): NaCl 136.87, KC1 5.36, NaH2P04 0.41, CaCl2

  
  <EMI ID = 159.1>

  
The solution is equilibrated with a gas mixture comprising 95% oxygen and 5% carbon dioxide. The preparation is allowed to come to equilibrium for an hour before adding any drug. The bath fluid is changed 3 or 4 times during the equilibration time. At the end of the equilibration period, the drug dissolved in vehicle, or vehicle alone, is added to the tissue bath and the total reaction is noted. The vehicle used is Tyrode's solution to which, if necessary, enough acid is added to cause the drug to dissolve. When the reaction reaches a maximum, it is stopped by three washes at 10 minute intervals or until pre-medication contraction force values are reached.

   In general, a reaction study on at least three doses is carried out in the same preparation.

  
IB Cardiotonic Test Procedure - Male cats weighing 0.8 to 1.5 kg were anesthetized with α-chloralose (80 mg / kg i.p.). We open the chest and remove the heart. The heart is immersed and stirred in Tyrode's solution to remove blood from the chambers. Then split the right ventricle and dissect the small, thin papillary muscles (approximately 1mm in diameter and 4-7mm in length). A silver wire is attached to each of the two ends of the papillary muscle. The ventricular end is attached to a platinum electrode and mounted in a tissue bath containing Tyrode's solution described above.

  
The silver wire at the valve end of the muscle is attached to a displacement transducer to measure the force and speed of the muscle contraction. The muscle is stimulated at a rate of three beats per second by rectangular pulses above the threshold lasting 5 milliseconds. The rest of the procedure is carried out as described previously.

  
Cardiotonic Test Procedure II - The in vivo test procedure described below is used: mongrel dogs of both sexes weighing 9 to 15 kg are anesthetized with 30 mg / kg sodium pentobarbital administered intravenously. .

  
  <EMI ID = 160.1>

  
We expose the trachea. and a cannula is attached to it. Then the tracheal cannula is attached to a Harvard breathing pump using room air. A cannula is placed through the right femoral artery and vein. The artery cannula is attached to a Statham P23A pressure transducer connected to a Grass polygraph for continuous recording of arterial blood pressure. The cannula of the vein is used for intravenous administration of drugs. Pin electrodes are attached to

  
the right front leg and the left rear leg. Then the electrodes are connected to a Grass polygraph for continuous recording of the electrocardiogram of classical lead II. A ventro-dorsal incision is made in the third intercostal space, the edges of the incision are laterally retracted and the pericardium is split open to expose the myocardium. Cut the base of the aorta and attach a flow probe around it. The flow sensor is attached to a square wave electromagnetic flowmeter (Carolina Medical Electronics). The flowmeter is then connected to a Grass polygraph to continuously record aortic blood flow. This rate is used as an index of cardiac output (actual cardiac output is

  
aortic blood flow + coronary blood flow). The force of contraction of the heart is measured by suturing a Walton-Brodie strain gauge onto the wall of the right ventricle. At the end of the surgery, the animal is allowed to rest and equilibrate for one hour by continuously recording blood pressure, EKG, cardiac contraction force and aortic blood flow. After the equilibration period, the vehicle or drug dissolved in the vehicle is administered by intravenous infusion (iv), intravenous bolus (iv bolus) or intraduodenal (id) and the reaction of all is recorded. parameters measured at the administration of the drug continuously for several periods of time depending on the route of administration of the drug.

   When the route of administration is inf. i.v., the drug is administered until maximum effect is reached and then the infusion is maintained for ten
-minutes. The systems described above are standardized using dopamine.

  
The product obtained according to parts E and F above, when an in vitro test as described above at a dose of

  
1 mg / ml, causes 62 and 52% increases in right atrium speed and right atrium strength, respectively, and a 14% decrease in papillary muscle strength.

  
At a dose of 10 µg / ml, 53 and 46% increases in right atrium speed and right atrium strength, respectively, and a 12% decrease in papillary muscle strength were observed.

  
When used intravenously at a dose of
10 &#65533; g / kg / min for 3 hours, in three anesthetized intact dogs, the product of this example caused a maximal increase in cardiac contraction force of 25 and 42% in two of the three dogs, with no significant change of heart speed. In the remaining dog, decreases in contraction force and heart rate were observed by 30% and 33%, respectively.

  
EXAMPLE 21

  
A. A solution containing

  
  <EMI ID = 161.1>

  
methyl> -3- (methylthio) benzenemethanol dextrorotatory prepared as described in Example 19A and 2.25 g of (-) - mandelic acid in
60 ml of isopropyl acetate. The precipitated solid is collected, this

  
  <EMI ID = 162.1>

  
= -20.9 [deg.] Which one calls "solid A" and which one puts aside. The filtrate is washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residual 6 g of gum are dissolved in 40 ml of isopropyl acetate and treated with a solution of 2.0 g of (+) - mandelic acid in 20 ml of isopropyl acetate and the the resulting solution is stirred overnight. The precipitate is collected to give 4.1 g of yellow-brown crystalline solid, m.p.

  
  <EMI ID = 163.1>

  
put aside. The solid is recrystallized by dissolving it in 55 ml of a 10: 1 mixture of isopropyl acetate and isopropyl alcohol and stirring overnight. After removing a small amount of a solid impurity, the clear solution is concentrated

  
to a volume of 30 ml, and the product then crystallizes to give 1.6 g of yellow-brown crystals, m.p. 89-106 [deg.], La] 25 = +48.7 [deg.], Which we call "solid B" and which we put aside. The filtrate is called "filtrate B".

  
The filtrate A is washed with a saturated aqueous solution of sodium bicarbonate, it is dried over anhydrous sodium sulfate and evaporated to dryness. The resulting 4.0 g of gum was dissolved <EMI ID = 164.1> yellow in 40 ml of ethyl acetate and treated with 1.0 g of (-) - mandelic acid. After standing overnight, the precipitated product is collected to give 2.5 g of crystalline solid, m.p.

  
  <EMI ID = 165.1>

  
we put aside. The filtrate is combined with the filtrate B above and evaporated to dryness, and the residue is combined with solid A. The combined materials are dissolved in ethyl acetate, the resulting solution washed with saturated aqueous solution. of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residual 6.4 g of yellow syrup are dissolved in 40 ml of ethyl acetate and treated with 1.5 g of (+) - mandelic acid. After stirring overnight, the precipitated solid was collected to give a first crop of 1.0 g of yellow-brown solid, m.p. 105-110 [deg.] C. Cooling the filtrate in ice provided a second crop of 1.3 g, m.p. 86-89 [deg.], [A] 25 = +48 [deg.]. The filtrate is called "filtrate C" and set aside.

   The first crop is combined with solid B above and recrystallized from ethyl acetate to give 1.65 g of a solid.

  
  <EMI ID = 166.1>

  
substance in the second harvest and recrystallized from isopropyl acetate to give 2.7 g of a yellow-brown crystalline solid, m.p. 89-92.5 [deg.] C, [a] 25 = +51.8 [deg.]. The latter solid is dissolved in 50 ml of ethyl acetate and the resulting solution is washed with a saturated aqueous solution of sodium bicarbonate,

  
it is dried over anhydrous sodium sulfate and evaporated to dryness, which leaves 1.7 g of product which corresponds to the dextrorotatory element of the pair of diastereoisomeric benzenemethanols present in the product of Example 19A. A 650 mg sample was dissolved in isopropyl acetate and the resulting solution acidified with glacial acetic acid and evaporated to dryness.

  
The residue is crystallized in a small volume of isopropyl acetate,

  
  <EMI ID = 167.1>

  
B. The filtrate is evaporated to dryness C. The residue is dissolved in a mixture of ether and ethyl acetate and the resulting solution is washed with a saturated aqueous solution of sodium bicarbonate, treated with 2 g of sodium bicarbonate. decolourising charcoal, it is filtered and the filtrate is evaporated to dryness, which leaves 3.8 g of residue. This residue is dissolved in 25 ml of isopropyl acetate and the resulting solution is treated with a solution containing 1.3 g of (-) - mandelic acid in 10 ml of isopropyl acetate. After two days of stirring, the precipitated product is collected and one obtains

  
  <EMI ID = 168.1>

  
3.25 g of white crystalline solid, m.p. 104-106 [deg.], .La] 25 30.4-. This material is combined with the solid C above and the whole is recrystallized successively in 25 ml of ethyl acetate, 40 ml of ethyl acetate and finally in a mixture of isopropyl alcohol and acetate d. ethyl, in each case allowing the product to slowly crystallize at room temperature. We thus obtain

  
  <EMI ID = 169.1>

  
the latter solid is dissolved in 50 ml of ethyl acetate, and the resulting solution is washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate

  
  <EMI ID = 170.1>

  
Example 19A. A sample of 1.1 g is converted into acetate, as described above for the dextrorotatory diastereoisomer, obtaining the crystalline acetate in the form of white flakes,

  
  <EMI ID = 171.1>

  
as described in Example 19C, with aqueous sodium carbonate and the free base is extracted into 1 l of ethyl acetate. The ethyl acetate solution is washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in hot ether and the solution filtered through a 2.5 cm pad of silica gel to remove a colored impurity. Evaporation of the ether leaves 83 g of a pale yellow gum which is dissolved in 200 ml of ethyl acetate and which is treated with a solution containing 22 g of (+) - mandelic acid. in
200 ml of ethyl acetate. The mixture is stirred overnight at room temperature and then overnight at 5 [deg.] C.

   The precipitated product is collected by filtration and washed with isopropyl acetate and ether. We put aside the mother liquors. The solid collected is recrystallized from isopropyl acetate containing a small amount of 2-propanol to obtain

  
  <EMI ID = 172.1>

  
in free base the mother liquors which had been set aside and they are treated again with 20 g of (+) - mandelic acid, to obtain after two recrystallizations from isopropyl acetate and one

  
  <EMI ID = 173.1>

  
= +47.6 [deg.]. The mother liquors from this second treatment with (+) - mandelic acid are enriched in the levorotatory diastereoisomer and are set aside for use in part D. The solids are combined and recrystallized twice from acetate d. 'ethyl, which gives 22 g of (+) - mandelate, mp 94-95.5 [deg.] C,

  
  <EMI ID = 174.1>

  
10% sodium carbonate and the free base is extracted with

  
300 ml of ethyl acetate. The ethyl acetate solution is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and acidified with 2 ml of acetic acid. The solution is concentrated and the resulting precipitate is collected which is recrystallized from ethyl acetate containing a few drops of acetic acid, to obtain

  
  <EMI ID = 175.1>

  
[a] 25 = +33.3 [deg.], corresponding to the dextrorotatory element of the pair of diastereomeric benzenemethanols present in the product of Example 19C.

  
A sample of this substance is reacted with p-toluenesulfonyl chloride in the presence of sodium hydroxide

  
  <EMI ID = 176.1>

  
m.p. 90-92 ', [a] 25 = +23.0 [deg.], Which liquid chromatography under high pressure shows that it has an isomeric purity greater than or equal to 99%.

  
D. The mother liquors of part C which have been enriched in levorotatory diastereoisomer are combined and evaporated to dryness. The residue is treated with aqueous sodium carbonate and the free base is extracted with ethyl acetate. Evaporation of the ethyl acetate leaves 58 g of oil. This substance is dissolved in
200 ml of ethyl acetate, treated with a solution containing
20 g of (-) - mandelic acid in 200 ml of ethyl acetate and the resulting mixture is stirred overnight. The precipitated salt is collected and recrystallized successively from a mixture of acetone and ether, from ethyl acetate and eight times from a mixture of methylene chloride and ethyl acetate, which gives 23 g of (-) - incompletely split mandela (as deter-

  
  <EMI ID = 177.1>

  
= -37.1 [deg.], Which is transformed by a classical procedure into <EMI ID = 178.1>

  
5.5 g of the latter on a silica gel column eluting with 7% methanol in ethyl acetate, does not allow much more purification of the acetate. A 2.6 g fraction of the material which eluted from the column was stirred with 25 ml of 35% aqueous sodium hydroxide, and the mixture was treated dropwise over 15 minutes with a solution containing 1, 3 g of chloride

  
  <EMI ID = 179.1>

  
The reaction mixture is treated with two additional 150 mg portions of p-toluenesulfonyl chloride. The acetate layer is separated, diluted with an equal volume of isopropyl acetate, washed with water then with a saturated aqueous solution of sodium chloride and evaporated to dryness. The residue is dissolved in ethyl acetate and the solution is acidified with acetic acid. The acetate which precipitates is recrystallized from ethyl acetate, and one obtains

  
  <EMI ID = 180.1>

  
+ 14.9 [deg.], According to the procedure described above in part C. This material is combined with an additional 250 mg, m.p. 157-

  
  <EMI ID = 181.1>

  
recrystallized from ethyl acetate and then converted by a conventional procedure into the corresponding acetate, which gives
700 ml of 4-p-toluenesulfonate acetate of 4-hydroxy-a- <{[3-

  
  <EMI ID = 182.1>

  
(ester) of the levorotatory element of the diaistereoisomeric benzenemethanol couple present in the product of Example 19C. High pressure liquid chromatography of the product shows that it has an isomeric purity greater than or equal to 98%.

