DK146386B - METHOD OF ANALOGUE FOR THE PREPARATION OR SALTS OF PHENYL ALKANOLAMINE COMPOUNDS - Google Patents

Description

(% (19) DENMARK ^

| J | (12) PUBLICATION NOTICE 146386 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No: 2817/77 (51) Lnt.CI.3: C 07 C147 / 10 (22) Date of filing: 24 Jun 1977 C 07 C 147/14 C07C 149/42 (41) Aim. available: 26 Dec 1977 (44) Submitted: 26 Sep 1983 (86) International Application No :- (30) Priority 25 Jun 1976 U $ 699856 03 Jun 1977 US 803372 (71) Applicant 'STERLING DRUG INC; New York, US.

(72) Inventor: Richard Everett 'Phlllon; US.

(74) Plaintiff: Holman-Bang & Boutard Patent Office (54) Analogous Process for the Preparation of Phenyl-Alkanolamine Compounds or Salts thereof

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to an analogous process for the preparation of novel phenylalkanolamine compounds of the general formula I or the acid addition salts thereof of claim 1 or salts thereof having salts of the compounds containing an unsubstituted phenol group.

GB Patent No. 1,321,701 discloses a group of compounds of the general formula 'R2 4

(O K v. / _ ^ OH FT

CO R1 -CH-CH-CH-NR5R6 t— n *

ISLAND

Wherein R38 is RS, RSO or RSC ^, wherein R is hydrogen or alkyl of 1-10 carbon atoms,

O * Z

R 1 and R 4 represent hydrogen, alkoxy of 1-4 carbon atoms or alkylthio of 1-4 carbon atoms, R 4 represents hydrogen or alkyl of 1-4 carbon atoms, and C

Rp and R individually represent hydrogen or alkyl of 1-16 carbon atoms optionally substituted with phenyl or substituted phenyl. The compounds are indicated to exert β-adrenergic blocking, peripheral vasodilating, antiarrhythmic and hypotensive activity.

U.S. Patent No. 3,917,704 discloses a group of α-aminoalkyl-4-hydroxy-3-alkylsulfonylmethylbenzyl alcohols of the formula rso2ch2 "" VV OH R2 HO tf ^ V-CH-CH-NHR1 wherein, inter alia, R is straight or branched alkyl of 1 Represents carbon, methyl or ethyl, R 4 represents hydrogen, hydroxy or methoxy, and represents hydrogen or methyl.

3 148386

The compounds are reported to have useful effect as α-adrenergic stimulants with relatively greater activity on respiratory smooth muscle than on cardiac muscle.

Kaiser et al., J. Med. Chem. 18, 674-683 (1975) mainly report the work described in the aforementioned U.S. Patent No. 3,917,704, and further disclose the compound of formula CH, SO

Va oh HO- (f \ - OH-OHg-NH-OfCHjJj which is reported to be weakly active as β-adrenergic agonist and exhibiting β-adrenergic antagonistic activity. The work described in the said publication by Kaiser et al. al., was reported orally at the 169th National Meeting of the American Chemical Society on April 10, 1975. 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) discloses an attempt to prepare 4-hydroxy-3-mercaptophenylethanolamine, i.e.

HS ^

/ ~ \ ° H

HO ft y — CH-CHg-NHg

However, the compound was not isolated as a single substance or characterized.

GB Patent No. 1,154,193 discloses as β-adrenergic agent α - [(isopropylamino) methyl] -3- (methylthio) benzene methanol, i.e.

4 146386

CH, S

3 y— f1 'y — ch-ch2-nh-ch (ch3) 2

In the field of antihypertensive therapy, the use of peripheral vasodilator agents to lower blood pressure often suffers from a serious disadvantage, namely the reflex tachycardia triggered by the hypotension induced by systemic vasodilatation. Recently, attempts have been made to overcome this problem by using hypotensive vasodilator in combination with $ -adrenergic blocking agents, the latter being to reduce the reflex tachycardia caused by the vasodilatatcr-induced hypotension. This type of therapy, of course, suffers from the lack of requiring two separate drugs and the consequent need for separate dose control as well as the increased possibility of patient error by forgetting to administer one or the other of the drugs.

The object of the present invention is to provide a process for the preparation of novel therapeutically useful compounds which have both hypotensive, vasodilating and β-adrenergic blocking activity and are therefore indicated for use as antihypertensive agents without the undesirable tachycardic agents. side effects associated with the currently used vasodilator agents.

This is the case with the compounds of the invention according to the general formula I and the acid addition salts thereof and the base salts of the compounds in which Y is hydrogen. As described in detail below, some of these compounds are also useful as antiarrhythmic agents.

The process according to the invention is peculiar to the characterizing part of claim 1.

5 146388

The benzene methanols of general formula I are prepared by the process of the invention by reducing the aminoalkylphenyl ketones of general formula II. The aminoalkylphenyl ketones of formula II are prepared by reacting a halogen ketone of formula _J ~ \ S * 1 Y0— (fy-c-ch-x v wherein R1, Q and Y have the meaning given in the preamble of claim 1 and X is chlorine, bromine or iodine, with an arylalkylamine of formula R 2

Ar- (CHa) n-i-NH 2 'R / VI · wherein R 1, R 2, n and Ar have the meaning given in the preamble of claim 1.

The 2- (Alkylsulfinyl) benzene methanols of formula I wherein R, R, R 5, n, Ar and Y are as defined in the preamble of claim 1 and Q is alkylsulfinyl of 1-4 carbon atoms can be prepared by oxidation of 3- (alkylthio) benzene methanols of formula I wherein 121¾R, R, R, n, Ar and Y have the same meaning and Q is alkylthio having 1-4 carbon atoms.

In the general formulas, "toluenesulfonyl" should include ortho-, meta-and para-toluenesulfonyl.

Mammalian blood pressure can be reduced by administering to said mammals an effective blood pressure lowering amount of a benzene methanol of Formula I. Vasodilatation of mammal 6 146386 can be produced by administering said mammal to a benzene methanol of formula I in an effective amount. to produce vasodilatation.

The known compounds propranolol and papaverine listed as positive controls at the end of Table III of GB Patent No. 1,321,701 have also been tested for comparison with the compounds of the invention. Propranolol, a known $ adrenergic blocking agent, exhibited an AEDED of 0.025 mg / kg in the following example and in particular Table E, footnote (e) of the β-blockade test, and papaverine, a known vasodilator, was found to reduce the perfusion pressure (rabbit artery) by 25-37% at a concentration of 2 x 10 4 M. The preferred compound prepared according to claim 2 of the present application (disclosed in Example 7A and Book in various of its stereoisomeric forms, in the Examples 10, 12A-F, 14A and B, 19A and B, 20-22, 23C and 48), had an AED ^ q of 0.025 mg / kg as a ^ -adrenergic blocking agent and produced a 50% reduction in perfusion pressure at a concentration of Thus, this compound is an equally potent $ -adrenergic blocking agent as propranolol and about 8 times more potent than papaverine as a vasodilator.

The subjective nature of the test data set out in GB 1 321 701 precludes an extrapolation of the above data to a general comparison of the compounds referred to in the application with the compounds specified therein. Nevertheless, it is possible to make an indirect comparison of the preferred compound prepared according to claim 2 with a few compounds from Table III of the GB patent, which, although their overall chemical structure is rather remote from it, have certain individual substituents in common with it. This applies to compound # 146, the only designated N- (1-methyl-3-phenylpropyl) amino compound, compound # 149, a 4-methylthio-3-methoxy-substituted compound in the phenyl group (the only one containing an oxygen substituent in the ring), and compound # 155, a 4-methylsulfonyl-substituted compound in the phenyl group (the only one containing an oxidized sulfur atom). These three compounds are all considered to be less active than propranolol and papaverine, and are therefore also all less active than the compounds of claim 2 7 146386 in the present application.

Since all the compounds encompassed by formula I of claim 1 are closely related to the compound of claim 2 and have been shown to have the same useful biological activities as this one, they should be expected to be more active than the compounds known from GB U.S. Patent No. 1,321,701.

In carrying out the process of the invention, the compounds of formula I are prepared by reducing the amino alkylphenyl ketones of formula II with a suitable reducing agent in a suitable solvent such as e.g. sodium borohydride or lithium borohydride in water or a lower alkanol, lithium aluminum hydride in ether, tetrahydrofuran or dioxane, diborane in tetrahydrofuran or diglym and aluminum sopropic oxide in 2-propanol, or by hydrogenation in the presence of a precious metal catalyst such as palladium or platinum.

When the amine alkylphenyl ketone contains a carboxylic ester group (Formula II wherein Y is alkanoyl of 1-6 carbon atoms) and it is desired to retain the ester group of the reducing product (Formula I, wherein Y is alkanoyl of 1-6 carbon atoms), the use of reducing agents leading to reduction of carboxylic ester groups, of course, is avoided. Therefore, the reduction in such cases is preferably carried out with an alkali metal borohydride or by catalytic hydrogenation, which reducing agents lead to selective reduction of the keto group. If, as a final product, the free phenol (formula I wherein Y is hydrogen) is desired, the above reduction may be followed by hydrolysis of the ester group, or alternatively, the esterified aminoalkylphenyl ketone (formula II wherein Y is alkanoyl of 1-6 carbon atoms) may be reduced with a reducing agent capable of reducing both keto and carboxylester groups, e.g. lithium aluminum hydride.

The borohydride reduction method is conveniently carried out by treating the aminoalkylphenyl ketone with sodium borohydride in methanol at about -10 to about 65 ° C for from about 15 minutes to about 2.5 hours or until the reduction is in δ 146386. substantially complete, as indicated by thin layer chromatography.

If the starting material contains an ester group (Formula II wherein Y is alkanoyl of 1-6 carbon atoms or benzoyl) and it is desired to retain it in the final product, the reduction mixture is quenched with acid and the esterified benzene methanol (Formula I wherein Y is alkanoyl with 1 -6 carbon atoms or benzoyl) are isolated by conventional means. On the other hand, if the free phenol (formula I wherein Y is hydrogen) is desired, the reaction mixture is treated with an equivalent sodium or potassium hydroxide in water and stirred at from about 20 to about 65 ° C for about 30 minutes to about 15 hours. The resulting phenol is isolated by conventional means.

The catalytic hydrogenation process is conveniently carried out in a suitable solvent, e.g. Ν, Ν-Dimethylformamide, at 20-50 ° C under a hydrogen pressure of 137 - 345 kPa in the presence of a precious metal catalyst such as palladium. Hydrogenation is continued until the theoretical amount of hydrogen is absorbed.

After removal of the catalyst, the reduction product is isolated in conventional manner.

Although the 3- (alkylsulfinyl) benzene methanols (formula I wherein Q is alkylsulfinyl of 1-4 carbon atoms) can be obtained by reducing the corresponding ketones (formula II, wherein Q is alkylsulfinyl of 1-4 carbon atoms) according to the above procedures, it is preferred generally preparing the sulfinyl compounds by oxidation of the corresponding 3- (alkylthio) benzene methanols (Formula I wherein Q is alkylthio of 1-4 carbon atoms) with a suitable oxidizing agent such as a peracid, hydrogen peroxide or sodium metaperiodate.

The oxidation is preferably carried out by treating the 3- (alkylthio) benzene methanol with commercial 50% peracetic acid in methanol at from about -10 to about 10 ° C for about 15 minutes to about 1.5 hours, or until the oxidation is substantially completed as indicated by thin layer chromatography.

Alternatively, the oxidation is produced with 30% hydrogen peroxide in methanol at from about 20 to about 65 ° C for 24-72 hours or until the oxidation is substantially complete as indicated by thin layer chromatography. The oxidation product is isolated by conventional methods.

The aminoalkylphenol ketones of formula II above can be obtained by reacting a halogen ketone of formula V with an excess of an arylalkylamine of formula VI in a suitable solvent such as acetonitrile, dimethylsulfoxide or Ν, dim-dimethylformamide, at from about -65 to about 25 ° C for 1-4 hours, or until the reaction is substantially complete as indicated by thin layer chromatography.

In the cases where Y of formula V is alkanoyl of 1-6 carbon atoms, the reaction with an arylalkylamine may result in partial cleavage of the ester group, or the ester of formula II, i. wherein Y is as defined above can be hydrolyzed to the free phenol in a separate step. If desired, the partially deacylated or hydrolyzed product can be re-esterified according to known procedures, e.g. with an acyl halide in the presence of a strong acid such as trichloroacetic acid. Similarly, a free phenol of formula I or III can be converted to the corresponding ester by such esterification.

Although the 3- (alkylsulfinyl) phenyl ketones (formula II, wherein Q is alkylsulfinyl of 1-4 carbon atoms) can be obtained by reacting a halogen ketone of formula V, wherein Q is alkylsulfinyl of 1-4 carbon atoms, with a suitable arylalkylamine of formula VI , it is generally preferred to prepare the 3- (alkylsulfinyl) phenyl ketones of formula II by oxidation of the corresponding sulfides (formula II, wherein Q is alkylthio of 1-4 carbon atoms) as described above in the preparation of 3- (alkylsulfinyl) benzene. the methanols of formula I wherein Q is alkylsulfinyl of 1-4 carbon atoms.

The arylalkylamines of formula VI are generally known or, if specifically new, can be prepared according to the procedures described for the preparation of the known compounds.

Thus, e.g. tertiary carbinamines, i.e. arylethylcylamines of formula VI, wherein both R and R are alkyl of 1-4 carbon atoms, are prepared from the corresponding generally known tertiary phenols via the well-known Ritter reaction [Organic Reactions 17 »213 (1969)] U6386 followed by hydrolysis of the resulting tertiary carbinamides.

7 2

Arylalkylamines of formula VI wherein one or or R and R are hydrogen may be prepared by reacting an aldehyde or ketone of appropriate carbon content with ammonia or an ammonia derivative according to the procedures described in Organic Reactions 4, 1? 4 ( 1948) and Organic Reactions 301 (1949).

The halogen ketones of formula V are prepared by halogenating the appropriate phenyl ketone of the formula y! R Λ jj Y0 \ / ^ CH2R1

WE YOU

wherein R 1 and Q are as defined in the preamble of claim 1 and Y is alkanoyl of 1-6 carbon atoms, with chlorine or bromine.

The reaction is conveniently carried out by treating the ketone of formula VII in an inert solvent, such as chloroform, with bromine at about 25 ° C, optionally in the presence of an inorganic base, e.g. calcium carbonate. The reaction usually has a start-up period, and in some cases it may be advantageous to start the reaction by subjecting the mixture to ultraviolet radiation until the bromination has begun as shown by decolorization and accompanying evolution of the hydrogen bromide. If desired, the Y substituent in the resulting halogen ketone can be removed according to well known procedures, e.g. ester hydrolysis when Y is alkanoyl of 1-6 carbon atoms.

The corresponding iodo ketones (formula V, wherein X is iodo) can be prepared by reacting the chloro or bromo ketones with sodium or potassium iodide in acetone under the conditions of the well-known Finkelstein reaction.

Thus, e.g. The 3- (alkylthio) phenyl ketones of formula VII wherein Q is alkylthio of 1-4 carbon atoms and Y is alkanoyl of 1-6 carbon atoms by alkylation of the 3-mercapto-4-hydroxyphenyl ketones (formula VII, wherein Q is mercapto) and Y is hydrogen) with a suitable alkyl halide having 1-4 carbon atoms in a suitable solvent, such as a lower alkanol, in the presence of an acid binder, e.g. an alkali metal carbonate, followed by esterification of the resulting 3- (alkylthio) -4-hydroxyphenyl ketones (Formula VII, wherein Q is alkylthio of 1-4 carbon atoms and Y is hydrogen) with a suitable acylating agent such as an alkanoyl halide or anhydride in an inert solvent such as methylene chloride, chloroform, benzene or toluene, in the presence of an acid binder such as triethylamine or pyridine. The 3-Mercapto-4-hydroxyphenyl ketones, in turn, are prepared by chlorosulfonation of the commonly known 4-hydroxyphenyl ketones of formula VII, wherein Q and Y are hydrogen, with excess chlorosulfonic acid at from about 0 to about 25 ° 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- (alkyl thio) phenyl ketones of formula VII wherein Q is alkylthio of 1-4 carbon atoms and Y is alkanoyl of 1-6 carbon atoms can be prepared by alkylating the commonly known o- (alkylthio) phenols with a suitable acyl halide (for example, R 1 H 2 COCl) under Friedel-Crafts conditions followed by esterification of the resulting 3- (alkylthio) -4-hydroxy-phenyl ketones as described above.

It will be appreciated that although the 3- (alkylsulfinyl) phenyl ketones of formula VII can be prepared by oxidation of the corresponding sulfides (formula VII wherein Q is alkylthio of 1-4 carbon atoms), it is generally preferred to use the latter as starting material and that perform any desired oxidation of the sulfide to sulfoxide at a later stage of the synthesis as described above.

Due to the presence of the basic amino group, the free base forms of the final products of formula I and also of the intermediates of formula II react with organic or inorganic acids to form acid addition salts. The compounds of the process according to the invention are useful both in the free base form and in the form of acid addition salts, and both forms are within the scope of the invention. The acid addition salts are simply a more convenient form of use, and in practice the use of the salt form corresponds to the use of the base form.

The acid addition salts are prepared from any organic or inorganic acid. They are obtained in a conventional manner, e.g. either by direct mixing of the base with the acid or, if this is not appropriate, by dissolving the base and the acid separately. dissolve in water or an organic solvent and mix the two solutions or by dissolving both 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 give the acid addition salt as residue. The acid moieties or anions of these salt forms are themselves neither new nor critical and can therefore be any acid anion or any acid-like substance capable of forming salt with the base.

Representative acids to form acid addition salts include formic acid, acetic acid, isobutyric acid, α-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinic acid, tannic acid, glutamic acid, tartaric acid, tartaric acid, dibenzoylacetic acid, , glycolic acid, gluconic acid, sugar acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, quinic acid, picric acid, picric acid, picric acid , barbituric acid, cyclohexylsulfamic acid, isethionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1,4-naphthalene disulphonic acid, butylarsonic acid, methane phosphonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid glutaric acid, phosphoric acid and arsenic acid.

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All the acid addition salts are useful as sources of the free base form by reaction with an inorganic base. Thus, it will be appreciated that if one or more of the properties, such as solubility, crystallinity, molecular weight, physical appearance, toxicity or the like, of a given base or an acid addition salt thereof render it unsuitable for the present purpose, it can easily be converted into a second, more suitable form according to procedures well known in the art.

When the compounds prepared by the process of the invention are to be used for pharmaceutical purposes, the acids used to prepare the acid addition salts preferably include those which, in combination with the free base, provide pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless to the animal organism in medical doses of the salts so that the inherent beneficial properties of the free base are not destroyed by the side effects attributable to the anions.

Suitable pharmaceutically 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 and phosphoric acid.

Obviously, the compounds of formula I and the intermediates of formula II wherein Y is hydrogen are amphoteric in that they have both acidic phenol and basic amino groups and thus form salts with both acids and bases.

Due to the presence of at least one οσ as many as four asymmetric centers in the compounds of formula I prepared by the process of the invention (i.e., the carbinol carbon atom, the carbon atom to which R 3 with 1-4 carbon atoms, the carbon atom to which R and Rr are attached when different, and the sulfur atom when Q is alkylsulfinyl of 1-4 carbon atoms), said compounds may exist in up to 16 stereochemically isomeric forms , all of which, either individually or as mixtures of two or more, are considered to be within the scope of the invention. If desired, the isolation or fabrication of a particular stereochemical form or a mixture of two or more stereochemical forms can be carried out using general principles known in the art.

