CA1091245A - 4-hydroxyphenylalkanolamine derivatives and preparation thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Alpha-(aminoalkyl)-4-hydroxy-3-(alkylthio, alkylsulfin-yl or alkylsulfonyl)benzenemethanols and 2-[4-hydroxy-3-(alkyl-thio, alkylsulfinyl or alkylsulfonyl)phenyl]ethylamines useful as antihypertensive agents are prepared by reduction of the corre-sponding aminoalkyl 4-hydroxy-3-(alkylthio, alkylsulfinyl or alkyl-sulfonyl)phenyl ketones and 2-chloro, bromo or indo-2-[4-hydroxy-3-(alkylthio, alkylsulfinyl or alkylsulfonyl)phenyl]ethylamines respectively.

Description

l~Z4S

The present invention relates to 4-hydroxyphenylalkan-olamine derivatives and specifically derivatives of ~-(aminoalkyl)-4-hydroxy-3-(alkylthio, alkylsulfinyl or alkylsulfonyl)-benzene-methanols and 2-[4-hydroxy-3-~alkylthio, alkylsulfinyl or alkyl-sulfonyl)phenyl]ethylamines, to processes and intermediates forthe preparation thereof.
United Kingdom Patent 1,321,701 discloses a group of compounds embraced by the generic formula:

C~--:IR5R6 wherein, inter alia:
Rl is RS, RSO or RSO2 ~R=H, or Cl-C10 alkyl);
R2 and R3 are hydrogen, C1-C4 alkoxy or Cl-C4 alkylthio;
R4 is hydrogen or C1-C4 alkyl; and R5 and R6 are independently hydrogen or Cl-C16 alkyl optionally substituted by a phenyl or sub~tituted phenyl group.
The compounds are stated to exhibit ~-adrenergic blocking, peripheral vasodilator, anti-arrhythmic and hypotensive activities.

U.S. Patent 3,917,704 discloses a group of ~-amino-alkyl-4-hydroxy-3-alkylsulfonylmethylbenzyl alcohols having the formula:

N0 ~ IOH 12 whereln, inter alla:
R represents lower alkyl o~ from 1 to 5 carbon atoms, ~traight or branched chain;
Rl represents R2 repre~ents hydrogen, methyl or ethyl;
R3 and R4 repre~ent hydrogen, hydroxy or methoxy;
and R5 represents hydrogen or methyl. The compound~
are stated to have utlllty a~ ~-adrenergic ~timulant~ with relatively greater actlvity on re~piratory ~mooth muscle than on cardlac muscle.
Kai~er, et al. J. Med..Chem. 18, 674-683 (1975) report essentially the work described ln above-identified U.S. Patent 3,917,704 and ln addltion disclo~e the com~ound having the formula _ _ , _. _.. .. , .. , .. ... .. . , .... . .. .. .. ... . ...... .... .... ..... _. . ~ ____ .. _ _ _ _, _ __ _ ~J'lZ45 CH ~S2 HC)~ CH- CH2-NH- C ( CH3 ) 3 which i~ stated to be weakly actlve a8 a ~-adrener~ic agonist and which exhibitæ ~-adrenergic ~ntagonistic activity~ The work described in the Kaiser publication was reported orally April 109 1975 at the 169th nation~l meet-lng of the Amerlca.n Chemlcal SocletyO An ab~tract of the oral presentation appear~d at Abstracts of Papers, ACS
Meeting 169: Medi 54 (Ap,ril 1975)o Lutz, et al., J. MedO ChemO 15~ 795-802 ~1972)~
disclo~e the attempted preparatlon of 4-hydroxy-3-mercapto-phenylethanolamine, l.e.:

HS

HO ~ CH-CH2-NH2 .
The compound however was neither isolated as a single entity nor characterizedO
United Kingdom Patent 1,154,193 discloses as a ~-adrenergic agent ~-[~isopropylamino)methyl]-3-(methylthio)-benzenemethanol, i.e.:

CH3S OH`
~ CH-CH2-NH-CH(CH~)2 _. .. . . . ... . . , . _ . _ .. . . , _, In the rleld Or antlhypertenslve therapy the use of perlpheral vasodllator agents to lower blood pre~sure h~s o~ten ~ufrered a serious diRadvantage, namely the reflex tachycardia ellcited by the hypoten~ion induced by systemic vasodilation. Recently efforts have been made to overcome this problem by employlng hypotensive v~sodilators in combl-natlon wlth ~-adrenerglc blocklng ~gents, the functlon o~
the latter belng to reduce the reflex tachycardla caused by the vasodilator-induced hypotension. Thl3 mode of therapy of course su~ers the lnconvenience of requiring two separate drug~ and the attendant need for separate dosage regulatlon as well as the lncreased pRtentlal for ~atient error ln falllng to administer either one or the other of the drug~. .
The present inventlon provides novel, therapeu-tically u~eful compounds which have both hypoten~i~e vasodllator and ~-adrenergic blocking activity and whlch are thererore lndlcated for u~e as antihyperten~ive agent~
free of the undesirable tachyoardic side ef~ects associated wlth ;c~rrently-:u9ed ~asQdilator agentsO
The invention relates to a-{[(arylalkyl)amino]alkyl}-4-Y0-3-(lower alkylthio, lower alkylsulfinyl or lower alkyl-sulfonyl benzenemethanols which are useful as antihypertensive agents having Formula I hereinbelow:

. .

Q

yo ~ CH- TH-NH- f - ( CH2 ) n -A r R~

wherein:
Rl, R2 and R3 are independently hydrogen or lswer alkyl;
n is an integer from 1 to 3;
Ar is phenyl or phenyl having from one to three halo, lower alkyl, hydroxy or lower alkoxy substituents;
~ is lower alkylthio, lower alkylsul~inyl or lower alkylsulfonyl Y is hydrogen, lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl;
and acid-addition salts thereof. As described more fully herein-below certain of these compounds are also useful as antiarrhythmic agents.
A further aspect of the invention resides in [(arylalkyl)-aminoJalkyl 4-Y0-3-~lower alkylthio, lower alkylsulinyl or lower alkylsulfonyl)phenyl ketones having Formula II hereinbelow:

yo ~ I_CH_NH_C_(-CH2)n_Ar wherein Rl, R2, R3, n, Ar, Q and Y have the above-given meanings;
and acid addition salts thereof.
These compounds are useful as intermediates i~ the prepa-ration of the corresponding benzenemethanols of Formula I herein-`
above. A9 described more fully hereinbelow, certain of the ketones are also useful as antihypertensive or antiarrhythmic agents.

Particular embodiments reside in the compounds of Formulas I and II hereinabove wherein Rl, R2, R3, n, Q and Y
have the previously indicated meanings and Ar is phenyl or phenyl having one or two lower alkyl, hydroxy or lower alkoxy.
The invention also deals with N-(arylalkyl)-2-[4-YO-3-(lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl)-phenyl~ethylamines having Formula III hereinbelow Q
yo - ~ - C~ CH-NH-ç-(cH2)n-Ar III
wherein Rl, R2, R3, n, Ar, Q and Y have the previously indicated meanings; and acid-addition salts thereof.
These compounds are useful as antihypertensive agents and as more fully described hereinbelow, certain of them are also useful as antiarrhythmic agents.
The invention also deals with N-(arylalkyl)-2-chloro, bromo or iodo-2-[4-YO-3-~lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl~phenyl]ethylamines having Formula IV herein-below: Q

yo ~ CH-cH-NH-c-(cH2)n-Ar IV
wherein Rl, R2, R3, n, Ar, Q and Y have the previously indicated meanings; x is chloro, bromo or iodo; and acid-addition salts thereof.
These compounds are useful as intermediates in the preparation of the compounds of Formula III hereinabove.

The benzenemethanols of formula I hereinabove can be prepared by reducing the aminoalkyl phenyl ketone~ having Formula II hereinabove. The aminoalkyl phenyl ketones of formula II can be prepared by reacting a haloketone having Formula V hereinbelow:

YO~ CH-X

.
V
wherein Rl, Q and Y have the previously given me~ningS and X

- 1~ chloro, bromo or lodo, with an (arylalkyl)amlne havlng Formula VI
hereinbelow: R
Ar-(CH2) -~-NH2 VI
. .
wherein R2, R3, n and Ar have the previou~ly glven meaning~.

The 3-(lower alkylsulfinyl)benzenemethanols of Formula I hereinabove, wherein Rl, R2, R3, n, Ar and Y have the above-given meanings and Q is lower alkylsulfinyl can be prepared by oxidizing the 3-(lower alkylthio)benzenemethanols of Formula I
wherein Rl, R2, R3, n, Ar and Y have the above-given meanings and Q is lower alkylthio.
The 2-phenylethylamines of Formula III hereinabove can be prepared by reducing the 2-chloro, bromo or iodo-2-phenylethyl-amines of Formula IV hereinabove.
The 2-[3- ~ower alkylsulfinyl)phenyl]ethylamines o Formula III hereinabove, wherein Rl, R2, R3, n, Ar and Y have the~

. -8-_, ... _. __ ,,_ __ ... .. . .. . . . . ; . . _. _ _ previously indicated meanings ant Q is lower alkylsulfinyl, can be prepared by oxidizing the 2-~3-(lower alkylthio)ph~nyl]ethylamines of Formula III wherein Rl, R2, R3, n, Ar and Y have the previously indicated meanings and Q is lower alkylthio~
The 2-chloro, bromo or iodo-2-phenylethylamines of Formula IV can be prepared by reacting a benzenemethanol of Formula I hereinabove with a halogen acid HX or an inorganic acid chloride or bromide.
One can reduce blood pressure in mammals by administering to said mammals a blood pressure lowering effective amount of benzenemethanol of Formula I hereinabove. One can produce vasodilation in mammals by administering to said mammals, in an amount effective to produce vasodila~ion, a benzenemethanol of Formula I hereinabove. One ean reduce blood pressure in mammals by administering to said mammals a blood pressure lowering effective amount of a compound of Formula III
hereinabove.
In the terms lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl, "lower" denotes an alkyl moiety having from 1 to 4 carbon atoms which can be arranged as straight or branched chains. There are included methyl, ethylJ n-propyl, isopropyl, n-butyl, sec-butyl, and the like, methyl and ethyl being preferred.
By "lower alkanoyl" is meant straight or branched-chain alkanoyl radicals containing from 1 to 6 carbon atoms as illustrated by formyl, acetyl, propionyl, butyryl, isobutyryl, pivalyl, caproyl and the like.

4,~

The term "halo" a~ used herein denote~ fluoro, chloro, bromo or iodo.
The term "aroyl" as uBed herein 15 intended to lnclude benzoyl ~nd benzoyl ~ubstltuted by from one to tws lower alkyl groups, ~or exampleg o-toluyl, m-toluyl, ~-toluyl, 3~4-dimethylbenzoyl, 3,5-dlmethylbenzoyl 2,5-dlmethylbenzoyl, m-i~opropylbenzoyl, p-tert-butylbenzoyl and the like.
It will be appreclated that Y in Formula~ I and II can repre8ent acyl re~idue~ other than the above since it is well known that such ester~ undergo hydrolytic cleavage under physiologlcal condltlons to produce in sltu the parent phenols whlch, of cour~e, have the prevlously lndl-cated blologlcal actlvlty.
As used hereln ~toluenesulfonyl~ i3 intended to lnclude ortho, meta and ~ara-toluenesulfonyl~
' The benzenemethanol~ represented by Formula I hereinabove are obtalned by reduoing the aminoalkyl phenyl ketones of Formula II wlth an approprlate reducing agent ln a sultable solvent as for example sodium borohydride or llthium borohydrlde in water or a lower alkanol; lithium alumlnum hydride in ether, tetrahydro~uran or dloxane; di-borane in tetrahydrofuran or diglyme; alu~lnum lsopropoxlde ln 2-propanol; or by hydrogenation ln the presence of a noble metal catalyst ~uch as palladium or platinum.
When the aminoalkyl phenyl ketone contains a carboxyllo ester group (Formula II whereln Y 1~ lower alkanoyl .

24~

or aroyl~, and it 1~ deslred to retaln the ester group ln the reductlon product (Formula I wherein Y i~ lower alk~noyl or aroyl), the use Or reducing means resulting ln reduction of carboxylic ester group~ should of course be avolded.
Accordlngly in such lnstances reduction i8 pre~erably effected with an alkali metal borohydrlde or by catalytlc hydrogena-tion which reduclng means re~ult in selective reduction of the ketone functionO When the u~timately desired product is the free phenol (For~ula I whereln Y ls hydrogen) the above .
reduction reactlon can be followed by hydrolysis of the ester group, or alternat~vely, the e~teri~ied amlnoalkyl phenyl ketone (Formula II wherein Y is lower alkanoyl or aroyl) can be reduced with a reagent capable of reducing both ketone and carboxylic ester functions e.g. lithlum alumlnum hydrlde.
The borohydride reductlon method is convenlently carried out by treatlng the aminoalkyl phenyl ketone with-sodium borohydrlde in methanol at about -10C. to 65C~
~or approximately 15 minutes to 2.5 hour~ or until reduction iB substantially complete as indicated by thin layer chroma- -tography. If the starting material contains an ester group (Formula II wherein Y is ~ower alkanoyl or aroyl) and it is desired to retain the latter in the final product~ the reaction mixture i8 quenched wlth acid and the esterified benzenemethanol (Formula I wh~reln Y i8 lower alkanoyl or aroyl) i5 isolated in conventional rashion. If on the other hand the free phenol (Formula I wherein Y is hydrogen) i~
desired the reactlon mixture is treated with an equivalent o~ sodium or potassium hydro~ide in water and stlrred at .

about 20C. to 65C. for approxlmately ~0 mlnute~ to 15 hours. The re~ulting phenol is isolatéd in a conventlonal manner.
The catalytlc hydrogenation proces~ ls convenlently carried out ln a ~uitable solvent, for example N,N-dlmethyl-formamlde, at 20C.-50C. under a hydrogen pressure of ~rom 20-50 p.8.1. ln the pre~ence of a noble metal catalyst such a~ palladlum. The hydrogenation i~ continued untll the theoretlcal amount of hydrogen 18 absorbed. After removal of the catalyst, the reduction product is i801ated in con-ventional ~a~hion.
Although the 3-(lower alkyl~ul~inyl)benzenemethanols (Formula I whereln Q is lower alkyl~ulflnyl) can be obtained by reduclng the corresponding ketones (Formula II ~hereln Q
18 lower alkylsulrlnyl) according to the roregoing procedures, lt 18 ordlnarlly prererr~d to prepare the sulfinyl compound~
by oxidizing the corresponding 3-(lower alkylthio)benzenemethanol6 ~Formula I wherein Q is lower alkylthio) with an appropriate oxidizing agent such as a peracid, hydrogen peroxide or sodium metaperiodate.
- The oxidation is prererably carried out by treat-~ng the 3-(lower slkylthlo)benzenemethanol ~lth commercial 50% peracetlc acld in methanol at about -1`0C. to 10C. ror approximately 15 minutes to 1.~ hours or untll oxidation i~
substantlally complete a8- lndicated by thin layer chroma-tography.
Alternatively, oxidatlon is effected wlth 30%
hydrogen peroxide ln methanol at about 20C. to 65C. for from 24 to 72 hours or untll oxidation i9 ~ubstantially complete 88 indlcated by thln layer chromstography. The oxidatlon product is isolated according to conventional methods.

. . ' .... ~

l~lZ4~i The aminoalkyl phenyl ketones of Formula II herein above can be obtained by reacting a haloketone of Formula V
with an excess of an ~rylalkyl)amine of Formula VI in a suitable solvent such as acetonitrile, dimethylsulfoxide, or N,N-dimethyl-formamide at about -65C. to 25C. for from 1 to 4 hours or until the reaction is substantially complete as indicated by thin layer chromatography.
In those instances wherein Y in Formula V is lower alkanoyl or aroyl, reaction with an (arylalkyl~amine may result in partial cleavage of the ester function, or the ester of Formula II (i.e., when Y is as defined above) can be hydrolyzed to the free phenol in a separate step. When desired the partially deacylated or hydrolyzed product can be re-esterified according to known procedures for example with ~n acyl halide in the presence of a strong acid such as trifluoroacetic acid.
Similarly one can convert a free phenol of Formula I or III to the corresponding ester by such esterification.
Although the ~-(lower alkylsulflnyl)phenyl ketones . (Formula II wherein Q iB lower alkylsulflnyl) can be obtalned by reactlng a ha!loketone o~ Formula ~ wherein Q 18 lower alkylsulflnyl wlth an appropriate (arylalkyl)amine o~ Formula ~l lt ls generally prererred to prepare the 3-(lower alkyl-sulrinyl)phenyl ketones Or Formula II by oxldatlon o~ the l~Z45 corre~pondlng sulflde~ (Formula II, Q 1~ lower alkylthlo) a~
descrlbed herelnabove for the prepar~tlon Or the 3-(lower alkyl8ulflnyl)benzenemethanols tFormula I whereln Q 18 lower alkylsulfinyl).
The (arylalkyl)amlnes Or Formula VI are generally known, or lr speclrlcally new are obtalned accordlng to the procedures described for the preparatlon of the known compounds.
~hu~ for example tertlary carblnamlnes, l~eO.
(arylalkyl)amlnes Or Formula VI whereln both R2 and R~ ~re lower alkyl can be obtalned from the co.rrespondlng generally known tertlary carblnol8 vl~ the well known Rltter reaction [Organic Reaction~ ! 17, 213 (1969)] ~ollowed by hydrolysls of the resulting tertiary ~arblnamlde~.
(Arylalkyl)amlnes Or FormulaVI wherein one Or or both R2 and R3 a`re hydrogen can be obtalned by reactlon o~
an aldehyde or ketone o~ appropriate carbon content wlth ammonla or an ammonla derlvative ln accordance wlth the procedures descrlbed ln Organic Reaction~ 4, 174 (1948) and Organlc Reactlons 5, 301 (1949)~
The haloketones o~ Formula V are obtained by halogenatlng with chlorlne or bromlne the appropriate phenyl ketone having the Formula VII herelnbelow:

Q~

YO ~l!CH2R

VII

whereln Rl and Q have the previously glven meanlngs and Y i8 methyl, lower alkanoyl or aroyl. The reactlon i~ convenlently . , . . . . ........ . . -l~51Z4S

carrled out by treating the ketone o~ Formul~ VII ln an inert solvent auch as chlorororm with bromine at approximately 25C. optionally ln the pre~ence 0~ ~n inorganic baae~e.g.
calclum carbonate. The reaction generally has an inductlon perlod and ln certaln lnstancea lt may be advantageous to lnltlate the reactlon by exposing the mlxture to uitraviolet radiation until bromination has commenced a~ evldenced by decolorization and concomitant evolution o~ hydrogen bromlde.
If de~lred the Y substituent of the resulting haloketone can be removed according to well known procedure~, for example by ester hydrolysis when Y ~s lower alkanoyl or aroyl and by 0-demethylation with a Lewis acld ~such as aluminum chloride, hydrogen bromlde or boron tribromlde when Y 18 methyl.
The correæponding lodoketone~ (Formula V wherein X is iodo) can be obtained by reacting the chloro or bromo-ketones with sodium or potassium iodide in acetone under - the condition~ Or the well known Finkelsteln reaction.
The phenyl ketones of Formula VII herelnabove can be obtained by a variety Or procedures which are generally known in the art.
Thus ~or example the 3-(lower alkylthio)phenyl ketones of Formula VII wherein Q is lower alkylthio and Y is lower alkanoyl or aroyl are obtalned by alkylatlon of the parent 3-mercapto-4-hydroxyphenyl ketones (Formula VII whereln Q 18 mercapto and Y i~ hydrogen) with an appropriate lower alkyl halide in a sui'table sol~ent such as a lower alkanone ln the presence o~ an acid acceptor,e.g~ an alkali metal carbonate-, ~ollowed by esterification of the resultlng 3-~Z45 (lower alkylthio)-4-hydroxyphenyl ketone~ (Formula VII where-in Q 1~ low~r alkylthio and Y 18 hydrogen~ wit~ an ~ppropriate acylating agent auch a~ a lower alkanoyl or aroyl hallde or anhydride in ~n inert solvent ~uch as methylene chloride, chloroform, benzene or toluene ln the pre~ence of an acid ~cceptor ~uch a~ triethylamine or pyrldineO The 3-mercapto-4-hydroxyphenyl ketones are in turn obtalned by chloro-sulfonation Or the generally known 4-hydroxy~henyl ketone~ of Formula VII whereln Q and Y are hydrogen wlth exce~s chloro-sul~onic acld at about 0CO to 25C. pre~erably in the absence of a solvent followed by reductlon o~ the resultlng 3-chlorosulfonyl-4-hydroxyphenyl ketone~ wlth a sultable re-duclng agent such aæ stannous chloride and hydrochlorlc acld or zlnc and sulrurlc acid.
Alternatively the 3-(lower alkylthlo)phenyl ketones O, Formula VII wherein Q ls lower alkylthlo and Y 1B lower alkanoyl can be obtained by acylating the generally known o-(lower alkylthlo)phenols with an approprlate acyl halide (e~g. RlCH2C0~)) under Friedel-Crafts condltlons ~ollowed by esterlficatlon Or the re~ulting 3-(lower alkylthio)-4-hydroxyphenyl ketones as descrlbed aboveO
It will be appreciated that although the ~-(lower alkylsulflnyl)phenyl ketones Or Formula VII can be obtalned by oxidizlng the corresponding sulfides (Formula V wherein Q i8 low~r alkylthio) it is generally preferred to employ the latter as a startlng material and to carry out any de~lred oxidatlon Or sul~ide to ~ulroxide at a later stage ln the synthesia as prevlou~ly descrlbedO

z~s The 3-(lower alkylsulfonyl)phenyl ketones o~ Formula VII where~n Q is lower alkylsulronyl and Y iR methyl are obtalned by oxidizing the 3-(lower alkyl~ulronyl)~anlsole~ Or Formula VIII

hereinbelow: -CH30 ~ -CH2CH2R

VIII

wherein Rl has the previously given meaning and Q 1~ lower alkylsulfonyl wlth an appropriate oxidizing Feagent 3uch as ammonium persulfate in the presence o~ silver nitrate ln aqueous medium ln the approximate temperature range 20C. to 70C. ~or about 2 to 3 hours. In turn the 3-(lower alkyl~ul~onyl)anisoles are obtained by sulronating the generally known anlsoles o~ Formula VIII wherein Q i3 hydrogen wlth an appropriate lower alkylsulfonic anhydride in an inert solvent, e.g. ~m-tetrachloroethane at about 130 C. to 180 C.

The ?-phenylethylamines or Formula III horelnabove can be obtained by reducing a 2-halo-2-phenylethylamine of Formula IV with a suitable reducing agent such as lithium aluminum

2 Y/ ~ e ~~ hydride in ether, tetrahydrofuran or ~*a~e, sodium borohydride in a lower alkanol or N,N-dimethylformamide: or by catalytic hydrogenation.
Reduction is conveniently achieved employing sodium borohydride in N,N-dimethylformamide at -10C. to 25C. for about 0.25 to 2 hours or until the reaction is substantially complete as indicated by thin layer chromatography.
of course, when the 2-halo-2-phenylethylamine contains another redùcible function such as an ester group (e.g., Formula IV wherein Y is lower alkanoyl or aroyl) and it is desired to retain such function in the reduction proauct, the precautions described hereinabove for reducing the aminoalkyl phenyl ketone ~Formula II) should be taken. Similarly, if the free phenol ~Formula III where Y is hydrogen) is desired, an esteri~ied product obtained ~Formula III where Y is lower alkanoyl or aroyl) is hydrolyzed with a base.
The 2-halo-2-phenylethylamines of Formula IV herein-above are obtained by reaction of an appropriate benzenemethanol of Formula I with a halogen acid or an inorganic acid halide in a suitable solvent, e.g., hydrogen chloride in tetrah~drofuran or dioxane, hydrogen bromide in acetic acid, sodium or potassium iodide in phosphoric acid, thionyl chloride, thionyl bromide, phosph4rus oxychloride, phosphorus oxybromide, phosphorus tri-c~loride or phosphorus tribromide in benzene, toluene, chloro-~orm or pyridlne.
Although the 2-phenylethylamines of Formula III wherein Q i~ lower alkylsulfinyl can be obtained by the above-described ~equence of halogenation of the appropriate benzenemethanol (Formula I wherein Q i9 lower alkylsulfinyl) followed by reduction of the ' resulting halo compound ~Formula IV wherein Q is lower alkyl-sul~inyl), it is or~inarily preferred to carry out the successive halogenation and reduction starting with the corresponding lower alkylthio benzenemethanol (Formula I wherein Q is lower alkyl-thio) and then ~xidizing in the last step to the desired loweralkylsulfinyl c~mpound. The oxidation is carried out in accordance with the methods earlier described for the prepara-`tion of the benzenemethanols of Formula I wherein Q is lower alkylsulfinyl.
Due to the presence o~ the ba~ic amino grouping, the rree base ~orm~ o~ the ~inal products repre~ented by Formulas I and III and also Or the intermediates represented by Formulas II and IV react wlth organic and inorganlc aclds to ~orm acld-addition salts. The compounds o~ the invention are use~ul both in the free b~e ~orm and in the ~orm of acid-, additlon salts, and both-~orms are within the purvlew o~
the invention. The acid-addition salts are ~imply a more convenlent form ~or use, and in practice? u~e o~ the salt form lnherently amounts to use o~ the base form.

~t~ 4~

The acld-addltlon ~alts are prepared rrom any organic or lnorganic acld. They are obtained ln conventlonal fashion~ for instance either by dlrect mixlng of the base with the acid, or, when this 18 not appropriate3 by dl~aolv-lng either or both the ba~e and the acld separately ln water or an organic solvent and mlxing the two solutions, or by dissolving both thé base and the acid together in a ~olventO The resulting acld-addition salt is isolated by filtration, lf it i5 insoluble in the reactlon medium, or by evaporation of the reaction medium to leave the acid-addition salt as a resldue. The acid moieties or anions in these ~alt form~ are in themselves neither novel nor critical and therefore can be any acid anion:or acid-llke substance capable of ~alt formatlon wlth the base~
Representative acids for.the formation of the acid-addition salts include formic acld, acetic acld, i~o-butyric acid, alpha-mercaptop~bplonic acld, trlfluoro-acetic acld, malic acid, fumarlc acld, ~ucclnlc acid, succlnamic acid, tannic acid, glutamic acld, tartaric acid, dibenzoyltartaric acid, oxalic acid,. pyromuclc acld, cltrlc acid, lactlc acld~ mandellc acld, gly.colic acid, gluconic acld, saccharic acld, a~corblc acid, pe~LcillinJ.benzolc acld, phthallc acld, salicylic acid, 3,5-dlnltrobenzolc acld, anthranllic.acid,;cholic acld, 2-pyridinecarboxyllc acid, pamoic acid, 3-hydroxy-2-n~phthoic acld, plcrlc acid, qulnlc acld, tropic acid, 3-lndoleacetlc acld, barblturlc acld, cyclohexylsulfamic acld, lsethlonlc acld, methane-.

1(35124~

sulfonic acld, benzene~ulfonic acid, ~-toluenesulfonic acld, 1,4-naphthalenedi~ulronlc acld, butylarsonic acld~ methane-phosphonic acld, acldlc re~ln~, hydro~luorlc acld, hydro-chloric acld, hydrobromic acld, hydrlodic acld, perchlorlc acld, nitrlc acid. sulfurlc acld, sulramlc acld, glutarl~
acld, phosphoric acid, arsenic acld, and the like.
All the acid-addltion salts are useful a~ ~ource~
of the free base formg by reaction wlth an lnorganlc ba~eO
It will thus be appre^iated that lf one or more o~ the characteristlcs such as solubility, crystallinity molecular welght~ physical appearance~ toxiclty, or the llke Or a ~iven base or acid-addition salt thereof render that ~orm un-sul~able ror the purpose at hand lt can be readlly converted, in accordance with procedures well known in the art, to - 15 another more suitable ~orm.
When the compounds of the lnvention are to be utllized for pharmaceutical purposes, the aclds used to prepare the acid-addltlon salts lnclude prererably those whlch produce, when complned wlth the rree base9 medlclnally' aceeptable salts, that i8, ~alt~ whose anlons are rel~ttvely lnnocuous to the anlmal organlsm ln medlclnal dose~ Or the salts so that the beneflcial properties inherent ln the free base are not vitlated by slde e~rects a~crlbable to the anlons. Approprlate medlclnally acceptable salts withln the scope Or the lnvention'are those derlved from acids such 8~ hydrochloric acid, acetlc acid, lactic acld, tartarlc acld, cyclohexylsul~amlc acld~ methanesulfonlc acldg phos-phorlc acld and t'he llke.
The compound~ o~ the lnvention respresented by Formula~ V wherein Y iæ hydrogen are Or coursë

amphoterlc, havlng both acldlc phenol ~nd b~slc amlno groups, and thu~ form salt~ wlth both acids and base~.
Due to the pre~ence of at least one and as many as ~our asymmetric centers in the compounds o~ the lnvention represented by Formula I (l.e. the carblnol carbon atom, the carbon ~atom to which Rl when lower-alkyl io attachedg the carbon atom to which R2 and R3 when dls~lmllar are attached, and the sul~ur atom when Q is lower alkyl~ulrlnyl), sald compounds can exl~t in as many as 16 stereochemically lsomerlc forms, all Or whlch either indivldually or as mixture9 of any two or more are considered wlthln the purvl0w of this lnvention. I~ deslred, the isolatlon or the productlon of a partlcular stereochemical rorm or o~ a mlxture of two or more gtereochemlcal ~orms can be accompllshed by appllcation of general princlples kn~wn ln the art.
When preparing either a partlcular stereoisomer or a specl~ic mlxture of any two or more stereoisomers it i9 advantageous to employ intermedlates of flxed stereo-c}iemlcal conflguratlon thereby llmiting the number Or stereo-isomerlc forms present ln the flnal product and thus simpllf'y-lng isolatlon o~ the deslred componentsO Accordingly prlor to reactlon with a haloketone of Fbrmula V an (arylalkyl)-amlne o~ Formula YI containing an a~ymmetric center (i.e.
the carbon bearlng non ide*tIcal subs~ltue~t&~ and R3) 18 resolved lnto lts (+) and (-) optlcal antipodes accordlng to conventional techniques and employing c~nventional resolv-lng agents ~uch as optlcally active tartaric acid, QDO-dlbenzoyl tartaric acld, mandelic acid, malic acld, and lO~iZ9~S

the llke. A~ deslred, elther the (+) or the ~ (aryl-alkyl~amlne can then be reacted with a haloketone accord~ ng to the pre~iously descr~bed procedure to pro-duce an aminoalkyl phenyl ketone of Formula II having a fixed stereochemlcal configuration at the carbon bearlng substltuents R2 and R3~
When the haloketone also contalns an a~ymmetrlc center (Formula ~ wherein Rl is lower alkyl and Q i.8 lower alkylthio or lower alkyl~ul~onyl) reaction wlth elther the (+) or (~ arylalkyl)amine produces a palr of diastereomeric aminoalkyl phenyl ketones Or Formula II
(Rl is lower alkyl, Q is l.owe-r aIkylthlo or lower alkyl-sulfonyl) whlch can be separated accordlng to conventional method~9 e.g. fractlonal cry~talllzatlon of a sultable ~.
acid addition salt~ .
Of course when the haloketone contains no asymmetric center (Formula ~ whereln Rl is hydrogen and Q is lower alkylthio or lower alkylsulfonyl) reaction wlth either the (+) or (-)-(arylalkyl)amine produces directly a single (+) or (-) stereoisomer of the aminoalkyl phenyl ketone or Formula II (Rl is hydrogen and Q iB lower alkylthio or lower alkylsulfonyl)~
Reduction of the s~e ~ chemically fixed amino.-. alkyl phenyl ketone as described hereinabove creates a nsw asymmetric center (i.e. the carbinol carbon atom) and there-fore produces a pair of diastereomeric 3-(lower alkylthlo or lower alkylsulfonyl)benzenemethanols of Formula I. If de~ired the diastereomers can be separated accordlng to known methods, for example, by fractlonal crystsllizatlon S

of the acid-addltion salt of an optically sctlve acid such a~ (+) or (-) mandelic acld, tartarlc acid, 0,0-dibenzoyl-tartaric acid, mallc acld and the like, or by converting the diastereomeric mlxture to a suitable ester derlvative (i.e. Y in Formula I is lower alkanoyl, aroyl~ benzene sulronyl or p-toluenesulfonyl~ e.g~ the acetateJ benzoate, or p-toluenesulfonate and separating the esters by chroma-tography or by fractional crystalli~ation of a suitable acld-additlon salt thereo~O
Each of the individual diastereomers o~ the ~-(lower alkylthio)benzenemethanol (Formula I, whereln Q i8 lower alkylthlo) as ~bove-produced can be oxidized as descrlbed hereinabove again giving rise to a new center o~ a~ymmetry (l.e. the sulfur atom) and producln~ thereby a palr o~
diastereomeric ~ul~oxldes (Formula I, Q is lower alkyl~ul~lnyl3 whlch also can be separated in accordance with the conventional procedures described aboveO
Alternatively the palr of dlastereomerlc ~-(lower alkylthlo)benzenemethanols can be oxldlzed dlrectly to give a mixture of four diastereomeric sul~oxides which if deslred can also be separated according to the above-descrlbed procedure3, for example by fractlonal cry9talliza-tlon of a suitable acid-addition salk such as the hydro-chlorlde or cyclohexylsul~amate.
The 2-phenylethylamine of Fornula III, having three potential centers of asymmetry, can thus exist in as many as 8 stereochemically isomeric forms. All such forms either individually or as mixtures of any two or more are, of course, considered within the ambit of the present invention. The pro-duction of a particular isomer or mixture of isomers is most _ . .... __ .. _,_, . ..

1()5~1245 conveniently achieved by starting with a benzenemethanol of Formula I having the desired stereochemistry as obtained in accordance with the above-described procedures.
The compounds o~ the present lnventlon havlng Formula I herelnabove exhibit use~ul antihypertenslve, vasodllator and ~-adrenerglc blocking actlvlty. Of par-ti cular advantage i~ the combinatlon ln a single compound o~ va~odilator and ~-adrenergic blocking actlvlty whereby ......

Z~5 the reflex tachycardla assoclated with the reduction ln blood pres~ure through vasodilation 18 e~fectively reduced or elimlnated by ~-adrenergic blockade. The compounds are thererore effective ~n lowering blood pres~ure without causing undesirable tachycardic ef~ects.
It should be noted, however, that although both vasodllator and ~-adrenergic blocking activi~y re~ide in the same compound, the time of on~et o~ each of these actions appears to be somewhat different, vasodllation usually preceding ~-adrenergic blocka~eO Thi~ can of cour~e give ri3e to a moderate transient ~ncrease in heart rate observable on the first day or two o~ repeated medication.
~hereafter, however, ~-adrenergic blocka~e takes ~ull effect and subsequent continuou~ medicatlon effects sustained blood pressure lowerlng with no appreciable elevatlon Or heart rateO Moreover as opposed to the antlhypertensive response which i~ directly dose-related, the heart rate elevation observed at the lower doses tested i~ not appreciably increased either in magnitu~e or in duration at hlgher doses. It is ~herefore pos~ible to raise the dosage aevel in order to achieve a further reduction in blood pressure without causing a corresponding increase in heart rate~
A preferred embodiment of thi~ invention is 4-hydroxy-a-~3-(4-methoxyphenyl)-l-methylpropyl]amino methyl? 3-tmethylsulfinyl)benzenemethanol (Formula I
wherein Rl, R2 and Y are hydrogen; R3 is methyl; n is 2, Ar 18 4-methoxyphenyl; and Q is methylsulfinyl) whlch ha~
high antihypertenslve activity and a particularly e~ective .
--- . . .