  
Attempts to cut the p-toluenesulfonate (ester) to obtain the isomerically pure levorotatory phenol were not successful, however, the latter compound was obtained from the corresponding benzoate as described in Example 28 below. below.

  
EXAMPLE 22

  
A. To a stirred solution containing 1.05 g (0.003 mole) of

  
  <EMI ID = 183.1> of Example 21A in 15 ml of methanol at 0 [deg.] C, a solution of 0.45 ml (0.003 mol) of peracetic acid is added dropwise over half an hour at 40% of the trade in 5 ml of methanol. When the addition is complete, the reaction mixture is evaporated to dryness in vacuo. The residue is dissolved in a 45: 5 mixture of ethyl acetate and methanol and adsorbed on a column of silica gel. After elution with ethyl acetate, the product is eluted with a 90:10 mixture of ethyl acetate and methanol. The material thus obtained is dissolved in a mixture of ethyl acetate and methanol, the resulting solution is acidified with glacial acetic acid and evaporated to dryness. The residue is taken up in 5 ml of chloroform, the resulting solution is cooled to -65 [deg.] C and diluted with ether.

   The resulting solid is dissolved in tetrahydrofuran, the solution is acidified with glacial acetic acid and evaporated to dryness. The residue is dissolved in chloroform, the solution is cooled to -65 [deg.] C and diluted with ether. The resulting solid is collected and dried to give 550 mg of the acetate.

  
  <EMI ID = 184.1>
-3- (methylsulfinyl) benzenemethanol in the form of a dextrorotatory pair of diastereoisomeric sulfoxides, la] 25 = + 28.5 [deg.].

  
B. A 5.0 g sample of 4-hydroxy-a- acetate is oxidized as described in part A above. <{[3- (4-methoxy-

  
  <EMI ID = 185.1>

  
according to the method of Example 21C. When the oxidation is complete, the reaction mixture is evaporated to dryness and the residue is crystallized from ethyl acetate to give 4.2 g of a product.

  
  <EMI ID = 186.1>

  
sample in a mixture of acetone and methanol and the solution is treated with cyclohexylsulfamic acid. The salt which precipitates is collected and the cyclohexylsulfamate is obtained after drying

  
  <EMI ID = 187.1>

  
corresponds to the products of Examples 30 and 32.

  
EXAMPLE 23

  
A. Following a similar procedure to that described in Example 9C but using 128 g (0.72 mol) of (+) - 3-

  
  <EMI ID = 188.1>

  
of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone, a first crop of 82 g is obtained, m.p. 172-174 [deg.] C, and a second crop of 43 g, m.p. 171-174 [deg.] C. The crops were pooled and a 16 g sample recrystallized from 95% ethanol to give 10 g of (+) - 4'-hydroxy-2 - {[3 4'-benzoate hydrobromide. -

  
  <EMI ID = 189.1>

  
containing 160 g (0.384 mol) of 2-bromo-4'-hydroxy3 '- (methylthio) acetophenone 4'-benzoate in 500 ml of N, N-dimethylformamide. Stirring is continued for an additional half hour.

  
The reaction mixture is acidified with hydrobromic acid at
48% and extracted with methylene dichloride. The organic extracts are washed with water and concentrated to approximately
320 ml. The concentrate is diluted with 400 ml of isopropyl acetate and cooled. The solid which precipitates is collected and dried to give 167 g of (+) - 4'- 4'-benzoate hydrobromide.

  
  <EMI ID = 190.1>

  
thio) optically pure acetophenone, m.p. 171-173 [deg.] C, [a] 25 =

  
+ 11.8 [deg.]. A 7.0 g sample was recrystallized from aqueous methanol containing a small amount of HBr to give, after

  
  <EMI ID = 191.1>

  
EXAMPLE 24

  
A. To a solution containing 106 g (0.195 mol) of (+) - 4'-hydroxy-2 - {[3- (4-methoxyphenyl) - 4'-benzoate hydrobromide

  
  <EMI ID = 192.1>

  
split, prepared according to the procedure of Example 23A, in
700 ml of methanol at 0 [deg.] C, 6 g (0.16 mol) of sodium borohydride are added over half an hour. Stirring is continued at 0 [deg.] C for an additional half hour. A 150 ml aliquot of the reaction mixture is concentrated under reduced pressure below 50 [deg.] C. The concentrate is dissolved in ether and the ethereal solution is washed thoroughly with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is dissolved in 75 ml of isopropyl acetate and the resulting solution is acidified with acetic acid, then diluted with ether until cloudy and dissolved. stir for 3 hours.

   The solid which precipitated was collected by filtration, washed with isopropyl acetate and ether and dried to give 6.4 g of the 4- acetate.

  
  <EMI ID = 193.1>

  
amino} methyl> -3- (methylthio) benzenemethanol, m.p. 107-110 [deg.] C. B. The remainder of the initial reaction mixture is hydrolyzed with a solution containing 9 g of potassium hydroxide in
100 ml of water, according to the procedure of Example 10, which gives 46 g of the acetate (salt) of 4-hydroxy-a- <{[3- (4-methoxy-

  
  <EMI ID = 194.1>

  
C. To a solution containing 10.0 g (0.0188 mole) of (+) - 4'-hydroxy-2 - {[3- (4-metthoxy-) 4'-benzoate hydrobromide

  
  <EMI ID = 195.1>

  
at 0 [deg.] C, 380 mg of sodium borohydride are added in portions. After adding several ml of acetic acid, the mixture is evaporated to dryness. The residue is dissolved in a mixture of ethyl acetate and ether, and the resulting solution is washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, acidified with 2.5. ml of acetic acid and evaporated to dryness. Recrystallization of the residue from a mixture of isopropyl acetate and ether affords 6 g of the acetate (salt) of 4-hydroxy-a- 4-benzoate. <{[3- (4-methoxy-

  
  <EMI ID = 196.1>

  
[a] 25 = +6.4 [deg.], in the form of a dextrorotatory pair of diastereomeric benzenemethanols corresponding to the products of the Examples
27A and B. A similar test gives a product, m.p. 101-102.5 [deg.] C and +7.6 - EXAMPLE 25

  
To a stirred solution containing 8.0 g (0.0147 mole) of (+) - 4'-hydroxy-2 - {[3- (4-methoxy-) 4'-benzoate hydrobromide.

  
  <EMI ID = 197.1>

  
= +11.1 [deg.], In 60 ml of trifluoroacetic acid at 0 [deg.] C, 3 ml of commercial 40% peracetic acid are added dropwise. When the addition is complete, the reaction mixture is evaporated to dryness. The residue is dissolved in benzene and the resulting solution is evaporated to dryness. The residual gum is dissolved in isopropyl acetate and acidified with ethanolic hydrochloric acid. The solid which precipitates was collected and recrystallized from a mixture of methanol and isopropyl acetate, to give 6.0 g of 4'-benzoate hydrochloride of 4'-.

  
  <EMI ID = 198.1>

EXAMPLE 26

  
The acetate of 4-hydroxy-a- 4-benzoate is oxidized with 1.5 ml of commercial 40% peracetic acid, following a procedure similar to that of Example 22. <{[3- (4-

  
  <EMI ID = 199.1>

  
0.0095 mol) prepared according to a procedure similar to that of Example 24B. When the oxidation is complete, the reaction mixture is treated with 0.9 g of sulfuric acid and cooled. The solid which precipitates is collected and dried to give 2.8 g of 4-hydroxy-a- 4-benzoate hemisulfate. <{[3-

  
  <EMI ID = 200.1>

  
EXAMPLE 27

  
A. To a solution containing 7.4 g of the free base from the acetate of 4-hydroxy-a- 4-benzoate <{[3- (4-methoxyphenyl) -

  
  <EMI ID = 201.1>

  
a solution containing 1.8 g of (+) - mandelic acid in 20 ml of isopropyl acetate. The resulting solution is diluted with ether until slightly cloudy and stirred for two days at room temperature. The precipitate is collected and the mother liquors which are enriched in the levorotatory diastereoisomer are set aside for use in part B below. The solid collected eight times is recrystallized from a mixture of methylene chloride and ether, to give 3.3 g.

  
  <EMI ID = 202.1>

  
= +26.7 [deg.], Corresponding to the dextrorotatory element of a pair of diastereoisomeric benzenemethanols present in the product of Example 4B.

  
  <EMI ID = 203.1> in free base, they are dissolved in isopropyl acetate, treated with 1.5 g of (-) - mandelic acid and the solution dissolved with ether. The precipitate is collected, recrystallized once from a mixture of isopropyl acetate and ether, which

  
  <EMI ID = 204.1>

  
to the levorotatory element of the pair of diastereoisomeric benzenemethanols present in the product of Example 24B.

  
EXAMPLE 28

  
A mixture containing 600 mg of 4-hydroxy-a- 4-benzoate acetate is stirred for 10 minutes at room temperature. <{[3--

  
  <EMI ID = 205.1>

  
of 35% aqueous sodium and several ml of methanol, then diluted with 20 ml. of water and stirred for another 10 minutes in a lukewarm water bath. The pH is adjusted to 9 with acetic acid and the methanol is evaporated off under reduced pressure. The residue is extracted with ethyl acetate and, after drying

  
over anhydrous sodium sulfate, the extracts are evaporated to dryness. The residue is dissolved in isopropyl acetate, the resulting solution is acidified with acetic acid and cooled. The solid which precipitated was collected by filtration and dried in vacuo to give 500 mg of the 4-hydroxy-a- acetate. <{[3-

  
  <EMI ID = 206.1>

  
determinations). corresponding to the levorotatory element of the pair of diastereoisomeric benzenemethanols present in the product of Example 19C.

  
EXAMPLE 29

  
A. To a stirred solution containing 1.0 g (0.003 mol) of

  
  <EMI ID = 207.1>

  
method of Example 21B, in 15 ml of methanol at 0 [deg.] C, is added dropwise over half an hour a solution of 0.45 ml of 40% peracetic acid of commerce in 5 ml of methanol. When the addition is complete, the reaction mixture is evaporated to dryness in vacuo. The residue is diluted with 10 ml of benzene, the resulting solution is acidified with glacial acetic acid and evaporated to dryness. The residual gum is crystallized from a mixture of tetrahydrofuran and ether and then recrystallized from a mixture of ethyl acetate and 2-propanol, which gives

  
  <EMI ID = 208.1>

  
In the procedure of Example 28, the resulting pair of diastereomeric sulfoxides has a rotational power la] 25 = -18.8 [deg.] (determined on the reaction mixture).

  
The pair of diastereoisomeric sulfoxides of this example corresponds to the products of Examples 31 and 33.

  
EXAMPLE 30

  
The mother liquors obtained in the preparation of several batches of 4- acetate are combined and evaporated to dryness.

  
  <EMI ID = 209.1>

  
to that described in Example 20B. The residual oil is triturated successively with ether and isopropyl acetate. The residue (90 g) is dissolved in 300 ml of acetone and the resulting solution is treated with 33 g of cyclohexylsulfamic acid in

  
200 ml of acetone. The cyclohexylsulfamate which precipitates is collected and recrystallized five times from aqueous methanol, to give 7.3 g of product which is combined with 7.4 g of product obtained in previous tests and which is converted into hydrochloride. Recrystallization of the latter from a mixture of methanol and isopropyl alcohol provides 6.3 g of the hydrochloride.