In the preparation of either a particular stereoisomer or a specific mixture of two or more stereoisomers, it is advantageous to use intermediates of a fixed stereochemical configuration, thereby limiting the number of stereoisomeric forms present in the final product, thus simplifying the isolation of the desired components. Accordingly, an arylalkylamine of formula VI containing an asymmetric center (i.e., the carbon atom bearing various substituents R and R) is separated prior to the reaction with a halogen ketone of formula IV into its (+) and (-) optical antipodes according to conventional techniques. and using conventional separation agents such as optically active tartaric acid, 0,0-dibenzoyltartaric acid, mandelic acid and malic acid. Then, as desired, either (+) or (-) - (arylalkyl) amine can be reacted with a halogen ketone according to the previously described procedure to form an aminoalkylphenyl ketone of formula II having a fixed stereochemical configuration at the carbon atom bearing substituents R2 and R3 .

When the halogen ketone also contains an asymmetric center (Formula V wherein R R is alkyl of 1-4 carbon atoms and Q is alkylthio or alkylsulfonyl of 1-4 carbon atoms) gives reaction with either (+) - or (-) - ( the arylalkyl) amine a pair of diastereoisomeric aminoalkylphenyl ketones of formula II (R 1 is alkyl of 1-4 carbon atoms, G is alkylthio or alkylsulfonyl of 1-4 carbon atoms) which can be separated by conventional methods such as e.g. fractional crystallization of a suitable acid addition salt.

If the halogen ketone contains no asymmetric center (formula I wherein R 1 is hydrogen and Q is alkylthio or alkylsulfonyl of 1-4 carbon atoms), reaction with either the (+) - or (-) - (arylalkyl) amine will of course directly give a single (+) - 146386 or (-) stereoisomer of the aminoalkylphenyl ketone of formula II (R 1 is hydrogen and Q is alkylthio or alkylsulfonyl).

1-4 carbon atoms).

Reduction of the stereochemically determined aminoalkylphenyl ketone as described above creates a new asymmetric center (i.e., the carbinol carbon atom) and therefore yields a pair of diastereoisomeric 3- (alkylthio or alkylsulfonyl) benzene methanols of formula I.

If desired, the diastereoisomers can be separated by known methods, e.g. by fractional crystallization of the acid addition salt with an optically active acid such as (+) or (-) mandelic acid, tartaric acid, 0,0-dibenzoyltartaric acid and malic acid, or by converting the diastereoisomeric mixture into a suitable ester derivative (i.e.

The formula I is alkanoyl having 1-6 carbon atoms, benzoyl, benzenesulfonyl or p-toluenesulfonyl) e.g. the acetate, benzoate or p-toluenesulfonate, and separation of the esters by chromatography or by fractional crystallization of a suitable acid addition salt thereof.

Each of the individual diastereoisomers of the 3- (alkylthio) benzene methanol (Formula I wherein Q is alkylthio of 1-4 carbon atoms) as prepared above can be oxidized as described above, thereby again creating a new center of asymmetry (i.e., the sulfur atom ), thereby forming a pair of diastereoisomeric sulfoxides (Formula I wherein Q is alkyl sulfoxide of 1-4 carbon atoms) which can also be separated according to the conventional procedures described above.

Alternatively, the pair of diastereoisomeric 3- (alkylthio) benzene methanols can be directly oxidized to form a mixture of four diastereoisomeric sulfoxides which, if desired, can also be separated according to the procedures described above, e.g. by fractional crystallization of a suitable acid addition salt, such as the hydrochloride or cyclohexyl sulfamate.

The compounds of formula I prepared by the process of the invention exhibit useful antihypertensive, vasodilatory and β-adrenergic blocking activity. Of particular advantage is the combination in a single compound of vasodilating and β-adrenergic blocking activity, thereby effectively reducing or eliminating the reflex tachycardia associated with the reduction in blood pressure by vasodilatation by adrenergic blockade. The compounds are therefore effective in lowering blood pressure without causing undesirable tachycardic effects.

However, it should be noted that although both vasodilating and β-adrenergic blocking activity are present in the same compound, the timing of onset of these effects appears to be somewhat different, with vasodilatation usually occurring prior to β-adrenergic blockade. Of course, this can give rise to a moderate transient increase in heart rate, which can be observed on the first day or two of repeated drug intake. Thereafter, however, β-adrenergic blockade will reach full effect and subsequent continuous drug intake causes sustained blood pressure lowering without any detectable increase in heart rate. Furthermore, in contrast to the antihypertensive reaction which is directly dose dependent, the increase in heart rate observed at the lower doses is not significantly increased in magnitude or duration at higher doses. Therefore, it is possible to raise the dosage level to achieve a further reduction in blood pressure without producing a corresponding increase in heart rate.

A preferred compound which can be prepared by the process of the invention is 4-hydroxy-α- / {[3- (4-methoxyphenyl) -1-methylpropyl] amino} -methyl> -3- (methylsulfinyl) benzene methanol

η J O Z

(Formula I, wherein R, R and Y are hydrogen, is methyl, n is 2, Ar is 4-methoxyphenyl, and Q is methylsulfinyl), which has high antihypertensive activity and a particularly effective distribution of vasodilating and β-adrenergic blocking activity. and therefore is particularly effective as an antihypertensive agent without any unwanted tachycardic side effects.

The compound described above contains three centers of asymmetry (i.e., the carbon atom bearing the methyl group, the carbinol carbon atom and the sulfur atom) and can therefore exist as a mixture of up to eight stereoisomers. Particularly preferred among these are the four diastereoisomers derived from (+) - 4 * -hydroxy-2- <[3- (4-methoxyphenyl) -1-methylpropyl] amino ', -3' - (methylthio) -acetophenone ( formula II wherein R, R and Y are hydrogen, R 1 is methyl, n is 2, Ar is 4-methoxyphenyl, and Q is methylthio) by reduction of the carbonyl group followed by oxidation of the methyl thio group. These isomers individually or as mixtures of two or more isomers exhibit potent antihypertensive activity without any undesirable tachycardic side effects. Although each of the four diastereoisomers can be separated from the mixture as described above, this is generally unnecessary and it is therefore economically advantageous to use the mixture prepared.

The molecular structures of the compounds prepared by the process of the invention were ascribed to their method of preparation and examination of their IR and NMR spectra and confirmed by the agreement between calculated and found values for elemental analyzes of representative examples.

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

The process according to the invention is further illustrated by the following examples. Unless otherwise stated, optical turns were determined on a 2% solution of the compound in methanol.

PREPARATION 1 A. To 100 g (0.085 mole) of chlorosulfonic acid at 5 ° C, 20 g (0.15 mole) of p-hydroxyacetophenone was added over 25 minutes. The temperature was allowed to gradually rise to 22 ° C while the reaction mixture was stirred overnight. The temperature was then raised to 55-60 ° C and stirring was continued for an additional hour. The reaction mixture was quenched in ice water and the precipitated solid was collected and washed with water. The product was dissolved in ethyl acetate and the resulting solution dried and evaporated to dryness. The residue was recrystallized from benzene to give 12.5 g of 4'-hydroxy-3 '- (chlorosulfonyl) aceto-phenone, m.p. 138-142 ° C. The filtrate gave a different amount of 5.0 g, m.p. 124-136 ° C.

B. Hydrogen chloride was bubbled into a stirred mixture of 105 g (0.46 mole) of stannous chloride dihydrate and 400 ml of glacial acetic acid until an almost clear solution was obtained. To this solution was added portionwise over 20 minutes 18 g (0.077 mole) of crude 4, -hydroxy-3, - (chlorosulfonyl) acetophenone while maintaining the temperature at 25-30 ° C. After the addition was complete, stirring was continued for another 0.5 hours. The reaction mixture was then poured into 400 ml of 12N hydrochloric acid, diluted with 800 ml of water and extracted with chloroform. The extracts were washed with saturated aqueous sodium chloride solution and evaporated to dryness. The residue was recrystallized from benzene to give 4 g of 4-hydroxy-3'-mercaptoaceto-phenone, m.p. 117-120 ° C.

C. A mixture of 1.0 g (0.006 mol) of 4'-hydroxy-3 * mercapto-acetophenone, 0.9 g (0.0063 mol) of methyl iodide, 0.83 g (0.006 mol) of potassium carbonate and 12 ml of acetone was stirred for 2.5 hours at room temperature. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in chloroform and the resulting solution was washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in hot benzene and the solution was filtered through a 6.3 mm layer of silica gel to remove a colored impurity. Evaporation of the filtrate gave 0.9 g of 4'-hydroxy-3 '- (methylthio) aceto-phenone, m.p. 117-120 ° C.

D. Alternatively, a stirred solution of 61.4 g (0.435 mole) of o- (methylthio) phenol and 35 g (0.45 mole) of acetyl chloride in 170 ml of nitrobenzene was added 80 g (0.60 mole) of aluminum chloride portionwise. within 20 minutes. The reaction mixture was stirred overnight at room temperature and then for 1 hour at 65 ° C.

Then, the reaction mixture was cooled, diluted with ice and water and extracted with methylene chloride. The organic extracts were evaporated in vacuo and the residue diluted with ether and allowed to stand for 2 days in a refrigerator. The precipitated product was collected and dried to give 27 g of 4'-hydroxy-3 '- (methylthio) acetophenone.

E. To a cooled stirred solution of 24.5 g (0.134 mol) of 4'-hydroxy-3 '- (methylthio) acetophenone and 21 g (0.21 mol) of triethylamine in 400 ml of methylene chloride was added dropwise over 30 min. 16.4 g (0.21 mol) of acetyl chloride. After stirring overnight at room temperature, the reaction mixture was washed with water, dried over anhydrous sodium sulfate and concentrated to a small volume. The concentrate was diluted with ether and cooled in an ice bath. The resulting precipitate was collected to give 23.5 g of 4'-hydroxy-5 '- (methylthio) aceto-phenone-41-acetate.

F. To a stirred mixture of 23.2 g (0.108 mol) of 4'-hydroxy-3 '- (methylthio) acetophenone-4'-acetate and 9 g of calcium carbonate in 300 ml of chloroform was added dropwise over a period of 2 hours. 6 ml (0.108 mol) of bromine in 30 ml of chloroform. The reaction mixture was filtered and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and evaporated to dryness. The residue was dissolved in ether and the ether solution diluted with cyclohexane and cooled in ice. The resulting precipitate was collected and dried to give 26.5 g of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone-4'-acetate.

G. To a stirred solution of 16.5 g (0.10 mol) of 2- (4-methoxy-phenyl) -1-methylethylamine and 5 g (0.051 mol) of triethylamine in 40 ml of Ν, Ν-dimethylformamide at -65 ° C was added dropwise over 2 hours 15.5 g (0.051 mole) of 2-bromo-4'-hydroxy-3 '- (nitylthio) acetophenone-4'-acetate in 40 ml of Ν, Ν-dimethylformamide. After the addition was complete, stirring was continued at -65 ° C for an additional 1 hour. The reaction mixture was then acidified. 10 ml of 12N hydrochloric acid and diluted with 100 ml of water. After shaking the aqueous mixture with 200 ml of a 2: 1 mixture of ether and methylene chloride, the product began to precipitate from the aqueous phase. The layers were separated and the aqueous portion was cooled in ice. The resulting precipitate was collected and dried for 3 hours over phosphorus pentoxide in a vacuum oven at 65 ° C to give 12.1 g of 4 * -hydroxy-2-f [2- (4-methoxyphenyl) -1-methylethyl] amino} 3 '- (· methyl thio) acetophenone-acetate * 4-hydro-chloride.

EXAMPLE 1

A stirred solution of 12.5 g (0.029 mol) of 4 * -hydroxy-2- {[2- (4-methoxyphenyl) -1-methylethyl] amino} -3 '- (methylthio) acetophenone-4 * acetate hydrochloride in 200 ml of methanol was cooled in an ice-acetone bath and treated portionwise over 15 minutes with 0.9 g of sodium borohydride. After the addition was complete, stirring was continued for another 20 minutes. The reaction mixture was then brought to pH 7 with glacial acetic acid and evaporated to dryness. The residue was diluted with ether and washed thoroughly with saturated aqueous sodium hydrogen carbonate solution.

The ether solution was dried over anhydrous sodium sulfate and concentrated to a small volume. The concentrate was acidified with ethereal hydrogen chloride and cooled overnight in a refrigerator. The precipitated product was collected and recrystallized from methanol / isopropyl alcohol to give 2.1 g of 4-hydroxy-α- <β [2- (4-methoxyphenyl-1-methylethyl] amino} methyl> -3- (methylthio ) benzene methanol-4-acetate hydrochloride, m.p.

143-145 ° C.

In addition to the antihypertensive activity, this compound was also found to have β-adrenergic stimulating activity as shown. by its ability to block histamine-induced bronchoconstriction in the dog.

EXAMPLE 2

To a stirred suspension of 6.9 g (0.016 mol) of 4 'hydroxyl] 2- (4-methoxyphenyl) -1-methylethyl] amino} -3' - (methylthio) acetophenone-4 * acetate hydrochloride in 120 ml of methanol were added 400 mg of sodium borohydride. After 25 minutes, all the starting material had dissolved. The reaction mixture was treated with 10 ml of water and stirred overnight at room temperature. Then a solution of 900 mg of potassium hydroxide in 10 ml of water was added and the mixture was heated at reflux for 5 hours.

The resulting solution was concentrated to half the volume and the concentrate slightly acidified with 12N hydrochloric acid and evaporated to dryness. The residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate, acidified with glacial acetic acid and concentrated until crystallization began. The product was collected, triturated with chloroform and finally recrystallized from chloroform / methanol to give 3.9 g of 4-hydroxy-α- <[[2- (4-methoxyphenyl) -1-methylethyl] amino} methyl> -3 - (methylthio) benzene methanol acetate m.p. 163-165 ° C.

EXAMPLE 3

A solution containing 1.5 ml of 30% hydrogen peroxide and the free base liberated from 9 g of 4-hydroxy-α- [2- (4-methoxyphenyl) -1-methylethyl] amino} methyl> -3- (methylthio) benzene methanol -4-acetate hydrochloride in 150 ml of methanol was stirred for 2 days at room temperature and then for 1.5 hours at reflux.

The reaction mixture was then evaporated to dryness. The residue was dissolved in water and the solution was filtered to remove insoluble impurities. The filtrate was acidified with 12N hydrochloric acid and evaporated to dryness. The residue was triturated with ether / isopropyl acetate at -65 ° C. The resulting amorphous solid was dissolved in hot water, filtered to remove insoluble impurities, and the filtrate evaporated to dryness. The residue was triturated with ether and cyclohexane, and the resulting solid was collected and dried over phosphorus pentoxide for 6 hours at 85 ° C to give 4.6 g of 4-hydroxy-α- <'{[2- (4- methoxyphenyl) -1-methylethyl] amino} methyl> -3- (methylsulfinyl) benzene-methanol hydrochloride as an amorphous light brown solid, m.p.

115 ° C.

In addition to its antihypertensive activity, this compound was also found to have β-adrenergic stimulating activity, as demonstrated by its ability to "block histamine-induced" bronchoconstriction in the dog.

PREPARATION 2 A. A solution of 65 g of p-ethylanisole and 92 g of methanesulfonic anhydride in 300 ml of symtetrachloroethane was heated under reflux for 17.5 hours. After washing with warm water, the reaction mixture was evaporated to dryness in vacuo leaving 20 g of darkness. oil, which was combined with the product from two previous experiments and distilled under reduced pressure, the fraction boiling at 90-120 ° C / 0.5 Hg was collected and distilled again through a short Vigreux column. 45-65 ° C / 0.5 mmHg was discarded and the remainder of the flask was distilled again The impurities boiling at 175-187 ° C / 10 mmHg were discarded leaving 30 g of almost pure 4-ethyl -2- (methylsulfonyl) anisole.

B. A solution of 55 g (0.242 mol) of ammonium persulfate, 520 mg of silver nitrate and 26 g (0.121 mol) of 4-ethyl-2- (methylsulfonyl) anisole in 300 ml of water was stirred at 20 ° C. After one hour, the temperature had risen to 48 ° C and after 2.5 hours it had dropped to 30 ° C. The product was extracted with chloroform and after drying over anhydrous sodium sulfate the chloroform extracts were evaporated to dryness. The residue was adsorbed on a column of silica gel, deactivated with 20% by weight water. Impurities were washed out of the column with ether and the product eluted with hot methylene chloride to give 18 g of 4'-methoxy-3 * - (methylsulfonyl) aceto-phenone, m.p. 146-148 ° C.

C. To a solution of 14.5 g (0.063 mol) of 4'-methoxy-3 '- (methylsulfonyl) acetophenone in 200 ml of chloroform was added dropwise a solution of 10.2 g of bromine in 40 ml of chloroform. After a half hour start period, the bromine began to be consumed. After the addition was almost complete, the product began to precipitate. The reaction mixture was diluted with methylene chloride and the resulting solution washed successively with saturated aqueous sodium hydrogen carbonate and water and evaporated to dryness. Recrystallization of the residue from methylene chloride / carbon tetrachloride gave 17.9 g of 2-bromo-4-methoxy-3 '- (methylsulfonyl) acetophenone, m.p. 168-170 ° C.

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

E. To a stirred solution of 10 g (0.06 mol) of 2- (4-methoxyphenyl) -1-methylethylamine in 50 ml of N, N-dimethylformamide at -30 ° C (dry ice / carbon tetrachloride) was added dropwise a solution of 7 g (0.024 mol) of 2-bromo-4'-hydroxy-3,3- (methylsulfonyl) acetophenone in 20 ml of Ν, Ν-dimethylformamide. After the addition was complete, the reaction mixture was stirred for 2.75 hours at 0 ° C and then diluted with water and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, acidified with ethanolic hydrogen chloride and stored in a refrigerator overnight. The product which precipitated was collected and recrystallized from chloroform to give 3.7 g of 4'-hydroxy-2- to (4-methoxyphenyl) -1-methylethyl] amino] -3 '- (methylsulfonyl) -ac eto -phenon hydrochloride.

EXAMPLE 4

A solution of 3.7 g of 4'-hydroxy-2- [Z- (4-methoxyphenyl) -1-methyl-ethyl] amino} -3- (methylsulfonyl) -acetophenone hydrochloride in 100 ml of Ν, Ν-dimethylformamide was obtained. hydrogenated under a hydrogen initial pressure of 345 kPa in the presence of 1 g of 10% palladium-on-carbon hydrogenation catalyst. After 15 minutes, 1 molar equivalent of hydrogen had been absorbed. The catalyst was then removed by filtration and the filtrate evaporated to dryness. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate solution was dried over 24 U6386 anhydrous sodium sulfate and concentrated to 100 ml. The concentrate was acidified with glacial acetic acid, concentrated to about 70 ml and cooled. The resulting crystalline precipitate was collected to give 2.9 g of 4-hydroxy-α- [beta] 2- (4-methoxy-phenyl) -1-methylethyl] amino methyl-3- (methylsulfonyl) benzene-methanol acetate , m.p. 130-131 ° C.