24~

distributlon of vasodllator and ~-adrenerglc blocking actlvlty and 1~ accordlngly especially efficacious as an antihypertenslve agent with no unde~irable tachy~ardic ~lde effects.
The above-de~cribed compound contalns three center~
of asymmetry (l.e. the carbon atom bearing the methyl group, the carbinol carbon atom and the sulfur atom) and can therefore exist as a mlxture of up to eight ~tereo-isomers. Particular~y prererred among these are the four dia~tereomers derlved from (+)-4'-hydroxy-2-{[3-(4-methoxyphenyl)-l-methylpropyl]amino~-3'-(methylthlo)-acetophenone (Formula II wherein Rl, R2 and y are hydrogen;
R3 is methyl; n 18 2; Ar i~ 4-methoxyphenyl; and Q is methylth~o) by reduction of the carbonyl group followed by oxidatlon of the methylthio group. These isomers either individually or as mixtures o~ any two or more exhibit potent antihypertensive activity with no undeslrable tachycardic side effects. Although each of the four dlastereomers can be separated from the mixture as described hereinabove thls 18 generally unneeessary and it 18 therefore economically advantageous to use the mixture as producedO
In carrying out the method aspect of thls lnven-tion, i.e. the method of reducing hypertension ln mammals which comprlses admlnlsterlng to sald mammals an antl-hypertensively~ effectlve amount of a compound havlng Formula in a suitable pharmaceutical composition, e.g., I, sald compounds can be administere~7~rally in the form of pills, tablets, capsules, e,g. ln admixture with talc~
starch, mllk sugar or other inert, i.e. non-toxlc or pharma-cologically acceptable pharmaoeutlcal carrler, or ln the , . , . , _ .~

~ 5 form o~ aqueou~ aolution~, su~pen~ion~, encap2ulated su~pen~lons, gels, elixir~, aqueous alcohollc ~olutlon~, e.g. ln admlxture wlth sugar or other ~weetening agents, flflvoring~, coloPants, thlckener~ and other conventional pharmaceutical excipients.
When inJected subcutaneou~ly, intramuscularly, or intravenously, :they can be adminlstered, e.gO, as an aqueou~ or peanut oll ` solution or ~uspen~ion using e~cipient~ and carrlers con-.ventlonal for thls mode Or admlnistr~tlonJ The best route o~ admlnistration and the be~t dosage wlll be apparent from the labora~bry tests ~or activlty and toxicity o~ the selected compound conventionally undertaken as part o~ the develop-ment phase of a pharmaceutical.
The molaoular structures o~ the compounds o~ the lnvention were assigned on the basi~ o~ the method o~ thelr preparation and study o~ thelr IR and N~R spectra, and ¢on-fl~ed by the correspondence betwoen calculated and round values ~or the elemental analyses o~ representatlv~ examples, The ldentlty and purlty of lndlvidual ~tereol~omer~
as well as the..compositlon o~ ~tereoisomeric mixture~ were determined on ~he bas~s o~ optical rotation and high pressure llquld chromatography.
The lnventlon 18 illu~trated by the following examples wlthoutJ however, being limlted thereto. ~nless otherwise speciried optlcal rotations werc determined on a 2% sol~tion o~ the compound ln methanol~

Example 1 A. To 100 g. (o.o85 mole) o~ ohlorosulfonlc a¢ld at 5C. was added oYer a perlod o~ 25 minute~ 20 g. (0.15 mole) of p-hydroxyacetophenone. The .te~perature was allowed ` .

Z~5 to gradually ri~e to 22C. as the reaction wa~ stlrred overnight. The temperature wa~ then raised to 55-60C.
and stirring was continued an additional hour. The reactlon mixture was quenched ln ice-water and the precipitated ~olid was collected and washed with water. The product was dis~olved in ethyl acetate and the re~ulting solutlon was dried and evaporated to dryne~. The residue was recry~tallized from benzene to glve 1205 gO of 4'-hydroxy-~'-(chlorosulfonyl)-acetophenone, mOpO 1~8-142C~ The filtrate afforded a second crop of 5.0 gOJ m.p. 124-136Co Bo Hydrogen chloride wa~ bubbled lnto a stirred mix-ture containing 105 g. (o.46 mole) of stannous chlorlde di-hydrate and 400 mlO o~ glacial acetic acld until a nearly clear solution was obtained. To the latter ~olution was added p~rtionwise over 20 minutes 18 g. (0.077 mole) of crude 4'-hydroxy-3'-(chlorosulfonyl)acetophenone while the temperature was maintained at 25-~0C. After the addition was complete ~itrring wa~ continued an additional 005 hours.
The reaction mixture wa~ then poured into 400 mlO of 12N
hydrochloric acid, diluted wlth 800 ml. of water and extracted wlth chloroform. The extracts were washed with saturated aqu~ou~ ~odium chloride and evaporated to dryne~0 The residue was rec~ystallized from benzene to give 4 g. of 4-hydroxy-3'-mercaptc~cetophenone, m.p~ 117-120Co C. A mlxture containing 1.0 g. (0. oo6 mole) Or 4'-hydroxy-3'-mercaptoacetophenone, 009 gO (o.0063 mole) of methyl iodide, 0.~3 g. (0. oo6 mole) of potassium carbonate and 12 ml. of acetone ~a9 ~tlrred 2.5 hours at room tempera-ture. The reaction mlxture was riltered and the filtrate l{~Z~5 evaporated to dryne~s. The residue was dissolved in chloro-form and the resulting solu~lon wa8 washed with lN hydro-chlorlc acld, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dlssolved in hot benzene and the solution was ~iltered through a 1/4" pad of silica gel ln order to remove a colored impurityO
Evaporation o~ the filtrate afforded 0.9 g. of 4'-hydroxy-

3'-(methylthio)acetophenone3 mOpo 117-120Co Do Alternatively, to a ~tirred solution containing 6104 g. (0.4~5 mole) of o-(methylthio)phenol and 35 g.
(0045 mole) of acetyl chloride in 170 mlO of nitrobenzene was added portionwise over a period of 20~minutes 80 g.
(0.60 mole) of aluminum chloride. The reaction mixture was stirred overnight at room temperature and then one hr. at 65C. The reaction mixture was cooled, diluted with ice and water and extracted with methylene chloride. The organic extracts were evaporated in vacuo, the residue diluted with ether and allowed to stand two days in the refrigerator~ The preclpitated product was collected and dri~d to give 27 g. of 4'-hydroxy-3'-(methylthio)-acetophenone.
E. To a cooled, stirred sol~bion containing 24.5 g.
(0.13~ mole) of 4'-hydroxy-3l-l(methylthio)acetophenone and 21 g. (0.21 mole) of triethylamine in 400 mlO of methylene chloride was added dropwise over a period of ~0 minute~
16.4 g. (0.21 mole) of acetyl chloride. After stirring overnight at room temperature the reaction mixture was wa~hed with water, d~i~ed over anhydrous sod~um sulrate, and concentrated to a ~mall volume. The concentrate was _30-~ 4~

dlluted with ether and c~oled ln an lce bath. The result-ing precipitate was collected to give 2~o 5 g~ Or 4'-hydroxy-3'-(methylthio)~cetophenone 4'-acetate.
F. To a stirred mixture contalnlng 23~2 g. (00108 mole) of 4'-hydroxy-3'-(methylthio)acetophenone 4'-aceta~e and 9 gO of calcium carbonate ln 300 ml~ Or chloro-form was added dropwise over a period of two hours a ~olution containing 6 ml~ (0~108 mole) of bromine in 30 ml. of chloro-formO The reaction mi~ture was ~iltered, and the ~lltrate washed with ~aturated ~queous ~odium bicarbonate, and evaporated to drynes~O The res~due was dissolved ln e~her and the ethereal solution diluted with cyclohexane and cooled in ice. The resultlng precipitate was collected and dried to give 2605 gO of 2-bromo-4'-hydroxy~
(methylthio)acetophenone 4'~acetate.
G. To a stirred solution containing 16 5 gO (OolO
mole) of 2-(4-methoxyphenyl)-1-methylethylamlne and 5 gO
(00051 mole) of triethylamine in 40 mlO of N,N-dlmethyl-formamide at -65Co was added dropwise over a period o~ 2 hours 15~5 go (00051 mole) of 2-bromo-4'-hydroxy-~'-(methylthio)acetophenone 4'-aoetate in 40 mlO of N,N-dimethylformamide. After the addition was complete stirring at -65co was contlnued an additional hourO The reaction mixture was then acidified wlth 10 mlO of l?N
hydrochloric acid and diluted with 100 mlO of waterO Upon shaking the aqueous solution with 200 mlO of a 20ol mix~ure of ether-methylene chloride the product began to precipitate ~rom the aqueous phase. The layers were separated and the aqueou~ portion ~as cooled in ice. The re~ulting precipitate 1~124~

was collected and dried 3 hour~ over pho~phorou~ pentoxide in a 65 vacuum oven to give 12.1 gO of 4'-hydroxy-2-{[2-(4-methoxyphenyl)-1-methylethyl]amino~'3''(methylthio)-acetophenone 4'-acetate hydrochlorlde.

Example 2 A stirred solution containing 1205 g~ (0~029 mole) of 4'-hydroxy-2-~2-(4-methoxyphenyl)-1-methylethyl]-amino~-3'-(methylthio)acetophenone 4~-acetate hydrochlorlde in 200 mlO of methanol wa~ cooled in an ice-acetone bath and treated portlonwi~e over 15 minutes with 009 gO of sodium ~orohydride. After the additlon was complete stirring was continued an additional 20 minutesO The reaction mixture was then brought to pH 7 with glacial acetic acld and evaporated to dryness. The residue was dlluted with ether and washed thoroughly with saturated aqueous sodlum bicarbonate. The ethereal solution was dried over anhydrou~ sodium ~ulfate and concentrated to a ~mall volume.
The concentrate Was acidifled with ethereal hydrogen chlor~de a~ cQoled overnight ln a refrigeratorO The precipitated product Was collected and recrystallized from methanol-l~opropyl alcbhol to give 201 gO of 4-hydroxy-a-~{[2-(4-methoxyphenyl-l-methylethyl]amlno~methyl~3-(methylthio)-benzenemethanol 4-acetate hydrochloride, mOpO 143-145~Co In addition to its antihypertensive activlty thls compound was also found to possess ~-adrenergic ~timulant activlty as evldenced by its ability to block histamine- -induced bronchoconstriction in the dog~

1~S~245 Example 3 To a stlrred suspension of 609 g. (00016 mole) of 4~-hydroxy-2-{L2-(4-methoxyphenyl)-1-methylethyl]amino}-3~-(methylthlo)acetophenone 4'-acetate hydrochloride in 120 mlO of methanol was added 400 mg~ of sodlum borohydrlde~
After 25 minutes all the starting mater~al had gone lnto solutlon. The reaction mi~ture wa~ treated with 10 mlO
of water and stlrred overnight at room temperatureO A
~olution contalning 900 mg~ of potas~lum hydroxide in 10 ml.
of water wa~ then added and the mixture he~ted under re~lux 005 hour. The resulting ~olution wa~ concentrated to one hal~ volume, the concentrate made slightly acidic with 12N
hydrochloric a¢id and evaporated nearly to drynes~0 The residue was di~t~d~with saturated aqueou~ sodium bicarbonate and extracted with ethyl acetateO The organic extract~
were dried over anhydrous sodlum ~ulfate, acidified with glacial acetic acid~ and concentrated untll crystalliza-tion beganO The product was collected, trlturated with ¢hloroform and flnally recrystallized from chloroform-methanol to give 309 gO of 4-hydroxy-a ~ l2-(4-methoxY-phenyl)-l-methylethyl]amino}methyr~3-(methylthio)benzene-methanol acetate salt, mOpO 163-165Co Ex~le 4 A solution containing 105 mlO of 3~ hydrogen peroxide and the free base liberated from 9 g of 4-hydroxy-a ~ L2-(4-methQxyphenyl)-l-methylethyl]amino~methyl~-3-(methylthlo)benzenemethanol 4-acetate hydrochloride in 150 ml. o~ methanol WaB stirred 2 days at room temperature and then 1.5 hours ~t re~luxO The reaction mixture wa~ then evaporated to drynessO The re~ldue was dl~olved in water, and the ~olution ~lltered to remove in~oluble impuritles.
The rlltrate wa~ acldifled with 12N hydrochlorlc acld and evaporated to drynessO The resldue was ~riturated wlth ether isopropyl acetate at -65Co The re~ultlng amorphous solld was dis~olved in hot water9 ~iltered to remove in-~oluble lmpuri.tie~9 and the ~lltrate evaporated to dryne~0 The residue wa~ triturated ~lkh ether and cyclohe~ane and the resultlng ~olld was collected and dried o~er pho~phoru3 pentoxlde. 6 hour~ at 85~Co a~ording 406 gO o~ 4 hydro~y~a-<t~2-~4-methoxyphenyl~ l~methyle~hyl]amin~o~met~y V 3~met~yl-~ulfinyl)benzenemethanol hydrochloride a~ an amorphou~ tan solidO mOpO 115Co In addltion to lts antihyperten~lve actlvity thls compound wa~ ~180 found to posseas ~-adrenerglc stlmulant activlty as evidenced by lts ability to block hlstamine-lndueed bronchoconstriction in the dogO

Example 5 Ao A solution containing 65 gO of p-ethylani~ole and 92 gO o~ methane~ulfonlc anhydride in 300 mlO of 8y~-tetrachloroethane wa~ heated under rer~ux 1705 hour~0 After washing with hot water khe reaction mlxture was evaporated to dryness in vacuo leaving 20 gO of dark oil which wa9 com-bined with the product of two previous runs and di~tilled under reduced pre~sureO The fr~ctio~ boiling at 90-120Co/005 mm. was collected and redi~tilled through a short Vigreux columnO The impuritie~ boiling at 45-65~Co/005 mmO were dis-c.arded and the pot residue was redl3tilledO The lmpurlties bolling at 175-187Co /10 mmO were diacarded leav~ng 30 ~0 Or nearly pure 4-ethyl-2-(methylsul~onyl)anisoleO

1~12~S

B. A ~olution containlng 55 g. (0.242 mole) of ammonium per~ulfate, 520 mg. o~ ~ilver nltr~te and 26 g. (00121 mole) of 4-ethyl-2-(methyl~ulfonyl)anl~ole ln 300 ml. o~
water was stlrred at 20C~ After one hour the temperature had ri~en to 48C. and a~ter 20 5 hours had dropped to 30C.
~he product was extracted with chloroform and a~ter drying over anhydrou~ sodium ~ulfate the ohloroform extracta were evaporated to dryneas. The resldue was ad~orbed on a column of ailica gel deactivated with 20% by weight of waterO
Impuritles were washed rrom the column wlth ether and the product was eluted with hot methylene chlorlde to glve 18 g.
Or 4'-methoxy-3'-(methyl~u~fonyl)acetophenone~, m.p. 146-148C.
C. To a solution containing 14.5 g. (0~ o6~ mole) of

4'-methoxy-3'-(methylsulronyl)acetophenone in 200 ml. o~
chloroform was added dropwi~e a ~olutlon contalnlng 10.2 g.
of bromlne in 40 ml. of chloro~orm. A~ter a 0.5-hr. lnduc-tlon perlod the bromine began to be con~umed. When the addition was nearly complete the product began to precipitate.
The reaction mixture wa~ diluted with methylene chlorlde and the resulting solutlon washed succe~sively wlth saturated aqueou~ ~odium bicarbonate and water and e~aporated to dryness.
Recryatallization Or the resldue ~rom methylene chloride-carbon tetrachloride afforded 17.9 g. of 2-bromo-4'-methoxy-3'-(methyl~lfonyl)acetophenone, m.p~ 168-170C.
D. A vigorously stirred mixture oontalning 4.5 g. o~
2-bromo-41-~ethoxy-3'-(methyl~ulfonyl)acetophenone, 4.5 g.
o~ aluminum chloride and 100 ml. Or chlorobenzene wa~ heated under reflux 2 hours. ~he reaction mixture was poured into ice-water and extracted wlth ether-ethyl acetate. The , ~U~

organic extract~ were dried over anhydrou~ sodlum ~ulrate and evaporated to dryness. The re~idue wa8 trltur~ted wlth ether and the resulting tan crystalllne solid was collected to glve 3.0 e. of 2-bromo 41-hydroxy-3'-(methyl~ulfonyl)-acetophenoneO
Eo To a ~tirred solution containing 10 g. (00 o6 mole) of 2-(4-methoxyphenyl)-1-methylethylamine in 50 ml~
of N,N-dimethylformamide at -30Co (dry ice-carbon tetra-chloride) was added d-ropwise a solution containing 7 g~
(00024 mole) of 2-bromo-4'-hydro~y-3'-(~ethylsulfonyl)-acetophenone in 20 ml. of N,N-dimeth~lformamideO After the addition was complete the reactlon mi~ture was stirred 2075 hour~ at 0C0 and then diluted with water and extracted with chloroformO The chloroform extracts were drled over anhydrous sodlum sulfate, acidir~ed with ethanolic hydrogen chloride and stored in a refrigerator overnlghtO The pro-duct which crystallized was collected and recrystallized - from chloroform affording 307 gO of 4'-hydroxy-2-~2-~4-methoxyphenyl)-l-methylethyl]amino}-3'-(methyl~ulfonyl)-acetophenone hydrochlorideO

Example 6 A solution containing ~07 g~ of 4'-hydroxy-2-{[2-(4-methoxyphenyl)-1-~ethylethyl~amino~-3'-(methylsul~onyl)-acetophenone hydrochloride in 100 ml. of N,N-dimethyl-formamide wa~ hydrogenated under an lnitial hydrogen pres~ure Or 50 p. 8 oi~ in the presence o~ 1 g. of 10~ palladium-on-charcoal hydrogenation catalyst. After 15 minutes one molar equlvalent o~ hydrogen had been ab~orbedb The catalyst was then removed by ~iltration and the filtrate evaporated to Z9:5 dFyne~R. The resldue wa~ dlluted with ethyl acetate and wa~hed wlth saturated'aqueous so~Lum blcarbonate. The ethyl acetate ~olution was dried over anhydrous sodium sul~ate and concentrated to 100 ml. The concentrate wa~
acldl~led with glaclal acetlc acld, conc~ntra,ted to approxl-mately 70 mlO and cooled. The re~ultlng crystalline pre-cipitate was collected to af~ord 20 9 go 0~ 4-hydroxy-~--<~2-(4-methoxyphenyl)-1-methylethyl]amino~methy V-3-(methyl-sul~onyl)benzenemethanol acetate saltJ mOp~ 130-131Co Example 7 To a stirred solution containing 24 gO (0.135 mole) o~ 3-(4-methoxyphenyl)-1-methylpropylamine ln 40 mlO
of N,N-dimethylformamide at -50Co waB added dropwise over 15 mlnutes a solution containing 15 gO (0005 mole) o~ 2-.

lO~lZq~5 bromo-4~-hydroxy-3'-(methylthio)acetophenone 4'-aceta$e in ~5 mlO of ~,N-dimethylformamideO After the addition was complete 3tirring was continued an'addltional 1025 hours~ The reaction mixture wa~ then treated wlth 4 ml~ o~
12N hydrochloric acld, dlluted wlth 100 mlO of water and extracted wlth ether-ethyl a~etate. The organlc extracta were dried over anhydrous aodlum sulfate, acldified with ethanolic hydrogen chloride and evaporated to drynes~0 The crude product contalnlng both the 4'-acetate and 4'-hydroxy compoundæ was di~solved ln a solution contalnlng 10 mlO of acetyl chloride ln 120 ml. of tri~luoroacetic acid and stlrred 2 hours at room temperature. The solution was then evaporated to drynes~ and the resldue partltioned between ether and water~ The ether layer was drl~ed over anhydrou~ sodlum sulfate and acidlfied wlth ethanolic hydrogen 1~1245 chlorlde. The resultlng preclpltate was collected and trl-turated wlth acetone-ether to glve 6.0 gO of 4'-hydroxy-2-{~3-(4-methoxyphenyl)-1-methylpropyl]amino~-3'-(methyl-thio)acetophenone 4'-acetate hydrochloride, mOp. 160-165C.