  
  <EMI ID = 210.1>

  
+ 126.60, corresponding to the dextrorotatory element of the pair of diastereoisomeric sulfoxides present in the product of Example
22B.

  
EXAMPLE 31

  
The mother liquors resulting from the fractional crystallization of the product of Example 30 are evaporated and the residue crystallized from acetone. The resulting 12.4 g of solid were recrystallized twice from a mixture of methanol and acetone to give 5.1 g of product, [a] 25 = + 49.3 [deg.]. The latter material is combined with 3.5 g obtained in a previous test and converted into the hydrochloride which crystallizes from 2-propanol, which

  
  <EMI ID = 211.1>

  
of the diastereomeric pair of sulfoxides present in the product of Example 29B.

  
EXAMPLE 32

  
The reaction mixture resulting from the oxidation of 12.1 g of (+) - 4-hydroxy-a- mandelate is evaporated to dryness. <{[3- (4-

  
  <EMI ID = 212.1>

  
  <EMI ID = 213.1>

  
the residue is dissolved in a mixture of 70 ml of methanol and

  
15 ml of water, treated with one molar equivalent of cyclohexylsulfamic acid and seeded with the cyclohexylsulfamate of the product of Example 30. The 7.9 g of product which crystallized was collected and set aside. . The mother liquors are evaporated to dryness and the residue is crystallized from a mixture of acetone and methanol. The product is converted into 1.1 g of hydrochloride and combined with the additional 850 mg obtained from the mother liquors resulting from the fractional crystallization of the diastereomer of Example 31. The combined solids are recrystallized from 2-propanol, which gives 1.4 g of the chlo-

  
  <EMI ID = 214.1>

  
Diastereomeric sulfoxides present in the product of Example 22B.

  
EXAMPLE 33

  
A. The reaction mixture resulting from the oxidation of 3 g of 4-hydroxy-a- acetate is evaporated to dryness. <{[3- (4-methoxyphenyl) -

  
  <EMI ID = 215.1>

  
according to the procedure of Example 29B, the residue is dissolved in a 90:10 mixture of acetone and methanol, treated with a molar equivalent of cyclohexylsulfamic acid and inoculated with the cyclohexylsulfamate of the product of Example 31 1.6 g of product are collected which crystallizes and it is set aside. We evaporate

  
the mother liquors to dryness and the residue is crystallized twice from aqueous methanol to give 1.85 g of crystalline solid.

  
  <EMI ID = 216.1>

  
of Example 21D, following a procedure similar to that of Example 29A and the product is isolated in the form of

  
  <EMI ID = 217.1>

  
(methylsulfinyl) crude benzenemethanol in the form of a pair of diastereomeric sulfoxides.

  
A solution containing the last product and 15 ml of 10% aqueous potassium hydroxide in 100 ml of ethanol is stirred for one and a half hours at 45 [deg.] C. Then the reaction mixture is concentrated, diluted with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic extracts are dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in acetone and treated with one molar equivalent of cyclohexylsulfamic acid. The product which precipitates is collected and recrystallized from a mixture of acetone and methanol, which gives 1.15 g of salt corresponding to the cyclohexylsulfamate of the product of Example 31. The mother liquors are evaporated to dryness and the residue is crystallized from acetone. Four recrystallizations from methanol

  
25

  
  <EMI ID = 218.1>

  
C. The levorotatory products of parts A and B are combined, recrystallized once from aqueous methanol and then converted into the hydrochloride, which gives 1.1 g of the hydrochloride of

  
  <EMI ID = 219.1>

  
corresponding to the levogyrene element of the pair of diastereomeric sulfoxides present in the product of Example 29B.

  
EXAMPLE 34

  
To a stirred solution containing 20 g (0.134 mol) of 1,1dimethyl-2-phenylethylamine in 40 ml of N, N-dimethylformamide at
- 50 [deg.] C, a solution containing 14.5 g (0.048 mol) of 2-bromo-4'-hydroxy3 '- (methylthio) acetophenone 4'-acetate in 35 ml is added dropwise over 15 minutes. of N, N-dimethylformamide. After the addition is complete, stirring is continued for an additional 1.25 hours. Then the reaction mixture is treated with 3.5 ml of 12N hydrochloric acid, diluted with 100 ml of water and carefully extracted with ether. The ethereal extracts were dried over anhydrous sodium sulfate, acidified with ethanolic hydrochloric acid and cooled in a refrigerator overnight.

   The 12.5 g of product which precipitated are collected and combined with 6.0 g of product obtained in a previous test and the whole is recrystallized twice from a mixture of chloroform and methanol, which gives
15 g of 2 - [(1,1-dimethyl-2-phenyl- 4'-acetate hydrochloride

  
  <EMI ID = 220.1>

  
with decomposition ..

EXAMPLE 35

  
To a stirred suspension of 15 g (0.037 mole) of chlo-

  
  <EMI ID = 221.1>

  
4'-hydroxy-3 '- (methylthio) acetophenone in 200 ml of methanol at
- 5 [deg.] C, 750 mg (0.020 mole of sodium borohydride) are added in portions over 10 minutes. After stirring for a further 10 minutes, the reaction mixture is brought to pH 7 with glacial acetic acid and evaporated to dryness. The residue is dissolved in a mixture of ether and ethyl acetate and the resulting solution washed with a saturated aqueous solution of sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate, acidified with methanesulfonic acid and concentrated to a small volume. The concentrate is diluted with benzene and evaporated to dryness. Then the process is repeated using toluene.

   The resulting solid residue is recrystallized from a mixture of ethanol and ether to give 12 g of methane. <EMI ID = 222.1>

  
EXAMPLE 36

  
A solution containing 9.5 g (0.020 mol) of a - {[(1,1-) 4-acetate methanesulfonate is stirred overnight under nitrogen.

  
  <EMI ID = 223.1>

  
of water in 200 ml of 95% ethanol. The reaction mixture is neutralized with glacial acetic acid and concentrated to a small volume. The concentrate is diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate and concentrated to a volume of 100 ml. We wear the <EMI ID = 224.1>

  
solution concentrated to a pale yellow color by the dropwise addition of glacial acetic acid and crystallization then begins. The product is collected by filtration and recrystallized from a mixture of chloroform and methanol, to give

  
  <EMI ID = 225.1>

  
EXAMPLE 37

  
Following a similar procedure to that described in Example 34, but using 18.3 g (0.135 mol) of 1-methyl-2-phenylethylamine and 15 g (0.050 mol) of 4'-acetate.

  
  <EMI ID = 226.1>

  
EXAMPLE 38

  
Following a procedure similar to that described in Example 8 but using 7.4 g (0.019 mol) of 4'-hydroxy-2 - [(1-methyl-3-phenylethyl) 4'-acetate hydrochloride -

  
  <EMI ID = 227.1>

  
EXAMPLE 39

  
To a stirred solution containing 4.7 g (0.012 mole)

  
  <EMI ID = 228.1>

  
hydroxy-3- (methylthio) benzenemethanol in 100 ml of methanol at 0 [deg.] C is added dropwise over half an hour a solution containing 2 ml (0.012 mole) of 40% peracetic acid of commerce in 10 ml of methanol. When the addition is complete, the reaction mixture is evaporated to dryness and the residue crystallized from a mixture of ethanol and ether, to give 4.3 g of α-acetate.

  
  <EMI ID = 229.1>

  
sulfinyl) benzenemethanol which softens at 100 [deg.] C and melts at 138-140 [deg.] C.

  
EXAMPLE 40

  
A. To a stirred solution containing 35 g (0.25 mole) of o-
(methylthio) phenol and 27.6 g (0.30 mol) of propionyl chloride in 100 ml of nitrobenzene, added in portions over 25 minutes
46.5 g (0.35 mole) of aluminum chloride. The reaction is exothermic and the temperature rises to 45-50 [deg.] C. When the addition is complete, the reaction mixture is stirred for two hours at 60 [deg.] C and one hour at 70 [deg.] C. The reaction mixture is cooled, diluted with water and extracted with ether. The ethereal extracts are dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residual oil is adsorbed onto a silica gel column and eluted continuously with boiling methylene chloride.

   The eluate is evaporated to dryness and the residue is recrystallized from ether, which gives 25 g of crystalline product which is then triturated with ether at 65 ° C., which gives 17 g of. Pure 4'-hydroxy-3 '- (methylthio) propiophenone.

  
B. To a stirred solution containing 17.4 g (0.089 mole) of

  
  <EMI ID = 230.1>

  
triethylamine in 200 ml of methylene chloride, 7.65 g (0.098 mole) of acetyl chloride are added dropwise over half an hour. Once the addition is complete, stirring is continued for two more hours. Then the reaction mixture is washed successively with 3N hydrochloric acid and water and evaporated to dryness. The residual oil is dissolved in ether,

  
it is treated with decolorizing carbon and filtered through a bed of silica gel. The filtrate is evaporated to dryness, which provides

  
  <EMI ID = 231.1>

  
as a pale yellow oil.

  
C. To a stirred solution containing 21.4 g (0.088 mol) of 4'-hydroxy-3 '- (methylthio) propiophenone 4'-acetate in 250 ml of chloroform is added a solution containing 14.4 g (0.090 mole) of bromine in 40 ml of chloroform. After an induction period of 15 minutes, the bromine begins to be consumed. After one hour, the reaction mixture is washed with 5% aqueous sodium bicarbonate solution followed by water. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to dryness, yielding 19 g of 2-bromo-4'-hydroxy-3'- 4'-acetate.
(methylthio) propiophenone.

  
D. To a stirred solution containing 30 g (0.185 mol) of 2-

  
  <EMI ID = 232.1>

  
formamide, 19.6 g (0.062 mol) of 2-bromo-4'-hydroxy-3 '- (methylthio) propiophenone 4'acetate are added dropwise. When the addition is complete, stirring is continued for a further two hours. Then the reaction mixture is diluted with chloroform and washed successively with water, dilute hydrochloric acid and saturated aqueous sodium bicarbonate solution. The chloroform solution is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in ether, acidified with glacial acetic acid and cooled. The product which precipitates is collected and triturated with chloroform to give 6.35 g of the acetate.

  
  <EMI ID = 233.1>

  
EXAMPLE 41

  
To a stirred solution containing 6.2 g (0.0148 mole) of

  
  <EMI ID = 234.1>

  
0.5 g of sodium borohydride is added in portions. When the addition is complete, stirring is continued for a further half hour. The reaction mixture is then acidified with glacial acetic acid and evaporated to dryness. The residue is diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts are evaporated to dryness and the residue is dissolved in ether. The ethereal solution is acidified with glacial acetic acid and cooled. The product which precipitated was collected and dried to give 5.0 g of 4-hydroxy-a- acetate. <{[2- (4-

  
  <EMI ID = 235.1>

  
methanol, m.p. 160-162 [deg.] C.

EXAMPLE 42

  
Has a stirred mixture of 2.35 g (0.0056 mole) of the acetate

  
  <EMI ID = 236.1>

  
dropwise adds a solution containing 1 ml (0.0056 mol) of 40% commercial peracetic acid in 5 ml of methanol. Once the addition is complete, stirring is continued for an additional half hour. Then the reaction mixture is evaporated to dryness and the residual oil is suspended in chloroform and diluted with ether to give a granular solid which is collected and dried. and we obtain 2.2 g

  
  <EMI ID = 237.1>

  
ethyl] amino} ethyl> -3- (methylsulfinyl) benzenemethanol, m.p. 110 [deg.] C.