PREPARATION 3

To a stirred solution of 24 g (0.135 mol) of 3- (4-methoxyphenyl) -1-methylpropylamine in 40 ml of Ν, Ν-dimethylformamide at -50 ° C was added dropwise over 15 minutes a solution of 15 g (0, 05 mole) 2- bromo-4, -hydroxy-3Γ- (methylthio) acetophenone-4, acetate in 35 ml of Ν, Ν-dimethylformamide. After the addition was complete, stirring was continued for an additional 1.25 hours. The reaction mixture was then treated with 4 ml of 12N hydrochloric acid, diluted with 100 ml of water. and extracted with ether / ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate, acidified with ethanolic hydrogen chloride and evaporated to dryness. The crude product containing both the 41-acetate and the 41-hydroxy compound was dissolved in a solution containing 10 ml of acetyl chloride in 120 ml of trifluoroacetic acid and stirred for 2 hours at room temperature. The solution was then evaporated to dryness and the residue partitioned between ether and water. The ether layer was dried over anhydrous sodium sulfate and acidified with ethanolic hydrogen chloride.

The resulting precipitate was collected and triturated with acetone / ether s to give 6.0 g of 4'-hydroxy-2- [[3- (4-methoxy-phenyl) -1-methylpropyl] amino] -3f - (methyl 'thi o) acetophenone-4' acetate hydrochloride, m.p. 160-165 ° C.

EXAMPLE 5

To a stirred mixture of 9.0 g (0.021 mol) of 4'-hydroxy-24-methoxyphenyl) -1-methylpropyl] amino J -3 '- (methylthio) ac etophenone-4'-acetate hydrochloride and 100 ml of methanol at between -5 and 0 ° C, 0.5 g (0.015 mol) of sodium borohydride was added portionwise. After stirring for an additional half hour, a solution containing 1.0 g of potassium hydroxide in 10 ml of water was added and the resulting mixture was stirred at room temperature under nitrogen overnight and then under reflux for half an hour. The pH was adjusted to 7 with glacial acetic acid and the resulting solution U6386 was concentrated to a small volume, diluted with saturated aqueous sodium hydrogen carbonate 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 separated product was collected and recrystallized from ethyl / ethanol to give 7 »2 g of 4-hydroxy-α- <£ [3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylthio) benzene methanol acetate, m.p. 132-134 ° C.

PREPARATION 4 A.

To a stirred solution of 100 g (0.55 mol) of 4'-hydroxy-3 '- (methyl-thio) acetophenone in 600 ml of pyridine at 15-18 ° C was added dropwise over an hour 68 ml (0.58 mole) benzoyl chloride. After the addition was complete, stirring was continued at room temperature for 1.5 hours. The reaction mixture was then quenched in 1.5 liters of ice-cold water. The solid which precipitated was collected by filtration, washed successively with water, cold 2-propanol and n-hexane, and dried to give 146 g of 4'-hydroxy-3 '- (methylthio) acetophenone-4'- benzoate, m.p. 126-131 ° C.

B.

To a stirred suspension of 145 g (0.51 mol) of 4'-hydroxy-3 '- (methyl thio) acetophenone-4' benzoate in 1200 ml of benzene at 20 ° C was added 15 ml of a solution of 85 g (0 , 53 moles) of bromine in 100 ml of benzene. The mixture was irradiated with ultraviolet light for about an hour to start the reaction. As the reaction began (as shown by decolorization), a slow stream of nitrogen was bubbled through the reaction mixture and the rest of the bromine solution was added over two hours while maintaining the temperature at 20-24 ° C. The reaction mixture was stirred for a further half hour and then cooled to 16 ° C. The solid which precipitated was collected by filtration, washed with water and n-hexane and dried to give 90 g of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone-4'-benzoate, mp. 127-129 ° C. The benzene solution gave an additional 21 g of product, m.p. 126-129 ° C.

C.

To a stirred solution of 36 g (0.2 mol) of 3- (4-methoxyphenyl) -1-methylpropylamine in 175 ml of Ν, Ν-dimethylformamide at -60 ° C was added over a hour a solution of 25 g (0.068 mole) 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone-4'-benzoate in 120 ml of N, N-dimethylformamide. After the addition was complete, stirring was continued at -60 ° C for an additional 20 minutes. The reaction mixture was then diluted with 200 ml of chloroform, treated with 20 ml of k5% hydrobromic acid and further diluted with 200 ml of cold water. The layers were separated and the aqueous layer was re-extracted with chloroform. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to about 100 ml. The concentrate was 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'-hydroxy-2- [3- (4-methoxyphenyl) -1-methylpropyl} amino 3 -3 - (methylthio) -acetophenone-4'-benzoate hydrobromide.

EXAMPLE 6

To a stirred mixture of 25 g (0.046 mol) of 4 * -hydroxy-2- [3- (4-methoxyphenyl) -1-methylpropyl} amino] -3 '- (methylthio) acetophenone-4'-benzoate hydrobromide and 160 ml of methanol at 0 ° C were added portionwise over a half hour of 1.4 g (0.037 mole) of sodium borohydride.

After stirring for a further 20 minutes, the reaction mixture was treated with a solution of 2.5 g of potassium hydroxide in 30 ml of water and heated under reflux for 40 minutes. The reaction mixture was concentrated in vacuo until a cloudy suspension formed. The suspension was brought to pH 3 with 6N hydrochloric acid and then basified with saturated aqueous sodium hydrogen carbonate solution. The remaining methanol was removed by evaporation in vacuo. The resulting suspension was diluted with 200 ml of ethyl acetate and the resulting two-phase mixture was allowed to stand overnight. The solid which was precipitated was collected, washed with water followed by n-pentane and recrystallized from 2-propanol to give 6 g of 4-hydroxy-α- [β- (4-methoxyphenyl) -1- methylpropyl] amino} -methyl> -3- (methylthio) benzenemethanol, m.p. 126-129 ° C.

The ethyl acetate layer in the filtrate was separated, washed successively with dilute aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The resulting solution was diluted with 120 ml of isopropyl acetate, treated with 3 ml of glacial acetic acid, seeded and cooled. The resulting precipitate was collected, washed with isopropyl acetate and dried at 65 ° C in vacuo to give 7 g of product as the acetate salt, m.p. 132-134 ° C.

EXAMPLE 7 Å. To a stirred solution of 3.5 g (0.0083 mole) of 4-hydroxy-α- [β (3- (4-methoxyphenyl) -1-methyl-propyl] amino} methyl} -3- (methyl thio) benzene methanol Acetate in 100 ml of methanol at -5 ° C was added dropwise over a half hour to a solution containing 630 mg (0.0083 mole) of commercial 40% peracetic acid in 10 ml of methanol. When the addition was complete, the reaction mixture was evaporated to dryness. The resulting oil was diluted with ethyl acetate and the rubber which separated was allowed to stand for 2 days under a mixture of ethyl acetate and ethanol, the resulting almost white amorphous solid being collected to give 3.2 g of 4-hydroxy-α-4β (3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylsulfinyl) benzene methanol acetate, which was softened at 95 ° C and melted at 100-105 ° C.

B. To a stirred solution of 50 g (0.119 mole) of 4-hydroxy-oxo [3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylthio) benzene methanol acetate in 500 ml methanol at 0 ° C was added dropwise over 70 minutes to 20.2 ml (0.119 mol) of commercial 40% peracetic acid. When the addition was complete, the reaction mixture was evaporated to dryness in vacuo. The residual oil was taken up in 50 ml of ethyl acetate and again evaporated to dryness in vacuo. The residual oil was dissolved in 150 ml of tetrahydrofuran, and the resulting clear solution was stirred and rendered slightly cloudy by gradual addition of ether. After inoculation, the mixture was stirred for 2 days at room temperature, after which a fine white solid had begun to precipitate. The mixture was treated dropwise with 50 ml of ether and stirred for 5 hours followed by dropwise addition of an additional 50 ml of ether and stirring for a further 4 hours. After stirring overnight in a refrigerator, the mixture was cooled to 0 ° C while 200 ml of ether was added dropwise over 3 hours. Stirring at 0 ° C was continued for an additional 3 hours. The precipitated product was then collected and redissolved in 1250 ml of tetrahydrofuran. The resulting solution was filtered to remove a small amount of insoluble material and concentrated to a volume of 250 ml. The concentrate was cooled in the refrigerator overnight. The resulting white crystalline precipitate was collected, washed with tetrahydrofuran and ether and dried to give 14.5 g of 4-hydroxy-α <β (3- (4-methoxyphenyl) -1-methylpropyl] amino]; methyl> -3- (methylsulfinyl) benzene methanol acetate, mp 131-133 ° C.

PREPARATION 5

To a stirred solution of 19 g (0.123 mol) of 3- (4-methoxyphenyl) -1-methylpropylamine in about 50 ml of Ν, Ν-dimethylformamide at -65 ° C was added dropwise a solution of 12 g (0.042 mol) of 2-bromo -4, -hydroxy-3, - (methylsulfonyl) acetophenone-4'-acetate in about 70 ml of Ν, Ν-dimethylformamide. After the addition was complete, stirring was 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 were cooled to -65 ° C and diluted with ether. The supernatant was decanted from the precipitated rubber, which was then dissolved in a minimal volume of chloroform and allowed to stand for 2 days in the refrigerator. The resulting 3 g of hydrobromide salt was dissolved in saturated aqueous sodium hydrogen solution and the resulting solution was extracted with n-butanol / ethyl acetate. The organic extracts were acidified with glacial acetic acid and evaporated to dryness to give 2.2 g of 4'-hydroxy-2- [beta] 3- (4-methoxyphenyl) -1-methylpropyl] amino] -3T- (methylsulfonyl ) acetophenone acetate as a yellow oil.

EXAMPLE 8.

A solution of 2.2 g of 4'-hydroxy-2- [[3- (4-methoxyphenyl) -1-methylpropyl] amino] -3 '- (methylsulfonyl) acetophenone acetate in 100 ml of Ν, Ν-dimethylformamide was hydrogenated hydrogen initial pressure of about 345 kPa in the presence of 0.5 g of 10% palladium-on-carbon hydrogenation catalyst. After 2 hours, a molecular equivalent of hydrogen had been absorbed. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was adsorbed on a column of silica gel which was eluted first with a 95: 5 mixture of ethyl acetate and methanol and finally with a 90:10 mixture of ethyl acetate and methanol to give 1.4 g crystalline product. After tearing off with acetone and filtration, 1.25 g of 4-hydroxy-oc- [[[3- (4-methoxyphenyl) -1-methylpropyl] amino] methyl] -3- (methylsulfonyl) benzene methanol acetate were obtained. mp. 151-153 * 0th

PREPARATION 6

To a stirred solution of 376 g (1.0 mole) of (-) - dibenzoyltartaric acid in a mixture of 5 liters of methanol and 550 ml of water at 42 ° C was added 179 g (1.0 mole) of (-) -3- (4). methoxyphenyl) -l-methylpropylamine. The mixture was stirred for 26 hours at 40 ° C and then for 20 hours at room temperature. The resulting precipitate was collected and dried to give an initial amount of 176.5 g of (-) - 3- (4-methoxyphenyl) -1-methylpropylamine - (-) - dibenzoyl tartrate m.p. 175-176 ° C (dec.), [V] + = -88.0 °. On cooling the filtrate to 0 ° C for 7 hours a second amount of 58.5 g, m.p. 167-171 ° C (dec.), [V The final mother liquids were set aside for use in Part B below. The first amount was recrystallized from 90% methanol to give 145.3 g mp. 179-180.5 ° C (Vjp'5 = -87> 5 ° · This salt was treated with aqueous sodium hydroxide solution and the released amine extracted in chloroform. The chloroform extracts were dried over anhydrous potassium carbonate and evaporated to dryness. The residual oil was dissolved. in 2-propanol and the resulting solution was acidified with 25 ml of 12N hydrochloric acid and evaporated to dryness The solid residue was dried, crystallized from 2-propanol and dried again to give 52.0 g (-) - 3 - (4-methoxyphenyl) -1-methylpropylamine hydrochloride, mp 126-129 ° C, [α] D = -6.0 ° (2% in water).

B. The mother liquors from the isolation of the (-) - 3- (4-methoxyphenyl) -1-methylpropylamine - (-) - dibenzoyl tartrate were concentrated to a volume of 500 ml and cooled to 0 ° C for 2 hours. The resulting precipitate was collected and dried to give 283 g of (+) - 3- (4-methoxyphenyl) methylpropylamine - (-) - dibenzoyl tartrate, m.p. 159-162 ° C (dec.). This salt was treated with aqueous sodium hydroxide solution and the released amine was extracted in chloroform. Evaporation of the chloroform left 80 g of oil which was then added to a solution of 168 g (+) - dibenzoyl tartaric acid in 18βο ml of 90% methanol. After stirring for 20 hours at room temperature, the precipitated salt was collected and dried to give 173.5 g (+) of 3- (4-methoxy-phenyl) -1-methylpropylamine (+) - dibenzoyl tartrate, m.p. 179-180 ° C (dec.), = 87.1 °. Recrystallization from 90% methanol gave 149 g, m.p. = + 90.3 ° · According to the procedure described in Part A, the amine was released from the (+) - dibenzoyl tartrate salt and converted to the hydrochloride to give 55.0 g (+ -3 - (4-methoxy-phenyl) -1-methylpropylamine hydrochloride, mp 127-130 ° C, [α] D = + 5.6 ° (2% in water). The RMR spectrum of this product in the presence of shifts The reagent tris- (trifluoromethyl) hydroxymethylene-α-camphorato europium (III), EU (TFC) ^ showed pollution with about 10-15% of the levo isomer.

C. (+) - 3- (4-methoxyphenyl) -1-methylpropylamine - (-) - dibenzoyl tartrate (8781 g) prepared according to Part B above, was recrystallized from aqueous methanol to give 7690 g, m.p. 163-165 ° C.

A 700 g sample was recrystallized twice from aqueous methanol to give 558 g of the salt which was then converted to the free amine and distilled under reduced pressure to give 180.5 g (+) - 3- (4). -methoxy-phenyl) -1-methylpropylamine, b.p. 88-100 ° C / 0.1 mmHg. The MRI spectrum of this product in the presence of the shift reagent Eu (TFC) + showed an optical purity> 97%.

D. Alternatively, (+) - 3- (4-methoxyphenyl) -1-methylpropylamine was prepared as follows:

A solution of 300 g (1.67 mole) of dl-3- (4-methoxyphenyl) -1-methylpropylamine in 2 liters of 95% ethanol was added in one portion to a stirred hot solution (40-45 ° C) of 250 g ( 1.67 mole) of d-tartaric acid in 2.6 l of water and 4.2 l of 95% ethanol. The clear solution was seeded at about 38 ° C and then allowed to cool to room temperature overnight with stirring. The crystallized solid was filtered off and pressed thoroughly with a rubber spatula; it was then washed twice with sufficiently ice-cold 8% aqueous ethanol to cover the cake and was thoroughly pressed dry. The product was dried at 60 ° C in vacuum for 5 hours to give 276 g of crude D-amine bitartrate, m.p. 181-182 ° C. Five recrystallizations from aqueous ethanol gave 125 g of the bitrate, m.p. 188-190 ° C. The optical purity of the released (+) - 3- (4-methoxyphenyl) -1-methylpropylamine was shown to be ^ 97%.

E. To a stirred solution of 35 »7 g (0.172 mol) incompletely separated (-) - 3- (4-methoxyphenyl) -1-methylpropylamine hydroxychloride, r <xlp = -6.0 ° (2% in water) Into 125 ml of Ν, dim-dimethylformamide was added 25 ml of triethylamine, which produced immediate precipitation of triethylamine hydrochloride. The mixture was stirred for 20 minutes and then cooled to -50 ° C. The remainder of the preparation was carried out according to a procedure similar to that of Preparation 3 but using 20 g (0.66 mol) of 2-bromo-4'-hydroxy-3- (methylthio) ace-tophenone-4'-acetate and 8 ml of acetyl chloride to give 15 g of incompletely separated (-) - 4'-hydroxy-2- [[3- (4-methoxyphenyl) -1-methylpropyl] amino] -31- (methylthio) acetophenone-41-acetate hydrochloride, m.p. 179-181 ° C, = -10.3 ° EXAMPLE .9

To a stirred solution of 12 g (0.027 mol) incompletely separated (-) - 4'-hydroxy-2- [beta [3- (4-methoxyphenyl) -1-methylpropyl] amino} -3 '- (methylthio) acetophenone -4'-acetate hydrochloride (mp 179-181 ° C, [α] D = -10.3 °) in 150 ml of methanol at 0 ° C was added 0.8 g (0.020 mol) of sodium borohydride in portions. After stirring for a further 15 minutes, a solution of 1.6 g of potassium hydroxide in 25 ml of water was added, where the resulting mixture was heated at reflux under nitrogen for 1/2 hour. The reaction mixture was concentrated to a small volume, acidified with 3N hydrochloric acid, then basified with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the ethyl acetate solution was evaporated to dryness, leaving 11 g of a pale yellow oil. This oil was dissolved in 200 ml of ethyl acetate and a 40 ml aliquot was adsorbed on a column of silica gel and the product eluted with 92: 8 ethyl acetate / methanol to give 1.7 g of an oil which was converted to the acetate salt to give 1.22 g of left-turn 4-hydroxy-α- <{[> (4-methoxyphenyl) -1-methylpropyl] amino 3 'methyl ^ -3- (methylthio) benzenemethanol acetate, m.p. 124-125 ° C, [α] D = -6.4.

EXAMPLE 10

Following the same procedure as that described in Example 7, but using 1.2 g (0.0028 mol) of left-turn 4-hydroxy-ct - <(β [3- (4-methoxyphenyl) -1-methylpropyl] amino}} methyl> - 3- (methylthio) benzene methanol acetate (mp 124-125 ° C, [α] D = -6.4 °) and 216 mg of commercial 40% peracetic acid, 0.9 g 4-hydroxy-α- [alpha] [3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylsulfinyl) benzene methanol acetate, mp 103-106 ° C, [a] | 5 = -3.0 °.

PREPARATION 7 A. According to the same procedure as that described in Preparation 6-E, but using 43 g (0.20 mole) of incompletely separated PC (+) - 3- (4-methoxyphenyl) -1-methylpropylamine- hydrochloride, [α] D = + 5.6 ° (2% in water) and 23 g (0.077 mol) of 2-bromo-4, hydroxy-3, ~ (methylthio) acetophenone-4'-acetate were obtained 17.1 g incompletely separated (+) - 41-hydroxy-2- [3- (4-methoxyphenyl) -1-methylpropyl] amino3 · -3 '- (methylthio) acetophenone-41-acetate hydrochloride, m.p. 178-180 ° C, [α] D = + 10.2 °.

B. Following the same procedure as above, but acidifying the reaction mixture with 48% hydrobromic acid instead of 12N hydrochloric acid and omitting the gene acetylation step, after recrystallization twice from chloroform / isopropyl acetate and once from chloroform / acetone, obtained incompletely separated (+) - 4 * -hydroxy-2- {[3- (4-methoxyphenyl) -1-methylpropyl] -amino3 · -3 '- (methylthio) acetophenone-4'-acetate hydrobromide, m.p. 182-183 ° C, [.alpha.] + 9.0 °.

EXAMPLE 11 A. Following the same procedure as that described in Example 9, but using 17.1 g (0.039 mol) (+) - 4'-hydroxy-2 - {[3- (4-methoxyphenyl) - 1-methylpropyl] amino -3 '- (methylthio) -acetophenone-4'-acetate hydrochloride (mp 178-180 ° C, [α] D = + 10.2 °), 1.0 g (0.025 mol) sodium borohydride and 2.0 g of potassium hydroxide, 15 g of 4-hydroxy-α- <{[2- (4-methoxyphenyl) -1-methylpropyl] amino3 'methyl> -3- (methylthio) benzene methanol were obtained as a right-turn pair of slides stereoisomeric benzene methanol. A sample of 3.0 g of 33 146386 was dissolved in isopropyl acetate and the resulting solution acidified with glacial acetic acid. The product was allowed to crystallize slowly over 2 days to give 2.75 g of crystalline acetate salt, m.p. 124-126 ° C, [α] D = + 7.7 °.