Example 8 To a stlrred'mixture of 9.0 gO (00021 mole) o~
4'-hydroxy-2~[3-(4-methoxyphenyl)-1-methylpropy~]amino~ ~31 ~
(methylthlo)acetophenone 4'-acetate hydrochlorlde and 100 mlO of methanol at -5 to O~C. there was added portion-wise 005 g. (00015 mole) Or sodlum borohydrlde~ After stlrring an additional 005 hour, a solutlon containlng 1.0 g. of potasslum hydroxide in 10 ml. o~ water wa~ added and the re~ultlng mixture ~a8 ~tlrred at room temperature under nltrogen overnlght, and then at reflux 0O5 hour. The pH wa~ ad~u~ted to 7 wlth glaclal acetlc acld and the re-sulting ~olutlon was concentrated to a small volume, dlluted wlth saturated aqueou~ sodlum bicarbonate and extracted with ethyl acetateO ~he ethyl acetate solutlon wa~ drled over anhydrous sodium ~ulrate, acidifled wlth glacial acetic acid, coneentrated to a small volume and cooledO The pro-duct whi¢h ~eparated was collected and recrystallized from ethyl acetate~ethan~l affordlng 7O2 gO Or 4-hydroxy-a-<~[3-(4-methoxyphenyl)-1-methylpropyl]amlno~methyl~3-(methylthio)benzenemethan~l acetate salt, mOpo 132-134Co Example 9 A. ~o a ~tlrred solutlon containlng 100 gO (0O55 mole) Or 4'-hydroxy-3'-(methylthlo)acetophenone in 600 mlO Or - . ~ .

lO~Z45 pyridine at 15-18Co there w~38 added dropwi~e over one hour 68 ml~ (0. 58 mole) of benzoyl chlorideO After addition wa~ complete stirring was continued at room temperature for 1.5 hour~0 The reaction mixture wa~ then quenched ln lo 5 liters of ice-cold water. The solid which preclpitated wa~ collected by filtratlon, washed auccessively wlth water, cold 2-propanol, and n-hexane and dried to give 146 gO of 4'-hydroxy-3'-(methylthio)acetophenone 4'-benzoa~e, mOpO
126-1~1C~
Bo To a stirred suspen~ion contalning 145 gO tOo51 mole) of 4'-hydroxy-3'-(methylthio)acetophenone 4'-benzoate in 1200 mlO of benzene at 20Co was added 15 ml~ of a solution containlng 85 g. (005~ mole) of bromine ln 100 ml of benzeneO The mixture was irradlated ~lth uv light for about 1 hour in order to in~tlate the reactlon. When the reaction oommenced (a~ indicated by decolorization) a slow stream of nltrogen was bubbled through the reaction mixture and the remalnder of the bromine solution was added over a perlod of 2 hours while the temperature wa~ maintained at 20-24Co l~he reactlon mlxture was ~tlrred an additlonal 0~5 hour and then cooled to 16C. The solid which precipl-tated was collected by filtration, washed with water and n-hexane, and dried to give 90 gO of 2-bromo-4'-hydro~cy-3'-(methylthio)acetophenone 4'-benzoate, m.pO 127-129Co The benzene solution afforded an additlonal 21 g. of product m~pO 126-129OCD
C. To a stirred ~olution contalnlng 36 g. (Oe2 mole) of 3-(4-metho~yphenyl)-1-methylpropylamine in 175 mlO of N,N-dlmethylformamide at -60C. was added over one hour a --~u--.

lt~lZ~5 solution containlng 25 g. (o.o68 mole) of 2-brom~-4~-hydroxy-~'-(methylthio)acetophenone 4'-benzoate in 120 mlO or N,N-dlmethylformamide. After the addltion was complete stirr-ing at -60C. was continued an addltional 20 mlnutesO The reaction mlxture was then diluted with 200 mlO o~ chloro-rorm, treated wlth 20 mlO Or 45~ hydrogen bromide and ~urther diluted wlth 200 mlO of col~ waterO The layers were separat-ed and the aqueous layer wa~ re-extr~cted with chlorG~ormO
~he organic layers were combined9 wa~hed wlth ~ater9 d~ied over anhydrous magnesium sul~ate and concentrated to about 100 mlO The cancentrate wa~ diluted with 400 ml~ of ether and cooledO ~he ~sulting precipikate was collected by filtration, washed ~uccesslvely wlth cold 2-propanol and ether and dried to give 26 g~ of 4'-hydroxy-2-~[3-~4-methoxyphenyl)-l-methylpropyl]amino~-~'-(methylthlo)-acetophenone 4'-benzoate hydrobromide.

Example_10 To a stlrred mlxture o~ 25 gO (oOo46 mole) of 4'-hydroxy-2-{[3-(4-me~hoxyphenyl)-1-methylpropyl]amlno~-3'-(methylthio)acetophenone 4'-benzoate hydrobromide and 160 ml.
of methanol at 0C0 was added portlonwise over 005 hour lo 4 gO
( 0. 037 mole ) Or sodlum borohydrlde 0 A~ter stirring an additional 20 minutes the reaction mixture was treated with a solution containing 205 gO of pota~sium hydroxide in ~0 ml. of water and heated under reflux 40 minute~0 The reaction mixture was concentrated in vacuo until a cloudy suspension formed. The suspension was brought to pH 3 with 6N hydro-chlorlc acld and then made baslc with saturated aquaous sodlum blcarbonate. The remaining methanol was removed by , lU~Z~5 evaporation in vacUo. The re~ultlng ~uspension was diluted with 200 ml. of ethyl acetate and the re3ulting biphasic mixture was allowed to ~tand overnight. ~he ~olld whlch precipitated was collected, wa~hed wlth water ~ollowed by n-pentane and recry~tallized ~rom 2-propanol to give 6 g.
of 4-hydroxy-a-~t[3-(4-methoxyphenyl)-l-methylpropyl]amino~-methy~ -(methylthio)benzenemethanol, mOp D 126-129C.
The ethyl acetate layer in the riltrate was separatedJ Washed succes~ively with dilute aqueous ~odlum bicarbonate and water, and dried over anhydrou~ magneaium ~ulfate. ~he resulting solution was diluted with 120 ml.
of isopropyl acetate, treated with 3 ml. ~ glacial acetlc acid, seeded and cooled. The resultlng preclpltate was collected, washed with i~opropyl acetate and dried at 65C.
ln vacuo arrordlng 7 gO o~ product as the acetate salt, m.p. 132-l~gC.

Example 11 A. To a stirred solution containlng 305 g. ~o.oo83 mole) Or 4-hydroxy-a-~ ~3-(4-methoxyphenyl)-1-methyl-propyl3amlno~ meth~ -3-(methylthio)benzenemethanol acetate ~alt in 100 ml. Or methanol at -5co wa~ added dropwlse over 0.5 hour a ~olution contalnlng 630 mgO (oOoo83 mole) of commercial 40% peracetic acid in 10 mlO o~ methanol.
When the additlon wa~ compleke the reaction mixture Was evaporated to drynes~. The re~ulting oll was diluted wlth ethyl acetate and the gum which separated wa~ allowed to stand 2 days in a rerrigerator under a mixture o~ ethyl acetate and ethanol. The re~ulting o~r-white amorphou~
solld was collected arrordlng 3.2 g. of 4-hydroxy-a- ~3-.

1~245 (4-methoxyphenyl)-1-methylpropyl]amlnoJmethy:~ 3-(methyl-sulfinyl )benzenemethanol acetate salt, whlch ~o~tened at 95Co and metled at 100-105C.
~0 To a ~tirred solutlon containing 50 go ( 0~119 mole) of 4-hydroxy-a-~[3-(4-methoxyphenyl)-1-methylpropyl]-amino~methy~-3-(methylthio)benzenemethanol acetate salt ln 5Qo ml. of methanol at 0C. there wa~ added d.ropwi~e over 70 minutes 2002 m10 (Ooll9 mole) of commercial 40~
peracetic acid. When the addition wa~ complete the reaction mixture was evaporated to dryness in vacuoO The re~idual oll was taken up ln 50 mlO of ethyl acetate and agaln evaporated to dryness in vacuo~ The remalning oil was dis~olved in ~50 mlO of tetrahydro~uran and the re~ulting clear solution was stirred and made alightly cloudy by the gradual addltlon of etherO After seeding, the mi~ture was stirred 2 days at room temperature at which polnt a fine, white solid had begun to precipitateO The mlxture wa~
treated dropwise with 50 mlO of ether and stirred 5 hours followed by the dropwlse addition of another 50 ml~ o.f ether and stirring an additional 4 hoursO A~ter stlrrlng overnight in a refrigerator the mixture was cooled to oDcO
while 20p ml~ of ether was added dropwi~e over 3 hoursO
Stirring at 0C0 was continu~d a~ additional ~ hoursO The precipitated product was then collected and redi~sol~ed in 1250 mlO o~ tetrahydro~uran~ The resulting solution was ~lltered to remove a small amount of insoluble materlal, and concentrated to a volume of 250 ml~ The concentrate was cooled in a refrigerator overnightO The resulting white crystalline precipitate was collec~ed, Na~hed with tetra-. .

4~

hydr~ruran and ether and dried a~fordlng 14. 5 g. of 4-hydroxy-~ ~ {L~-(4-methoxyphenyl)-l-methylpropyl]amino}methyl~-3-(methylsulrinyl)benzenemethanol acetate salt, m.p. 131-133C.

Example 12 To a ~tirred ~olution containing l9 gO (0012 mole) of 3-(4-methoxyphenyl)-l-methylpropylamine ln approxlmately 50 mlO of N,N-dimethyl~orma~lde at -65C~
was added dropwise a solutlon containlng 12 gO (0.042 mole) o O r 2-bromo-4'-hydroxy-~'-(methylsul~onyl)acetophenone 4~-acetake in approximately 70 mlO of N,N-dimethylformamide.
After the addition Was complete, 3tlrring wa~ continued an additlonal 1.5 hoursO The reactlon mixture was then acidified with 8 ml. o~ 48% hydrobromic acid and extracted wlth chloroform. The chloroform extracts were cooled to -65C. and diluted with ether. The supernatant wa~ decanted ~rom the preclpltated gum which was sub~equently diRsolved ln a minimum volume of chloro~Drm and allowed to stand 2 day~ ln the refrigerator. The re~ultlng ~ g~ o~ hydrobromide salt was di~solved in ~aturated aqueous sodium bicarbonate and the solutlon thus-obtained extracted wlth n-butanol-ethyl acetate. The organic extracts were acidified with glaclal acetic acld and ev~porated to dryness to give 202 g. of 4'-hydroxy-2-{~3-(4-methoxyphenyl)-l-methylpropyl]-amino3-3'-(methylRulfonyl)acetophenone acetate salt as a yellow oll.

1~124~ -Example 13 A solutlon contalning 2.2 g. of 4'-hydroxy-2- {[3-(4-methoxyphenyl)-1-methylpropyl]amlno3~ methyl~ulronyl)-acetophenone acetate ~alt in 100 ml. Or N,N-dimethylformamide was hydrogenated under an lnitial hydrogen pressure of approxlmately 50 p.~.i. ln the pre~ence o~ 0.5 g. of 10~
p~lladlum-on-carbon hydrogenation catRly~t. A~ter 2 hours one molecular equivalent of hydrogen had been absorbed. The catalyst was removed by ~iltration and the ~iltrate evaporat-ed to drynes~. The residue wa~ adsorbed on a column of ~illca gel whlch wa~ eluted rlrst wlth a 9505 mlxture o~ ethyl acetate-methanol and ~lnally wlth a 90.10 mlxture o~ ethyl acetate-methanol to ~lve 1.4 g. of crystalline product~
Following trlturatlon wlth acetone and ~lltration there wa~
obtained 1~25 g. Or 4-hydroxy-a-<{[3-(4-methoxyphenyl)-1-methylpropyl~amino) methy~3-(methylsul~onyl)benzenemethanol acetate salt, m.p. 151-153C.

Example 14 A. To a stlrred solution contalning 376 g. (1.0 mole) Or (-)-dlbenzoyltartaric acld in a mlxture o~ 5 1~ of methanol and 550 mlO of water at 42C~ there wa~ added 179 gO ( lo O
mole) of (+)-3-(4-methoxyphenyl)-1-methylpropylamine. ~he mixture was stirred 26 hours at 40C. and then 20 hours at room temperature. The re~ulting precipitate wa~ collected and drled a~ordlng a ~lrst crop of 176.5 g, of (-)-3-(4-methoxyphenyl)-l-methylpropylamine (-)-dlbenzoyltartrate salt, m.p. 175-176C. (dec.), ~25 ~ -88.o. By cooling the ~iltrat~ at 0C. rOr 7 hour~ a ~econd crop o~ 58.5 g, 1~124S

wa~ obtalned, m.p. 167-171C. tdec.), [a~25 ~ -86.3. ~he rinal mother llquor~ were set aside ~or u~e in part B
below. The fir~t crop wa~ recrystallized from 90% methanol to give 145.3 g., m.p. 179-180.5C. [~]25 s -87~5. This salt W~R treated wlth aqueous sodium hydroxide and the liberated amine extracted into chloro~orm. The chlorororm extracts were dried over anhydrou~ potasslum carbonate and evaporated to dryness. The re~idual oil was dlssolved in 2-propanol, the resuIting solution acidified with 25 mlO of 12N hydrochloric acld, and evaporated to dryness~ ~he ~olid residue was dried, recrystalllzed from 2-propanol and dried again to give 52.0 g. of (-)-3-(4-metho~yphenyl)-1-met~yl-propylamine hydrochlorlde, m.p. 126-129Co~ ~a]D5 = -6.o (2% in water).
~. The mother liquors remainlng after isolQtion of (-)-3-(4-methoxyphenyl)-1-methylpropylamine (-)-dibenzoyl-tartrate salt were concentrated to a volume of 500 mlO
and cooled at 0CO for 2 hours. The resulting preclpitate was collected and dried to give 283 g. of (+)-3-(4-methoxy-phenyl)methylpropylamine (-)-dibenzoyltartrate salt, m~p.
159-162C. (dec.)O This salt was treated with aqueou~ sodium hydroxide and the libert~d amine extracted into ¢hloroformO
Evaporation of the chloroform left ~0 g. of oil which was then added to a solution cdntaining 168 gO o~ (+)-dibenzoyl-tartaric acid in 1860 mlO of 90~ methanolO After ~tirring 20 hours at room temperature the precipitated salt was collected and dried affordlng 1730 5 go of (+)-3-(4-methoxy-phenyl)-l-methylpropylamine (+)-dlbenzoyltartrate, m~pO
179-180C. (de¢.), [a]D5~-+~7.1. Recrystallization from ; .
..... . _ .

90~ methanol a~forded 149 g., m.p. 181C. (dec~), [aJ25 = +90.3d.
Following the procedure described in part A the amlne wa~
liberated from the (+~)-dibenzoyltartrate salt and converted to the hydrochloride to give 55.0 g. of (+)-3-(4-methoxy-phenyl)-l-methylpropylamine hydrochlorlde, m.p~ 127-130C., ~a]D5 ~ +506 (2~ 1n water)0 ~he nmr spectrum of thl~ pro-duct in the pre3ence of the shift reagent trls[(trlfluoro-methyl)hydroxymethylene-~-camphorato]europium III. Eu(TFC)3 lndicated contaminatlon by approximately 10-15% o~ the levo l~omerO
C~ (+)-3-(4-Methoxyphen~ methylpropylamine (-)-dibenzoyltartrate salt (8781 g~) prepared according to part above ~a~ recry~tallized from aqueous methanol to give ~690 go~ mOp~ 163-165Co A 700-gram sample was recrystallized twice rrom aqueous methanol affordlng 558 gO of the salt whlch was then converted to the rree amine and dl~tilled under reduced pre~ure to give 18005 gO Or (+)-3-~4-methoxy-phenyl)-l-methylpropylamine, b~po 88-100C~/Ool mm~ The nmr spectrum of this product in the presence of the shlft re~gent Eu(TFC)~ lndicated an optlcal purlty 97%~

_47-., ' ~' ~

2~5 D. Alternatively (+)-3-~4-methoxyphenyl)-1-methylpropyl-amine was obtained as follows:
A solution of 300 g. ~1.67 moles) of dl-3-(4-methoxy-phenyl)-l-methylpropylamine in 2 1. of 95% ethanol was added in one portion to a stirred warm solution (40-45C.) of 250 g.
tl~67 moles) of d-tartaric acid in 2.6 1 of water and 4.2 1 of 95% ethanol. The clear solution was seeded at about 38C. and was then allowed to come to room temperature overnight with stirring. ~he crystallized solid was filtered and pressed thoroughly with a rubb-er dam; it was washed twice with enough ice-cold 8~ aqueous ethanol to cover the cake and was thoroughly pres~ed dry. The product was dried at 60 ln vacuo for five hours to afford 276 g. of crude d-amine bitartrate, m.p. 181-1~2C.
Five recrystallizations from aqueous ethanol afforded 125 g. of the bitartrite, m.p. 188-190C. The optical purity of the liberated (+)-3-~4-methoxyphenyl~-1-methylpropylamine was shown to be 297%.