  
EXAMPLE 43

  
To a stirred solution containing -16 g (0.082 mole) of 2-

  
  <EMI ID = 238.1>

  
add dropwise over three quarters of an hour a solution containing 12.5 g (0.041 mol) of 2-bromo-4'-hydroxy- 4'-acetate <EMI ID = 239.1>

  
Once the addition is complete, stirring is continued for an additional hour. The reaction mixture was then slightly acidified with 5 ml of 12N hydrochloric acid and extracted with chloroform. The organic extracts are evaporated to dryness and the residue is dissolved in trifluoroacetic acid and then treated with an excess of acetyl chloride. After stirring for one hour, the mixture is diluted with water and evaporated to dryness. The residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness,

  
  <EMI ID = 240.1>

  
EXAMPLE 44

  
Following a procedure similar to that described in Example 38 but using 12 g of 2 - ([2-

  
  <EMI ID = 241.1>

  
thio) acetophenone, 870 mg of sodium borohydride and 1.4 g of potassium hydroxide, 2.2 g of acetate (salt) of a-

  
  <EMI ID = 242.1>

  
3- (methylthio) benzenemethanol, m.p. 141-144 [deg.] C.

  
EXAMPLE 45

  
Following a procedure similar to that described in Example 42, but using 2.30 g (0.0052 mole) of acetate

  
  <EMI ID = 243.1>

  
4-hydroxy-3- (methylthio) benzenemethanol and 0.95 ml (0.0052 mol) of commercial 40% peracetic acid, one obtains 1.9 g of acetate

  
  <EMI ID = 244.1>

  
4-hydroxy-3- (methylsulfinyl) benzenemethanol as a light yellow amorphous solid.

  
EXAMPLE 4 6

  
To a stirred solution containing 19.5 g (0.12 mole) of

  
  <EMI ID = 245.1>

  
stirring for one hour at -35 [deg.] C. The reaction mixture was then acidified with 10 ml of 12N hydrochloric acid, diluted with 150 ml of chloroform and the resulting solution washed with water. The chloroform solution is cooled to -65 [deg.] C and diluted with ether. The resulting precipitate is collected and recrystallized from ethanol to give 12 g of hydrochloride.

  
  <EMI ID = 246.1>

  
hydroxy-3 '- (methylthio) acetophenone, m.p. 188-193 [deg.] C.

  
EXAMPLE 47

  
Following a similar procedure to that described in Example 8, but using 11.0 g (0.026 mole) of 2 - [(1,1-dimethyl-3-phenylpropyl) -amino 4 '-acetate hydrochloride ] -4'-hydroxy-3 '- (methylthio) acetophenone, 750 mg (0.02 mole) of sodium borohydride and 1.4 g (0.026 mole) of potassium hydroxide, one obtains 9.2 g of acetate (salt) a - {[(1,1-dimethyl-

  
  <EMI ID = 247.1>

  
methanol, m.p. 171-172 [deg.] C.

  
EXAMPLE 48

  
Following a procedure similar to that described in Example 11 but using 6.2 g (0.015 mole) of the acetate

  
  <EMI ID = 248.1>

  
3- (methylthio) benzenemethanol and 1.17 g (0.015 mole) of 40% peracetic acid of commerce, 5.5 g of acetate (salt) of a- are obtained.

  
  <EMI ID = 249.1>

  
sulfinyl) crude benzene methanol. After a double recrystallization from a mixture of chloroform and methanol and a single recrystallization from a mixture of ethyl acetate, acetone and ethanol, the product is dissolved in a mixture of ethyl acetate and methanol. and the resulting solution is acidified with glacial acetic acid and then evaporated to dryness. Recrystallization of the residue from a mixture of ethanol and ethyl acetate affords 1.4 g of the analytically pure material, m.p. 155-
157 [deg.] C.

  
EXAMPLE 49

  
A. To a stirred solution containing 65 g (1.0 mol) of

  
  <EMI ID = 250.1>

  
drop by drop in one hour 120 ml of concentrated sulfuric acid. When the addition is complete, stirring is continued for one hour

  
  <EMI ID = 251.1>

  
1200 g of ice, alkalinize with sodium carbonate and

  
it is extracted with ether. The ethereal extracts are dried over anhydrous sodium sulfate and evaporated to dryness. We heat up.

  
  <EMI ID = 252.1>

  
the 76.5 g of residual oil at reflux for 3 hours in

  
175 ml of 12N hydrochloric acid. The mixture is cooled, washed with ether, made basic with 35% aqueous sodium hydroxide and extracted with ether. The ethereal extracts are dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil is distilled off under reduced pressure and the fraction boiling at 161-162 [deg.] C / 22 mm is collected, which gives

  
35 g of 1,1-dimethyl-3- (4-methoxyphenyl) propylamine.

  
B. Following a procedure similar to that described in Example 7 but using 29 g (0.15 mole) of 1,1dimethyl-3- (4-methoxyphenyl) propylamine, 15 g (0.05 mole) of 4'-

  
  <EMI ID = 253.1>

  
hydroxy-3 '- (methylthio) acetophenone, m.p. 186-190 [deg.] C.

EXAMPLE 50

  
Following a procedure similar to that described in Example 8 but using 9.5 g (0.021 mole) of

  
  <EMI ID = 254.1>

  
EXAMPLE 51

  
Following a procedure similar to that described in Example 11 but using 3.9 g (0.009 mol) of the ac-

  
  <EMI ID = 255.1>

  
methyl> -4-hydroxy-3- (methylthio) benzenemethanol and 680 mg of commercial 40% peracetic acid, 3.0 g of acetate (salt) are obtained

  
  <EMI ID = 256.1>

  
hydroxy-3- (methylsulfinyl) benzenemethanol, m.p. 115 [deg.] C.

  
EXAMPLE 52

  
Following a procedure similar to that described in Example 7 but using 18 g (0.12 mole) of 1-methyl3-phenylpropylamine, 12 g (0.04 mole) of 2-bromo-4'-acetate 4'hydroxy-3 '- (methylthio) acetophenone and 8 ml of acetyl chloride, 8.3 g of 4'-hydroxy-2- 4'-acetate hydrochloride are obtained.

  
  <EMI ID = 257.1>

  
EXAMPLE 53 Following a similar procedure to that described in Example 8 but using 8.1 g (0.02 mole) of 4'-hydroxy-2 - [(1-methyl-) 4'-acetate hydrochloride. 3-phenylpropyl) aminol-3 '- (methylthio) acetophenone, 500 mg of sodium borohydride and 1.2 g of potassium hydroxide, 6.2 g of the acetate are obtained

  
  <EMI ID = 258.1>

  
methylthio) benzenemethanol, m.p. 140-142 [deg.] C.

  
EXAMPLE 54

  
Following a procedure similar to that described in Example 11 but using 4.2 g (0.011 mole) of acetate

  
  <EMI ID = 259.1>

  
(methylthio) benzenemethanol and 815 mg (0.011 mole) of 40% commercial peracetic acid, 4.0 g of 4-hydroxy-a - {[(1-methyl-3-phenylpropyl) acetate (salt) are obtained ) amino] methyl} -3- (methylsulfinyl) benzenemethanol as a pale yellow amorphous solid.

  
EXAMPLE 55

  
Following a procedure similar to that described in Example 34 but using 18.2 g (0.11 mole) of 3- (4methoxyphenyl) propylamine and 11.2 g (0.037 mole) of 4'-acetate of 2 -bromo-4'-hydroxy-3 '- (methylthio) acetophenone, 9 g of

  
  <EMI ID = 260.1>

  
be in the next step.

  
EXAMPLE 56

  
Following a similar procedure to that described in Example 8 but using 9 g of 4'-acetate hydrochloride

  
  <EMI ID = 261.1>

  
thio) acetophenone, 600 mg of sodium borohydride and 2.0 g of potassium hydroxide, 1.2 g of 4-hydroxy acetate are obtained.

  
  <EMI ID = 262.1>

  
methanol, m.p. 123-125 [deg.] C.

  
EXAMPLE 57

  
Following a procedure similar to that described in Example 11 but using 1.2 g (0.003 mol) of acetate

  
  <EMI ID = 263.1>

  
(methylthio) benzenemethanol and 0.44 ml (0.003 mol) of 40% peracetic acid from the market ,. 1.1 g of acetate (salt) of 4-

  
  <EMI ID = 264.1>

  
EXAMPLE 58 <EMI ID = 265.1>

  
80 g (1.77 mol) of formamide and 6 ml of formic acid, then

  
Treats it dropwise over 3.5 hours with 50 ml of formic acid while slowly allowing the water formed during the reaction to distill off. Stirring is continued at 165 [deg.] C for an additional 3 hours. Then the reaction mixture is cooled, diluted with 1 liter of ice and water and extracted with a mixture of ether and benzene. The organic extracts are evaporated and the residual oil is heated under reflux for one and a half hours in 130 ml of 12N hydrochloric acid. The mixture is cooled, diluted with 300 ml of water and washed with a mixture of ether and benzene. The aqueous layer is basified with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene.

   The organic layer was extracted with 1N hydrochloric acid and the acidic aqueous layer was basified with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. The extracts are dried over anhydrous sodium sulfate and the solvent is evaporated off in vacuo. The residual oil is distilled off under reduced pressure to give 37 g of 4- (4methoxyphenyl) -1-methylbutylamine, m.p. 163-166.5 [deg.] C / 18 mm.

  
B. To a stirred solution containing 15.5 g (0.08 mole) of

  
  <EMI ID = 266.1>

  
formamide at -600C, a solution containing 8.0 g (0.027 mol) of 2-bromo-4'hydroxy-3 '- (methylthio) acetophenone 4'-acetate in 25 ml is added dropwise over 0.75 hour of N, N-dimethylformamide. Once the addition is complete, stirring is continued for an additional hour at a temperature of -60 [deg.] To
- 45 [deg.] C. The reaction mixture was then acidified with 48% hydrobromic acid and extracted with chloroform. The chloroform solution is diluted with two and a half volumes of ether and <EMI ID = 267.1>

  
redissolved in chloroform and the resulting solution washed thoroughly with water. The chloroform solution is then dried over anhydrous sodium sulfate and evaporated to dryness, which gives 9 g of

  
  <EMI ID = 268.1>

  
EXAMPLE 59

  
By following a procedure similar to that described in Example 8 but using 9 g of 4'-acetate hydrobromide <EMI ID = 269.1>

  
(methylthio) acetophenone, 500 mg of sodium borohydride and 1 g of potassium hydroxide, 5.5 g of the acetate (salt) are obtained

  
  <EMI ID = 270.1>

  
3- (methylthio) benzenemethanol, m.p. 155-157 [deg.] C.

  
EXAMPLE 60 d Following a procedure similar to that described in Example 11 but using 3.0 g (0.007 mole) of the acetate

  
  <EMI ID = 271.1>

  
methyl> -3- (methylthio) benzenemethanol and 1.04 ml (0.007 mol) of 40% peracetic acid from the market, 2.6 g of ac-

  
  <EMI ID = 272.1>

  
amorphous yellow solid.

  
EXAMPLE 61

  
A. Has a stirred mixture of 52.5 g (0.253 mol) of 4- alcohol
(4-methoxyphenyl) -1,1-dimethylbutyl and 44.5 g (0.685 mol) of powdered potassium cyanide in 200 ml of n-butyl ether

  
at 60 [deg.] C, 80 ml of concentrated sulfuric acid are added dropwise over one hour. The temperature was maintained at 60-65 [deg.] C during the addition and stirring continued at 50-55 [deg.] C for an additional hour after the addition was complete. Then the reaction mixture is poured into 850 ml of ice, made alkaline with

  
35% aqueous sodium hydroxide and extracted with ether. The ethereal extracts are evaporated to dryness and the residual oil is heated under reflux for 3 hours in 125 ml of 12N hydrochloric acid. The resulting mixture is diluted with 300 ml of water and washed with a mixture of ether and benzene. The aqueous layer is basified with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. Then we extract the

  
  <EMI ID = 273.1>

  
Acidic aqueous layer with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. The extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 12.2 g of 4- (4-methoxyphenyl) -1,1-dimethylbutylamine as a straw-colored oil.

  
B. Following a procedure similar to that described in Example 58B but using 19 g (0.09 mol) of 4- (4-

  
  <EMI ID = 274.1>

VU /

  
by allowing the final product to crystallize in acetone in a refrigerator overnight, 10.5 g of the hydrobromide are obtained

  
  <EMI ID = 275.1>

  
butyl] amino} -3 '- (methylthio) acetophenone, crystalline, m.p. 180-
181 [deg.] C.

  
EXAMPLE 62

  
Following a procedure similar to that described in Example 8 but using 10.5 g (0.021 mol) of 4'-hydroxy-2 - {[4- (4-methoxyphenyl) - 4'-acetate hydrobromide.