B. When the same procedure as the one above was performed using (+) - 4'-hydroxy-2- - (4-methoxyphenyl) -1-methylpropyl] amino} -3 '- (methylthio) acetophenone-4'- acetate hydrobromide m.p. 182-183 ° C, [α] β + 9.0 °, right-turning 4-hydroxy-α-β [3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- ( methylthio) benzene methanol acetate, m.p. 128-129.5 ° C, [cc] jp = + 5.6 °.

C. Following the same procedure as that described in Example 6, but using 40 g (0.0758 mol) of optically pure (+) - 4 · - hydroxy-2- [[3- (4-methoxyphenyl) - 1-methylpropyl] amino} -3 '- (methylthio) acetophenone-4'-benzoate hydrobromide (m.p. 171-175 ° C, [α] d = = 11.8 °) prepared according to Preparation 8 below, 1 , 5 g of sodium borohydride and 4.5 g of potassium hydroxide, 25.1 g of 4-hydroxy-α - [α] [3- (4-methoxyphenyl) -1-methylpropyl] amino] methyl] - (methylthio) benzene methanol acetate, m.p. 125-127 ° C, (oQ-jp = + 7.3 °, as a right-turn pair of stereoisomeric benzene methanols.

Another trial of the same kind yielded a product with m.p. 129-130 ° C, [et] g5 = + 7.1 °. The hydrochloride had m.p. 153-155 ° C.

The pair of diastereoisomeric benzene methanol in this example corresponds to the products of Examples 3C and 18.

EXAMPLE 12 A. Following the same procedure as that described in Example 7, but using 2.5 g (0.0049 mole) of right-turn 4-hydroxy-α-β ["3" (4-methoxyphenyl) - 1-methylpropyl] aminoimethyl; - 3- (methylthio) benzene methanol acetate, (mp 124-126 ° C, [α] D = + 7.7 °) and 375 mg of commercial 40% peracetic acid were obtained 2.0 g of 4-hydroxy-oc - [α] [3- (4-methoxyphenyl) -1-methylpropyl] amino] methyl> 3- (methylsulfinyl) benzene methanol acetate as an amorphous yellow powder [α] β = +4, 2 ° containing a mixture of 4 diastereoisomeric sulfoxides In addition to its antihypertensive activity, this product was found to be as active as procaine as local anesthetic when tested according to the method described by Bulbring and Wadja, J.Pharm. Exp Therap 85, 78 (1945).

B. When the above oxidation was carried out on the right-turn 4-hydroxy-α- [α] β- (4-methoxyphenyl) -1-methylpropyl] -amino-methyl> -3- (methylthio) benzene methanol acetate prepared according to the procedure of Example 11c had the product m.p. 103-110 ° C and L <£ J D = -1.1 ° and consisted of a mixture of 4 diastereoisomeric sulfoxides.

C. A Sample of 4-Hydroxy-oc-β (3 - [(4-methoxyphenyl) -1-methylpropylamino] methyl] -3- (methylsulfinyl) benzene methanol acetate prepared by the same procedure as described in Part B above, by a conventional procedure was converted to the corresponding phosphate, mp 136-153 ° C = 0.0 ° C.

D. A Sample of 4-Hydroxy-Oc - <3 [3- (4-Methoxyphenyl) -1-methyl-propyl] amino] methyl ^ -3- (methylsulfinyl) benzene methanol acetate, prepared by the same procedure as that described in Part B above, by a conventional procedure, the corresponding methanesulfonate, m.p. 142-148 ° C, [α] D = + 5.0 °.

É. A sample of 4-hydroxy-α - η [3- (4-methoxyphenyl) -1-methylpropyl] amino | methyl / -3- (methyl sulfinyl) benzene methanol-ac etate, prepared by the same procedure as that described in Part B above, was converted to the corresponding hydrochloride by a conventional procedure, m.p. Alternatively, the hydrochloride salt was prepared directly as follows: 172-175 ° C.

To a stirred solution containing 844 g (2 moles) of 4-hydroxy-α - η [3- (4-methoxyphenyl) -1-methylpropyl] amino] methyl) -3- (methylthio) benzene methanol acetate in 7 L methanol at 0 ° C was added in 25 ml portions over about 40 minutes 308 ml of 40% commercial peracetic acid. Stirring was continued at 0-3 ° C for a further 45 minutes. The reaction mixture was then evaporated under reduced pressure while the temperature was kept below 35 ° C. The residue was diluted with 1 liter of 2-propanol and the solution evaporated to dryness in vacuo. This was repeated again and then the residue was dissolved in 6 l of 2-propanol and the resulting solution treated with a solution of 2.14 moles of hydrogen chloride in 2-propanol. The resulting pale yellow solution was cooled in ice. The precipitated product was collected, washed with 2-propanol / ether and dried to give 705g of 4-hydroxy-α- [α] 3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl -> - 3- (methylsulfinyl)

pc J

benzene methanol hydrochloride, £ aj ^ = -1.6.

The four diastereoisomeric sulfoxides contained in the salts prepared under B - F above are obtained separately as hydrochlorides in Examples 20, 21, 22 and 23.

A product prepared as described under F above was converted into phenol p-toluenesulfonate with p-toluenesulfonyl chloride in excess of sodium hydroxide and analyzed by high pressure liquid chromatography on microparticle silica gel using n-hexane / 2-propanol / 2- propylamine (85: 15: 0.4) as the eluent at a flow rate of 0.54 ml / min. and a pressure of about 8.3 MPa and was found to have the following composition:

Sulfoxide according to Example No. Concentration 20 19-23% 21 23-25.5% 22 25.5-28% 23 28-30%

The product prepared according to part E or F above, when tested by one or more of the standard biological testing procedures described below, was found to have useful cardiotonic activity. The efficacy of this compound was assessed in vitro on the basis of percent increase in contractile force in isolated cat atria and papillary muscle and in vitro on percent, increase in cardiac contractility in the intact anesthetized dog.

The in vitro assay procedures used are described as follows:

Cardiotonic Test Procedure I - Male cats weighing 0.8-1.5 kg were anesthetized with cc-chloralose (80 mg / kg i.p.). The chest was opened, the heart excised and the two atria dissected.

A silk suture was attached to each of the two opposite sides of the right atrium. One side of the atrium was attached to a glass rod and then placed in a 50 ml organ bath filled with Tyrode's solution. The second suture was attached to a power offset transducer and the atrial voltage was set to 1.5 - 0.5 g. The transducer was then connected to a Grass polygraph and the force and velocity of atrial contraction recorded continuously. The left atrium was treated in a similar manner using silver thread instead of silk sutures. The silver wire also served as a stimulating electrode. Both atria were placed in the same bath. The right atrium spontaneously struck due to the presence of the sinoatric node, while the left atrium was electrically stimulated at a rate of 3 beats / s at 5 ms duration rectangular pulses. The bath solution for the atria consisting of Tyrode's solution had the following composition (in mM): NaCl 136.87, KCl 5.36, NaH

CaCl2 1.80, Mg0126H2O 1.05, NaHCO3 11.90, glucose 5.55 and EDTA 0.04. The solution was equilibrated with a gas mixture of 95% O 2 and 5% CO 2. The preparation was allowed to equilibrate for one hour before any drug was added. The bath liquid was changed 3-4 times during the equilibration time. At the end of the equilibration period, the agent dissolved in a medium or medium alone was added to the tissue bath and the full reaction was recorded.

The medium used was Tyrode's solution, to which, if necessary, sufficient acid was added to produce solution of the agent. When the reaction reached a maximum, it was abrogated by 3 washes at 10 minute intervals, or until the values of the contraction force before the agent were reached. Generally, a reaction study of at least 3 doses was performed in the same preparation.

Cardiotonic Test Procedure IB - Male cats weighing 0.8-1.5 kg were anesthetized with α-chloralose (80 mg / kg i.p.). The chest was opened and the heart excised. The heart was dipped and shaken in Tyrode's solution to remove blood from the cavities. The right ventricle was then cut open, and the small and thin (about 1 mm in diameter and 4-7 mm in length) pillar muscles were excised. A silver thread was attached to each of the two ends of the papillary muscle. The ventricular end was attached to a platinum electrode and placed in a tissue bath containing the above-described Tyrode's solution. The silver wire on the valvular end of the muscle was attached to a force displacement transducer to measure the force and velocity of the muscle contraction. The muscle was stimulated at a rate of 3 beats / s with sub-threshold rectangular pulses of 5 ms duration. The rest of the procedure was continued as described above.

37 146386

Cardiotonic Test Procedure II - The in vivo test procedure used is described as follows: Both sex bastards, weighing 9-15 kg, were anesthetized with 50 mg / kg pentobarbital sodium administered intravenously. Trachea was exposed and cannulated. The tracheal cannula was then connected to a Harvard respirator pump using stool air. The right femoral artery and veins were cannulated. The arterial cannula was connected to a Statham P23A pressure transducer connected to a Grass polygraph for continuous recording of arterial blood pressure. The venous cannula was used for intravenous administration of drugs. Needle electrodes were connected to the right front leg and left hind leg. The electrodes were then blinded to a Grass polygraph for continuous recording of the standard extremity derivative II electrocardiogram. A ventro-dorsal incision was made at the third inter-castal compartment, the ribs pulled aside, and the pericardium cut open to expose the myocardium. The aorta base was cut and a flow probe placed around it. The flow probe was connected to a square wave electromagnetic flow meter (Carolina Medical Electronics). The flow meter was then connected to a Grass polygraph for continuous recording of the aortic blood flow. This flow was used as an index of cardiac output (the actual cardiac output is aortic blood flow + coronary blood flow). Cardiac contractility was measured by attaching a Walton Brodie strain gauge to the right ventricular wall. Following the surgical procedure, the animal was allowed to rest and equilibrate for one hour under continuous recording of blood pressure, ECG, cardiac contractile force and aortic blood flow.

After the equilibration period, the medium or drug dissolved in the medium was administered by intravenous infusion (iv inf), intravenous bolus (iv bol), or intraduodenal (id), and all of the measured parameters response to drug administration was recorded continuously for different periods depending on the administration. pathway for the agent. When the route of administration was i.v. inf., the drug was administered until a maximal effect was reached and the infusion was then maintained for 10 minutes. The test systems described above were standardized using dopamine.

The product prepared according to parts E and F above, when tested in vitro as described above at a dose of 1 mg / ml, increases of 62 and 52 percent in right atrial rate and right atrial force, respectively, and a decrease of lk% in pa - 38 146386 pillar muscle force. At a dose of 10 µg / ml, increases of 53 and 46 percent were observed in right atrial rate and right atrial force, respectively, and a 12 percent decrease in cardiovascular muscle strength.

When infused intravenously at a dose of 10 µg / kg / min. for 3 hours on 3 intact anesthetized dogs, the product of this example produced a maximal 25 and 42 percent increase in cardiac output in 2 of 3 dogs without any significant change in heart rate. In the remaining dog, reductions in contractile force and heart rate of 3o and 33 percent were observed, respectively.

EXAMPLE 13 Å. A solution of 10.5 g of right-turning 4-hydroxy-α-methoxyphenyl) -1-methylpropyl-amino-methyl-3- (methyl thi o) benzene-methanol prepared as described in Example 11A and 2.25 g of (-) mandelic acid in 60 ml of isopropyl acetate was stirred for 4.5 hours.

The precipitated solid was collected to give 3.7 g of white crystalline solid, m.p. 99-100 ° C = -20.9 ° which was labeled "solid A" and set aside. The filtrate was washed with saturated aqueous sodium hydrogen solution, dried over anhydrous sodium sulfate and evaporated to dryness. The remaining 6 g of gum was dissolved in 40 ml of isopropyl acetate and treated with a solution of 2 ° g (+) mandelic acid in 20 ml of isopropyl acetate and the resulting solution stirred overnight.

The precipitated product was collected to give 4.1 g of light brown crystalline solid, m.p. 89-93 ° C, [α] D = + 35 ° C. The filtrate was labeled "filtrate A" and set aside. The solid was recrystallized by dissolving in 55 ml of 10: 1 isopropyl acetate / isopropyl alcohol and stirring overnight. After removing a small amount of solid impurity, the clear solution was concentrated to a volume of 30 ml and the product crystallized to give 1.6 g of light brown crystals, m.p. 89-106 ° C, [bc] + = + 48.7 °, which was labeled "solid B" and set aside. The filtrate was labeled "filtrate B".

"Filtrate A" was washed with saturated aqueous hydrogen carbonate solution and dried over anhydrous sodium sulfate and evaporated to dryness. The resulting 4.0 g of yellow gum was dissolved in 40 ml of ethyl acetate and treated with 1.0 g of (-) - mandelic acid. After standing overnight, the precipitated product was collected to give 2.5 g of crystalline solid, m.p. 108-110.5 °, Ja] Jp = "33 °> which was labeled" solid C "and set aside. The filtrate was combined with" filtrate B "above and evaporated to dryness and the residue combined with" solid A ". The combined materials were dissolved in ethyl acetate, the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness, The remaining 6.4 g of yellow syrup was dissolved in 40 ml of ethyl acetate and treated with 1.5 g. (+) - mandelic acid. After stirring overnight, the precipitated solid was collected to give an initial amount of 1.0 g of light brown solid, mp 105-110 ° C. Cooling of the filtrate in ice gave a second amount of 1.3 g mp 86-89 ° C, [cf] + = +48 The filtrate was labeled "filtrate C" and set aside. The first amount was combined with "solid B" above and recrystallized from ethyl acetate to give obtained 1.65 g of light brown solid, mp 90.5-92 ° C, Γα1β ^ = + 52.2 ° This material was combined with the other men and the whole was recrystallized from isopropyl acetate to give 2.7 g of light brown crystalline solid, m.p. 89-92.5 ° C, [α] D = + 52.8 °. The latter was dissolved in 50 ml of ethyl acetate and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness, leaving 1.7 g of product corresponding to the right-rotating isomer in the pair of diastereoisomers. isomeric benzene methanols present in the product of Example 11A. A 650 mg sample was dissolved in isopropyl acetate and the resulting solution acidified with glacial acetic acid and evaporated to dryness. The residue was crystallized from a small volume of isopropyl acetate to give 700 mg of the acetate salt m.p. 70-72 ° C, = + 31.3 °.

B. "Filtrate C" was evaporated to dryness. The residue was dissolved in ether / ethyl acetate and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, treated with 2 g of decolorizing charcoal, filtered and the filtrate evaporated to dryness, leaving 3 »8 g of residue. This material was dissolved in 25 ml of isopropyl acetate and the resulting solution was treated with a solution of 1.3 g of (-) mandelic acid in 10 ml of isopropyl acetate. After stirring for 2 days, the precipitated product was collected to give 3.25 g of white crystalline solid, m.p. 104-106 ° C, [α] D = -30.4 °. This material was combined with "solid C" above and the whole was successively recrystallized from 25 ml of ethyl acetate, 40 ml of ethyl acetate and finally from isopropyl alcohol / ethyl acetate, the product being allowed to crystallize slowly at room temperature in each case. Thus, 3.5 g of white needles were obtained, m.p. 110-111 ° C, Joc = -33.4 °. These were dissolved in 50 ml of ethyl acetate and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness to give 2 4 g of product (£ of J = -5.1 °) which corresponds to the left-turn compound in the pair of diastereoisomeric benzene methanols present in the product of Example 11A. A sample of 1.1 g was converted to the acetate salt as described above for the right-turn diastereoisomer to give the crystalline acetate salt as white plates, m.p. 124-124.5 ° C, = -5.4 °.

C. A sample of 99 g right-hand end 4-hydroxy- <x- ^ C3- (4-methoxyphenyl) -1-methylpropyl3 aminoj methyl 3- (methylthio) benzene methanol acetate, mp 29-130 ° C , [α] D = + 7.1 °, prepared as described in Example 11C, was treated with aqueous sodium carbonate solution and the free base was extracted into 1 liter of ethyl acetate. The ethyl acetate solution was washed in water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in hot ether and the solution was filtered through a 2.5 cm layer of silica gel to remove a colored impurity.

41 146386

Evaporation of the ether left 83 g of a pale yellow gum which was dissolved in 200 ml of ethyl acetate and treated with a solution of 22 g (+) - mandelic acid in 200 ml of ethyl acetate. The mixture was stirred overnight at room temperature and then overnight at 5 ° C. The precipitated product was collected by filtration and washed with isopropyl acetate and ether. The mother liquids were set aside. The collected solid was recrystallized from isopropyl acetate containing a small amount of 2-propanol to give 27 g of product, m.p. 89-91 ° C, [α] D = + 49.4 °. The mother liquors, which had been set aside, were again converted to the free base and treated with 20 g (+) - mandelic acid, whereby, after two recrystallizations from isopropyl acetate and one from ethyl acetate, an additional 6.0 g of product was obtained. ] jp = + 47.6 °. The mother liquors from this second treatment with (+) - mandelic acid were enriched with the left-turn diastereoisomer and set aside for use in Part D.

The solids were combined and recrystallized twice from ethyl acetate to give 22 g of the (+) - mandelate, m.p. 94_95 ° C [a] §5 = + 54.0 °. This salt was treated with 80 ml of 109e aqueous sodium carbonate solution and the free base extracted into 300 ml of ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and acidified with 2 ml of acetic acid. The solution was concentrated and the resulting precipitate was collected and recrystallized from ethyl acetate containing a few drops of acetic acid to give 4.3 g of 4-hydroxy-α- <{[3- (4-methoxyphenyl) -1-methylpropyl] amino ) methyl ^ -3- (methyl thio) benzene methanol acetate, m.p. 133-134 ° C, [α] D = + 33.3 °, corresponding to the right-hand compound in the pair of diastereoisomeric benzene methanols present in the product of Example 11C.

A sample of this material was reacted with p-toluenesulfonyl chloride in the presence of sodium hydroxide to give the corresponding 4-p-toluenesulfonate acetate salt, m.p. 90-92 ° LocJD = + 23.0 °, which was shown by high-pressure liquid chromatography to have an isomeric purity> 99% D. The mother liquors of part C, which were enriched with the left-turn diastereoisomer, were combined and evaporated to dryness. The residue was treated with aqueous sodium carbonate solution and the free base extracted into ethyl acetate. Evaporation of the ethyl acetate left 58 g of oil. This material was dissolved in 200 ml of ethyl acetate, treated with a solution of 20 g of (-) - mandelic acid in 200 ml of ethyl acetate and the resulting mixture stirred overnight. The precipitated salt was collected and recrystallized successively from acetone / ether, ethyl acetate and eight times from methylene chloride / ethyl acetate to give 23 g incompletely separated (as determined by thin layer chromatography) (-) - mandelate salt, m.p. 116-117 ° C, [a] ip = -37> 1 °> which by a conventional procedure JJ pc was converted to the acetate salt [a] + = -10.6 °. Chromatography of a sample of 5 »5 g of the latter salt on a column of silica gel and elution with 7% methanol in ethyl acetate did not result in significantly greater purity of the acetate salt. A 2.6 g fraction of the material which had been eluted from the column was stirred with 25 ml of 35% aqueous sodium hydroxide solution and the mixture was treated dropwise over 15 minutes with a solution of 1.33 g of p-toluenesulfonyl chloride for 30 minutes. ml of acetone. Over the next 5 minutes, the reaction mixture was treated with two additional 150 mg portions of p-toluenesulfonyl chloride. The acetone layer was separated, diluted with an equal volume of isopropyl acetate, washed with water followed by saturated aqueous sodium chloride solution and evaporated to dryness. The residue was dissolved in ethyl acetate and the solution acidified with acetic acid. The acetate salt which precipitated was recrystallized from ethyl acetate to give 1.0 g m.p. 115-117 ° C, [α] D = -7.9 °. The filtrate gave an additional 0.5 g, m.p. 115-117 ° C. The amounts were combined and converted to 1.2 g (+) - mandible salt, m.p. 154-156 ° [α] D = + 14.9 ° according to the procedure described above in Part C. This material was combined with other 250 mg, m.p. 157-158 ° C [α] δ = + 14.3 ° prepared by a similar experiment, recrystallized from ethyl acetate and then by a conventional procedure converted to the corresponding acetate salt to give 700 ml of isomeric pure left-turning 4-hydroxy- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methyl thio) benzenemethanol-4-p-toluene sulfonate acetate, m.p. 117-119 ° C [α] β = -9.6 ° corresponding to the 4-p-toluenesulfonate ester of the left-turn compound in the pair of diastereoisomeric benzene methanols present in the product of Example 11C. This product was shown to have an isomeric purity ^ 98% by high-pressure liquid chromatography.