Example 15 - To a 8tirred solutlon containlng 3507 gO (00172 mole) of incompletely re801ved (-)-3-(4-methoxyphenyl)-1-methylpropylamlne hydrochlorlde~ ~a]D5 ~ -600 (2% in water) ln 125 ml. Or N,N-dlmethylformamide wa~ added 25 mlO of triethylamlne caualng lmmedlate precipitation of triethyl-amine hydrochlorlde. The mixture wa~ 8tirred 20 minutea and then cooled to -50Co The remainder o~ the preparation wa~ carri~d out rollowing a procedure 81mllar to that in . _ . _ _, _ .. . . , . . . :
....

l~lZ9~5 Example 7 but using 20 B~ (o,66 mole) of 2-bromo-4~-hydroxy-~'-(methylthio)acetophenone 4'-acetate ~nd 8 ml. of acetyl chlorlde to give 15 g. of lncompletely re~olved (-)-4'-hydroxy-2-~L3-(4-methoxyphenyl)-1-methylpropyl~mlno~-3'-(methylthio)acetophenone 4~-acetate hydrochlorlde, m.p.
7g-181co9 ~]D5 -10u3~

Example 16 To a stirred solution contalning 12 g~ (00027 mole) of incompletely resolved (-)-4' hydroxy-2-[3-(4-methoxyphenyl)-1-methylpropyl]amino~-3'-(methylthlo)-acetophenone 4'-ace~ate hydrochlorlde (mOpO 179-181C., [a]25 = -1003) in 150 mlO of methanol at 0CO was added portionwise 0~8 gO (0.020 mole) o~ sodium borohydride.
After stirring an additional 15 minutes, a solut~on con-taining 106 gO o~ potassium hydroxide in 25 mlO of water was added and the resulting mixture was heated at re~lux under nitrogen 0~5 hoursO ~he reaction mixture wa~ con-centrated to a small volumeJ acidiried with 3N hydrochloric acidg then made basic with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. After drying over anhydrous sodium sul~ate the ethyl acetate solution was evaporated to dryness leaving 11 gO of pale yellow oilO Th1s oil was dissolved in 200 mlO o~ ethyl acetate and a 40 ml~ allquot wa~ adsorbed on a column of silica ~el and the product ;eluted with 92:8 ethyl acetate metha`nol to give 107 g~ of oil which was converted to the acetate salt affording 1.22 g.
of levorotatory 4-hydro~y-a- 4[3~(4-methoxyphenyl)-1-methyl-propyl]amino } methy~-3-(methylthlo)benzenemethanol acetate salt, mOp. 124-125C., [a]25 - -604o Z~S

ExRmple 17 Followlng a procedure similar to that described in Example 11 but uslng 102 g- (0.0028 mole) of levorota-tory 4-hydroxy-a-<~[3-(4-methox~phenyl)-1-methylpropyl]-amlno~ methyr~-3-(methylthio)benzenemethanol acetate ~alt (m~p. 124-125C., [~]D5 = -604) and 216 mg~ of commerclal 40% peracetlc acid there W~8 obtained 009 gu o~ levorota-tory 4-hydroxy- ~ {[3-(4-methoxyphenyl)-1-methylpropyl]-amino~methyl~_3-(methyl~ulfinyl)benzenemethanol acetate salt, mOpO 103-106C~, [&]D5 G 3OoO

Example 18 Ao Following a ~ro¢edure simllar to that descrlbed in Example 15 but u~lng 43 go (0~ 20 mole) o~ incompletely re~olved (+)-3-(4-methoxyphenyl~-1-methylpropylamine hydro-chlorlde, Ca]25 - +506 (2% in water) and 23 g. (0O077 mole) of 2-bromo-4'-hydroxy-3'-(methylthlo)acetophenone 4'-acetate there Was obtained 17~1 gJ of lncompletely resolved (+)-4'-hydroxy-2-{[37(4-methoxyphenyl)-l-methylpropyl]-~ amino~-3i-(methylthio)acetophenone 4'-acetate h~drochlorlde, mOpo 178-180Co~ ~a]D5 ~ t1002o B. Followlng a procedure ~lmllar to the above but acldifying the reaction mlxture with 48% hydrogen bromide ln place of 12N hydrochloric acid and omltting the re6ctyla-tion step afforded, a~ter recrystall1zation twice ~rom chloro-form-lcopropyl acetate and once ~rom chloro~orm-acetone, lncompletely re~olved (~)-4'-hydroxy-2-~[3-(4-methoxyphenyl)-l-methylpropyl3amino~-3'-(methylthlo)acetophenone 4'-acetate hydrobromlde, m.p. 182-183C., La]D5 ~ 9Ø

_ . ... _ __. _.. _ . . . . .. , . . ..... . , . . .. .. ....... . ~ .. , . ... . . _ _ _ _ . _ _ . . . .
... . ...

Example 19 A. Following a procedure ~imllar to that descrlbed in Example 16 but u~lng 17.1 g. (00039 mole) o~ (+)-4'-hydroxy-2~ (4-methoxyphenyl)-1-methylpropyl~amino3-3'-(methylthio)acetophenone 4'-acetate hydrochloride (m~p. .
178-180C.9 [a]D5 ~ +1OD20)~ 1.0 g~ (0~025 mole) of sodium borohydride and 20 0 go 0~ potas~ium hydroxlde there wa~ obtained 15 gO of 4-hydro~y-a-~{[3-(4-methoxyphenyl)-1-methylpropyl]amino3methy D-3-(methylthio)benzenemethanol a B
a dextrorotatory pair of diastereomerlc benzenemethanol3.
A 30 0 -gram sample was di~solved in isopropyl acetate and the resulting solution acidi~ied with glacial acetic acld.
The proq~ct WaB allowed to crystallize slowly over 2 days to give 2075 g~ of crystalline acetate ~alt, mOp. 124-126C., [a]25 - +707O
B~ When a procedure simllar to the above was carrled out using (+)-4'-hydroxy-2-~[ 3~ ( 4-methoxyphenyl)-1-methylpropyl]-amino~-3'-(methylthio)-acetophenone 4'-acetate hydrobromide mOpo 182-183Co~ ~a]25 ~900 there wa~ obtalned dextrorota-tory 4-hydroxy-a-<{~3-(4-methoxyphenyl)-1-methylpropyl]- . .
amino¦methyl~-3-(methylthio)benzenemethanol acetate salt, m.pO 128-12905COJ [a]D5 - +5.6o C0 Following a procedure ~imilar to ~hat de~cribed in Example ~0 but employing 40 g. (00 o758 mole) of optically pure (+)-4'-hydroxy-2-{[ 3~ ( 4 -methoxyphenyl)-l-methylpropyl]-amino~-3'-(meth~lth~o)acetophenone 4'-benzoate hydrobromide (m.p~ 171-175C., [a]D5 = +11.8) prepared according to Example 23B hereinbelow, 1.5 gO of sodium borohydrlde and 4.5 g~ of pota~sium hydroxide there ~a~ obtained 25~1 g.
of 4-hydro~y-a ~ [3-(4-mekho~yphenyl)-1-methylpropyl~aminoJ-_51-___ _ _ _ _ _ . _ .. .. . .. , . . . ............ . ... _ _ _ _ _ , ~ .. ... _ '. ~

~ 45 methy~-~-(methylthio)benzenemethanol acetate ~alt~ mOp.
125-127C., La~D5 = +7.3, as a dextrorotatory palr o~ dia-stereomeric benzenemethanols. Another slmilar run a~orded a product with m~pO 129-130Co ~ [a]D5 - +701o The hydro-chlDride had m.pO 15~-155Co The pair of diastereomeric benzenamethanols o~
this Example correspond to the productg of Examples 21C and 28 o .

Exam~le 20 Ao Followlng a procedure slmllar to that described in Example 11 but using 20 5 gO (0~0049 mole) of dextroro-tatory 4-hydroxy-a-~[3-(4-methoxyphenyl)-1-methylpropyl]-amlno~methyr~-~-(methylthio)benzenemethanol acetate ~alt (m.pO 124-126C., [a]D5 ~7.7) and 375 mg. of commerclal 4% peracetic acid there was obtained 2.0 g. o~ 4-hydroxy--a-<~-(4-methoxyphenyl)-1-methylpropyl]amino}methy~-3-(methylsulfinyl)benzenemethanol acetate salt as an amorphous yellow powder [a]D5 ' +402 containing a mixture o~ 4 diastereomeric sulfoxldesO In additlon to its antl-hypertensive actlvity this product was round equiactive with procalne as a local anesthetic when tested according to the method of Bulbring and Wad~a, J0 PharmO Expo ~herap.
85J ~8 (1945)o B. When the above oxidation was carried out on dex-trorotatory 4-hydroxy-a ~ [3-(4-meth`oxyphenyl)-1-methylpropyl]-amino~methy~-3-(methylthiolbenzenemethanol acetate salt prepared accordlng to the method o~ Example l9C the product had m.p. 103-110 and [a]D5 --1.1 and conslsted o~ a mlxture o~ 4 diastereomerlc sul~oxides.

____ _ , . ,,, ., , . , ...................... ,, .. . _ _ ,, __ .. ".:. .

1Q~245 C. A ~ample of 4-hydroxy-a-~[3-(4-methoxyphenyl)-l-methylpropyl~amino¦methy V~-(methylsulfinyl)benzene-methanol acetate salt prepared by a procedure simllar to that de~cribed in part B above was converted by a conventlonal procedure to the corre~pondlng pho~phate, mOp. 136-153C., [JD5 = 0CO
Do A sample of 4-hydroxy-a-~{[~-(4-methoxyphenyl)-1-methylpropyl]amino~methyI~-3-(methylsulfinyl)benzenemethanol acetate calt prepared by a procedure similar to that des-cribed ln part B above was converted by a conventional pro-cedure to the corresponding methanesulfonate, mOp. 142-148C.J
~a ]D5 ~ ~5 Q
E. A sample o~ 4-hydroxy-a-<{~3-(4-methoxyphenyl)-1-methylpropyl]amino~methy~-3-(methylsul~inyl)benzenemethanol 1~ acetate salt prepared by a procedure simllar to that descrlbed ln part B above was converted by a conventional procedure to the corresponding hydrochlorlde, m.p. 172-175C., [a]25 --8~1~
F. Alternatively the hydrochloride salt was prepared directly as follows-To a stlrred solution containing 844 g. (2 moles) Or 4-hydroxy-a ~ ~3-~4-methoxyphenyl)-1-methylpropyl]-amino~methyr~-3-(methylthio)benzenemethanol acetate salt in 7 llters o~ methanol at 0C. was added ln 25-mlO portlons over a period of about 40 minutes ~o8 ml. of 40% commercial peracetic acid. Stirring was contlnued at 0-3C. an additional 45 mlnutes. The reaction mixture was then evaporat-ed under reduced pressure whlle malntalnlng the temperature below 35C. The residue was dlluted with 1 liter o~ 2-l~g~4S

propanol and the ~olution evaporated to dryne~s in vacuo.
Thls was repeated once more and then the resldue was dis~olved ln 6 liters of 2-propanol, and the resulting ~olutl.on treated with a ~olution containing 2.14 moles of hydrogen chloride in 2-propanol. The resulting pale yellow solution wa 5 cooled in iceO The precipltated product wa~ collected, washed with 2-propanol-ether and drled to glve 705 gO Or 4-hydroxy--~3-(4-methoxyphenyl)-1-methylpropyl]amino~methy~-3-(methylsulfinyl)benzenemethanol hydrochloride, Ca~D' ~
-106.
The four dlastereomeric sulfoxides produced ln accordance with the foregoing example~ correspond to the sulfoxldes of Example~ 30, 31~ 32 and 330 The products of several preparations carrled out as descrlbed above ln Example 20F were converted to the phenol ~-toluenesulfonates wlth ~-toluenesulfonyl chloride in excess sodium hydroxide and analyzed by hlgh pressure llquid chromatography on micropartlculate sllica gel uslng n-hexane-2-propanol-2-propylamine (850150004) a3 eluent at a flow rate of 0054 mlO/mlnO and a pressure of about 1200 posoio and were found to have the following compositlon:

Sulfoxide of Exo No. Concentratlon 3 19-2~%
31 23-2505%
32 250 5-28%
33 28-30%

_ _ _ _ _ _ .. -- .. .. .. . . . ..... .

24~

The product obtained according to part E or F above, when tested in one or more of the standard biological test procedures described hereinbelow, was found to possess useful cardiotonic activity. The efficacy of this compound was judged, ln vitro, on the basis Of percent increase in contractile force in isolated cat atria and papillary muscle and, ln vitro on the basis of percent increase in cardiac contractile force in the intact anesthetized dog.
The in v tro test procedures used are described as follows:
Cardiotonic Test Procedure I - Male cats weighing from 0.8 to 1.5 kg. were anesthetized with ~-chloralose (80 mg./kg.
i.p.). The chest was opened, the heart excised and the two atria dissected. A silk suture was tied to each of two opposite sides of the right atrium. One side of the atrium was tied to a glass rod and then mounted in a 50 ml. organ bath filled with Tyrode's solution. The second suture was attached to a force displacement transducer and the tension on the atrium was adjusted to 1.5 +
0.5 grams. The transducer was then connected to a Grass .

polysraph an~ the ~orce and rate Or atrlal contraction was recorded continuou~ly The lert atrlum was treated s1mllarly uqln~ sllver wire lnstead Or ~ilk 3ut~r~a. Thc sllver wlrc also served as a stlmulatln~ electrode. Both atrla were mounted ln the same bath. The rlght atrlum was beating spontaneously due to the presence Or the s1noatrial node, whlle the lert atrlum wa~ stlmulated electrically at a rate Or 3 beats/~ec. by suprathre~hold rectangular pulseq 'or 5 mlllisecond duratlon. The Tyrode's solutlon bathlng the atrla was Or the rollowing composltlon (in mM): NaCl 136.87, KCl 5.36, NaH2P04 0.41, CaC12 1.80, MgC126H20 1. 05, NaHC03 11.90, gluco~e 5.55~ and EDTA 0.04. The solution was equll-lbrated wlth a ~as mixture consistin~ Or 9~ 2 and 5% C02.
The preparatlon was left to equlllbrate ror one hour before any drug was added. The bathlng ~luld was changed 3 to 4 tlmes durln~ the equ~libratlon tlme. At the end Or equlll-bratlon period, the drug dl~solved ln a vehlcle or the vehiole alone was added to the tlssue bath and the rull response recorded. The vehlcle used was Tyrode's solutlon to whlch, lr required, su~rlcient acld was added to cause solutlon of the drug. When the response reached a maxlmum lt waq abollshed by 3 washes at 10 mln lnterval~ or untll pre-dr~
values or rorce of contractlon were reached. General~y, a dose response study Or at least 3 doses wa~s done ln the same preparatlon.
Cardlotonlc Test Procedure IB - Male cats 0.8 to .. .. ..
1.5 k~. were anesthetl~ed wlth a-chloralose (80 mg./kg. l.p.).
The chest was'opened and the heart exclsed.' The heart wa~
dlpped and shaken in Tyrode'~ solutlon ror the removal Or ~, , . ~
, .. . .. . .

~5:1Z9~5 blood rrom the cavlties. The right ven~rlclc was then sl~t open and the ~mall'and thln (a~out 1 mrn. ln dlameter and 4 to 7 mm. in len~th) paplllary muscles were dis~ected out.
A sllver w~re waa attached to each Or the two end~ Or the paplllary muscle. The ventricular end was attached to a pla~lnum electrode and rnounted ln a tissue bath contalnin~
Tyrode's 301utlon desGrlbed above. The sllver wire on ihe valvular end Or the muscle was attached to a ~orce displace-ment transducer for the measurement Or the rorce and rate Or muscle contraction. The mu~cle was stlmulated at a rate Or 3 beat~/sec. by suprathreshold rectan~ular puls~a of 5 millisecond duration. The rest Or the procedure wa.s continue'd as de~cribed above.
Cardlotonic Te~t Procedure II - The in vivo te,st procedure used ls descrlbed as rOllows: Mongrel dogs Or both ~exes and varylng ln welght rrom 9 to 15 kg. were anesthetized with 30 mg,/kg. pentobarbital sodlum admin-lstered lntravenously. .'rhe trachea was exposed and cannulated, The tracheal cannula was then attached to a Harvard refipira-tory pump using room air. The rlght remoral artery and vein were cannulated. The arterial cannula was attached to a Statham P23A.pre~sure transducer connected to a Gras~ po]y-graph ror tlle contlnuous recordlng Or arterlal blood pressur~.
The venous cannula was used ror'the lntravenous admlnl.stration Or drugs. Pin electrodes were attached to the rl~ht rorellmb and lert h'lndlimb. The electrodeQ were then connected to a Grass poly~raph ror the contlnuous recordln~ Or the' standard llmb lead II electrocardio~ram. A ventro-dor.o.al lncl,slon at the third lnter-costal space was made) the rils laterally rctracted and the'pcrlcardlum slit open to expoQe , _ . _ . ..... . . ........................................ .. . _ _ . _ _ . _ :':

24~:) the myocardium. The base of the aorta was dissected and a flow probe was fitted around it. The flow probe was attached to a square wave electromagnetic flowmeter (Carolina Medical Electronics). The flowmeter was then connected to a Grass polygraph for the continuous recording of aortic blood flow.
Thls flow was used as an index of cardiac output (actual cardiac output i8 aortic blood flow + coronary blood flow)O
Cardiac contractile force was measured by suturing a Walton-Brodie strain gauge to the wall of the right ventr1cleO
At the end of the surgical procedure~ the animal wa~ left to rest and equilibrate for one hour with continuous record-ing of blood pres3ure, EKG, cardiac contractile force and aortic blood flowO After the equilibration periodD the vehicle or the drug dissolved in the vehicle was administered by intravenous infusion (i.v. inf.), intravenous bolus (i.v. bol.) or intraduodenally (i.d.) and the response of all the parameters measured to drug administration was recorded cont~nuously for different periods of times depending on the route of drug administration. When the route of administration was i.v. inf., the drug was administered until a peak effect was reached and infusion was then maintained for ten minutesO

.
The above-described test systems were standardized using dopamine.

i24S

T~e product obtalned accordlng to part F and F

above, ~hen tested in ~ltro as above-descrlbed at a dose o~ 1 mg./ml.

caused lncrea~eq or 62 and 52 percent in right atrlal rate and ~ t atrial ~orce respectively and a decrease Or 14 percent in paplllary muscle ~orce. At a dose o~ 10 mcg/ml. increa~es o~

53 and 46 percent ln right àtrlal rate and rlght atrlal force respectlvely and a decrease Or 12 percent ln paplllary muscle force were o~served.
When infused intravenously at`a dQse o~ 10 mcg/kg/mln.

over ~ hrs. ln 3 intact anesthetlzed dogs the product of thl3 example caused a maximum lncrease ln cardlac contractlle force 0~

25 and 42 percent ln 2 of 3 dogs with no signl~icant change in heart the rate. In~remaining dog decreases ln contractlle rorce and heart rate or 30 and 33 percent respectively were ob~erved.