  
  <EMI ID = 276.1>

  
sodium borohydride and 1 g of potassium hydroxide and recrystallizing the product from a mixture of methanol and ether, it is

  
  <EMI ID = 277.1>

  
free base, m.p. 179-180 [deg.] C.

EXAMPLE 63

  
Following a procedure similar to that described in Example 42 but using 2.7 g (0.007 mol) of 4-

  
  <EMI ID = 278.1>

  
sulfinyl) benzenemethanol as a white amorphous powder.

  
EXAMPLE 64

  
A stirred mixture containing 7.4 g (0.015 mol) of the 4'-benzoate hydrobromide is heated at reflux for one and a half hours.

  
  <EMI ID = 279.1>

  
3 <1> - (methylthio) acetophenone optically pure and 100 ml of 48% hydrobromic acid. The reaction mixture is then evaporated to dryness and the residue is triturated with ethanol and isopropyl acetate, to give 5.3 g of the (+) - 4'- hydrobromide.

  
  <EMI ID = 280.1>

  
thio) acetophenone.

EXAMPLE 65

  
Following a procedure similar to that described in Example 41 but using 5.0 g (0.012 mole) of

  
  <EMI ID = 281.1>

  
EXAMPLE 6 6.

  
Following a procedure similar to that described in Example 22 but using 4.2 g (0.01 mol) of acetate

  
  <EMI ID = 282.1>

  
methyl> -3- (methylthio) benzenemethanol crude, and by eluting the oxidation product in a short column (1.5 m) of silica gel and then converting into cyclohexylsulfamate (salt), 2.3 g of

  
  <EMI ID = 283.1>

  
EXAMPLE 67

  
A. To a stirred solution containing 100 g (0.55 mol) of 4'-hydroxy-3 '- (methylthio) acetophenone in 650 ml of dioxane and
300 ml of ether, a solution containing 147 g of dioxane dibromide in 1050 ml of a 1: 1 mixture of dioxane and ether is added dropwise over 4 hours. After the addition is complete, the reaction mixture is diluted with 500 ml of ether and washed with water. The organic layer is separated, washed with a saturated aqueous solution of sodium chloride, filtered through cotton wool and the solvents evaporated in vacuo. The residue is stirred twice with benzene and the benzene is evaporated off. The final residue is crystallized from a mixture of benzene and ether, which gives

  
  <EMI ID = 284.1>

  
  <EMI ID = 285.1>

  
B. To a stirred solution containing 50 g (0.28 mol) of (-) 3-

  
  <EMI ID = 286.1>

  
150 ml of N, N-dimethylformamide at - 60 [deg.] C, a solution containing 30 g (0.12 mol) of 2- is added dropwise over half an hour.

  
  <EMI ID = 287.1>

  
dimethylformamide. After the addition is complete, stirring is continued at -60 [deg.] C to -40 ° C for an additional half hour. The reaction mixture is then acidified with
60 ml of 48% hydrobromic acid, diluted with 150 ml of water and washed with ether. The aqueous solution is evaporated to dryness in vacuo. The residue is dissolved in dichloromethane and the resulting solution washed with water and with a saturated aqueous solution of sodium chloride. The dichloromethane is evaporated and the residue is diluted with 2-propanol and cooled to 0 [deg.] C. The solid which precipitates is collected and 9.5 g of the white crystalline hydrobromide are obtained. Concentration of the filtrate provides an additional 2.9 g which is converted to the hydrochloride in a conventional manner, which provides 2.5 g of (-) - 4'- hydrochloride

  
  <EMI ID = 288.1>

  
EXAMPLE 68

  
Following a similar procedure to that described in Example 23B but using 25 g of 2-4'-benzoate

  
  <EMI ID = 289.1>

  
phenone.

  
EXAMPLE 69

  
Following a procedure similar to that described in Example 41 but using 9.3 g of (-) - hydrobromide

  
  <EMI ID = 290.1>

  
(methylthio) acetophenone and 1 g of sodium borohydride, and precipitating the hydrochloride directly from the ethyl acetate extracts, 8.4 g of 4-hydroxy hydrochloride is obtained.

  
  <EMI ID = 291.1>

  
of a mixture of two diastereomers.

  
EXAMPLE 70

  
Following a procedure similar to that described in Example 10 but using 29.6 g (0.055 mol) of (-) - 4'-hydroxy-2 - {[3- (4) 4'-benzoate hydrobromide. -methoxy-

  
  <EMI ID = 292.1>

  
(0.041 mol) of sodium borohydride and 30 ml of a 35% aqueous solution of sodium hydroxide, and by isolating the product in the form of the hydrochloride, 18.6 g of 4- hydrochloride are obtained.

  
  <EMI ID = 293.1>

  
(methylthio) benzenemethanol.

EXAMPLE 71

  
Following a procedure similar to that described in Example 11 but using 17.6 g (0.044 mole) of

  
  <EMI ID = 294.1>

  
amino} methyl> -3- (methylthio) benzenemethanol prepared according to the process of Example 70 and 3.36 g (0.044 mole) of 50% peracetic acid of commerce, 12.5 g of 4- hydrochloride are obtained. hydroxy-

  
  <EMI ID = 295.1> <EMI ID = 296.1>

  
form of a mixture of four diastereomers.

  
EXAMPLE 72

  
A chloroform solution containing sodium bicarbonate is washed thoroughly with a saturated aqueous solution of sodium bicarbonate.

  
10 g (0.0185 mol) of (+) - 4'-hydroxy- 4'-benzoate hydrobromide

  
  <EMI ID = 297.1>

  
phenone. The chloroform solution is then acidified with acetic acid and evaporated to dryness. The residue is oxidized with 2.2 ml of commercial 50% peracetic acid in trifluoroacetic acid, according to the process described in Example 25, to give 6.4 g of 4'- hydrochloride. 4'-hydroxy-2- benzoate

  
  <EMI ID = 298.1>

  
acetophenone, as a mixture of diastereomeric sulfoxides, m.p. 158-159 [deg.] C.

  
EXAMPLE 73

  
A mixture containing 15 g of (+) - 4'-hydroxy-2 - {[3- (4-metthoxy-) 4'-benzoate hydrobromide is stirred for 5 minutes.

  
  <EMI ID = 299.1>

  
of acetonitrile and 40 ml of concentrated ammonia and after 5 minutes a solid begins to precipitate. The mixture is cooled to 0 ° C. and the precipitated product is collected, which is washed with ether. Drying at 60 [deg.] C causes the product to become a black gum. The latter is dissolved in a mixture of methanol and ethyl acetate and filtered through silica gel. The filtrate is evaporated to dryness and the residue is dissolved in ethyl acetate. Acidification of the resulting solution with ethanolic hydrochloric acid affords 2.5 g of (+) - 4'-hydroxy-2 - {[3- hydrochloride.

  
  <EMI ID = 300.1>

  
pale yellow crystalline phenone.

  
EXAMPLE 74

  
Following a procedure similar to that described in Example 25 but using 2.46 ml (0.016 mole) of (+) -

  
  <EMI ID = 301.1>

  
(methylthio) acetophenone which was prepared in the form of the free base according to the procedure of Example 73 and which was used immediately after drying for 4 hours under vacuum at 45 [deg.] C, one obtains after precipitation with ethanolic hydrochloric acid from a mixture of acetone and 2-propanol, 2.5 g of

  
  <EMI ID = 302.1> <EMI ID = 303.1>

  
In addition to anti-hypertension and antiarrhythmic activity, this compound was also found to possess cardiotonic activity when tested according to the methods described in Example 20 above. In the in vitro assay, this compound at doses of 10, 30 and 100 pg / ml causes increases in the speed of the right atrium of 0, 3 and 8% respectively; the strength of the right atrium of 1, 5 and 6% respectively and the strength of the papillary muscle of 7, 23 and 38% respectively. In the in vitro assay, at doses of 1.0, 3.0 and 10.0 mg / kg, the compound causes increases in cardiac contraction force of 22, 25 and 59% respectively. In a second similar series of in vitro tests, increases in cardiac contraction force of 4, 12 and 50% were observed.

  
EXAMPLE 75

  
26.1 g (0.1 mole) of 2-bromo-4'-hydroxy3 '- (methylthio) acetophenone are reacted with 45 g (0.25 mole) of 3,4-dimethoxy-

  
  <EMI ID = 304.1>

  
Example 67B. The product initially obtained by evaporation of the aqueous solution is treated with hot methanol and the N, N-bis- [4-hydroxy-3- (methylthio) phenacyl] -3,4-dimethoxy- filtered.

  
  <EMI ID = 305.1>

  
2-propanol and cooled. The resulting solid is recrystallized from water and then the insoluble by-product is filtered again. The product thus obtained was recrystallized from aqueous ethanol and a sample of 5.5 g was converted into the hydrochloride in a conventional manner, to give 4.6 g of the hydrochloride of 2 - {[2-

  
  <EMI ID = 306.1>

  
acetophenone, m.p. 208-212 [deg.] C.

EXAMPLE 76.

  
By following a procedure similar to that described

  
  <EMI ID = 307.1>

  
  <EMI ID = 308.1>

  
of sodium, acidifying the reaction mixture with 6N hydrochloric acid and isolating the hydrochloride, 11.5 g are obtained

  
  <EMI ID = 309.1>

  
4-hydroxy-3- (methylthio) benzenemethanol, m.p. 124-126 [deg.] C.

  
EXAMPLE 77

  
Following a procedure similar to that described in Example 11 but using 5.6 g (0.014 mole) of chlo-

  
  <EMI ID = 310.1>

  
hydroxy-3- (methylthio) benzenemethanol and 2.13 ml of 50% peracetic acid of commerce, one obtains by crystallization in 2-propanol, 4.9 g of hydrochloride of a- <{[2- (3,4-dimethoxyphenyl) -

  
  <EMI ID = 311.1>

  
m.p. 173-175 [deg.] C.

EXAMPLE 78

  
To a stirred solution containing 72.3 g (0.4 mole) of

  
  <EMI ID = 312.1>
- 50 [deg.] C, a solution containing a solution containing
39.3 g (0.133 mol) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) acetophenone in 275 ml of N, N-dimethylformamide. Once the addition is complete, stirring is continued for one hour at a temperature of -40 [deg.] C to -45 [deg.] C, then an hour and a half at a temperature of -30 [deg.] C at -40 [deg.] C, and finally half an hour at a temperature of - 30 [deg.] C at -5 [deg.] C. The reaction mixture was cooled to -20 [deg.] C and acidified with 45 ml of 48% hydrobromic acid. The solvents are evaporated in vacuo and the residual syrup washed with ether. The syrup is dissolved in 200 ml of water and allowed to crystallize on a Saturday and Sunday.

   The solid which has precipitated is collected, washed with water and ether and recrystallized from 95% ethanol to give 32.31 g of hydrobromide. <EMI ID = 313.1>

  
sulfonyl) acetophenone, m.p. 220-227 [deg.] C. A 10 g sample is converted into the free base which is recrystallized from aqueous methanol and then which is converted into the hydrochloride; m.p. 227-233 [deg.] C with decomposition.

  
EXAMPLE 79

  
Stirred under an initial hydrogen pressure of

  
3.5 kg / cm <2> until the absorption of hydrogen stops, a mixture containing 14.3 g (0.03 mol) of 2 - {[2- hydrobromide

  
  <EMI ID = 314.1>

  
acetophenone and 1 g of a hydrogenation catalyst which is 10% palladium on carbon in 200 ml of N, N-dimethylformamide. The catalyst is removed by filtration and the filtrate is evaporated in vacuo. The residual oil is treated with 100 ml of a 5% aqueous solution of sodium bicarbonate, 20 ml of a solution

  
  <EMI ID = 315.1> 10% aqueous sodium carbonate and 40 ml ether. The solid which precipitates is collected and dissolved in 100 ml of methanol containing 10 ml of ethanolic hydrochloric acid. The solution is treated with decolorizing charcoal and evaporated to dryness. The residue is dissolved in 225 ml of hot methanol and the resulting solution is diluted with 125 ml of acetonitrile and concentrated.

  
to a volume of 125 ml. On standing a first crop of product crystallizes and is collected by filtration. Further concentration of the filtrate provides a second and third crop of product. The crops are combined and 11.2 g are obtained

  
  <EMI ID = 316.1>

  
4-hydroxy-3- (methylsulfonyl) benzenemethanol, m.p. 209-210 [deg.] C.