43 146386

Attempts to cleave the p-toluenesulfone ester to obtain the isomerically pure left-handed phenol were unsuccessful, but the latter compound was obtained from the corresponding benzoate as described in Example 18 below.

EXAMPLE 14 A. To a stirred solution of 1.05 g (0.005 mol) of right-turning 4-hydroxy-α- <{C3 - (4-methoxyphenyl) -1-methylpropyl] amino} methyl> - 5- (methylthio) benzene methanol, prepared in accordance with the procedure of Example 13A, in 15 ml of methanol at 0 ° C a solution of 0.45 ml (0.005 mol) of commercial 40% peracetic acid in 5 ml of methanol was added dropwise over 1/2 hour. After the addition was complete, the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in 45; 5 ethyl acetate / methanol and adsorbed on a column of silica gel. After eluting with ethyl acetate, the product was eluted with 90; 10 ethyl acetate / methanol. The material thus obtained was dissolved in ethyl acetate / methanol, the resulting solution acidified with acetic acid and evaporated to dryness. The residue was taken up in 5 ml of chloroform, the resulting solution cooled to -65 ° C and diluted with ether. The resulting solid was dissolved in tetrahydrofuran, the solution acidified with glacial acetic acid and evaporated to dryness. The residue was dissolved in chloroform and the solution cooled to -65 ° C and diluted with ether.

The resulting solid was collected and dried to give 550 mg of 4-hydroxy-α- [5- (4-methoxyphenyl) -1-methyl-propyl] amino} methyl> -5- (methylsulfinyl) benzene methanol -acetate as a right-turn pair of diastereoisomeric sulfoxides, [a] + p = + 28.5 °.

B. A sample of 5> 0 g of isomerically pure right-turn 4-hydroxy-α- 3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -5- (methylthio) benzene methanol acetate ([α] + - + 51.5 °), prepared according to the procedure of Example 13C, was oxidized as described in Part A above. After the oxidation was complete, the reaction mixture was evaporated to dryness and the residue crystallized from ethyl acetate to give 4.2 g of crystalline product, m.p. 107-115 ° C, [α] 25 D - + 28.2 °. A small sample was dissolved in acetone / methanol and the solution treated with cyclohexylsulfamic acid. The precipitated salt was collected to give, after drying, 4-hydroxy-α- <Ζ {[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylsulfinyl) ) benzene methanol-cyclohexyl sulfamate as a right-turn pair of diastereoisomeric sulfoxides, m.p. 152-154 ° C, [ct] + = + 35.9 °.

The pair of diastereoisomeric sulfoxides prepared as cyclohexylsulfamate salt in this example is obtained separately as the hydrochloride of Examples 20 and 22.

PREPARATION 8 A. Following the same procedure as that described in Preparation 4C, but using 128 g (0.72 mol) incompletely separated (+) - 3- (4-methoxyphenyl) -1-methylpropylamine, [ <x] p = + 4.4 ° (2% in water) and 120 g (0.33 mol) of 2-bromo-4'-hydroxy-3 '- (methylthio) -acetophenone-4'-benzoate were obtained an initial amount of 82 g, m.p. 172-174 ° C and a second amount of 43 gm.p. 171-174 ° C. The amounts were combined and a 16 g sample was recrystallized from 95% ethanol to give 10 g of completely separated (+) - 4 '-hydroxy-2- [13- (4-methoxyphenyl) -1-methylpropyl] amine. ) -3 '- (methylthio) acetophenone-4 * -benzoate hydrobromide, m.p. 174-175 ° C, [α] 25 = + 8.4 °.

B. To a vigorously stirred solution of 180 g (1.0 mol) (+) - 3- (4-methoxyphenyl) -1-methylpropylamine [optical purity> 97% as shown by NMR spectroscopy in the presence of Eu (TFC) ] and 55 ml of triethylamine in 300 ml of Ν, Ν-dimethylformamide at -60 ° C were added over 1.5 hours a solution of 160 g (0.384 mol) of 2-bromo-4'-hydroxy-3 '- (methylthio ) acetophenone-4'-benzoate in 500 ml of Ν, Ν-dimethylformamide. Stirring was continued for another 1/2 hour. The reaction mixture was acidified with 48% hydrogen bromic acid and extracted with methylene chloride. The organic extracts were washed with water and concentrated to about 320 ml. The concentrate was diluted with 400 ml of isopropyl acetate and cooled. The solid which precipitated was collected and dried to give 167 g of optically pure (+) - 4'-hydroxy-2- [[3- (4-methoxyphenyl) -1-methylpropyl] amino} '- 3 - (methylthio) acetophenone-4'-benzoate hydrobromide, m.p. 171-173 ° C, [α] D = + 11.8 °. A sample of 7> 0 g was recrystallized from aqueous methanol containing a small amount of HBr to give, after drying, 5.9 g, m.p. 175-177 ° C [α] D = + 11.6 °.

EXAMPLE 15 A. To a solution of 106 g (0.195 mol) incompletely separated (+) -4 '-hydroxy-2- [[3- (4-methoxyphenyl) -1-methylpropyl] amino]) -3 - (methylthio) acetophenone-4f-benzoate hydrobromide, prepared according to the procedure of Preparation 8A, in 700 ml of methanol at 0 ° C was added over 1/2 hour 6 g of CO, 16 moles of sodium borohydride. Stirring at 0 ° C was continued for an additional 1/2 hour. A 150 ml aliquot of the reaction mixture was concentrated under reduced pressure at below 50 ° C. The concentrate was dissolved in ether and the ether solution washed thoroughly with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was dissolved in 75 ml of isopropyl acetate, and the resulting solution was acidified with acetic acid and then diluted with ether until cloudy and stirred for 3 hours. The precipitated solid was collected by filtration, washed with isopropyl acetate and ether and dried to give 6.4 g of 4-hydroxy-α- ¢ [3- (4-methoxyphenyl) -1-methylpropyl] amine} Methyl 3 -3- (methylthio) benzene methanol-4-benzoate acetate, m.p. 107-110 ° C.

B. The remainder of the original reaction mixture was hydrolyzed with a solution of 9 g of potassium hydroxide in 100 ml of water, following the procedure of Example 10 to give 46 g of 4-hydroxy-α- ({[3- (4-methoxyphenyl) - 1-methylpropyl] amino) methyl) -3- (methyl- [beta] thio) benzenemethanol acetate, m.p. 130-132 ° C, [α] D = + 4.8 °.

C. To a solution of 10.0 g (0.0188 mol) of optically pure (+) - 4'-hydroxy-2- [[3- (4-methoxyphenyl) -1-methylpropyl] amino) -31 - (methyl -

^ PC

thio) acetophenone-4'-benzoate hydrobromide (mp 171-173 ° C, [α] D = + 11.8 °) in 100 ml of methanol at 0 ° C was added portionwise 380 mg of sodium borohydride. After adding several ml of acetic acid, the mixture was evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and ether, and the resulting solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, acidified with 2.5 ml of acetic acid and evaporated to dryness. Recrystallization of the residue from isopropyl acetate / ether gave 6 g of 4-hydroxy-α- (4-methoxyphenyl) -

1-methylpropyl] amino} methyl 11 ^ -3- (methyl thio) benzene methanol-4-benzoate acetate [a] + = 6.4 ° as a right-turn pair of diastereoisomeric benzene methanols corresponding to the products of Example 17A

46 146386 and B. A similar experiment gave the product with m.p. 101-102.5 ° C and rotation [oc] p5 = + 7.6 °.

EXAMPLE 16 4-Hydroxy-α - [([3- (4-methoxyphenyl) -1-methylpropyl] amino] methyl) -3- (ratylthio) benzene methanol-4-benzoate acetate (5.0 g, O 0095 mol), prepared according to the same procedure as in Example 15C, was oxidized with 1.5 ml of commercial 40% peracetic acid followed by a procedure similar to that of Example 14. After the oxidation was complete, the reaction mixture was treated with 0.9 g of sulfuric acid. and cooled. The precipitated solid was collected and dried to give 2.8 g of 4-hydroxy-oc- [[3- (4-methoxyphenyl) -1-methylpropyl] amino] methyl) -3- (methylsulfinyl) benzene methanol-4-benzoate hemisulfate, m.p. 193-195 ° C.

EXAMPLE 17 A. To a solution of 7.4 g of the free base derived from right-turn 4-hydroxy-α- [[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylthio ) benzene methanol-4-benzoate acetate, [a] * p = + 6.4 ° in 60 ml of isopropyl acetate was added a solution containing 1.8 g (+) - mandelic acid in 20 ml of isopropyl acetate. The resulting solution was diluted with ether until slightly cloudy and stirred for two days at room temperature. The precipitate was collected and the mother liquids enriched with the left-turn diastereoisomer were set aside for use in Part B below. The collected solid was recrystallized eight times from methylene chloride / ether to give 3 »3 g of the (+) - mandelate salt, m.p. 126-127 ° C, [cc] + p = + 49.1 ° which was then converted to the acetate salt to give 2.1 g of 4-hydroxy-α- <{[3- (4-methoxyphenyl) - 1-methylpropyl] amino} methyl ^ -3- (methylthio) benzene methanol-4-benzoate acetate, m.p. 88.5-90 ° C, [a] jp = + 26.7 °, corresponding to the right-turn compound in the pair of diastereoisomeric benzene methanols present in the product of Example 15c.

B. The parent liquids from Part A above were converted to the free base, dissolved in isopropyl acetate, treated with 1.5 g (-) - mandelic acid and diluted with ether. The precipitate was collected and recrystallized once from isopropyl acetate / ether to give 2.7 g of the (-) mandelate salt, m.p. 120-120.5 ° C, [oc] + = -35.0 ° which was then converted to 4-hydroxy-oc - {{3- (4-methoxy-phenyl) -1-methylpropyl] amino} methyl> -3- (methyl thio) benzene methanol-4-benzoate acetate, m.p. 82-83 ° C, [α] jp = -10.0 °, corresponding to the left-turn compound in the pair of diastereoisomeric benzene methanols present in the product of Example 15c.

EXAMPLE 18

A mixture of 600 mg of 4-hydroxy-α- {{[3- (4-methoxyphenyl) -1-methyl-propyl] amine} methyl ^ -3- (methylthio) benzene methanol-4-benzoate acetate, (m.p. 82-83 ° C, [α] β = -10.0 °), 5 ml of 35% aqueous sodium hydroxide solution and several ml of methanol were stirred for 10 minutes at room temperature, then diluted with 20 ml of water and stirred for a further 10 minutes. a hot water bath. The pH was adjusted to 9 with acetic acid and the methanol was evaporated under reduced pressure. The residue was extracted with ethyl acetate and after drying over anhydrous sodium sulfate the extracts were evaporated to dryness. The residue was dissolved in isopropyl acetate, the resulting solution acidified with acetic acid and cooled. The precipitated solid was collected by filtration and dried in vacuo to give 500 mg of 4-hydroxy-α - {{3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl] -3 - (me thyl thi o) benzene-methanol acetate, m.p. 117-120 ° C, [α] D = -17.0 ° (average of two determinations) corresponding to the left-turn compound in the pair of diastereoisomeric benzene methanols present in the product of Example 11C.

EXAMPLE 19 A. To a stirred solution of 1.0 g (0.003 mol) of 4-hydroxy-α- 3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl ^ -3- (methylthio) benzene methanol [a] jp = -5.1 °, prepared according to the procedure of Example 13B, in 15 ml of methanol at 0 ° C a solution of 0.45 ml of commercial 40% peracetic acid in 5 ml of methanol was added dropwise over 1/2 hour. After the addition was complete, the reaction mixture was evaporated to dryness in vacuo. The residue was diluted with 10 ml of benzene, the resulting solution acidified with glacial acetic acid and evaporated to dryness. The residual gum was crystallized from tetrahydrofuran / ether and then recrystallized from ethyl acetate / 2-propanol to give 1.05 g of 4-hydroxy-α-3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl ^ 3- (methylsulfinyl) benzene methanol acetate, as a left-turn pair of diastereoisomeric sulf oxides, m.p. 90-95 ° C, [cc] + = -9> 4 · B. When the above oxidation was carried out from isomerically pure left-hand 4-hydroxy-α- 3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl 1- [3- (methylthio) benzene methanol acetate (mp 117-120 ° C, [α] D = -17.0 °), prepared according to the procedure of Example 18, had the resulting pair of diastereoisomeric sulf oxides [α] D = -18.8 ° (determined on the reaction mixture).

The pair of diastereoisomeric sulfoxide ions prepared as acetate salt in this example are obtained separately as hydrochlorides in Examples 21 and 23C.

EXAMPLE 20

The parent liquids obtained by preparing several batches of 4-hydroxy-α- [[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl] -3- (methylsulfinyl) benzene methanol acetate according to the same procedure as the one described in Example 12B was combined and evaporated to dryness. The remaining oil was first triturated with ether and then with isopropyl acetate. The residue (90 g) was dissolved in 300 ml of acetone and the resulting solution treated with 33 g of cyclohexylsulfamic acid in 200 ml of acetone. The precipitated cyclohexyl sulfamate was collected and recrystallized five times from aqueous methanol to give 7.3 g of product which was combined with 7.4 g of material obtained in previous experiments and converted to the hydrochloride. Recrystallization of this from methanol / isopropyl alcohol afforded 6.3 g of 4-hydroxy- [+ - <{& - (4-methoxyphenyl) -1-methylpropyl] amine (3-methyl) -3- (methylsulfinyl) benzenemethanol hydrochloride, mp. 206-207 ° C, [<J = + 126.6 °, corresponding to the hydrochloride of the right-handed compound in the pair of diastereoisomeric sulfoxides which form the cyclohexylsulfamate salt of Example 14B.

EXAMPLE 21

The mother liquors from the fractional crystallization of the product of Example 20 were evaporated and the residue recrystallized from acetone. The resulting 12.4 g of solid was recrystallized twice from methanol / acetone to give 5.1 g of product [a] jp = +49) 3 °. This latter material was combined with 3.5 g obtained in a previous experiment and converted to the hydrochloride which was crystallized from 2-propanol to give 4-hydroxy-α- methoxyphenyl) -1-methylpropyl] amino} -methyl> -3- (methylsulfinyl) benzene methanol hydrochloride, m.p. 204-205 ° C, [+] p5 = + 70.5 °, corresponding to the hydrochloride of the right-handed compound in the pair of diastereoisomeric sulfoxides which form the acetate salt of Example 19B.

EXAMPLE 22

The reaction mixture from the oxidation of 12.1 g of right-turn 4-hydroxy-α- 3- (4-thoxyphenyl) -1-thylpropyl] amino} methyl} -3- (methylthio) benzene methanol - (+) - mandelate according to the procedure from Example 14B, was evaporated to dryness and the residue dissolved in a mixture of 70 ml of methanol and 15 ml of water, treated with a molar equivalent of cyclohexylsulfamic acid and seeded with the cyclohexylsulfamate salt of the product of Example 30. The 7.9g of product which crystallized, were collected and set aside. The mother liquors were evaporated to dryness and the residue crystallized from acetone / methanol. The product was converted to 1.1 g of the hydrochloride and combined with an additional 850 mg obtained from the mother liquors from the fractional crystallization of the diastereoisomers of Example 31. The combined solid was recrystallized from 2-propanol to give 1.4 g of 4 -hydroxy-α- 3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl -3- (methylsulfinyl) benzenemethanol hydrochloride, m.p. 138-140 ° C, [cc = -48.2 °, corresponding to the hydrochloride of the left-turn compound in the pair of diastereoisomeric sulfoxides which form the cyclohexyl sul famate salt of Example 14B.

EXAMPLE 23 A. The reaction mixture from the oxidation of 3 g of left-turning 4-hydroxy-cc-3- (4-methoxyphenyl) -1-methylpropyl] amino} methy 1- [3- (methylthio) benzene methanol acetate according to the procedure of Example 19B was evaporated to dryness and the residue was dissolved in 90:10 acetone / methanol, treated with a molar equivalent of cyclohexylsulfamic acid, and seeded with the cyclohexylsulfamate salt of the product of Example 21. The 1.6g of product which crystallized was collected. and set aside. The mother liquors were evaporated to dryness and the residue crystallized twice from aqueous methanol to give 1.85 g of crystalline solid, [α] D = -67.5 °.

B. Alternatively, 10.0 g of 4-hydroxy-α - {{[[3- (4-methoxyphenyl) -1-methylpropyl] amino] methyl ^ -3- (methylthio) benzene methanol-4-p-toluenesulfonate - (+) -mandelate, prepared according to the procedure of Example 13D, oxidized according to the same procedure as in Example 19A, and the product was isolated as the free base to give 10 g of crude 4-hydroxy-α-3- (4-methoxyphenyl) -1 -methyl-propyl] amino) methyl-3- (methylsulfinyl) benzene-methanol-4-p-toluene sulfonate as a pair of diastereoisomeric sulfoxides.

A solution of the latter product and 15 ml of 10% aqueous potassium hydroxide solution in 100 ml of ethanol was stirred for 1.5 hours at 45 ° C. The reaction mixture was then concentrated, diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in acetone and treated with a molar equivalent of cyclohexylsulfamic acid. The precipitated product was collected and recrystallized from acetone / methanol to give 1.15 g of cyclohexyl sulfamate salt similar to the hydrochloride prepared in Example 21. The mother liquors were evaporated to dryness, the residue crystallized from acetone. Four recrystallizations from aqueous methanol gave 450 mg of crystalline solid = -66.2 °.

C. The left-turning products of parts A and B were combined, recrystallized once from aqueous methanol and then converted to the hydrochloride to give 1.1 g of 4-hydroxy-α-3- (4-methoxyphenyl) -1-methylpr opyl] amino) methyl 3 - (methylsulfinyl) benzenemethanol-hydr o ehlor id, m.p. 178-180 ° C, [α] jp = -102.3 °, corresponding to the hydrochloride of the left-turn compound in the pair of diastereoisomeric sulfoxides which form the acetate salt of Example 19B.