Example 21 A. A ~olution containing lOo 5 go of dextrorotatory 4-hydro~y-a- ~3-(4-methoxyphenyl)-1-methylpropyl]amino~-methyI~-3-(methylthio)benzenemethanol prepared as described Z9~5 in Example l9A snd 2.25 g. of (-)-mandellc acld in 60 mlO
of isopropyl acetate was stirred 4O5 hoursO The precipitat-ed solld was collected to give 3.7 gO of white crystalline solld, mOp. 99-100C., [a~D5 ~ -2009 which was labeled "solid A" and set aside. The filtrate was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residual 6 g~ of gum was dissolved ln 40 mlO of isopropyl acetate and treated with a solution of ?.0 g. of (~)-mandelic acid ln 20 ml. of isopropyl acetate and the resultlng solution stirred overnightO The precipltated product was collected giving 4.1 gO of tan crystalline solid m.p. 89-933 [a]25 ~35.4~.
The ~lltrate was labeled "filtrate A" and set aside. The solid was recrystallized by dissolving ln 55 mlO Or 10 o 1 isopropyl acetate-isopropyl alcohol and stirring overnight.
After removlng a small amount o~ 901id lmpurlty the clear solutlon was concentrated to a volume of 30 mlO whereupon the product cryatallized to give 106 g~ of tan crystals m.pO 89-106, [a]D5 - +48.7 which was labeled "solid B"
and set asldeO The filtrate was labeled "flltrate B"~
"Filtrate A" was washed with saturated aqueous sodlum blcarbonate9 drled over anhydrous sodium sulfate and evaporated to dryness. The resulting 4Oo gO o~ yellow gum was dissolved ln 40 mlO of ethyl acetate and treated with 2~ 1.0 gO o~ (-)-mandelic acid. After standing overnight the precipitated product was collected to give 20 5 g. o~
crystalllne solld mOp. 108-110.5C., [a]D5 = ~33 whlch was labeled "solid C" and set a~ideO The filtrate was comb~ned with "filtrate B" above and evaporated to dryness, and the . . .. . . . . .

1~9~Z45 resldue comblned with "solid A~o The combined materials were dissolved in ethyl acetate, the re~ulting ~olution washed with satur2ted aqueous ~odium blcarbonate, dried over anhydrou~ sodlum sulfate ~nd evaporated to dryness.
The resldual 604 gO of yellow syrup was dlssolved in 40 ml.
Of ethyl acetate and treated with 1.5 gO of (+)-mandelic acidO After stirring overn1ght the precipltated solid was collected to give a first crop o~ l.o gO Or tan ~olld mOp.
105-110C~ Cooling the ~iltrate ln ice a~forded a second ~rop o~ 103 go mOp~ 86-89 ~aJD5 ~ +48o The filtrate was labeled "~iltrate C" and set asldeO The ~irst crop was combined with "solid B" above and recrystallized from ethyl ~cetate to give 1065 gO of tan ~olid mOpO 9005-92 [a]D
+5202o This material was combined wlth the ~econd crop and the whole recrystallized from lsopropyl acetate a~ford-ing 207 gO o~ tan cry talline solid mOpO 89-920 5Co [a~5 +5108. The latter was dissolved in 50 mlO o~ ethyl acetate and the resulting solution washed wlth saturated aqueous sodium bicarbonatej dried over anhydrou~ sodlum sulrate and evaporated to dryness leaving 1.7 gO o~ product which corresponds to the dextrorotatory member of the pair of diastereomeric benzenemethanols present ln the product of Example l9A. A 650 -mg~ sample was dlssolved in isopropyl acetate and the resulting solution acidified with glacial a¢etic acid and evaporated to drynessO The residue was crystallized frcm a small volume of isopropyl acetate to give 700 mgO Or the acetate salt, m.p. 73-72C. ~a]D5 -+31.3.
B. "Filtrate C" was evaporated to dryness~ ~he residue wa3 dlYsolved in ether-ethyl acetate and the ~ ~9 resulting solution washed with saturated aqueou~ sodium bicarbonate, treated with 2 gO of decolorizlng carbon, ~iltered and the filtrate evaporated to dryness leavlng 3.8 g. of residue~ Thi~ material was dissolved in 25 ml.
of isopropyl acetate and the resulting solution treated wlth a solution containing lo 3 g~ of (-)-mandelic acid in 10 mlO of isopropyl acetateu After stirrlng 2 days the precipltated product was collected to give 302~ gO Or white crystalline solidg m~pO 104 106~C~, La]D5 = -30~4~
This material was comblned with "~olid C" above and the ~hole recrystallized ~uccessively ~rom 25 mlO of ethyl acetate, 40 mlO of ethyl acetate and finally ~rom lsopropyl alcohol-ethyl acetate in each instance allowlng the pro-duct to crystallize slowly at room temperatureO There wa~ thus obtalned 305 gO of white needles mOpO 110-111C., La]25 = -3304O ~he latter was dis^~olved in 50 ml~ Or ethyl acetate, and the resulting solution washed with ~aturated a~ueous sodium bicarbonate, drled over anhydrous sodium ~ulfate and evaporated to dryness to give 2C4 gO
o~ product ~La]D5 ~ -501~) ~hich corresponds to the levoro-tatory member of the pair of dlastereomeric benzenemethanols present in the product of Example l9Ao A 1~1 -gram ~ample was converted to the acetate salt as de.~cribed above for the dextrorotatory d1astereomer affording the crystalline acetate salt as white platelets mOpO 124-12405Co [a]D5 ~5~4 L
C. A 99-gram 9ample of dexrorotatory 4-hydroxy-a-~{L3-(4-methoxyphenyl)-1-methylpropyl~amlno~methyr~-3-(methylthio)benzenemethanol acetate salt (m.p~ 129-130C., ___ _.. . . . ....

29~5 ~a]25 - +7.1) prepared as described ln Example 19~ was treated with aqueous sodium carbonate and the free base wa8 extracted into 1 liter of ethyl acetate. The ethyl acetate solution was washed with water and saturated aqueou~ sodium chloride, dried over anhydrou~ sodium sulfate and evaporated to dryness. The residual oil wa~ dis~olved in hot ether and the solution wa~ riltered through a l-lnch pad Or 8ilica gel ln order to remove a colored impurltyO Evaporation Or the ether lert 83 gO of a pale yellow gum which was dissolved in 200 mlO of ethyl acetate and treated wlth a solutlon con-tainlng 22 gO o~ (+)-mandellc acid ln 200 ml~ of ethyl acetate. The mixture was stirred overnight at room ~em-perature and then overnight at 5Co The precipltated pro-duct was collected by filtration and washed wlth lsopropyl acetate and ether. The mother llquors were set aslde. The collected solld was recrystalllzed from lsopropyl acetate contalnlng a small amount o~ 2-propanol to give 27 go Or product mOp. 89-91Co~ [a]25 = +49~4o The mother llquors whlch had been set aslde were reconverted to the fr~e base and agaln treated wlth 20 g~ of (+)-mandellc acld to give arter two recryst~lllzatlons ~rom lsopropyl acetate and one rrom ethyl acetate an additional 600 go of product [a~D5 a +47~6o The mother llquors ~rom thls second treatment with ~+~-mandellc acld were enriched ln the levorotatory dia~tereomer and were set aside for use in part D. The solld~ were combined and recrystallized twice ~rom ethyl acetate to glve 22 gO Or the (+)-mandelate salt, m.p. 94-95~5Co ~a]~5 - +5400~ ~hls salt was treated with 80 mlO of 10% aqueous ~odium oarbonate and the free base extracted into 300 ml. Or ethyl acetate.

. _ , . . . _ .

124~

The ethyl acetate solution was washed with saturated aqueous sodlum chloride, dried over anhydrou~ sodlum sul~ate and acldlfied wlth 2 ml. o~ acetic acldO The solutlon was con-centrated and the resultlng preclpltate wa~ collected and recrystallized from ethyl acetate contalning a rew drops of acetic acid to give 403 gD 0~ 4-hydroxy-a ~ [3-(4-methoxyphenyl)-l-methylpropyl]amino~methyr~ (methylthio)-benzenemethanol acetate salt, mOp~ 133-134C., [a]~5 s +33.3, corresponding to the aextrorotatory member o~ the pair of diastereomerlc benæenemethanols present in the product o~
Example 19Co A sample of thls material was reacted with ~-toluenesul~onyl chloride in the presence o~ sodium hydro~ide to a~ford the corresponding 4-p-toluenesulfonate acetate salt mOpO 90-92 ~a]25 _ +23.0 whlch was shown by high pressure liquid chromatography to have an isomerlc purlty ~99~0 D~ The mother liquors from part C which were enrlched ln the levoratctory dlastereomer were combined and evaporated to drynessO The residue was treated with aqueous sodlum carbonate and the free base extracted into ethyl acetate.
Evaporation of the ethyl acetate left 58 gO o~ oilO Thls material was dissolved in 200 mlO o~ ethyl acetate, treated with a solution contalning 20 gO o~ mandelic acld in 200 mlO of ethyl acetate and the resultlng mixture stlrred overnightO The preclpltated ~alt was collected and recrystalllzed successlvely from aeetone-ether, ethyl acetate, and elght times from methylene chlorlde-ethyl acetate to gi~ve 23 g. Or incompletely resolved (as determlned by thin layer ' ' ' ' ~ .
.. : .. .. . . ~ .

chromatography) (- )-mandelate ~alt, m.p. 116-117C., ~a]25 =
-37.1 which wa~ converted by a conventlonal procedure to the acetate ~alt La]D5 - -10.6. Chromatography of a 5.5-gram sample of the latter on a column of sllica gel and elution with 7% methanol ln ethyl acetate failed to subatantially further puri~y the acetate salt. A 2.6-gram ~raction o~
materlal whlch had been eluted ~rom the column was stirred with 25 ml. o~ 35% aqueous ~odlum hydroxlde and the mixture treated dropwise over 15 minutes with a ~olution containlng 1033 gO o~ p-tolueneaulfonyl chloride ln 30 mlO of acetone.
Over the next 5 minutes the reaction mlxture wa8 treated wlth two addltlonal 150-mg. portion~ o~ p-toluenesulfonyl chlorldeO The a¢etone layer wa9 ~eparated, dlluted wlth an equal volume o~ l~opropyl acetate, washed wlth water followed by saturated aqueous 30dium chloride, and evaporated to dryness. The residue was dissolved in ethyl acetate and the solution acidirled with acetic acid. The acetate aalt which preclpltated was recrystallized from ethyl acetate to glve loO g~ m~pO 115-117C~ [a]25 3 _7~9~ The flltrate ar~orded an additlonal 0. 5 g., mOp. 115-117Co The crops were comblned and converted to 1.2 g. of the (~)-mandelate salt, mOp. 154-156 ~a]D5 ~ +14~ 9 accordlng to the procedure de~crlbed above ln part C. This materlal wa~ combined wlth another 250 mg.~ m-pO 157-158Co [a]25 ~ +14~3 obtained in a similar run, recrystalllzed from ethyl acetate, and then converted by a conventlonal procedurè to the correapondlng acetate salt to give 700 ml. o~ lsomerically pure levorota-tory 4-hydroxy-a-<{[3-(4-methoxyphenyl)-l-methylpropyl]-amlno~methyI~-3-(methylthio)benzenemethanol-4-~-toluene-.. . . . . .. . ...

Z9~5 ~ulronate acetate ~alt, m.p~ 117-119C. []D5~ -9.6 corre9pondlng to the 4-p-toluenesulronate ester o~ the levoratatory member of the palr Or diastereomerlc benzene-methanol~ pre~ent ln the product of Example l9Co This pro-duct wa~ shown by hlgh preBBure liquld chromatography to have an lsomeric purity~98~.
Attempts to cleave the p-toluenequl~onate e~ter ln order to obtaln the i~omerically pure levoratatory phenol were unsuccess~ulg ho~ever the latter compound wa8 obtained from the correBpondlng benzoate as described in Example 28 hereinbelow~

Example 22 A~ To a stirred solutlon contalnlng lo 05 g~ ~ 0~ 00~
mole) o~ dextrorotatory 4-hydroxy-a- 4[3-(4-methoxyphenyl)-l-methylpropyl]amino~methyl~-3-(methylthio)benzenemethanol prepared accordlng to the method o~ Example 21A in 15 mlO
of methanol at 0C0 there was added dropwlse over 0.5 hour a ~olution Or 0.45 ml~ (0~00~ mole) o~ commercial 40~
peracetic acid ln 5 ml. of methanol. When the additlon was complete the reaction mixture was evaporated to dryness in vacuo. The resldue was dl~solved ln 45c5 ethyl acetate-~ethanol and adsorbed on a column of qllica gel. Following elution with ethyl acetate the product was eluted w1th 90olO
ethyl acetate-methanol. The material so-obtalned ~as dissolved in ethyl acetate-methanol9 the resultlng solutlon acldl~led with glaclal acetlc acid and evaporated to dryness.
The resldue wa 8 taken up ln 5 ml. o~ chloro~orm9 the re~ult-lng solutlon cooled to -65co and diluted with ether. The 3 resulting solid was dlssolved ln tetrahydroruran, the ~olution acldl~led wlth glaclal acetic acld and evaporated to dryness.

. . . . . . _ l~lZ45 The resldue was dlssolved in chloro~orm, the solution cooled to -65C~ and dil~ted with etherO The resulting ~olid was collected and dried a~for~ing 550 mg. o~ 4-hydroxy-a-~{[~-(4-methoxyphenyl)-l-methylpropyl]amino~methyI~3-(methyl8ul~inyl)benzenemethanol 2cetate ~alt a~ a dextroro-tatory palr of diaetereomeric sulfoxides, [a]25 - ~2805o Bo A 500-gram sample o~ i~omerically pure dextroro-tatory 4-hydroxy-a 4[ 3-(4-methoxyphenyl)-l-methylpropylJ-amlno~methy~-3-(met~ylthio)benzenemethanol acetate salt ([a]25 - +3105) prepared according to the method of Example 21C was oxidized as described in part A above~
When oxidation was complete the reaction mixture was evaporated to dryness and the resldue cry8tallized from ethyl acetate to give 402 gO o~ crystalline product, mOp.
107-115~ [a]25 ~ +2802o A small sample was dis~olved in acetone-~ethanol and the solution t.reated with cyclohexyl-sulramic acidO The precipitated salt wa~ collected to glve a~ter drying 4-hydroxy-a- ~ [3-(4-methoxyphenyl)-1~
methylpropyl]amlno~methy~-3-(methylsulflnyl)benzenemethanol cyclohexyl3ul~amate salt as a dextrorotatory pair of diastereo-merlc sulfoxides~ mOpO 152-154Co ~ [a]D5 = +350 9 o The pair of diastereomeric æulfo~ides of this example correspond to the products o~ Examples 30 and 3~0 Example ?3 Ao ~ollowlng a procedure similar to that described in Example 9C but employing 128 gO toO72 mole) of incompletely resolved (+)-3-(4-methoxyphenyl)-1-methylpropylamlne, [a]25 - +4-4 (~ in water), and 120 gO (0033 mole~ of 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4'-benzoate .
' ' there was obt~ined a flr~t crop of 82 g., m.p. 172-174C. and a second crop of 43 g., m.pO 171-174C~ The crops were combined and a 16-gram ~ample was recrystalllzed ~rom 95 ethanol to give 10 gO of incompletely re~olved (+)-4'-hydroxy-2-~3-(4-methoxyphenyl)-1-methylpropyl]amino~-3'-(methylthio)acetophenone 4~-benzoate hydrobromlde9 m.p.
174-175C.~ [a~D5 ~ +804o Bo To a vigorously ~tirred solution contalning 180 g.
(loO mole) of (+)-3-(4-methoxyphenyl)-1-methylpropylamine [optical purlty ~97% as indlcated by nmr spectroscopy in the presence of Eu(TFC)3] and 55 mlO of trlethylamine in 300 mlO
of N,N-dimethyl~ormamlde at -60Co there ~a~ added over 1~5 hours a solution containlng 160 g~ (o.384 mole) o~ 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4'-benzoate ln 500 mlO of N,N-dlmethyl~ormamideO Stlrrlng was con-tinued an addltional 005 hourO The reaction mlxture was acldi~led with 48~ hydrogen bromide and extracted with methylene dlchlorlde~ The or3anic extract~ were ~ashed with water and concentrated to about ~20 mlO The con-centrate was diluted with 400 mlO o~ lsopropyl acetate and cooled. The solid whlch precipitated was collected and dried to give 167 gO of optically pure (+)-4'-hydroxy-2-~ 3-(4-methoxyphenyl)-1-methylpropyl]amlno~-3~-(methylthlo)-acetophenone 4'-benzoate hydrobromlde, mOpO -171-173Co g [a~]25 = +1108o A 7-0~am Sa~ e was recrys~allized from aqueous methanDl oan~ining a small a~unt of Br to give, after dry~ng, 5.9 g., m.p. 175-177C.
[c~] 2~11.6 Example 24 . To a solutlon contalning 106 g. (0.195 mole) of lncompletely re301ved (+)-4'-hydroxy-2-{[3-(4-methoxyphenyl)-l-me~hylpropyl]amlno3-3'-(methylthlo)acetophenone 4'-benzoate ..........