  
EXAMPLE 80

  
Following a procedure similar to that described in Example 67B, 13.5 g (0.05 mol) of 2-bromo4'-hydroxy-3 '- (methylthio) acetophenone are reacted with 22 g (0.134 mol). of

  
  <EMI ID = 317.1>

  
conventionally the product initially obtained by evaporation of the aqueous solution. Recrystallization of the hydrochloride from aqueous methanol affords 7.1 g of 4'-hydroxy-2- hydrochloride.

  
  <EMI ID = 318.1>

  
205-208 [deg.] C.

EXAMPLE 81

  
To a solution containing 14.6 g (0.05 mole) of 2-bromo

  
  <EMI ID = 319.1>

  
amine in 100 ml of N, N-dimethylformamide. After adding about 30% of the solution in one hour, the rest of the solution is quickly added over 10 minutes. Stirring is continued for one hour and a quarter at -40 [deg.] C and then one hour at -10 [deg.] C. The reaction mixture is acidified with 21 ml of concentrated hydrochloric acid and diluted with 25 ml of water and 175 ml of a saturated aqueous solution of sodium chloride. After half an hour of stirring in the cold, the solid which precipitates is collected, washed with a saturated aqueous solution of sodium chloride and ether and recrystallized from 350 ml of water containing 20 ml of 6N hydrochloric acid. The product is collected by filtration and washed with water and acetone.

   A two day stand of the filtrate provides a second crop of product and a one month stand provides a third crop. The final filtrate is evaporated to dryness and the residue is recrystallized from water to give a fourth crop of product. Each of the four crops was recrystallized from a mixture of methanol and ethanol and the resulting products were combined to obtain 10.0 g of hydrochloride.

  
  <EMI ID = 320.1>

  
acetophenone, m.p. 210 [deg.] - 215 [deg.] C.

  
EXAMPLE 82

  
Stirred under an initial hydrogen pressure of

  
2.25 kg / cm <2>, until the absorption of hydrogen stops, a mixture containing 13 g (0.0327 mole) of 4'-hydroxy- hydrochloride

  
  <EMI ID = 321.1>

  
phenone and 0.9 g of a hydrogenation catalyst which is 10% palladium on carbon in 180 ml of N, N-dimethylformamide and 20 ml of water. The catalyst is removed by filtration and the filtrate is evaporated in vacuo. The residue is partitioned between ethyl acetate and 5% aqueous potassium bicarbonate. The aqueous phase is saturated with sodium chloride and extracted again with ethyl acetate. The organic extracts are combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated in vacuo. The residual oil is dissolved in 50 ml of hot ethanol and the resulting solution is acidified with ethanolic hydrochloric acid. The solvent is evaporated off and the residue crystallized from acetonitrile.

   The product is converted into the free base which is crystallized from aqueous methanol. Transformation into hydrochloride and crystallization of the latter in acetonitrile

  
  <EMI ID = 322.1>

  
178-1800C.

  
EXAMPLE 83

  
Following a procedure similar to that described in Example 80 but using 13 g (0.05 mol) of 2-bromo-4'-

  
  <EMI ID = 323.1>

  
EXAMPLE 84

  
To a stirred solution containing 44.5 g (0.23 mol) of 3- (4-methoxyphenyl) -1,1-dimethylpropylamine in 185 ml of N, N-

  
  <EMI ID = 324.1>

  
containing 27 g (0.092 mol) of 2-bromo-4 <1> -hydroxy-3 '- (methylsulfonyl) acetophenone in 185 ml of N, N-dimethylformamide. After the addition is complete, stirring is continued for a further three hours allowing the reaction mixture to warm to room temperature. Then the mixture is acidified with
23 ml of 48% hydrobromic acid and evaporated in vacuo. The residual oil is washed with ether and then diluted with
200 ml of acetone which allows the precipitation of the hydrobromide

  
  <EMI ID = 325.1>

  
by filtration and dilute the filtrate with ether to precipitate the desired product. The solid thus obtained is suspended in 500 ml of hot acetonitrile, cooled and collected by filtration. This last substance is suspended in
200 ml of hot chloroform, cooled and filtered, which

  
  <EMI ID = 326.1>

  
220-224 [deg.] C with decomposition. A 10 g sample is converted into free base by dissolving it in methanol; by basifying with a 10% aqueous solution of sodium carbonate; by evaporating the methanol; diluting with water; and allowing the base to crystallize to give 5.4 g, m.p. 159-165 [deg.] C, which is then converted to 2.93 g of hydrochloride, m.p. 222-232 [deg.] C with decomposition.

  
EXAMPLE 85

  
Following a procedure similar to that described in Example 79, but using 11.3 g (0.023 mole) of

  
  <EMI ID = 327.1>

  
204 [deg.] C.

EXAMPLE 86

  
25.4 g (0.097 mol) of 2-bromo-4'- are reacted

  
  <EMI ID = 328.1>

  
(4-methoxyphenyl) propylamine, essentially according to the method described in Example 67B. The product initially obtained by evaporation of the aqueous solution is treated with aqueous ethanol.

  
  <EMI ID = 329.1> <EMI ID = 330.1>

  
dryness and the residue crystallized from a mixture of 2-propanol and ethyl acetate. The product thus obtained is triturated with hot water and the residue crystallized from a mixture of ethanol and ethyl acetate, to give 6.5 g of the 4'- hydrobromide.

  
  <EMI ID = 331.1>

  
acetophenone.

EXAMPLE 87

  
Following a procedure similar to that described in Example 76 but using 6.5 g (0.0153 mole) of

  
  <EMI ID = 332.1>

  
(methylthio) acetophenone and 1.2 g of sodium borohydride, 5.1 g of 4-hydroxy-a- hydrochloride are obtained. <{[3- (4-methoxy-

  
  <EMI ID = 333.1>

  
151-152 [deg.] C.

  
EXAMPLE 88

  
To a stirred suspension of 31.6 g (0.14 mol) of Nbenzyl-3-phenylpropylamine in 280 ml of methanol at a temperature of -40 [deg.] To -45 [deg.] C is added all at once 20.5 g (0.07 mole) of

  
  <EMI ID = 334.1>

  
hours of stirring, the reaction mixture is allowed to warm to room temperature in one and a half hours. Evaporation in vacuo gave a gummy residue which was suspended in 400 ml of boiling ethyl acetate to give a solid precipitate of N-benzyl-3-phenylpropylamine hydrobromide. The solid is filtered off and the filtrate is evaporated to dryness in vacuo. The residue was dissolved in absolute ethanol and the resulting solution acidified with 35 ml of 6.8 N ethanolic hydrochloric acid. Evaporation of the acidic solution and crystallization of the residue from ethanol afforded 18. 3 g of 2- [N-benzyl-3- (phenylpropyl) amino] -4'-hydroxy-3'- hydrochloride
(methylsulfonyl) acetophenone, m.p. 190-1910C.

   This product is combined with the products of several other runs and recrystallized from absolute ethanol to give a substance having a melting point of 193.5-195 [deg.] C.

  
EXAMPLE 89

  
Stirred under an initial hydrogen pressure of 3.6 kg / cm <2> until the theoretical amount of hydrogen has been absorbed, a mixture containing 4.74 g (0.01 mole) of hydrochloride

  
  <EMI ID = 335.1> sulfonyl) acetophenone and 250 mg of a hydrogenation catalyst which is 10% palladium on carbon in 100 ml of 95% ethanol. It is necessary to dilute the reaction mixture with 200 ml

  
  <EMI ID = 336.1>

  
the solid which precipitated. The catalyst is then removed by filtration and the filtrate is evaporated to dryness in vacuo. The residue is triturated with 25 ml of hot ethanol, cooled and the solid collected by filtration. This product is combined with the products of other runs and recrystallized from aqueous methanol to give 12.0 g of 4'-hydroxy-3'- hydrochloride.

  
  <EMI ID = 337.1>

  
242 [deg.] C with decomposition.

  
EXAMPLE 90

  
Following a procedure similar to that described in Example 67B but using 61 g (0.29 mol) of mescaline

  
  <EMI ID = 338.1>

  
phenone, 33 g of crystalline product are obtained contaminated with a small amount of N, N-bis- [4-hydroxy-3- (methylthio) phenacyl] -3,4, 5-trimethoxyphenetylamine. The product is taken up in boiling water and the insoluble by-product is filtered off. Concentration of the filtrate to a small volume produces 18.2 g of 4'-hydrobromide.

  
  <EMI ID = 339.1>

  
acetophenone. The hydrochloride isolated in monohydrate form has a melting point of 193-195 [deg.] C.

  
EXAMPLE 91

  
Following a similar procedure to that described in Example 41 but using 16 g of 4'- hydrochloride

  
  <EMI ID = 340.1>

  
acetophenone and 2.5 g of sodium borohydride and isolating the product in the form of the hydrochloride, 14.6 g of the hydrochloride of

  
  <EMI ID = 341.1>

  
EXAMPLE 92

  
Following a procedure similar to that described in Example 11 but using 7.7 g (0.0175 mol) of hydrochloride

  
  <EMI ID = 342.1>

  
50% peracetic commercially available product and crystallizing the product from a mixture of methanol and ether, 6.8 9 hydrochloride is obtained.

  
4-hydroxy-3- (methylsulfinyl) -a- <{[2- (3,4,5-trimethoxyphenyl) -

  
  <EMI ID = 343.1>

  
ethyl] amino} methyl> benzenemethanol, m.p. 164-166 [deg.] C.

  
EXAMPLE 93

  
To a stirred solution containing 76.0 g (0.36 mol) of mescaline in 250 ml of N, N-dimethylformamide at -65 [deg.] C, a solution containing 35.2 g (deg.] C is added over three and a half hours ( 0.12 mol) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) acetophenone in 250 ml of N, N-dimethylformamide. Once the addition is complete, stirring is continued at a temperature of -40 to - 30 [deg.] C for one hour and then at a temperature of -30 to -5 [deg.] C for three quarters of an hour. . The mixture is cooled to -20 [deg.] C, acidified with 32 ml of 48% hydrobromic acid and evaporated in vacuo. The residual syrup is washed thoroughly with ether and crystallized from 2-propanol. The solid product is collected in several fractions, the first few of which contain significant amounts of mescaline hydrobromide.

   The latter fractions contain the desired product essentially free of mescaline hydrobromide. A 15 g sample of the last fractions is converted to free base and then to hydrochloride, which gives 5.52 g

  
  <EMI ID = 344.1>

  
amino} -3 '- (methylsulfonyl) acetophenone, m.p. 230-234 [deg.] C with decomposition.

  
EXAMPLE 94

  
Stirred under an initial hydrogen pressure of 3.36 kg / cm <2> until absorption of hydrogen ceases, a mixture of 16.47 g (0.0357 mole) of 4'-hydroxy-3'- hydrochloride

  
  <EMI ID = 345.1>

  
phenone and 1.2 g of a hydrogenation catalyst which is 10% palladium on carbon, in 180 ml of N, N-dimethylformamide and 20 ml of water. The catalyst is removed by filtration and the filtrate is evaporated in vacuo. The residual oil is crystallized from a mixture of methanol and ether and recrystallized from methanol. The resulting product is converted with ammonia to the free base which crystallizes in water. Conversion to the hydrochloride yields 12.56 g of 4-hydroxy-3- (methylsulfonyl) -a- hydrochloride.

  
  <EMI ID = 346.1>

  
m.p. 192-194 [deg.] C.