PREPARATION Q

To a stirred solution of 20 g (0.134 mol) of 1,1-dimethyl-2-phenyl-ethylamine in 40 ml of Ν, Ν-dimethylformamide at -50 ° C was added dropwise over 15 minutes a solution of 14.5 g (0.048 mol) of 2-bromo-4, -hydroxy-3 '- (methylthio) acetophenone-4'-acetate in 35 ml of N, N-dimethylformamide. After the addition was complete, stirring was continued for an additional 1.25 hours. The reaction mixture was then treated with 3.5 ml of 12N hydrochloric acid, diluted with 100 ml of water and extracted thoroughly with ether. The ether extracts were dried over anhydrous sodium sulfate, acidified with ethanolic hydrogen chloride and cooled in a refrigerator overnight. The 12.5 g of precipitated product was collected and combined with 6.0 g of product obtained from a previous experiment and recrystallized twice from chloroform / methanol to give 15 g of 2 - [(1,1-dimethyl-2- phenyl-ethyl) amino] -4 * -hydroxy-3 * - (methylthio) acetophenone-41-acetate hydrochloride, m.p. 205 ° C (dec.).

EXAMPLE 24

To a stirred suspension of 15 g (0.037 mol) of 2 - [(1,1-dimethyl-2-phenylethyl) amino] -4'-hydroxy-3 * - (methylthio) acetophenone-4 * acetate hydrochloride in 200 ml methanol at -5 ° C was added portionwise over 10 minutes 750 mg (0.020 mol) of sodium borohydride.

After stirring for an additional 10 minutes, the reaction mixture was brought to pH 7 with glacial acetic acid and evaporated to dryness. The residue was dissolved in ether / ethyl acetate and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution.

The organic layer was dried over anhydrous sodium sulfate, acidified with methanesulfonic acid and concentrated to a small volume. The concentrate was diluted with benzene and evaporated to dryness. The process was then repeated using toluene. The resulting solid residue was recrystallized from ethanol / ether to give 12 g of α- [1,1-dimethyl-2-phenylethyl) amino] methyl} -4-hydroxy-3- (methylthio) benzene-methanol -4-acetate-methane sulfonate, m.p. 112-115 ° C.

EXAMPLE 25

A solution of 9.5 g (0.020 mol) of α- [(1,1-dimethyl-2-phenylethyl) amino] methyl} -4-hydroxy-3- (methylthio) benzene methanol-4-acetate methanesulfonate, 3 g ( 0.045 mole of potassium hydroxide and 20 ml of water in 200 ml of 95% ethanol were stirred overnight under nitrogen. The reaction mixture was neutralized with glacial acetic acid and concentrated to a small volume. The concentrate was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated to a volume of 100 ml. The concentrated solution was brought to a pale yellow color by the dropwise addition of glacial acetic acid, upon which crystallization began. The product was collected by filtration and recrystallized from chloroform / methanol to give 5.1 g of α - [(1> 1-dimethyl-2-phenylethyl) amino] methyl] J · -4-hydroxy-3- ( methylthio) benzene methanol acetate, m.p. 165-167 * 0th

PREPARATION 10

Following the same procedure as that described in Preparation 9, but using 18.3 g (0.135 mole) of 1-methyl-2-phenyl-ethylamine and 15 g (0.050 mole) of 2-bromo-4 3'-(methylthio) -acetophenone-4'-acetate 7.1 g of 4'-hydroxy-2 - [(1-methyl-2-phenylethyl) amino] -3 * - (methylthio) acetophenone were obtained. -4'-acetate hydrochloride.

EXAMPLE 26

Following the same procedure as that described in Example 5, but using 7.4 g (0.019 mol) of 4'-hydroxy-2 - [(1-methyl-2-phenylethyl) amino] -3 '- (methylthio ) acetophenone-4T-acetate hydrochloride, 600 mg 0.015 mole of sodium borohydride and 1.1 g of potassium hydroxide were obtained 6.3 g of 4-hydroxy-cc - {"[(1-methyl-2-phenylethyl) -amino JmethylJ-3- (methylthio) benzene methanol acetate, mp 131-132 ° C.

EXAMPLE 27

To a stirred solution of 4.7 g (0.012 mol) of α- [[(1,1-dimethyl-2-phenylethyl) amino] methyl} -4-hydroxy-3- (methylthio) benzene methanol acetate in 100 ml of methanol at 0 ° C was added dropwise over 1/2 hour a solution containing 2 ml (0.012 mol) of commercial 40% peracetic acid in 10 ml of methanol. After the addition was complete, the reaction mixture was evaporated to dryness and the residue was crystallized from ethanol / ether to give 4.3 g of [[1,1-dimethyl-2-phenylethyl) amino] methyl} 4-hydroxy-3- (methylsulfinyl) benzene methanol acetate which was softened at 100 ° C and melted at 138-140 ° C.

Preparation 13- A. To a stirred solution of 35 g (0.25 mole) of o- (methylthio) phenol and 27.6 g (0.30 mole) of propionyl chloride in 100 ml of nitrobenzene was added portionwise over 25 minutes 46 , 5 g (0.35 mol) of aluminum chloride. The reaction was exothermic and the temperature rose to 45-50 ° C. After the addition was complete, the reaction mixture was stirred for 2 hours at 60 ° C and 1 hour at 70 ° C. The reaction mixture was cooled, diluted with water and extracted with ether. The ether extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residual oil was adsorbed on a column of silica gel and continuously eluted with boiling methylene chloride. The eluate was evaporated to dryness and the residue recrystallized from ether to give 25 g of crystalline product which was then triturated with ether at -65 ° C to give 17 g of pure 4'-hydroxy-3 '- (methylthio) propiophenone. .

B. To a stirred solution of 17.4 g (0.089 mol) of 4 * -hydroxy-3 * - (methylthio) propiophenone and 13 ml (0.090 mol) of triethylamine in 200 ml of methylene chloride was added dropwise over 1/2 hour 7, 65 g (0.098 mol) of acetyl chloride. After the addition was complete, stirring was continued for another 2 hours. The reaction mixture was then washed successively with 3N hydrochloric acid and water and evaporated to dryness. The remaining oil was dissolved in ether, treated with decolorizing charcoal and filtered through a layer of silica gel. The filtrate was evaporated to dryness to give 21.4 g of 4 'hydroxy-3' - (methylthio) propiophenone-4 * acetate as a pale yellow oil.

C. To a stirred solution of 21.4 g (0.088 mol) of 4'-hydroxy-3 '- (methylthio) propiophenone-4f-acetate in 250 ml of chloroform was added a solution of 14.4 g (0.090 mol) of bromine in 40 ml. ml of chloroform. After a 15 minute start period, the bromine began to consume. After 1 hour, the reaction mixture was washed with 3% aqueous sodium hydrogen carbonate solution and then with water. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to dryness to give 19 g of 2-bromo-4 * -hydroxy-3 * - (methylthio) propiophenone-4 * acetate.

D. To a stirred solution of 30 g (0.185 mole) of 2- (4-methoxyphenyl) -1-methylethylamine in 150 mL of Ν, Ν-dimethylformamide was added dropwise 54 1-46386 19.6 g (0.062 mole) of 2-bromine. 4'-hydroxy-3 '- (methyl thio ·) propiophenone 4'-acetate. After the addition was complete, stirring was continued for another 2 hours. The reaction mixture was then diluted with chloroform and washed successively with water, dilute hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution. The chloroform solution was dried anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in ether, acidified with glacial acetic acid and cooled. The precipitated product was collected and triturated with chloroform to give 6.35 g of 41-hydroxy-2- [2- (4-methoxyphenyl) -1-methylethyl] amine} -3 '- (methylthio) propiophenone acetate, m.p. 110-112 ° C.

EXAMPLE 28

To a stirred solution of 6.2 g (0.0148 mol) of 4'-hydroxy-2- [2- (4-methoxyphenyl) -1-methylethyl] amino} -3 '- (methylthio) propiophenone acetate In 100 ml of methanol at 0 ° C 0.5 g of sodium borohydride was added portionwise. After the addition was complete, stirring was continued for another 1/2 hour. The reaction mixture was then acidified with glacial acetic acid and evaporated to dryness. The residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were evaporated to dryness and the residue dissolved in ether. The ether solution was acidified with glacial acetic acid and cooled. The precipitated product was collected and dried to give 5.0 g of 4-hydroxy- <{C 2 - (4-methoxyphenyl) -1-methylethyl] ethanol} ethyl ^ -3- (methylthio) benzene methanol. acetate, m.p. 160-162 ° C.

EXAMPLE 29

To a stirred mixture of 2.35 g (0.0056 mol) of 4-hydroxy-α- <{[2- (4-methoxyphenyl) -1-methylethyl] solution} ethyl ^ -3- (methylthio) benzene-methanol acetate and 40 ml of methanol at -10 ° C were added dropwise a solution of 1 ml (0.0056 mol) of commercial CO ° / o peracetic acid in 5 ml of methanol. After the addition was complete, stirring was continued for another 1/2 hour. The reaction mixture was then evaporated to dryness and the remaining oil was suspended with chloroform and diluted with ether to give a granular solid which was collected and dried to give 2.2 g of 4-hydroxy-α - [2- (4-methoxyphenyl) -1-methylethyl] amino} ethyl> -3- (methylsulfinyl) benzenemethanol acetate, m.p. 110 ° C.

55 146386 PREPARATION 12

To a stirred solution of 16 g (0.082 mol) of 2- (3,4-dimethoxyphenyl) -1-methylethylamine and 6 ml (0.041 mol) of triethylamine in 60 ml of N, N-dimethylformamide at -65 ° C was added dropwise over 3/4 hours a solution of 12.5 g (0.041 mol) of 2-bromo-4, -hydroxy-3 '- (methylthio) -acetophenone-4 * acetate in 40 ml of Ν, Ν-dimethylformamide. After the addition was complete, stirring was continued for an additional 1 hour. The reaction mixture was then made slightly acidic with 5 ml of 12N hydrochloric acid and extracted with chloroform. The organic extracts were evaporated to dryness and the residue was dissolved in trifluoroacetic acid and treated with excess acetyl chloride. After stirring for 1 hour, the mixture was diluted with water and evaporated to dryness. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 12 g of crude 2- [2- (3,4-dimethoxyphenyl) -1-methyl-ethyl] amino} -4'-hydroxy-3 ' - (methyl thio) acetophenone-4 'acetate.

EXAMPLE 30

According to the same procedure as that described in Example 26, but using 12 g of 2 - ([2- (3,4-dimethoxyphenyl) -1-methylethyl] amino} -4-hydroxy-3 ') - (methyl thio) acetophenone-4 'acetate, 870 mg sodium borohydride and 1.4 g potassium hydroxide were obtained 2.2 g - <{[2 - (3,4-dimethoxyphenyl) -1-methylethyl] amino}' methyl 4-hydroxy-3- (methylthio) benzene methanol acetate, mp 144-1 144 ° C.

EXAMPLE 31

Following the same procedure as that described in Example 29, but using 2.30 g (0.0052 mol) of α - <3 - [2- (3,4-dimethoxyphenyl) -1-methylethyl] amino} methyl-4-hydroxy-3- (methyl thio) benzene-methanol acetate and 0.95 ml (0.0052 mol) of commercial 40% peracetic acid, 1.9 g of ex- {[2 - (3) 54-dimethoxyphenyl) -1-methyl-ethyl] amino} methyl ^ -4-hydroxy-3- (methylsulfinyl) benzene methanol acetate, as a pale yellow amorphous solid.

PREPARATION 13

To a stirred solution of 19.5 g (0.12 mol) of 1,1-dimethyl-3-phenyl-propylamine in 100 ml of N, N-dimethylformamide under nitrogen at -60 ° C was added dropwise over of 1/2 hour a solution of 12 g (0.04 mol) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone-4'-acetate in 40 ml of N, N-dimethylformamide. After the addition was complete, stirring was continued for 1 hour at -35 ° 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 was cooled to -65 ° C and diluted with ether. The resulting precipitate was collected and recrystallized from ethanol to give 12 g of 2 - [(1,1-dimethyl-3-phenyl-propyl) amino] -41-hydroxy-3 '- (methylthio) acetophenone-4'- acetate hydrochloride, m.p. 188-193 ° C.

EXAMPLE 32

Following the same procedure as that described in Example 5, but using 11.0 g (0.026 mol) of 2 - [(1,1-dimethyl-3-phenylpropyl) amino] -4'-hydroxy-3'- (methylthio) acetophenone-4 * acetate hydrochloride, 750 mg (0.02 mole) of sodium borohydride and 1.4 g (0.026 mole) of potassium hydroxide were obtained 9.2 g of α- - phenylpropyl) amino] methyl 4 -4-hydroxy-3- (methylthio) benzenemethanol acetate, m.p. 171-172 ° C.

EXAMPLE 33

According to the same procedure as that described in Example 7,. but using 6.2 g (0.015 mol) of α- (β (1,1-dimethyl-3-phenylpropyl) amino) methylmethyl-4-hydroxy-3- (methylthio) benzene methanol acetate and 1.17 g ( 0.015 mol) of commercial 40% peracetic acid 5.5 g of crude α - {[(1,1-dimethyl-3-phenylpropyl) amino] methyl] -4-hydroxy-3- (methylsulfinyl) benzene methanol acetate were obtained. After recrystallization twice from chloroform / methanol and once from ethyl acetate / acetone / ethanol, the product was dissolved in ethyl acetate / methanol and the resulting solution was acidified with glacial acetic acid and evaporated to dryness. Recrystallization of the residue from ethanol / ethyl acetate gave 1.4 g of analytically pure material, m.p. 155-157 ° C.

PREPARATION .14 A. To a stirred solution of potassium cyanide 65 g (1.0 mole) and 73.7 g (0.38 mole) of 4- (p-methoxyphenyl) -2-methyl-2-butanol in 300 ml n-butyl ether at 60 ° C was added dropwise 120 ml of concentrated sulfuric acid over 1 hour. After the addition was complete, stirring was continued for an additional 1 hour at 50-55 ° C. The reaction mixture was then poured over 1200 g of ice, basified with sodium carbonate and extracted with ether. The ether extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The 76.5 g of residual oil was heated under reflux for 3 hours in 175 ml of 12N hydrochloric acid. The mixture was cooled, washed with ether, basified with 35% aqueous sodium hydroxide solution and extracted with ether. The ether extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was distilled under reduced pressure and the fraction boiling at 161-162 ° C / 22 mmHg was collected to give 35 g of 1,1-dimethyl-3- (4-methoxyphenyl) propylamine.

B. Following the same procedure as described in Preparation 3, but using 29 g (0.15 mol) of 1,1-dimethyl-3- (4-methoxyphenyl) propylamine, 15 g (0.05 mol) 2-Bromo-4, -hydroxy-3 '- (methylthio) acetophenone-4 * acetate and 10 ml of acetyl chloride, 9.5 g of 2- [1,1-dimethyl-3- (4-methoxyphenyl) ) propyl] -amino} -4 'hydroxy-31 - (methyl thio) acetophenone-4' acetate hydrochloride, m.p. 186-190 ° C.

EXAMPLE 34

Following the same procedure as that described in Example 5, but using 9.5 g (0.021 mol) of 2 - {[1,1-dimethyl-3- (4-methoxyphenyl) propyl] amino} -4'- hydroxy-3 '- (methylthio) acetophenone-4 * acetate hydrochloride, 600 mg (0.015 mol) of sodium borohydride and 1.2 g of potassium hydroxide were obtained 2.3 g of α- [1,1-dimethyl-3 (4-methoxyphenyl) propyl] amino} methyl ^ -4-hydroxy-3- (methyl thio) benzene methanol acetate, m.p. 173-174 ° C.

EXAMPLE 35.

According to the same procedure as that described in Example 7,. but using 3.9 g (0.009 mol) of α- [[1,1-dimethyl-3- (4-methoxyphenyl) propyl] amino} methyl] -4-hydroxy-3- (methylthio) benzene methanol acetate and 680 mg of commercial 40% peracetic acid were obtained 3.0 g of α-1,1-dimethyl-3- (4-methoxyphenyl) propyl] -amino} methyl ^ -4-hydroxy-3- (methylsulfinyl) benzene methanol acetate, m.p. 115 ° C.

PREPARATION 15

According to the same procedure as that described in Preparation 3, but using 18 g (0.12 mol) of 1-methyl-3-phenylpropylamine, 12 g (0.04 mol) of 2-bromo-4'- hydroxy-3 '- (methylthio) aceto-phenone-4 * acetate and 8 ml of acetyl chloride 8.3 g of 4'-hydroxy-2 [(1-methyl-3-phenylpropyl) amino] -3' - ( methylthio) acetophenone-41-acetate hydrochloride.

EXAMPLE 36

Following the same procedure as that described in Example 5, but using 8.1 g (0.02 mol) of 4, -hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] -3 '- (methylthio) acetophenone-4'-acetate hydrochloride, 500 mg of sodium borohydride and 1.2 g of potassium hydroxide were obtained 6.2 g of 4-hydroxy-α- · [(1-methyl-3-phenylpropyl) -amino ] methyl J-3- (methylthio) benzene methanol acetate, m.p. 140-142 ° C.

EXAMPLE 37

Following the same procedure as that described in Example .7 but using 4.2 g (0.011 mol) of 4-hydroxy-α- {[(1-methyl-3-phenylpropyl) amino] methyl -3- (methyl thio) benzene methanol acetate and 815 mg (0.011 mol) of commercial 40% peracetic acid were obtained 4.0 g of 4-hydroxy-α- [[(1-methylethyl-3-phenylpropyl) amino] methyl] 3 } - 3- (methylsulfinyl) benzene methanol acetate as a pale yellow amorphous solid.

PREPARATION 16

Following the same procedure as described in Preparation 9 but using 18.2 g (0.11 mole) of 3- (4-methoxyphenyl) propylamine and 11.2 g (0.037 mole) of 2-bromo-4 '-hydroxy-3' - (methylthio) -acetophenone-4-acetate 9 g of crude 4 '-hydroxy-2-3- (4-methoxyphenyl) per opylamino} -3' - (methylthio) acet 41-acetate hydrochloride which was suitable for use in the next step.

EXAMPLE 38

Following the same procedure as described in Example 5, but using 9 g of crude 4T-hydroxy-2- {t3- (4-methoxyphenyl) propyl] amine}} - 3 '- (methylthio) acetophenone-4f Acetate hydrochloride, 600 mg of sodium borohydride and 2.0 g of potassium hydroxide were obtained · 1.2 g of 4-hydroxy-α- [[3- (4-methoxyphenyl) propyl] amino] methyl-> 3- (methylthio) benzene methanol acetate, m.p. 123-125 ° C.

EXAMPLE 39

Following the same procedure as that described in Example 7,. but using 1.2 g (0.003 mol) of 4-hydroxy-α-methoxyphenyl) propyl] amino]; methyl) -3- (methylthio) benzene methanol acetate and 0.44 ml (0.003 mole) of commercial $ 40 peracetic acid were obtained 1.1 g of 4-hydroxy-α- [{3- (4-methoxyphenyl) propyl] amino 3 -methyl 2 -3- (methylsulfinyl) benzene methanol acetate as an amorphous light brown solid.

PREPARATION 17 A. A stirred mixture of 64 g (0.334 mole) of 5- (4-methoxyphenyl) -2-pentanone, 80 g (1.77 mole) of formamide and 6 ml of formic acid was slowly heated to 165 ° C and treated dropwise in over 3.5 hours with 50 ml of formic acid, while the water formed during the reaction was allowed to distill slowly. Stirring at 165 ° C was continued for an additional 3 hours. The reaction mixture was then cooled, diluted with 1 liter of ice and water and extracted with a mixture of ether and benzene. The organic extracts were evaporated and the residual oil was heated under reflux for 1.5 hours in 130 ml of 12N hydrochloric acid. The mixture was cooled, diluted with 300 ml of water and washed with a mixture of ether and benzene. The aqueous layer was made basic with 35 $ aqueous sodium hydroxide solution 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 solution and extracted with a mixture of ether and benzene. The extracts were dried over anhydrous sodium sulfate and the solvent evaporated in vacuo. The residual oil was distilled under reduced pressure to give 37 g of 4- (4-methoxyphenyl) -1-methyl-βο 146386 butylamine, b.p. 163-166.5 ° C 18 mmHg.