1~3~1Z45 hydrobromide prepared accordlng to the procedure of Example 23A ln 700 mlO of methanol at 0C- was added over 075 hour 6 gO (0016 mole) of ~odium borohydrideO Stirrlng at 0C-wa~ continued an additlonal 0.5 hour. A 150-mlO aliquot of the reaction mixture wa~ concentrated under reduced pre~sure below 50C~ The concentrate wa~ di~solved in ether and the ethereal solutlon was washed thoroughly with water, dried over anhydrous magneaium sulrate and evaporated to drynes~0 The resl'due was dia~olved in 75 ml. of lsopropyl acetate and the resultlng solutlon was acidi~ied with ~cetlc acid thsn diluted with ether until cloudy and stirred for 3 hoursO The ~olld whlch pre-clpltated was collected by flltratlon, washed wlth lsopropyl .. ~
acetate and ether and drled to give 6.4 gO o~ 4-hydroxy-a-q [3-(4-methoxyphenyl)-1-methylpropyl~amlno~methyi~-3-(methylthio)benzenemethanol 4-benzoate acebate ~alt9 mOpO
107-110Co B- The remainder of the original reaction mixture was hydrolyzed with a ~olution contalnlng 9 gO o~ potassium hydroxide ln 100 ml~ of water according to the procedure of Example 10 to glve 46 g. of 4-h~droxy-a- d[3-(4-methoxyphenyl)-l-methylpropyl]amino~methy~-3-(methylthio)benzenemethPnol acetate ~alt, mOpo 130-132Co ~ [a]D5 - +408o C. To a ~olution containing lOoO go (000188 mole) of optically pure (+)-4'-hydroxy-~-~[3-(4-methoxyphenyl)-1-methylpropyl]amino~-3'-(methylthio)acetophenone 4'-benzoate hydrobromlde (m.p. 171-173C~J ~a~25 . +11.8) in 100 ml.
Or methanol at 0C. was added portionwise 380 mgO Or sodium borohydride. ~ollowing the addltion of ~everal mlO o~

.

~ Z45 _ ;ICCtiC ;Ici.-l, tl)c mi.~turc ~ cvLIporntcll to dryncss. Ille rcsi~uc ~as dissolved in a mixture o~ ethyl ~cctate and ethcr alld thc resultin~ solution w~s washe~l with saturatcd aql1cous sodium bicarbonatc, dried over allhydrolls sodium sul-fatc, acidified with 2.5 ml. of acctic acid an~ evaporated to dryness. Recrystalli7ation of the residue from isopro~yl acctatc-cther afforded 6 g. of 4-hydroxy~ {L3-~4-methoxy-phcnyl)-l-methylpropyl]amino}met}lyl~ -3-(methyltllio)benzene-meth;lnol 4-benzoate acetate salt ~]D5 = +6.4 as a dextro-rotatory pair of diastereomeric benzenemethanols correspond-ing to the products of Example 27A and B. A similar run afforded product having m.p. 101-102.5C and rotation of l7.6.
Example 25 To a stirred solution containing 8.0 g. (0.0147 mole) (+)-4'-hydroxy-2-~3-(4-methoxyphenyl)-1-methylpropyl]-amino}-3'-(methylthio)acetophenone 4'-benzoate hydrobromide, I~]D5 = ~11.1 in 60 ml. of trifluoroacetic acid at 0C. was added dropwise 3 ml. of commercial 40% peracetic acid. When the addition was complete the reaction mixture was evaporated 20 to dryness. The residue was dissolved in benzene and the resulting solution was evaporated to dryness. The residual gum was dissolved in iso~ropyl.acetate and acidified with ethanolic hydrogen chloride. The precipitated solid was col-lected and recrystallized from methanol-isopropyl acetate to give 6.0 g. of 4'-hydroxy-2-~I3-(3-bromo-4-methoxyphenyl)-1-methylpropyl]amino}-3'-(methylsulfinyl)acetophenone 4'-benzo-ate hydrochIoride, m.p. 165-167C.
The product obtained in this example was originally identified as being 4'-hydroxy-2-{ [3~-~ethO~YPhenY1)~
methylpropyl]amino}-3-(methylsulfinyl)acetophcnone 4'-benzoate ~ -hydrochloride.

.

Example _ 4-Hydroxy-a-<~L3-(4-methoxyphenyl)-1-methyl-propyl]amlno~methy~benzenemethanol 4-benzoate acetate ~lt (5.0 g., 000095 mole) prepared according to a procedure similar to that of Example 24B was oxldized wlth 1.5 ml.
of commercial 40~ peracetic acid following a procedure simllar to that of Example 220 When the oxidation waB complete the reaction mlxture was treated with 0.9 g. of aulfurlc acid and cooledO ~he solid which precipitated was collected and dried to give 2.8 gO o~ 4-hydroxy-a- ~L3-(4-methoxyphenyl)-l-methylpropyl]amino~methyl~ 3-(methyl3ulflnyl)benzene-methanol 4-benzoate hemi-sulfate9 mOpO 193-195C.

Example 27 A. To a solution contalning 7.4 g. of the free ba~e derlved from dextrorotatory 4-hydroxy-a-~{[3-(4-methoxy-phenyl)-l-methylpropyl]amlno~methy ~ 3-(methylthlo)benzene-methanol 4-benzoate acetate salt3 [a]D5 ~ +6.4 ln 60 ml.
of lsopropyl acetate was added a 801ution containing 108 g.
of (+)-mandellc acld in 20 ml. of i~opropyl acetateO The re~ulting solution was dlluted with ether untll slightly turbld and ~tirred two days at room temperatureO The pre-cipitate was collected and the mother liquors which were enriched in the levorotatory dlastereomer were set as~de for use in part B belowO The collected solid was re-crystallized elght times from methylene chloride-ether to give 3.3 g. of the (+)-mandelate salt9m.p. 126-127Cog [a]25 +49.1 which was subsequently converted to the acetate salt to give 201 g. of 4-hydroxy-a ~ {~3-(4-methoxy-phenyl)-l-methylpropyl]amino~methy~>-3-(methylthio)benzene-.

.

methanol 4-benzoate acetate ~alt, m~pO 880~-goc., La~D5 =
+26.7, corre~pondlng to the dextrorotatory member Or the palr o~ dlastereomerlc benzenemethanols present in the pro-duct of Example 24Bo B. The mother liquors from part A above were converted to the free basel dissolved in isopropyl acetate9 treated with 1~5 gO o~ (-)-mandelic acid, and the solution diluted with ether. The precipltate was collected, recrystallized once ~rom i~opropyl a~etate-ether to glve 207 gO of the (-)-mandelate salt, m.pO 120-12005C~, [~]25 = _~5~0o which was subsequently converted to 4 hydroxy-a- ~[3-(4-methoxyphenyl)-l-methylpropyl]amino3methyI~-3-(methylthlo)benzenemethanol 4-benzoate acetate salt9 mOpo 82-83C~ J ~a]25 ~ -lOoOJ
corresponding to the levorotatory member of the pair of diastereomeric benaenemebhanols pre~ent in the pr~duct Or Example 24Bo Example 28 mixture contalning 600 mg. o~ 4-hydroxy a-~[3-(4-methoxyphenyl)-1-methylpropyl]amino~methyl~ 3-(methylthio)benzenemethanol 4-benzoate acetate salt (m.p.
82-83Co~ ~a]D5 - -10~0~ 5 mlO O~ 35% aqueous sodium hydroxide and several mlO of methanol wa~ stirred 10 minutes at room temperature, then dlluted wlth 20 mlO of water and stirred an additional 10 minutes in a warm-water bathO The pH WaB ad~u~ted to 9 with acetic acid and the methanol wa3 evaporated under reduced pressureO The residue was extract-ed with ethyl acetate, and after drying over anhydrous sodlum sulrate the extracts were evaporated to dryness.
~he residue was dls~olved in isopropyl acetate, the resultin~

solution ~cidlfled with acetic acld and cooled. The pre-cipitated solld wa~ collected by flltration and dried under vacuum to give 500 mg. of 4-hydroxy-a-~{[3-(4-methoxyphenyl)-l-methylpropyl]amln~ methyr>-3-~methylthio)-benzenemethanol acetate ~alt, m.p. 117-120Co J ~a]D5 ~
-1700 (average Or two determlnations) corresponding to the levorotatory member Or the pair of diastereomerlc benzenemethanols present in the product of Example l9C.

Éxam~ 2 A. To a stlrred ~olution contalnlng 1.0 g. ~GoO03 mole) of 4-hydroxy-a-~3-~4-methoxyphenyl)-1-methylpropyl]-amino~methy~-3-(methylthio)benzenemethanol [a]D5 ~ -5.1) prepared according to the method of Example 21B~o ln 15 ml.
of methanol at 0C. there was added dropwise over 0.5 hour a solutlon of 0.45 ml. of commercial ~0% peracetic acld ln 5 mlO of methanolO When the addition was complete the reactlon mixture was evaporated to dryness in vacuo. ~he residue was diluted with 10 mlO of benzene, the resulting solution acidified with glacial acetic acid and evaporated to dryne~sO The re idual gum was cry~tallized ~rom tetra-hydrofuran-ether and then recry~tallized from ethyl acetate-2-propanol to glve lo 05 gO of 4-hydroxy-a-~{[3 ~4-methoxy-phenyl)-l-methylpropyl]amino~methyl~ 3-(methyl~ulflnyl)-benzenemethanol acetate salt a~ a levorotatory palr of diastereomerlc sulfoxides, mOpO 90-95C., [a]D5 - -904O
Bo When the above oxidatlon was carried out starting with isomerically pure levorotatory 4-hydroxy-a- ~L3-(4-methoxyphenyl)-l-methylpropyl]amino~methyl~-3-(methylthio)-benzenemethanol acetate salt (mOp. 117-120Co~ [a]D5 -l~lZ45 -17.0) prepared according to the meth~nol of Example 28 the resulting pair of dla~tereomerlc ~ulfoxldes h~d ~a]25 =
-18.8 (determined on the reactlon mlxture)~
The pair of diastereomeric ~ulfoxides of thi~
example correspond to the products of Examples 31 and 33.

Example 30 Mother llquors obtalned in the preparation of several batches of 4-hydroxy-a-~{[3-(4-methoxyphenyl)-1-methylpropyl]amlno~methy V-3-(methylsulflnyl)benzenemethanol acetate salt accordlng to a procedure similar to that described in Example 20B were combined and evaporated to dryness. The residual oil was trlturated successlvely with ether and isopropyl acetateO The residue (90 gO) was dlssolved in 300 ml. acetone and the resulting ~olution treated wlth 33 g. of cyclohexylsul~amic acld ln 200 mlO
o~ acetone~ The precipltated cyclohexylsulfamate wa~
collected and recrystallized ~ive timea from aqueou~ methanol to glve 7 o 3 gO of product whlch was comblned wlth 7.4 g.
Or material obtained in previous run~ and converted to the hydrochlorideO Recrystalllzation o~ the latter from methanol-lsopropyl alcohol afforded 6.3 gO of 4-hydroxy-a-~{[3-~4-methoxyphenyl)-1-methylpropyl]amlno~methyl~3-(methylsulfinyl)benzenemethanol hydrochloride, m.pO 206-207Co ~ ~a]D5= +~6~ oorresponding to the dextrorotatory member of the palr of diastereomeric~sulfoxldes present in the product of Example 22B.

... . . . ..
. .

Z~

Example 31 The mother li.quors resultlng from the fractional crystallization of the product of Example 30 were evaporated and t,he res~e crystallized from acetone~ The resulting 12.4 gO of solld was recrystallized twi~e ~rom methanol-~cetone to give 501 g. of product [a]D5 = +49u~o The latter material was combined with ~05 gO obtained in a previous run and converted to the hydrochloride which was crystalllzed from 2-propanol to give 4-hydroxy-a-~3-(4-methoxyphenyl)-1-methylpropyl3amino~ methy V~3-(methyl-sulfinyl)benzenemethanol hydrochlorldeg mOpO 204-205~Co~
[a]D5 = +7005, corresponding to the dextrorotatory member o~ the dlastereomeric pair of sulfo~ldespresent ln the pro-duct of Example 29~

Example 32 The reactlon mlxture resulting from the oxidation of 1201 g. of dextrorotatory 4-hydroxy-a- 4[3-(4-methoxy-phenyl)-l-methylpropyl]amino~methy~-3-(methylthio)benzene-meth~nol (+)-mandelate salt according to the procedure of Example 22B was evaporated to dryness, the re~idue diæsolved in a mixture of 70 mlO of methanol and 15 mlO of water~
treated with a molar e~uiva ~ nt of cyclohexylsulfamic acid and seeded with the cyclohexylsulfamate salt of the product of ~xample 300 The 709 gO of product which crystallized was collected and set asideu The mo`ther liquors were evaporated to dryness and the residue crystallized from acetone-methanolO The product wa~ converted to lo 1 go of the hydrochlorlde and comblned wlth an additlonal 850 mg~
obtained from the mother liquors resulting from the ' . '' . ~ ''' ''''''.'''-' ' " ~ , '-. . .

fractional cry8talllzation of the diastereomer of Example 31. The combined solids were recryatallized from 2-propanol to give 1.4 g. of 4-hydroxy-a- ~ ~-(4-methoxyphenyl)-1-methylpropyl]amino~methy]~-~-(methylsulfinyl)benzenemethanol hydrochloride, m.p~ 138-140C~, [a]D5 - -48.2, corre~ponding to the levorotatory member of the pair of diastereomeric ~ulfoxides present ln the product of Example 22B.

Example 33 Ao The reaction mixture resulting from the oxidation of 3 gO o~ levorotatory 4 hydroxy-a-<{L3-(4-methoxyphenyl)-l-methylpropyl]amino~methyl~ (methylthio~benzenemethanol acetate salt according to the procedure of Example 29B was evaporated to dryness, the resldue di~801ved in a 90glO
mixture of acetone-methanolg treated wlth a molar equivalent of cyclohexylsulfamic acid, and ~eeded wlth the cyclohexyl-~ulfamate salt of the product of Example 310 The 106 go of product whlch cryætallized was collected and set asideO The mother liquors were evaporated to dryness and the resldue crystalllzed twice from aqueous methanol to give 1~85 g~ of crystalllne solld, ~~25 ~ -6705o Bo Alternatively, lOoO go of 4-hydroxy-a- ~[3-~4-methoxyphenyl)-1-methylpropyl]amino~methyl~3-(methylthlo)-benzenemethanol 4-p-toluenesulfonate (+) mandelate salt prepared according to the procedure of Example 21D wa~
oxidized following a procedure simllar to that of Example 29A and the product was lsolated as the free base to glve 10 go of crude 4-hydroxy-a- ~[3-(4-methoxyphenyl)-1-methyl-propyl~amlno~methyl~ ~-(methyls~lrinyl)benzenemethanol 4-p-toluenesulfonate as a palr of dlastereomeric sulfoxldesO

~ 2 ~5 A solution contalning the latter product and 15 ml.
Or 10% ~queous p~tassiUm hydroxlde in 100 ml. of ethanol was stirred 1.5 hours at 45C. ~he reaction mi~ture w~ then concentrated, diluted with æaturated aqueous ~odium blcar-bonate and extracted wlth chloroform~ The organlc extracts were dried over anhydrous sodlum ~ulfate and evaporated to drynessO The residue was dlssolved ln acetone and treated with a molar equlvalent of cyclohexyl~ulfamic acidO ~he product which precipitated wa~ collectedy and recrystalllzed from acetone-m~ hanol to give 1~15 gO o~ 8alt corre9pondlng to the cyclohe~ylsulPamate salt of the product o~ Example 310 The mother liquor~ were evaporated to dryness and the re~idue crystalllzed ~rom acetone~ Four recrystalllza-tlons rrom aqueou8 methanol a~forded 450 mg. of crystalline solld [a]D5 = -66.2~
C0 The levorotatory products of parts A and B were combinedJ recry~tallized once from aqueou~ methanol and then converted to the hydrochloride to give 1.1 gO Or 4-hydroxy-~-~[3-(4-methoxyphenyl)-1-methylpropyl]amlno~methy~>-3-(methylsulfinyl)ben~enemethanol hydrochlorlde~ mOpO 178-180Co, Ca]D5 - -102~3, correspondlng to the levoro~atory member Or the palr of dlastereomerlc sulfoxide~ pre8ent ln the product o~ Example 29Bo Example 34 To a ~tlrred solutlon contalnlng 20 gO '~0.134 mole) of l,l-dl~ethyl-2-phenylethylamine ln 40 mlO of N,N-dlmethylformamide at -50C. was added dropwi~e over 15 mlnutes a solutlon contalnlng 14.5 gO (oOo48 mole) o~ 2-bromo-4'-hydroxy-~'-(methylthlo)acetophenone 4'-acetate ln 35 ml. o~ N~N-dimethylformamlde. A~ter the additlon was com-plete stlrring was contlnued an sddi~ional 1025 hours. The reactlon mixture wa~ then treated with 3.5 ml. o~ 12N
hydrochlorlc acid. diluted with 100 ml. o~ water and extracted thoroughly with ether. The ethereal extract~
were drled over anhydrous sodium 3ul~ate, aoidlfled with ethanolic hydrogen chlorlde and cooled ln a refrlgerator overnightO The 12~5 g, of precipltated product wa8 collected and combined wlth 6 ~ o gO of product obtained from a previous run and recrystallized twice rrom chloroform-methanol af~ording 15 g. of 2-[(1,1-dimethyl-2-phenylethyl)amino]-4'-hydroxy-3'-(methylthlo)acetophenone 4'-acetate hydro-chloride, m,pO 205C, (dec.).

Example 35 To a stlrred suspenslon of 15 g~ (00037 mole) of 2-[(1,1-dlmethyl-2-phenylethyl)amlno~-4'-hydro~y-3'-(methylthlo)acetophenone 4'-acetate hydrochlorlde ln 200 ml~
of methanol at -5C. was added portlonwlse over I0 mlnutes 750 mg. (00020 mole) o~ sodium borohydrideO After stlrring an additlonal 10 minutes the reactlon mlxture was brought ~ to pN 7 with glaclal acetlc acld and evaporated to dryne~s~0 ; The resldue was dls~olved ln ether-ethyl acetate and the resulting solutlon wa~hed wlth saturated aqueous 80dium bi-:: .
carbonate. The organlo Iayer was drled over anhydr0us sodlum as sulfate, aoldifIed with methane~ulfonlc acid and concentrated to a small volume. The conoentrate wa~ diluted with benzene - and evaporated to dryne~q. The proce~s was then repeated employlng tolueneO ~he resultlng solld re~ldue was recrystallized rom ethanol-ether to give 12 g. o~ a~ 1-dimethyl-2-. ~ , .