EXAMPLE 95

  
To a stirred solution containing 12 g of 4-hydroxy-a- <{[3-

  
  <EMI ID = 347.1>

  
benzenemethanol, prepared according to Example 19, in 50 ml of chloroform at 50 [deg.] C, 20 ml of thionyl chloride are added. The temperature is maintained at 50 [deg.] C and after a short period of stirring the product begins to crystallize. After 2 hours of stirring, the mixture is cooled and the precipitated product is collected which is washed with benzene to obtain, after drying

  
11 g of 4-hydroxy-a- chloride hydrochloride <{[3- (4-methoxy-

  
  <EMI ID = 348.1>

  
EXAMPLE 96

  
To a stirred solution containing 9.6 g (0.0226 mole) of

  
  <EMI ID = 349.1>

  
methylpropyl] amino} methyl> benzyl in 80 ml of N, N-dimethylformamide at 0-10 [deg.] C under nitrogen, 1.9 g (0.05 mol) of borohydride are added in portions over a quarter of an hour sodium. After an additional hour of stirring, the reaction mixture is neutralized with glacial acetic acid, diluted with chloroform and washed with saturated aqueous sodium bicarbonate solution. The chloroform solution is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in a 9: 1 mixture of 2-propanol and methanol and the resulting solution is acidified with ethereal hydrochloric acid. By concentration and cooling, 5.5 g of hydrochloride are obtained.

  
  <EMI ID = 350.1>

  
(methylthio) phenol, m.p. 184-185 [deg.] C.

EXAMPLE 97

  
To a stirred solution containing 5.0 g (0.0135 mole) of

  
  <EMI ID = 351.1>

  
50% peracetic acid from the market. The reaction mixture is then cooled to 0-5 [deg.] C and treated with an additional 10 ml of peracetic acid. After the addition is complete, the reaction mixture is concentrated to 20 ml and diluted with 50 ml of 2-propanol. On standing at 50 [deg.] C overnight, the product crystallizes. It is collected and dried to give 4.5 g of 4- hydrochloride.

  
  <EMI ID = 352.1>

  
EXAMPLE 98

  
A mixture of 50 g (0.925 mol) of (+) - 4'-benzoate hydrobromide is stirred and refluxed for one hour.

  
  <EMI ID = 353.1>

  
(methylthio) acetophenone and 500 ml of 48% hydrobromic acid.

  
On cooling, the product crystallizes. It is collected and recrystallized from a mixture of ethanol and isopropyl acetate, which gives 26.7 g of (+) - 4'-hydroxy-2- hydrobromide.

  
  <EMI ID = 354.1>

  
phenone.

  
EXAMPLE 99

  
Following a procedure similar to that described in Example 76 but using 33 g (0.0765 mol) of (+) - 4'-hydroxy-2 - {[3- (4-hydroxyphenyl) -1 hydrobromide -methyl-

  
  <EMI ID = 355.1>

  
use directly in a subsequent reaction.

  
EXAMPLE 100

  
A stirred solution containing 0.075 moles of 4-hydroxy-a- is saturated with hydrochloric acid over an hour and a half.

  
  <EMI ID = 356.1>

  
crude benzenemethanol in 50 ml of dry dioxane. After stirring overnight, the reaction mixture is diluted with ether, filtered through cotton wool and then concentrated to a volume of

  
150 ml. The concentrate was cooled and the product which precipitated was collected and dried to give 27.8 g of the hydrochloride.

  
  <EMI ID = 357.1>

  
EXAMPLE 101

  
To a stirred solution containing 27.8 g (0.0685 mol) of

  
  <EMI ID = 358.1>

  
methylpropyl] amino} methyl> -3- (methylthio) benzyl in 150 ml of

  
  <EMI ID = 359.1>

  
hour 4 g of sodium borohydride. After another half hour of stirring, the reaction mixture is acidified with 6N hydrochloric acid, concentrated to almost dryness, diluted with saturated aqueous sodium bicarbonate solution and carefully extracted with sodium bicarbonate. ethyl acetate. The extracts are washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in a mixture of ether and ethyl acetate and the resulting solution is acidified with ethanolic hydrochloric acid and cooled. The solid which crystallizes is collected and recrystallized from a mixture of acetone, methanol and ether, to give 15.0 g of

  
  <EMI ID = 360.1>

  
amino} ethyl> -2- (methylthio) phenol. Recrystallization of a sample from a mixture of methanol, acetone and ether then from a mixture of ether and 2-propanol, and drying for 4 hours under vacuum at 100-115 [deg.] C, provide a product with a melting point of 150-151 [deg.] C.

  
EXAMPLE 102

  
To a stirred solution containing 4.2 g (0.0114 mole) of

  
  <EMI ID = 361.1>

  
1.73 ml of 50% peracetic acid are added over 20 minutes
- traded in 5 ml of methanol. When the addition is complete, the reaction mixture is evaporated to dryness and the residue is crystallized from a mixture of acetonitrile and 2-propanol, which gives after 3 hours of drying under vacuum at 100 [deg.] C 5.7 g of chlo- <EMI ID = 362.1>

  
(methylsulfinyl) phenol, m.p. 204-205 [deg.] C.

  
Additional examples of benzenemethanols and aminoketones having the formulas I and II above, respectively, and obtainable according to the procedures described above, are given in Table A below.

  
Further examples of haloketones and corresponding parent phenylketones having the above formulas V and VII, respectively, which are intermediates useful in the preparation of amino ketones of formula II (Table A) and which can be prepared according to the modes The procedures described above are given below in Tables B and C. The phenylketones of Table C are obtained according to the procedures described above by acylating the generally known o- (lower alkylthio) phenols using a halide of appropriate acyl under Friedel-Crafts conditions, followed by esterifying the resulting 3- (lower alkylthio) -4-hydroxyphenyl ketones with an appropriate lower alkanoyl or aroyl halide according to conventional esterification procedures.

  
Other examples of 2-phenylethylamines and 2-halo-2phenylethylamines respectively of formulas III and IV above and which can be obtained according to the procedures described above are given in Table D below.

TABLE A

  

  <EMI ID = 363.1>


  
benzenemethanols of formula I: Z is CHOH aminoketones of formula II: Z is C-0
  <EMI ID = 364.1>
 TABLE A (continued)

  

  <EMI ID = 365.1>
 

TABLE B

  

  <EMI ID = 366.1>
 

  
  <EMI ID = 367.1>

  

  <EMI ID = 368.1>
 

TABLE D

  

  <EMI ID = 369.1>


  
2-phenylethylamines of formula III: B is hydrogen 2-halo-2-phenylethylamines of formula IV: B is chlorine, bromine or iodine.

  

  <EMI ID = 370.1>
 

  
TABLE D (continued)

  

  <EMI ID = 371.1>


  
Remarks.

  
- Example 25.

  
The product obtained in this example was initially erroneously identified as being the hydrochloride of

  
  <EMI ID = 372.1>

  
propylj amino &#65533; -3- (methylsulfinyl) acetophenone.

  
- In the examples, when the name of the acid derivative carries an indication of position (4 or 4 '), it is the ester derivative formed on the hydroxy group in position 4 or 4'. Otherwise it is the acid addition salt.

  
The compounds of this invention of formula I have been shown to have anti-hypertension activity, vaso-

  
  <EMI ID = 373.1>

  
This can be seen from the results of standardized pharmacological tests performed on representative examples as described below.

  
Antihypertensive activity was determined based on the observed reduction in systolic blood pressure measured according to the method of H. Kersten et al., J. Lab. and Clin. Med. 32,
1090 (1947), after a single oral administration in the normally hypertensive and non-anesthetized rat, described by Okamato et al., Japan Circulation J. 27, 282 (1963).

  
Anti-hypertensive activity was also judged on the basis of the prolonged reduction in blood pressure observed in the trained, non-anesthetized renal hypertensive dog after repeated oral administration, according to the procedure described by Lape et al. Arch. int. Pharmacodyn. 160, 342 (1966).

  
Vasodilation activity was judged on the basis of the observed reduction in perfusion pressure in the vascular system of the hind paw of an anesthetized dog, determined according to the procedure described by Jandhyala et al., European J. Pharm. 17, 357 (1972), and also on the basis of the percent reduction in perfusion pressure measured in the isolated rabbit ear artery, according to the method described by De La Lande et al., Aust. J. Exp. Biol. Med. Sci. 43, 639 (1965).

  
The S-adrenergic blocking activity is determined in the pentobarbital anesthetized dog, depending on the ability of the test compound to inhibit the increase in heart rate due to intravenous injection of 0.5 mg / kg isoproterenol. .

  
The acute intravenous and oral toxicity in mice, for the compound of Example 11A, was determined as follows: the compound was dissolved in distilled water and administered as the base, at a volume of 10 mg / kg for iv DLA50 or 10-40 ml / kg for DLA50 po The compound is administered in graduated doses to groups of three mice each

  
  <EMI ID = 374.1>

  
Lity occurs within 1 minute of i.v. administration and within ten minutes after oral administration. Symptoms of acute poisoning for fatal cases include atoxia, loss of righting reflex, clonic convulsions and dyspnea, followed by respiratory arrest. No untoward symptoms are seen for up to seven days for

  
  <EMI ID = 375.1>

  
1500 mg / kg.

  
  <EMI ID = 376.1>

  
determined for two separate lots of the compound of Example 20B and

  
found it to be 1850 and 1940 mg / kg, respectively. No change in body weight or macroscopic tissue change was observed in animals sacrificed seven days after medication.

  
The results of the pharmacological tests described above are given in Table E below.

  
As indicated above, some of the compounds of this invention also exhibit antiarrhythmic activity. The latter is determined in vivo and the efficacy is judged on the ability of the test compound to transform the arrhythmia induced by intoxication with barium ion or ouabain into a normal rhythm. The test procedures are carried out as follows:
Ba ++ induced arrhythmia

  
Adult rabbits of either sex, weighing 1.7-2.3 kg, are anesthetized with 30-35 mg / kg sodium pentobarbital intravenously through a marginal ear vein. Monopolar electrocardiogram electrodes are inserted

  
for derivation II, on a Grass Model polygraph? 5 using standard procedures for electrocardiography.

  
A hypodermic needle is inserted, attached by a polyethylene catheter to a 10 cm syringe <3>, in the same vein as that used for anesthesia. Then a solution of BaC12.2H20 in saline is infused at a constant volume of 0.2 ml / minute using a Harvard Apparatus Model infusion pump.
600. This infusion is not stopped until the experiment is stopped. In some studies barium chloride was used in distilled water without detecting any differences. The normal infusion rate of BaC12.2H20 was established at 0.3 mg / kg / minute (1.2

  
  <EMI ID = 377.1>

  
requested in each case to take into account the weight of the rabbit.

  
When the desired arrhythmia has been established, the compound is introduced as a solution in water or saline into the marginal ear vein of the unused ear.

  
The volume used is between 0.5 and 2.0 ml / kg and is injected as a bolus in about 30 seconds. Changes in the conventional vehicle, injection rate and total volume delivered are left to the discretion of the operator. The normal starting dose of an unknown compound in the first rabbit is

  
  <EMI ID = 378.1>

  
determining the antiarrhythmic activity and the dose range producing this activity; several doses are administered. Once activity and dose have been found, two more rabbits are used to confirm antiarrhythmic activity against multifocal tachycardia.

  
Ouabain-induced arrhythmia

  
Adult mongrel dogs of either sex, after fasting for 16-20 hours, are anesthetized with 35 mg / kg sodium pentobarbital i.v. and fixed on their backs on the operating table. Air passage is provided by inserting a cannula into the trachea, and the animal breathes spontaneously. Two cannulas are introduced into a femoral vein, one cannula for injection and one as the site of ouabain infusion. A cannula is inserted into the femoral artery on the same side to measure blood pressure. Sodium pentobarbital supplements are administered intravenously as needed.

  
Statham P23A blood pressure transducers are used to measure blood pressure, and electro-

  
  <EMI ID = 379.1>

  
polar. Both parameters are recorded on a Grass polygraph. Each dog is administered 36 µg / kg of ouabain intravenously over one minute (the solution contains 50 µg / ml of ouahaine in isotonic saline solution) followed by a constant infusion of ouabain (0.6 ± g / kg / minute) starting 5 minutes later. The infusion solution is prepared so that the appropriate dose per minute is supplied in 0.5 ml.

  
When the predominant rhythm of the resulting arrhythmia is ventricular (or sometimes nodal) tachycardia, an attempt is made to transform this arrhythmia with the test compound. We admit

  
  <EMI ID = 380.1>

  
1 ml / kg over a 5 minute infusion period. If a transformation or cardiotoxic effect is seen before administration of
10 4 M / kg, record the dose and repeat on a second dog.