B. To a stirred solution of 15.5 g (0.08 mol) of 4- (4-methoxy-phenyl) -1-methylbutylamine in 80 ml of Ν, Ν-dimethylformamide at -60 ° C was added dropwise over 3 4 hours a solution of 8.0 g (0.027 nol) of 2-bromo-4 '-hydroxy-3' - (methylthio) acetophenone-4 'acetate in 25 ml of Ν, Ν-dimethylformamide. After the addition was complete, stirring was continued at between -60 and -45 ° C for an additional hour. The reaction mixture was then acidified with 48% hydrogen bromic acid and extracted with chloroform. The chloroform solution was diluted with 2.5 volumes of ether and cooled to -65 ° C. The resulting precipitate was collected and redissolved in chloroform and the resulting solution washed thoroughly with water. The chloroform solution was then dried over anhydrous sodium sulfate and evaporated to dryness to give 9 g of crude 4'-hydroxy-2- [4- (4-methoxyphenyl) -1-methylbutyl] amino -3 '- (methylthio ) acetophenone-41-acetate hydrobromide.

EXAMPLE 40

Following the same procedure as that described in Example 5, but using 9 g of crude 4'-hydroxy-2 - [4- (4-methoxyphenyl) -1-methylbutyl] amino} -? - (methylthio) acetophenone-4 'acetate hydrobromide, 500 mg sodium borohydride and 1 g potassium hydroxide were obtained 5.5 g of 4-hydroxy-α-4- (4-methoxyphenyl) -1-methylbutyl] -amine} methyl} -3- ( methylthio) benzene methanol acetate, mp, 155-157 ° C.

EXAMPLE 41

Following the same procedure as that described in Example 7, but using 3.0 g (0.007 mol) of 4-hydroxy-α - β - {[4- (4-methoxyphenyl) -1-methylbutyl] amino methyl} -3- (methylthio) benzene-methanol acetate and 1.04 ml (0.007 mol) of commercial 40% peracetic acid were obtained 2.6 g of 4-hydroxy-α - {{4- (4-methoxyphenyl) -1- methylbutyl] amino} methyl} -3- (methylsulfinyl) benzene methanol acetate as an amorphous yellow solid.

Preparation 18 A. To a stirred mixture of 52.5 g (0.253 mole) of 4- (4-methoxyphenyl) -1,1-dimethylbutyl alcohol and 44.5 g (0.685 mole) of powdered potassium cyanide in 200 ml of n- butyl ether at 60 ° C was added dropwise over one hour 80 ml of concentrated sulfuric acid. The temperature was kept at 60-65 ° C during the addition and stirring was continued at 50-55 ° C for an additional hour after the addition was complete. The reaction mixture was then poured onto 850 ml of ice, basified with 35% aqueous sodium hydroxide solution and extracted with ether. The ether extracts were evaporated to dryness and the resulting oil was heated under reflux for 3 hours in 125 nil of 12N hydrochloric acid. The resulting mixture was diluted with 300 ml of water and washed with a mixture of ether and benzene. The aqueous layer was made basic with 55% aqueous sodium hydroxide solution and extracted with a mixture of ether and benzene. The organic layer was then extracted with 1N hydrochloric acid, the acidic aqueous layer was basified with 35% aqueous sodium hydroxide solution 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-methoxy-phenyl) -1,1-dimethylbutylamine as a straw oil.

B. By the same procedure as that described in Preparation 17B, but using 19 g (0.09 mol) of 4- (4-methoxyphenyl) -1,1-dimethylbutylamine and 10.0 g (0.033 mol) of 2-bromo -4'-hydroxy-3 '- (methylthio) acetophenone 4'-acetate and allowing the final product to crystallize from acetone in a refrigerator overnight, 10.5 g of crystalline 4'-hydroxy-2 -, {[ 4- (4-methoxyphenyl) -1,1-dimethylbutyl] amine} -3 * - (methylthio) acetophenone-4 'acetate hydrobromide, m.p. 180-181 ° C.

EXAMPLE 42

Following the same procedure as that described in Example 5, but using 10.5 g (0.021 mol) of 4, -hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethylbutyl] amino} -31- (methylthio) acetophenone-4'-acetate hydrobromide, 250 mg of sodium borohydride and 1 g of potassium hydroxide, and the product was recrystallized from methanol / ether, 4 g of 4-hydroxy-α- 4-methoxyphenyl) -1,1-dimethyl-butyl] amino] -me thyl-3- (methylthio) benzene methanol as the free base, m.p. 179-180 ° C.

EXAMPLE 45

Following the same procedure as that described in Example 29, but using 2.7 g (0.007 mol) of 4-hydroxy-α - <{β * - (4-methoxyphenyl) -1,1-dimethylbutyl] amino} 1.8 g of 4-hydroxy-α- (4-methoxyphenyl) -1,1-dimethylbutyl] amino} methyl ^ -3- (methyl sulfinyl) benzene methanol was obtained. as an amorphous white powder.

PREPARATION 19

A stirred mixture of 7.4 g (0.015 mol) of optically pure (+) - 4 * -hydroxy-2 - ([3- (4-methoxyphenyl) -1-methylpropyl] amine} 3 '- (methylthio) acetophenone -4 * -benzoate hydrobromide and 100 ml of 48% hydrogen-bromic acid were heated at reflux for 1.5 hours, then the reaction mixture was evaporated to dryness and the residue was triturated with ethanol and isopropyl acetate to give 5.3 g (+ ) -41-hydroxy-2 - f [3- (4-hydroxyphenyl) -1-methylpropyl] aminqy-3 '- (methylthio) acetophenone hydrobromide.

EXAMPLE 44

By the same procedure as that described in Example 28, but using 5> 0 g (0.012 mol) (+) - 41-hydroxy-2- [[3- (4-hydroxyphenyl) -1-methylpropyl] amino} - 31- (methylthio) acetophenone hydrobromide and 0.455 g of sodium borohydride, 4.2 g of 4-hydroxy-α- 3- (4-hydroxyphenyl) -1-methylpropyl] amino} methyl] -3- (methylthio) was obtained. benzene methanol acetate, [α] D = + 5 °.

EXAMPLE 45

Following the same procedure as that described in Example .14 but using 4.2 g (0.01 mole) of crude 4-hydroxy-α - <{[3- (4-hydroxyphenyl) -1-methylpropyl] amino ^ -methyl ^ -3- (methylthio) benzene methanol acetate, and eluting the oxidation product from a short (1.5 m) column of silica gel followed by conversion to the cyclohexyl sulfamate salt, 2.3 g of right-turning 63.63838 were obtained. 4-hydroxy-α- (4-hydroxyphenyl) -1-methylpropyl] amino} methyl) -3- (methylsulfinyl) benzenemethanol-cyclohexylsplamate,

149-151 ° C, [α] D = 2.1 °.

PREPARATION 20 A. To a stirred solution of 100 g (0.53 mol) of 4'-hydroxy-3 '- (methylthio) acetophenone in 650 ml of dioxane and 300 ml of ether, a solution of 147 g of dioxane dibromide was added dropwise over 4 hours. in 1050 ml of 1: 1 dioxane / ether. After the addition was complete, the reaction mixture was diluted with 500 ml of ether and washed with water. The organic layer was separated, washed with saturated aqueous sodium chloride solution, filtered through cotton wool, and the solvents evaporated in vacuo. The residue was collected in benzene and the benzene evaporated twice. The final residue was crystallized from benzene / ether to give, after drying, 107.5 g of 2-bromo-4, -hydroxy-3 '- (methylthio) acetophenone.

B. To a stirred solution of 50 g (0.28 mol) of (-) 3- (4-methoxyphenyl) -1-methylpropylamine (optical purity> 94%) in 150 ml of N, N-dimethylformamide at - At 60 ° C, a solution of 30 g (0.12 mol) of 2-bromo-41-hydrox "-3" - (methyl · thio) - * acetophenone in 80 ml of Ν, Ν was added dropwise over a 1/2 hour. dimethylformamide. After the addition was complete, stirring was continued at between -60 and -40 ° C for an additional 5.5 hours. The reaction mixture was then acidified with 60 ml of 48% hydrobromic acid, diluted with 150 ml of water and washed with ether. The aqueous solution was evaporated to dryness under vacuum. The residue was dissolved in dichloromethane and the resulting solution was washed with water and saturated aqueous sodium chloride solution. The dichloromethane was evaporated and the residue was diluted with 2-propanol and cooled to 0 ° C. The precipitated solid was collected to give 9.5 g of white crystalline hydrobromide salt. Concentration of the filtrate gave an additional 2.9 g which was converted to the hydrochloride salt in conventional manner to give 2.5 g of (-) - 41-hydroxy-2- [[3- (4-methoxyphenyl) -1-methylpr] opyl] amine ^ -3 '- (methyl thi o) acetophenone hydrochloride, m.p. 195-197 ° C, [α] D = -11.4 °.

EXAMPLE 46

Following the same procedure as that described in Example 28, but using 9.3 g of (-) - 41-hydroxy-2- - (4-methoxyphenyl) -1-methylpropyl] amino} · -3 '- ( methylthio) acetophenone hydrobromide and 1 g sodium borohydride, and the hydrochloride salt precipitated directly from the ethyl acetate extracts yielded 8.4 g of 4-hydroxy-α-3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl 3 -3- (methylthio) benzene methanol hydrochloride, mp, 156-157 ° C, [α] D = -9.3 ° as a mixture of two diastereoisomers.

EXAMPLE 47

Following the same procedure as that described in Example 6, but using 29.6 g (0.055 mol) of (-) - 41-hydroxy- (4-methoxyphenyl) -1-methylpropyl] amino ^ -3 * - ( methylthio) aceto-phenone-4'-benzoate hydrobromide, 1.55 g (0.041 mol) of sodium borohydride and 30 ml of 35% aqueous sodium hydroxide solution, and as the product was isolated as hydrochloride salt, 18.6 g of 4-hydroxy-a - {- {[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl} -3- (methylthio) benzene methanol hydrochloride.

EXAMPLE 48

According to the same procedure as that described in Example 7,. but using 17.6 g (0.044 mol) of 4-hydroxy-2- <{[3- (4-methoxyphenyl) -1-methylpropyl] amine] -methyl-3- (methyl thio) benzene-methanol hydrochloride, prepared According to the procedure of Example 47, and 3.36 g (0.044 mol) of commercial 30% peracetic acid, 12.5 g of 4-hydroxy-2- <("{[3- (4-methoxyphenyl) -1-methylpropyl]] was obtained. -aminoj -methyl) - 3- (methylsulfinyl) benzene methanol hydrochloride, mp 107-117 ° C, [α] D = + 7.6 °, as a mixture of four diastereoisomers.

PREPARATION 21 2-Bromo-41-hydroxy-3 '- (methylthio) acetophenone (26.1 g, 0.1 mol) was reacted with 3,4-dimethoxyphenethylamine (45 g, 0.25 mol) mainly according to the method of as described in Example 67B. The product which was first obtained by evaporation of the aqueous solution was treated with hot methanol and the insoluble N, N-bi s- [4-hydroxy-3- (methylthio) phenacyl] -3,4- dimethoxyphenethylamine was filtered off. The filtrate was concentrated, diluted with 2-propanol and cooled. The resulting solid was recrystallized from water, again dissolving the by-product. The product thus obtained was recrystallized from aqueous ethanol and a sample of 5 »5 g was converted to the hydrochloride salt in a conventional manner to give 4.6 g of 2- [2- [3- (3,4-dimethoxyphenyl) ethyl] amine] -4'-hydroxy-3 '- (methylthio) acetophe- non-hydrochloride, m.p. 208-212 ° C.

EXAMPLE 4 <?

According to the same procedure as that described in Example 28, but using 13.1 g (0.033 mol) of 2- [2- [2- (3,4-dimethoxy-phenyl) ethyl] amino] -4'-hydroxy-3 ' - (methyl ylthio) acetophenone hydrochloride and 2.0 g (0.053 mol) of sodium borohydride, and as the reaction mixture was acidified with 6N hydrochloric acid and the hydrochloride salt was isolated, 11.5 g of a dimethoxy-xyphenyl) ethyl] amino] methyl ^ -4-hydroxy-3- (methylthio) benzene-methanol hydrochloride, m.p. 124-126 ° C.

EXAMPLE 50

Following the same procedure as that described in Example 7 but using 5.6 g (0.014 mol) - (3,4-dimethoxyphenyl) ethyl] amino] methyl ^ -4-hydroxy-3- (methylthio) benzene methanol hydrochloride and 2.13 ml of commercial 50% peracetic acid yielded 4.9 g of [2- (3,4-dimethoxyphenyl) ethyl] amino] by crystallization from 2-propanol. methyl) - 4-hydroxy-3- (methylsulfinyl)

• J Q

benzene methanol hydrochloride, m.p. 173-175 C.

PREPARATION 22

To a stirred solution of 72.3 g (0.4 mole) of 3,4-dimethoxyphenethylamine in 275 ml of N, N-dimethylformamide at -50 ° C, a solution of 39.3 g was added over 2.25 hours. (0.133 mol) of 2-bromo-4'-hydroxy-3 * - (methylsulfonyl) acetophenone in 275 ml of Ν, Ν-dimethylformamide. After the addition was complete, stirring was continued for one hour at between -40 ° C and -45 ° C, then for 1.5 hours at 66 ° C -30 ° C to -40 ° C and finally for half an hour at between -30 ° C 5 ° C. The reaction mixture was cooled to -20 ° C and acidified with 45 ml of 48% hydrogeribromic acid. The solvents were evaporated under vacuum and the residual syrup washed with ether. The syrup was dissolved in 200 ml of water and allowed to crystallize over the week-end. The precipitated solid was collected, waxed with water and ether and recrystallized from 95% ethanol to give 32.31 g of 2- [C 2- (3,4-dimethoxyphenyl) ethyl] amino] -4'-hydroxy-3 ' - (methylsulfonyl) acetophenone hydrobromide, m.p. 220-227 ° C. A sample of 10 g was converted to the free base which was crystallized from aqueous methanol and then converted to the hydrochloride, m.p. 227-233 ° C (dec.).

EXAMPLE 51

A mixture of 14.3 g (0.03 mole) of 2- [2- (3,4-dimethoxyphenyl) ethyl] amino] -4'-hydroxy-31- (methylsulfonyl) acetophenone hydrobromide and 1 g of 10% palladium-on-carbon hydrogenation catalyst in 200 ml of Ν, Ν-dimethylformamide was shaken to a hydrogen initial pressure of 345 kPa until the absorption of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated under vacuum. The remaining oil was treated with 100 ml of 5% aqueous potassium hydrogen carbonate solution, 20 ml of 10% aqueous sodium carbonate solution and 40 ml of ether. The precipitated solid was collected and dissolved in 100 ml of methanol containing 10 ml of ethanolic hydrogen chloride. The solution was treated with decolorizing charcoal and evaporated to dryness. The residue was dissolved in 225 ml of hot methanol and the resulting solution was diluted with 125 ml of acetonitrile and concentrated to a volume of 125 ml.

Upon standing, an initial amount of product crystallized, which was collected by filtration. Further concentration of the filtrate gave a second and third amount of product. The amounts were combined to give 11.2 g of α- [([2- (3,4-dimethoxyphenyl) ethyl] amino] methyl)> - 4-hydroxy-3- (methylsulfonyl) benzene methanol hydrochloride, m.p. 209-210 ° C.

67 146386 PREPARATION 2.5

To a solution of 14.6 g (0.05 mol) of 2-bromo-4, -hydroxy-3, ~ (methylsulfonyl) acetophenone in 100 ml of N, N-dimethylformamide at between -40 ° and -50 ° C A solution of 22.6 g (0.15 mol) of 1-methyl-3-phenylpropylamine in 100 ml of N, N-dimethylformamide was added. After about 30% of the solution was added over 1 hour, the remaining solution was added rapidly over 10 minutes. Stirring was continued for 1.25 hours at -40 ° C and then for 1 hour at -10 ° C. The reaction mixture was acidified with 21 ml of concentrated hydrochloric acid and diluted with 25 ml of water and 175 ml of saturated aqueous sodium chloride solution. After stirring for 0.5 hours in the cold, the precipitated solid was collected, washed with saturated aqueous sodium chloride solution and ether and recrystallized from 350 ml. water containing 20 ml of 6N hydrochloric acid. The product was collected by filtration and washed with water and acetone. After standing for 2 days, the filtrate gave a different amount of product and after. delay for a month a third amount was obtained. The final filtrate was evaporated to dryness and the residue recrystallized from water to give a fourth quantity of product.

Each of the four amounts was recrystallized from methanol / ethanol and the resulting products combined to give 10.0 g of 41-hydroxy-2- [(1-methyl-3-phenylpropyl) amino] -3 '- (methylsulfonyl) acetophenone hydrochloride, m.p. 210-215 ° C.

EXAMPLE 52

A mixture of 13 g (0.0327 mol) of 4, -hydroxy-2 - (- 1-methyl-3-phenyl-propyl) amino -3- (methylsulfonyl) acetophenone hydrochloride and 0.9 g of 10% palladium hydrochloride on-charcoal hydrogenation catalyst in 180 ml of N, N-dimethylformamide and 20 ml of water was shaken under a hydrogen initial pressure of 262 kPa until the absorption of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous potassium hydrogen carbonate solution. The aqueous phase was saturated with sodium chloride and re-extracted with ethyl acetate. The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The remaining oil was dissolved in 50 ml of hot ethanol and the resulting solution acidified with ethanolic hydrogen chloride. The solvent was evaporated and the residue crystallized from acetonitrile. The product was converted to the free base which crystallized from aqueous methanol. The conversion to the hydrochloride and crystallization thereof from acetonitrile yielded 8.95 g of 4-hydroxy-α- (1-methyl-3-phenylpropyl) amino] methyl? -3- (methylsulfonyl) benzenemethanol-hydr ochloride, m.p. 178-180 h.

PREPARATION 24

To a stirred solution of 44.5 g (0.23 mol) of 3- (4-methoxyphenyl) -1,1-dimethylpropylamine in 185 ml of Ν, Ν-dimethylformamide at -50 ° C was added over 2.25 hours. solution of 27 g (0.092 mol) of 2-bromo-4, -hydroxy-3, - (methylsulfonyl) acetophenone in 185 ml of Ν, Ν-dimethylformamide. After the addition was complete, stirring was continued for an additional 3 hours while the reaction mixture was allowed to warm to room temperature. The mixture was then acidified with 23 ml of 48% hydrogen bromic acid and evaporated under vacuum.

The residual oil was washed with ether and then slurried in 200 ml of acetone to precipitate 3- (4-methoxyphenyl) -1,1-dimethylpropylamine hydrobromide. The solid was separated by filtration and the filtrate was diluted with ether to precipitate the desired product. The solid thus obtained was slurried in 500 ml of hot acetonitrile, cooled and collected by filtration. This material was slurried in 200 ml hot chloroform, cooled and filtered to give 21.9 g of 4'-hydroxy-2- [[3- (4-methoxyphenyl) -1,1-dimethylpropyl] amino] -31- ( methylsulfonyl) acetophenone hydrobromide, m.p. 220-224 ° C (dec.). A 10 g sample was converted to the free base by dissolving in methanol, basification with 10% aqueous sodium carbonate solution, evaporation of the methanol, dilution with water and crystallization of the base to give 5.4 g, m.p. 159-165 ° C which was then converted to 2.93 g of the hydrochloride, m.p. 222-232 ° C (dec.).