  
The test is carried out in a conventional manner using pairs of dogs with a difference of 15 minutes from the time of departure. All measurements of duration and interval of electro- <EMI ID = 381.1>

  
  <EMI ID = 382.1>

  
100 mm / second paper. Heart rates are recorded on lead II with a paper speed of 100 mm / second. Heart rates are taken from lead II QRS complexes at 25 mm / second. Blood pressure is measured using a pencil displacement sensitivity of 10 mm Hg / mm.

  
The results of the tests described above are given in Table F below. The compounds are indicated as being active (A) or inactive (I) at the dose tested, expressed in M / kg.

  
  <EMI ID = 383.1>

PHARMACOLOGICAL PROPERTIES

  

  <EMI ID = 384.1>
 

TABLE E

PHARMACOLOGICAL PROPERTIES

  

  <EMI ID = 385.1>
 

PHARMACOLOGICAL PROPERTIES TABLE

  

  <EMI ID = 386.1>
 

  
  <EMI ID = 387.1>

  
(aa) DHA40 - Single oral dose required to induce

  
40 mm mean reduction in systolic blood pressure in normally hypertensive, non-anesthetized rats.

  
  <EMI ID = 388.1>

  
necessary to carry out a continuous lowering

  
blood pressure of 10% or more in trained, non-anesthetized dogs with renal hypertension.

  
  <EMI ID = 389.1>

  
cause a 50% reduction in perfusion pressure in the anesthetized dog's hind paw.

  
  <EMI ID = 390.1>

  
reduction of the infusion pressure from the control level at the indicated molar dose.

  
  <EMI ID = 391.1>

  
induce a 50% inhibition of the increase in heart rate due to isoproterenol in the pentobarbital anesthetized dog.

  
  <EMI ID = 392.1>

  
mercury) observed at the indicated dose.

  
  <EMI ID = 393.1>

  
blood level observed at the indicated dose.

  
  <EMI ID = 394.1>. Infusion observed at the indicated dose.

  
(ii) Actual percent inhibition of the increase in

  
the speed of the heart relative to the control value, observed at the indicated dose.

  
  <EMI ID = 395.1>

TABLE F

  
Anti-arrhythmic activity
  <EMI ID = 396.1>
(a) M / kg.
(b) Toxic at 2.5x10 -5 inactive below 2.5x105 <EMI ID = 397.1>

CLAIMS

  
1. Compound having in free base form the formula I
(in the thesis), in which

  
  <EMI ID = 398.1>

  
gene or lower alkyl group;

  
n is an integer of 1 to 3;

  
Ar is a phenyl or phenyl group having one to three halogen, lower alkyl, hydroxy or lower alkoxy substituents;

  
Q is a lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group; and

  
Y is a hydrogen atom or a lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl group;

  
or one of its acid addition salts.


    

Claims (1)

2. A compound according to claim 1, wherein Ar is a phenyl or phenyl group having one or two lower alkyl, hydroxy or lower alkoxy substituents. 3. A compound according to claim 2, where R 1 is a hydrogen atom and Q is a methylthio, methylsulfinyl or methylsulfonyl group. 4. A compound according to claim 3, wherein Y is a hydrogen atom or a lower alkanoyl or aroyl group. <EMI ID = 399.1> hydroxy-3- (methylthio) banzenemethanol or an acid addition salt thereof. 6. 4-Hydroxy-a - {[(1-methyl-3-phenylpropyl) amino] -methyl} 3- (methylthio) benzenemethanol or an acid addition salt thereof. <EMI ID = 400.1> tion of acid. 8. A compound according to claim 3 or 4, wherein Ar is a 4-methoxyphenyl group. <EMI ID = 401.1> methyl> -4-hydroxy-3- (methylthio) benzenemethanol or an acid addition salt thereof. <EMI ID = 402.1> addition of acid. <EMI ID = 403.1> methyl> -3- (methylsulfinyl) benzenemethanol or an acid addition salt thereof. <EMI ID = 404.1> addition of acid. of a 13. Hydrochloride according to claim 12, in the form / stereoisomer identifiable by a rotatory power [a] 25 = + 126.6 [deg.] (2% in methanol). <EMI ID = 405.1> of a stereoisomer identifiable by a rotary power [a] 25 = - 48.2 [deg.] (2% in methanol). 15. Hydrochloride according to claim 12, in the form of a stereoisomer identifiable by a rotatory power [a] 25 + 70.5 [deg.] (2% in methanol). 16. Hydrochloride according to claim 12, in the form of a stereoisomer identifiable by a rotatory power [a] 25 = - 102.3 [deg.] (2% in methanol). <EMI ID = 406.1> methyl, Q is a methylthio, methylsulfinyl or methylsulfonyl group, Ar is a lower alkoxyphenyl group and Y is a hydrogen atom. 18. Compound having in free base form the formula III (in the specification) in which <EMI ID = 407.1> a lower alkyl group; n is an integer of 1 to 3; Ar is a phenyl or phenyl group having one to three halogen, lower alkyl, hydroxy or lower alkoxy substituents; Q is a lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group; and Y is a hydrogen atom or a lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl group; or one of its acid addition salts. 19. A compound according to claim 18, wherein R is a hydrogen atom and Q is a methylthio, methylsulfinyl or methylsulfonyl group. 20. A compound according to claim 19, wherein Ar is <EMI ID = 408.1> 4-methoxyphenyl group and Y is a hydrogen atom. 21. A process for producing a compound according to claim 1, characterized in that reducing a compound having in the form of free base the formula II (in the specification) or one of its acid addition salts, where in the case where Y in the starting compound is a lower alkanoyl or aroyl group and that the reduction is carried out with a reducing agent which can reduce the two ketone and carboxylic ester functions, Y in the resulting compound is a hydrogen atom ; if desired, the compound obtained in which Y is a lower alkanoyl or aroyl group is hydrolyzed to obtain the corresponding compound in which Y is H, or a compound obtained in which Y is a hydrogen atom is esterified to obtain the corresponding compound in which Y is a lower alkanoyl or aroyl group; if desired, the compound obtained in which Q is an alkylthio group is oxidized to obtain the corresponding compound in which Q is an alkylsulfinyl group; and if desired, the compound obtained is converted in the form of the free base into one of its acid addition salts or a basic salt of a compound obtained when Y is a hydrogen atom is formed. 22. A process for producing a compound according to claim 18, characterized in that reducing a compound of formula IV (in the specification) or one of its acid addition salts, where in the case where Y in the starting compound is a lower alkanoyl or aroyl group and when the reduction is carried out with a reducing agent which can reduce the two ketone and carboxylic ester functions, Y in the resulting compound is a hydrogen atom; if desired, the compound obtained in which Y is a lower alkanoyl or aroyl group to obtain the corresponding compound in which Y is H, or the compound obtained in which Y is hydrogen is esterified to obtain the corresponding compound in which Y is a lower alkanoyl or aroyl group; if desired, the compound obtained in which Q is an alkylthio group is oxidized to obtain the corresponding compound in which Q is an alkylsulfinyl group; and if desired, the compound obtained is converted in the form of the free base into one of its acid addition salts or the basic salt of a compound obtained in which Y is a hydrogen atom is formed. 23. The method of claim 21 or 22, which does not include esterification of a compound obtained according to one <EMI ID = 409.1> compound obtained according to claim 18. 24. A process for preparing a compound according to claim 1 or 18, substantially as described herein with reference to Examples. 25. A process for preparing a compound according to claim 2, substantially as described herein with reference to Examples 1-66. 26. A compound prepared by the process according to any one of claims 21 to 25. 27. A compound according to claim 1 or 18, substantially as described herein with reference to Examples. 28. A compound according to claim 2, substantially as described herein with reference to Examples 1 to 66. 29. A compound having in free base form the formula II (in the specification) in which <EMI ID = 410.1> or a lower alkyl group; n is an integer of 1 to 3; Ar is a phenyl or phenyl group having from one to three halogen, lower alkyl, hydroxy or lower alkoxy substituents; Q is a lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group; Y is a hydrogen atom or a lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl group; or one of its acid addition salts. 30. A compound according to claim 29, wherein Ar is a phenyl or phenyl group having one or two lower alkyl, hydroxy or lower alkoxy substituents. <EMI ID = 411.1> hydrogen atom and Q is a methylthio, methylsulfinyl or methylsulfonyl group. 32. A compound according to claim 31, wherein Q is a methylthio group and Y. is a hydrogen atom or a lower alkanoyl or aroyl group. 33. A compound according to claim 31 or 32, wherein Ar is a 4-methoxyphenyl group. <EMI ID = 412.1> 1AI <EMI ID = 413.1> addition of acid. 36. (+) - 4'-Hydroxy-2 - {[3- (4-methoxy- 4'-Benzoate <EMI ID = 414.1> of its acid addition salts. 37. A compound according to claim 30, wherein R- is a methyl group, Q is a methylthio, methylsulfinyl 'or methylsulfonyl group and Ar is a lower alkoxyphenyl group. 38. A compound according to claim 37, wherein Q is a methylthio group and Y is a hydrogen atom. 39. Compound having in its free base form the formula IV (in the specification) in which X is a chlorine, bromine or iodine atom; <EMI ID = 415.1> a lower alkyl group; n is an integer of 1 to 3; Ar is a phenyl or phenyl group having one to three halogen, lower alkyl, hydroxy or lower alkoxy substituents; Q is a lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group: Y is a hydrogen atom or a lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl group; or one of its acid addition salts. <EMI ID = 416.1> hydrogen atom and Q is a methylthio, methylsulfinyl or methylsulfonyl group. 41. A compound according to claim 40, wherein X is a chlorine atom and Y is a hydrogen atom. 42. A process for producing a compound according to claim 29, characterized in that a haloketone of formula V (in the specification) is reacted with an amine of formula VI (in the specification), and if desired, esterifies the compound obtained in which Y is a hydrogen atom to obtain the corresponding compound in which Y is a lower alkanoyl or aroyl group, or a compound obtained in which Y is a lower alkanoyl or aroyl group is hydrolyzed to obtain the corresponding compound wherein Y is a hydrogen atom; if we have it <EMI ID = 417.1> It is desired to oxidize a compound obtained in which Q is a lower alkylthio group to obtain the corresponding compound in which Q is a lower alkylsulfinyl group; and if desired, the compound obtained is converted in the form of the free base into one of its acid addition salts or a basic salt of a compound obtained in which Y is a hydrogen atom is formed. 43. The method of claim 42, wherein X is bromine. 44. A process for the production of a compound according to claim 39, characterized in that a compound of formula I (in the specification) is reacted with HX or a mineral acid chloride or bromide, and if desired , the compound obtained is converted in the form of a free base into one of its acid addition salts or a basic salt of a compound obtained in which Y is a hydrogen atom is formed. 45. A method according to claim 42 making it possible to obtain a compound according to claim 29 or 30, which does not comprise the hydrolysis of the compound obtained. 46. A process for producing a compound according to claim 29 or 39, substantially as described herein with reference to Examples. 47. A process for producing a compound according to claim 30, substantially as described herein with reference to Examples 1-66. 48. A compound prepared by a process according to any one of claims 42 to 47. 49. A compound according to claim 29 or 39, substantially as described herein with reference to Examples. 50. A compound according to claim 30, substantially as described herein with reference to Examples 1 to 66. 51. A method of lowering blood pressure in a mammal, excluding man, which comprises administering to said mammal an effective blood pressure lowering amount of a compound according to any one of the claims 1 to 20, 27 and 28. <EMI ID = 418.1> mammal, excluding man, which consists in administering to said mammal an amount effective to induce vasodila- <EMI ID = 419.1> indications 1 to 17, 27 and 28. STERLING DRUG INC. The undersigned is aware that no attached document in the file of an invention patent cannot be such as to make either the description or the drawings, substantive changes and declares that the content of this note does not no such changes and has no other purpose than to report one or more material errors. He recognizes that the content of this note cannot have the effect of making <EMI ID = 420.1> in whole or in part under the legislation currently in force. He authorizes the administration to attach this note in the patent file and to issue a photocopy.