EXAMPLE 53

Following the same procedure as that described in Example 51 but using 11.3 g (0.023 mol) of 4'-hydroxy-2- (3- (4-methoxyphenyl) -1,1-dimethylpropylamino) 31 - (methylsulfonyl) acetophenone hydrobromide was obtained 9.66 g of 4-hydroxy-α - <{t3- (4-methoxyphenyl) -1,1-dimethyl propyl] amino} methyl 1> -3- (methyl sulfonyl) benzene methanol hydrochloride, mp 202-2Q4 ° C.

PREPARATION 2 2-Bromo-4 * -hydroxy-3 '- (methylthio) acetophenone (25.4 g, 0.097 mol) was reacted with 3- (4-methoxyphenyl) propylamine (40 g, 0.242 mol) essentially according to the present invention. method described in Preparation 2OB. The product which was first obtained by evaporation of the aqueous solution was treated with aqueous ethanol. The precipitated N, N-bis- [4-hydroxy-3- (methylthio) phenacyl] -3- (4-methoxyphenyl) propylamine was filtered off. The filtrate was evaporated to dryness and the residue was crystallized from 2-propanol / ethyl acetate. The product thus obtained was triturated with hot water and the residue crystallized from ethanol / ethyl acetate to give 6.5 g of 4 * -hydroxy-2 - [[3- (4-methoxyphenyl) propyl] aminoj-3 * - (methylthio ) acetophenone hydrobromide.

EXAMPLE 54

Following the same procedure as that described in Example 49, but using 6.5 g (0.0153 mol) of 4'-hydroxy-2- [[3- (4-methoxyphenyl) propyl] amino] -31- ( methylthio) acetophenone hydrobromide and 1.2 g of sodium borohydride were obtained 5.1 g of 4-hydroxy-α - ({[3- (4-methoxyphenyl) propyl] amino] methyl} -3- (methylthio) benzene methanol hydrochloride, m.p. 151-152 ° C.

PREPARATION 26

Following the same procedure as described in Preparation 20B, but using 61 g (0.29 mol) of mescaline and 28 g (0.107 mol) of 2-bromo-4'-hydroxy-31- (methylthio) acetophenone, obtained 33 g of crystalline product contaminated with a small amount of N, N-bis- [4-hydroxy-3- (methylthio) phenacyl) -3,4,5-trimethoxyphenethylamine. The product was taken up in boiling water and the undissolved by-product was filtered off. Concentration of the filtrate to a small volume gave 18.2 g of 4, -hydroxy-3T- (methylthio) -2- [2- (3,4,5-trimethoxyphenyl) ethyl] amino] ac an ophenone hydrochloride The hydrochloride isolated as the monohydrate had mp.193-195 ° C.

EXAMPLE 55

According to the same procedure as that described in Example 28, but using 16 g of 4, -hydroxy-3, - (methylthio) -2- {[2- (3,4,5-trimethoxyphenyljethyl) aminol acetophenone hydrobromide and 2.5 g of sodium borohydride, and as the product was isolated as the hydrochloride, 14.6 g of 4-hydroxy-3- (methylthio) -oc- [2- [3,4,5-trimethoxyphenyl) ethyl] amino acid methyl benzene methanol hydrochloride, s.p. 168-169.5 ° C.

EXAMPLE 56

Following the same procedure as described in Example 7, but using 7.7 g (0.0175 mol) of 4-hydroxy-3- (methylthio} - ct- (3,4,5-trimethoxyphenyl) ethyl ] amino 2 -methyl-benzene methanol hydrochloride and 2.66 ml (0.0175 mole) of commercial $ 50 peracetic acid, and crystallizing from methanol / ether, 6.8 g of 4-hydroxy-3- ( methylsulfinyl) -C- (1 - [(2- (3,4,5-trimethoxyphenyl) ethyl) amino] methylbenzene methanol hydrochloride, m.p. 164-166 ° C.

PREPARATION 27

To a stirred solution of 76.0 g (0.36 mol) of mescaline in 250 ml of Ν, Ν-dimethylformamide at -65 ° C was added over 3.5 hours a solution of 35.2 g (0.12 mol) 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) acetophenone in 250 ml of Ν, Ν-dimethylformamide. After the addition was complete, stirring was continued at between -40 and -30 ° C for 1 hour and then between -30 and -5 ° C for 0.75 hours. The mixture was cooled to -20 ° C, acidified with 32 ml of 48 $ hydrobromic acid and evaporated under vacuum. The residual syrup was washed thoroughly with ether crystallized from 2-propanol. The solid product was collected in several fractions, the first containing significant amounts of mescaline hydrobromide. The later fractions contained the desired product substantially free of mesalcine hydrobromide. A sample of 15 g of the later fractions was converted to the free base and then to hydrochloride to give 5.52 g of 4'-hydroxy-2 - [{2- (3,4,5-trimethoxy-xyphenyl) ethyl 3 aminoj -5 '- (methylsulfonyl) acetophenone hydrochloride, m.p. 230-234 ° C (dec.).

EXAMPLE 57

A mixture of 16.47 g (0.0357 mol) of 4'-hydroxy-3 '- (methylsulfonyl-2- [Q2- (3,4,5-trimethoxyphenyl) ethyl] amino] acetophenone hydrochloride and 1, 2 g of 10% palladium-on-carbon hydrogenation catalyst in 180 ml of Ν, Ν-dimethylformamide and 20 ml of water was shaken under a hydrogen initial pressure of 331 kPa until the absorption of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated The residual oil was crystallized from methanol / ether and recrystallized from methanol The resulting product was converted with ammonia water to the free base which crystallized from water. Conversion to the hydrochloride gave 12.56 g of 4-hydroxy-3- (methylsulfonyl) -α- [[2- (3,4,5-trimethoxyphenyl) ethyl] amine> J methylbenzene methanol hydrochloride, mp 192-194 ° C.

The compounds of formula I prepared by the process of the invention have been shown to have useful antihypertensive, vasodilating and β-adrenergic blocking activity as can be seen from the results of standard pharmacological tests performed on representative examples as described below. .

Antihypertensive activity was determined based on the observed reduction in systolic blood pressure as measured by the method described by H. Kersten et al., J. Lab. and Clin. With. 32, 1090 (1947), followed by a single oral drug administration to the anesthetized spontaneously hypertensive rat, as described by Okamato et al., Japan Circulation J. 27, 282 (1963).

Antihypertensive activity was also assessed on the basis of prolonged reduction of blood pressure observed on the undeesthetized trained renally hypertensive dog followed by repeated oral drug intake according to the procedure described by Lape et al., Arch, int. Pharmacodyn. 160, 342 (1966).

72 146386

Vasodilator activity was assessed on the basis of observed reduction in perfusion pressure in the hind leg vasculature of the anesthetized dog, as determined by the procedure described by Jandhyala et al., European J. Pharm. 1, 357 (1972), and also based on percent reduction in perfusion pressure as measured in the isolated rabbit ear artery according to the method described by De La Lande et al., Aust. J. Exp. Biol. With. Sci. 4, 639 (1965).

The β-adrenergic blocking activity was determined on the pentobarbitalized dog as judged by the ability of the test compound to inhibit the increase in heart rate triggered by a 0.5 mg / kg i.v. injection of isoproterenol.

Acute intravenous and oral toxicity in mice was determined for the compound of Example 11A as follows: the compound was dissolved in distilled water and administered as the base in a volume of 10 ml / kg for i.v. ALD ^ q or 10-40 ml / kg for p.o. ALD ^ q. The compound was administered in graded doses to groups of every three mice (Swiss-Webster strain male mice weighing 20 + 2 g). The mortality occurred within a minute of i.v. and within 10 minutes of oral administration. Symptoms of acute intoxication for the cases included atoxia, loss of equilibrium reflex, clonic convulsions and dyspnoea, followed by respiratory arrest. No injury symptoms were observed for up to 7 days for the survivors. ALD ^ q i.v. was 75 mg / kg and ALD ^ q p.o. was 1500 mg / kg.

7-day oral LD 2 in rats were determined for two separate batches of the compound of Example 20D and found to be 1850 and 1940 mg / kg, respectively. No changes in body weight and no major tissue changes were observed in animals sacrificed 7 days after drug administration.

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

As noted above, some of the compounds prepared by the process of the invention also have antiarrhythmic activity. This was determined in vivo and the efficacy was judged on the ability of the test compound to convert the arrhythmia induced by barium ion or ouabain intoxication into normal rhythm. The test procedures were performed as follows:

Ba ++ - induced arrhythmia

Adult rabbits of both sexes weighing 1.7-2.3 kg were anesthetized with 30-35 mg / kg Na pentobarbital i.v. via a marginal ear vein. One-polar ECG needle electrodes were inserted for a lead II view on a Model 5 Grass polygraph using standard electrocardiographic procedures. A 0.71 mm cannula connected via a polyethylene catheter to a 10 cm syringe was inserted into the same vein used for anesthesia. A BaCl 2 H 2 O solution in saline was then infused at a constant volume of 0.2 cm 2 / min. from a Harvard Apparatus Model 600 infusion pump. This infusion was not stopped until the end of the experiment. In some studies, barium chloride was used in distilled water without appreciable differences. The standard rate of BaCl2 ™ infusion was established at 0.3 mg / kg / min.

(1.2 x 10 6 moles / kg / min) and the concentration was adjusted appropriately in each case to correspond to the rabbit weight.

Once the desired arrhythmia was established, the test compound was introduced as a solution in water or saline into the marginal ear of the unused ear. The volume used was between 0.5 and 2.0 cm 2 / kg and it was injected as a bolus over about 30 seconds. Deviations from the standard medium, injection rate and total administered volume were up to the examiner. The standard starting dose of an unknown compound on the first rabbit was 5 x 10- 5 moles / kg. Generally, 2-3 rabbits were used to determine antiarrhythmic activity and the dose range of activity; multiple doses were administered. Once activity and dose were indicated, two additional rabbits were used to confirm antiarrhythmic activity against a multifocal tachycardia.

74 146386

Ouabain-induced arrhythmia

Adult bastard dogs of both genders were anesthetized after 35 to 18 hours with 35 mg / kg Na-pentobarbital i.v. and tied in a supine position on an operating table. An open airway was provided by insertion of an endotracheal cannula and the animal breathed spontaneously. One femoral vein was double cannulated with one needle for injection and the other as a site for ouabain infusion. The ipsilateral femoral artery was cannulated for blood pressure measurement. Na-pentobarbital supplements were given i.v as needed.

Statham P23A blood pressure transducers were used to measure blood pressure, and electrocardiograms (lead II or V 1) were taken with single-polar needle electrodes. Both parameters were printed on a Grass polygraph. Each dog was given 36 µg / kg ouabain i.v. over 1 minute (the solution contained 50 µg / ml ouabain in isotonic saline) followed by a constant ouabain infusion (0.6 µg / kg / min) starting 5 minutes later. The infusion solution was prepared such that the appropriate dose per minute was delivered in 0.5 ml.

When the predominant rhythm of the arrhythmia occurred was a ventricular tachycardia (or sometimes nodal), an attempt was made to transform this arrhythmia with the test compound.

Up to 10 "4 mol / kg of the test compound was delivered in a volume of 1 ml / kg for a 5 minute infusion period. If a conversion or cardiotoxic effect was seen before 10-4 mol / kg was delivered, the dose was noted and repeated. on another dog.

The test was routinely conducted using pairs of dogs with a 15 minute difference in start time. All ECG interval and duration measurements were made on Lead II with a drawing speed of 100 mm / s. Heart rates were measured on Lead II with a draw rate of 100 mm / s. Heart rates were taken from derivation II QRS complexes at 25 mm / s. Blood pressure was measured using a sensitivity of 10 mmHg / mm pen rash.

75 146386

The results of the tests described above are given in Table F. The test compounds are stated to be active (A) or inactive (i) at the tested dose expressed in moles / kg.

TABLE E

Pharmacological Properties 76 143386

Antihypertensive vasodilator activity Adrenergic seizure activity

Renalt '| Dogs "- hyper- .Ibens- Rabbit ears- Dogs β-" SH rat tensive jperfu artery blockade, AHD,, n (a) dog (b) j sion (c) vasodila- AEDKn (e) n MED / -, n AED [-n tatioii (d) mtr £ i No. mg / kg po / 10 50 (molar mg / kg mg / kg mg / kg Sranc.) 1 10.0 0.5 50% <1.0 (60%) 1 (1x10_5M) 2 20.0 0.5 56% 0 1 (2x10l5M) 3 2.0 1.25 0.25 53% 0.04 (6.25x10 “5M) 4> 50.0 (-26) f 0.5 90% <1.0 (70 %) (1x10_ZfM) 5 15.0? 2.5 (0) g 0.5 55% 0.1 (1x10'4M) 7A 2.0 0.0316 0.5 50% 0.025 (5x10 5mm) 7B 9 .0 0.5 20% 0.025 (5x10_5M) 8> 50.0 (-20)> 0.5 (0) 0.5 50% 0.1 (3.5x10 5 M) 10> 20.0 (-33 ) 0.5 10% approx. 0.5 (1x10 4 M) UB> 0.1 (45%) 12a 3.0 0.0316 0.5 49% 0.125 (5x10 5M) 12C 4.0 50% <0.25 (70%) (5x10 "5M) 12D 4.0 71% (lx10_ZfM) 12® 64% (1x10" 4M) 13A 0.5> 0.1 (14%) 13B 0.5 0.1 <77 146386 TABLE Ε

Pharmacological properties

Antihypertensive- | vasodilator activity In adrenergic activity · activity

Renal 'Dogs-F, hyper-bone-Rabbit ears- Dogs β-v, * SH rat tensive perfusion artery blockade AHD / 10 (a) dog (b) sion (c) vasodila- AEDj-n (e) ® fs * "MED1n AEEun tation (d) No. ms / ltgp.o. ^ 10 ^ 50 "*** 14A 15.0> 0.025 (25%) * 58% 0.25 (5x10" 5M) 15A> 50, O (-IO) 16 9 19A 20.0> 0.025 (25%) 61% 0.0125 (5x10 5M) 20> 16.0 (-17)> 0.5 (8%) 50%> 0.10 (23%) (2x10-4M) 21> 16.0 (-14 ) <0.5 (14%; 38% 0.25 (1x10-ZtM) 22) <0.5 (14%; 50% 0.05).

(2χ10 “^) 23 3 <0.5 (17%: 50% 0.0125 (1x10 "4M) 25.50.50 0.5 71% <1.0 (56%) (1x10 “5M) 26 35.0 0.5 33% <1.0 (60%) (2x10 5m) 27 20.0 0.5 29% <1.0 (87%) (1x10 6m) 28> 20.0 ( -23) 29-> 20.0 (-25) 31 15.0 0.5 75% -> 0.1 (38%) (5x10_5M) 32 about 10.0 0.5 70% <1.0 ( 100%) (5x10 5 M)

TABLE E

Pharmacological Properties 78 146386. £? Sg £ iSd · Vasogilator Activity In jgggS *

Renal Dog- p. hyper-bones- Rabbit ears- Dogs β- ΰΟΓο. make rat tensive perfusion artery blockade p * AHD /, n (a) dog (b) sion (c) vasodilation AEDj -.- (e) eKS ·, 7U MED, 0 AEDcration (d) No. mg / kg po 10 50 (mnlfPr 1 mg / kg ........... mg / kS wife.) 33> 20.0 (-37) 0.5 50% 0.05 (5x10 5 M) 34 20, 0 0.5 0.5 50% <1.0 (72%) (9x10 5 M) 35> 20.0 (-26) 0.125 (0) 0.5 42% <1.0 (100%) (1x10 -4M) 35 0.5 0.5 81% 0.1 (5x10 5 ') 37 20.0 0.125 (0) 0.5 50% <0.025 (67%) (5x10 5') 39 7.0> 0.125 (0) 0.5 (constrictor) <0.1 (67%) 40> 50.0 (-17) 41> 40.0 50% (1x10 "3M) 43> 50.0 (-12) 45 40, 0 <0.025 (80%) 11D ca. 0.10 15B> 50 (-31) For approx. 0.50 48> 50 (-12) approx. 0.50 49> 50 (-13) approx. 1.0 50> 50 (-26) approx. 0.10 51> 50 (-22) approx. 0.10 52> 50 (-12) approx. 0.05 53 ^ 50 (-18) approx. 0.50 54> 50 (-13) <1.0 (67%) 55 <50 (-51) 55> 50 (-15) 79 146386 (a) AHD ^ q = simple oral dose required to induce a 40 mm average reduction in systolic blood pressure in the anesthetized spontaneously hypertensive rat.

(b) MED1q = minimal repeated oral daily dose required to produce a prolonged lowering of blood pressure of 10% or more in the anesthetized trained renally hypertensive dog.

(c) AED ^ 0 = approximately intra-arterial dose required to produce a 50% reduction in perfusion pressure in the hind leg of the anesthetized dog.

(d) Vasodilatation is expressed as the percentage reduction in perfusion pressure from the control level at the indicated molar dose.

(e) AEDjjq = approximately intravenous dose required to produce 50% inhibition of the heart rate increase triggered by isoproterenol in the pentobarbitalized dog.

(f) Actual reduction in blood pressure (in mmHg) observed at the indicated dose.

(g) Actual percentage reduction in blood pressure observed at the indicated dose.

(h) Actual percent reduction in perfusion pressure observed at the indicated dose.

(i) Actual percent inhibition of the heart rate increase above the control level, observed at the dose indicated.

(j) Submitted once per day.

80 146386

TABLE F

Antiarrhythmic activity

Conversion of Conversion of Ba ++ -

Conn. from ouabain-induced induced Ex. No. arrhythmia arrhythmia 4 A, 5x10O ~ ^ a A, 5χ1θ "5 11C A, 2.5x10O" 5 A, 5xlO "6 12EfF A, 5x10" ^ A, 1x10 "^ 33 A, 5x10O6 A, 2.5x10 "6 35 A, 5x10" 6 37 A, 5x10 "" A, 2.5x10- 5Λ I 2.5x10 "5 A, 10x10-5; ____ (a) mol / kg.

(b) Toxic at 2.5x10 “^, inactive at 2.5x10“ ^.

Claims (3)

81 146386 Patent Claim p 1. Analogous Process for the Preparation of Phenylalkanol-Amine Compounds of General Formula 1 2 N-- OH Rx R YO-P y-iH-CH-NH-C-tCHgJjj-Ar I \ = / R3 12 ^ wherein R, R and R are each independently hydrogen or straight chain or branched alkyl of 1-4 carbon atoms, n is 1, 2 or 3, Ar means phenyl optionally having 1-3 substituents selected from alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms, Q means alkylthio, alkylsulfinyl or alkylsulfonyl of 1-4 carbon atoms in each alkyl moiety, and Y is hydrogen, straight or branched alkanoyl of 1-6 carbon atoms, benzoyl, benzenesulfonyl or toluenesulfonyl, or acid addition salts thereof, or base salts of the compounds wherein Y is hydrogen, characterized in that a compound of formula K - -CH-NH- | - (CH 2) n-Ar II p X 2 wherein R, R, R, n, Ar, Q and Y have the above meaning, or an acid addition salt thereof, is reduced, the reduction, if Y in the starting compound is alkanoyl having 1-6 carbon atoms