;', : . .

phenylethyl)amino~methyl~-4-hydroxy-3-(methylthio)benzene-methanol 4-acetate m~thanesulfonate, m.pO 112-115C, Example 36 A 901ution contalnlng 9.5 g. (0.020 mole) of a-{[(1,1-dimethyl-2-phenylethyl)amlno]methyl~-4-hydroxy-3-(methylthlo)benzenemethanol 4-acetate methane~ulfonate, 3 g.
(00045 mole) of potasslum hydroxlde and 20 mlO of water in 200 mlO Or 95~ ethanol wa~ stlrred overnight under nitrogen.
The reaction mixture was neutralized wlth glaclal acetlc acld and concentrated to a small volumeO The concentr3te was dlluted with saturated aqueous sodlum bicarbonate and extracted wlth ethyl acetate. The organlc extracts were drled over anhydroUs Rodium sulfate and concentrated to a volume of 100 mlO The concentrated solution was brought to a pale yellow color by dropwise addition of glaclal acetic acid whereupon c~ystallizatlon beganO The product was collected by flltratlon and reorysta~lized from chloro-form-methanol to give 501~ of a-~[(1,1-dimethyl~2-phenylethyl)-amino~methyl~-4-hydroxy-3-(methylthio)benzenemethanol acetate s21t, mOpO 165-167C.

Example 37 Follo~ing a procedure similar to that described in Example 34 but using 1803 gO (00135 mole) of l-methyl-2-phenylethylamine and 15 gO ~00050 mole) of 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4'-acetate there was ` obtained 7.1 g. of 4'-hydroxy-2-[(1-methyl-2-phenylethyl)-amino]-3'-(methylthlo)acetophenone 4'-acetate hydrochloride.

.

l~g~Z45 ~xample ~8 Following a procedure similar to that de~crlbed in Example 8 but u~ing 704 gO (OoOl9 mole) of 4'-hydroxy-2-[(1-methyl ~-phenylethyl)amino]-3'-(methylthio)aceto-phenone 4'-acetate hydrochloride, 600 mgO 00015 mole) of ~odium borohydride and lo 1 go of pota3slum hydroxlde there wa~obtalned 6D3 gO of 4-hydro~y-a-{~(1-methyl-3-phenylethyl)-amino]methyl~-3-(methy].thlo)benzenemethanol acetate ~altg mO po 131-132Co Example 39 To a ~tirred solution containing 407 g. (0u01.2 mole) of a-~[(l,l-dimethyl-2-phenylethyl)amino~methyl~-4-hydroxy-3-(methylthlo)benzenemethanol acetate ~alt in 100 mlO of methanol at 0C. was added dropwise over 005 hours a solution containing 2 mlD ~00012 mole) of commercial 40%
peracetic acid in 10 mlO of methanolO After the add~tion was complete the reaction mixture was evaporated to dryne~s and the residue was crystallized from ethanol-ether to glve 4.3 gO of a-~[(l,l-dlmethyl-~-phenylethyl)amino~-methyl3-4-hydroxy-3-(methylsulfinyl)benzenemethanol acet~te salt which softened at 100Co and melted at 138-140C~
~ .
A O To a stirred solution containin~ 35 g~ ~0025 mole) of o-(methylthio)phenol and 27~6 gO ~0030 mole) of propionyl chloride in 100 mlO of nitrobenzene there was added portion-wise over 25 minutes 4605 gO (0.35 mole) of alumi.num chlorldeO The reaction was exothermic and the temperature rose to 45-50Co When the addition wa~ complete the reactlon _ _ mixture was ~tirred 2 hours at 60Cu and 1 hour at 70C.
The reaction mlxture waB cooled, diluted with water and extracted with ether. The ethereal extracts were dried over anhydrous ~odium ~ulfate and evaporated to dryne~s in vacuo.
The residual oil was adsorbed on a column of ~ilica gel and continuously eluted wlth boiling methylene chlorideO The eluate was evaporated to dryness and the residue recry~tallized f~om ether giving 25 gO of crystalline product which wa~ then triturated with ether at -65co to give 17 g~ of pure 4'-hydroxy-~'-(methylthio)proplophenoneO
B~ To a stirred solution containing 1704 gO (ouo89 mole) of 4'-hydroxy-3'-(methylthlo)propiophenone, and 13 ml~
(OOO9O mole) of trlethylamine in 200 mlO of methylene chloride there was added dropwi~e over 0O5 hour 7065 gO
(o~og8 mole) of acetyl chlorideO After the addition was complete stirring was continued an additional 2 hour~ $he reaction mixture was then washed ~uccessively with 3~
hydrochloric acld and water and evaporated to dryness. The resldual oil was dissolved in ether, treated with decoloriz-ing carbon and ~iltered through a bed of silica gelO ~e filtrate was e~aporated to dryne~s affording 21~4 g. of 4'-hydroxy-3'-(methylthlo)propiophenone 4'-acetate as a pale yellow oll~
CO To a stlrred solution contalning 210 4 gO (OoO88 mole) of 4'-hydroxy-3'-(methylthio)propiophenone 4'~acetate in ~50 mlO of chloroform was added a solution containing 14.4 gO (0~090 mole) of bromine ln 40 ml~ of chloroform~
After a 15-minute lnduction period the bromine began to be consumedO After 1 hour the reactlon mlxture was wa~hed ~0 with 5% aqueous sodium bicarbonate and then waterO The l~Z4S

chloro~orm solution WB~ drled over anhydrous sodium sulfate and evaporated to dryness to eive 19 g~ of 2-bromo-4'-hydroxy-3'-(methylthlo)propiophenone 4'-acetate.
Do To a stirred solution contalning 30 g. (0.185 mo~le) o~ 2-(4-methoxyphenyl)-1-methylethylamine ln 150 ml.
of N,N-dlmethyl~ormamlde there was added dropwlse 19.6 g~
(oOo62 mole) of 2-bromo-4'-hydroxy-3'-(methylthlo)propiophenone 4'-acetate. After the addition was complete stirrlng was contlnued an additlonal 2 hours. The reaction mixture was then diluted with chloroform and washed ~ucce~slvely wlth water, dllute hydrochlorlc acid and ~aturated aqueous sodium bicarbonateO The chloro~orm ~olution was drled over anhydrou~ sodlum sulfate and evaporalted to drynessO
The resldue was dlssolved in ether, acidi~ied wlth glaclal acetic acid and ¢ooled. The precipitated product was collected and triturated wlth chloroform to glve 60 3~ g~
of 4'-hydroxy-2-~[2-(4-methoxyphenyl)-1-methylethgl]amln~ -~'-(methylthio)propiophenone acetate salt, mOpO 110-112C.

Example 41 To a stirred solutlon containing 602 gO (000148 mole) of 4'-hydroxy-2-{[2-(4-methoxyphenyl)-1-methylethyl]-amino}-3'-(methylthio)propiophenone acetate salt in 100 mlO
Or methanol at 0C0 there was added portionwise 005 gO of sodium borohydrideO After the addition was complete stirring was contlnued an additional 0~5 hour~ The reaction mixture was then acidified with glacial acetic acid and evaporated : to drynessO ~he residue was diluted with saturated aqueous ~odlum bl¢arbonate and extracted ~ith ethyl acetateO The organic extracts were evaporated to dryness and the re~idue .

dlscolved in ether. The ethereal solutlon was acidlfied wlth glacial acetlc acld and cooled. The precipitated product was collected and dried to glve 5.0 g. of 4-hydroxy-a-~{[2-(4-methoxyphenyl)-1-methylethyl]amino3ethy D-3-(methylthio)benzenemethanol acetate salt, m.p. 160-162Co Example 42 To a stirred mixture of 20 35 g O ( oO oos6 mole) of 4-hydroxy-a-<~[2-(4-methoxyphenyl)-1-methylethyl]amino~ethy 3-(methylthio)benzenemethanol acetate salt and 40 ml. of methanol at -10Co there was added dropwise a solutlon containing 1 mlO (oOoo56 mole) of ¢ommercial 40% peracetlc acld ln 5 ml. of methanol~ After the addition was complete stirring was continued an additional 0.5 hour. The reaction mlxture was then evaporated to dryness and the resldual oil suspended in chloroform and diluted with ether producing a granular ~olld whlch was collected and drled to give 2.2 g.
of 4-hydroxy-a ~ {1-[2-(4-methoxyphenyl)-1-methylethyl]
amino~ethyl~-(methylsul~inyl)benzenemethanol acetate salt, m.pO 110C.

Example 4~
To a stirred solution contalning 16 g. (0.082 mole) of 2-(3,4-dimethoxyphenyl)-1-methylethylamine and 6 ml.
(00041 mole) of trlethylamlne ln 60 ml. of N,N-dimethyl-formamide at -65Co there was added dropwise over 0075 hour a solution containing 12~ 5 g~ (0.041 mole) of 2-bromo-4'-hydroxy-~'-(methylthio)acetophenone 4'-acetate in 40 ml. of N,N-dimethylformamlde. After the addltion was complete stirring Was contlnued an additlonal hour. The reaction mlxture was then made slightly ~cidlc with 5 ml. of 12N
hydrochloric acid and extracted with chloroform. The organlc extracts were evaporated to dryness and the residue was dissolved in trifluoroacetic acid and treated with exce88 acetyl chloride. After ~tirring 1 hour the mixture was dlluted with water and evaporated to dryness. The resldue was partitioned between ethyl acetate and saturated aqueous sodlum bicarbonateO The organic layer was dried over an-hydrous sodium sulfate and evaporated to dryne~s to give 12 g, of crude 2-~[2-(3,4-dimethoxyphenyl)-1-methylethyl]amlno~-4'-hydroxy-3'-(methylthio)acetophenone 4'-acetateu Example 44 Following a procedure similar to that de8crlbed in Example 38 but using 12 g, of 2- l[2-(3,4-dlmethoxy-phenyl)-1-methylethyl]amino~-4'-hydroxy-3'-(methylthio)-acetophenone 4'-acetate, 870 mgO of sodium borohydride and 1.4 g. of potassium hydroxide there Was obtalned 2.2 g~
of a-~[?-(~,4-dlmethoxyphenyl)-1-methylethyl]amino~methy~-4-hydroxy-3-(methylthio)benzenemethanol acetate saltg m.p.
141-144C.

Example 45 Following a procedure similar to that described in Example 42 but using 2O30 g~ (0.0052 mole) of a- ~ [2-(3,4-dimethoxyphenyl)-1-methylethyl]amino)methy ~ 4-h~droxy-3-(methylthio)benzenemethanol acetate salt and 0.95 ml~ (0.0052 mole) o~ commercial 40% peracetic acid there was obtained 1.9 g. of a ~ [2-(3,4-dimethoxyphenyl)-1-methylethyl~amino~methyl~ 4-hydroxy-3-(methylsulflnyl)-1~!5~24S

benzenemethanol acetate salt as a llght yellow amorphous solid.

Exa mp le 46 To a ~tirred ~olution containing 19.5 g. (0.12 mole) o~ dimethyl-3-phenylpropylamine in 100 ml. o~
N,N-dimethyl~ormamlde under nitrogen ~t -60C. there was added dropwi~e over 00~ hour a ~olution contalnlng 12 g.
(0.04 mole ) of 2-bromo-4l-hydroxy-3'-( me thylthio)-acetophenone 4'-acetate in 40 mlO of N,N-dimethylformamlde.
After the addition ~as complete ~tirrlng was continued 1 hr.
at -~5C~ The reaction mlxture was then acidified with 10 ml.
of 12N hydrochlorlc acid, dlluted with 150 ml. of chloro-~orm and the resulting aolution washed with water. The chloroform solution wa~ cooled to -65C. and dlluted wlth ether. The resulting precipltate wa~ collected and re-crystalllzed from ~thanol to glve 12 g. Or 2-~(191-dimethyl-3-phenylpropyljamlno]-4'-hydroxy-3'-(methylthio)acetophenone 4'-acetate hydrochloride, m.p. 188-193C.

Example 47 Followlng a procedure ~imilar to that de~cribed in Example 8 but using 11.0 g~ (0~026 mole) of 2-~
dlmethyl-3-phenylpropyl)amlno]-4'-hydroxy-3'-(methylthio)-acetophenone 4'-acetate hydrochloride, 750 mg~ (0.02 mole) af sodlum borohydrlde and 1~4 g. (00026 mole) of pota~lum hydroxide there wa~ obtained 902 gO o~ a-~(l,l-dimethyl-3-phenylpropyl)amlno~methyl~-4-hydroxy-3-(methylthio)benzene-methanol acetate ~alt, m. pO 171-172C.

.
..

29:5 Example 48 Following a procedure slmllar to that descrlbed in Example 11 but using 6.2 g. (0.015 mole) of a~
dlmethyl-3-phenylpropyl)amino]methy~ -4-hydroxy-3-(methylthlo)-benzenemethanol acetate salt and 1.17 g. (0.015 mole) of commercial 40% peracetic acid there waæ obtained 5.5 g. of crude o~(l,l-dlmethyl-3-phenylpropyl)amlno]methyl~-4-hydroxy-~ ethylsul~inyl)benzenemethanol acetate salt.
Following recrystalllzation twice from chloro~orm-methanol and once ~rom ethyl acetate-acetone-ethanol the product was dissolved in ethyl acetate-methanol and the resulting ~olutlon acidi~led with glacial acetic acid and evaporated to dryneas, Recrystalllzation o~ the residue from ethanol-ethyl acetate af~orded 1.4 g. of analytically pure material, m.p. 155-157C.

Example 49 A. To a stirred solutlon contalnlng 65 g. (1.0 mole) of potassium cyanide and 73.7 g. (o.~8 mole) of 4-(~-methoxyphenyl)-2-methyl-2-butanol in 300 mlO o~ n-butyl ether at 60C. there was added dropwise over 1 hour 120 ml.
of concentrated sulfurlc acidO When the addition wa~ com-plete stirring wa~ continued an additlonal hour at 50-55C~
The reaction mixture was then poured over 1200 g. o~ ice, made baslc with sodium carbonate and extracted with ether.
The ethereal extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The 76.5 g. of re~idual oil was heated under reflux 3 hour~ in 175 ml. of 12N hydro-chloric acid. The mixture was cooled, waæhed ~ith ether, made basic wlth 35% aqueous sodium hydroxide and extracted with ether. The ethereal extracts were dried over anhydrous ~ 45 sodium sulfa~e and evaporated to dryness. The re~idual oll WaB distilled under reduced pre~ure and the ~ractlon boll-ing at 161-162C~/22 ~n. was collected af'rordlng 35 g. of 1,1-dimethyl-3-(4-me~hoxyphenyl)propylamlne.
B. Following a procedure simllar to that described in Example 7 but u~lng 29 g. (0.15 mole) of 1,1-dlmethyl-3-`(4-methoxyphenyl)propylamlne, 15 g. ~0.05 mole) of 2-bromo-4'-hydroxy-~'-(methylthio)acetophenone 4'-acetate and 10 ml.
of acetyl chloride there was obtalned 9~5 g. of 2-~[1,1-dimethyl 3-~4-methoxyphenyl)propyl~amino¦-4'-hydroxy-3'-(methylthio)acetophenone 4'-acetate hydrochloride, m~p.
186-190C.

Example ~0 Following a procedure similar to that described in Example 8 but uslng 905 g. (00021 mole) of 2-~Ll~l-dimethyl-3-(4-methoxyphenyl)propyl3amino~ -4'-hydroxy-3'-(methylthio)acetophenone 4'-acetate hydrschloride, 600 mg.
(00015 mole) of sodium borohydride and 102 g. o~ potassium hydroxlde there wa6 obtained 2.3 gO o~ a~ l,l-dimethyl-3-(4-methoxyphenyl)propyl]amino~methyI~-4-hydrbxy-3-(methyl-thio)benzenemethanol acetate ~alt, m~p. 173-174C~

Example 51 Following a procedure ~imilar to that descrlbed in Example 11 but u~ing 3O9 g~ (0.009 mole) of o~
dimethyl-3-(4-methoxyphenyl)propyl]amino~methy~-4-hydroxy-3-(methylthio)benzenemethanol acetate salt and ~80 mg. of commercial ~0% peracetic acid there was obtained 3.0 g. of a-~{L 1, 1-dlmethyl-3-(4-methoxyphenyl)propyl]amlno~methy~-_ ,.... ~ ., . , . . . , :

. ~

4-hydroxy-3-(methylsulfinyl)benzenemethanol acetate salt, m.p. 115~C.

Example 52 Following a procedure similar to that de~crib0d in Example 7 but u~ing 18 g, (0.12 mole) of 1-methyl-3-phenylpropylamine, 12 gO (0Oo4 mole) of 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4'-acetate and 8 ml.
of acetyl chloride there wa~ obtained 8.3 g. o~ 4'-hydroxy-2-~(1-methyl-3-phenylpropyl)amino]-3'-(methylth~o)aceto-phenone 4'-acetate hydrochloride.
Example 53 Following a procedure similar to that descrlbed ln Example 8 but u~ing 8.1 g. (0~02 mole) of 4'-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]-3'-(methylthlo)aceto-phenone 4'-acetate hydrochloride~ 500 mg. of sodium boro-hydride and 1.2 g. of potas~ium hydroxide there was obtalned 602 g. cf' 4-hydroxy-a-{[(1-methyl-~-phenylpropyl)amino]-methyl~-3-methylthio)benzenemethanol acetate salt, m.p.
140-142C.

~xample 54 Following a procedure ~imilar to that described ln Example 11 but using 4.2 g. (0.011 mole) of 4-hydro~y--~[(l-methyl-3-phenylpropyl)amino]methyl~-3-(methylthlo)-benzenemethanol acetate ~alt and 815 mg. (0.011 mole) of commercial 40% peracetic acld there was obtained 4.0 g.
Or 4-hydroxy--~[(1-methyl-3-phenylpropyl)amlno]methyl~-3-(methylsul~inyl)benzenemethanol acetate 6alt as a pale yello~ amorphous solid.

Example 55 Following a procedure ~imilar to that described in Example 34 but uslng 18.2 g. (0.11 mole) of 3-(4-methoxyphenyl)propylamlne and 11.2 g. (0.037 mole) of 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4'-acetate there wa~ obtained 9 gO o~ crude 4'-hydroxy-2-~[3-(4-methoxy-phenyl)propyl]amino~-3'-(methylthio) a cet ophenone 4 ' -acetate hydrochloride which was suitable ~or use in the ne~t stepO

Example 56 Following a procedure similar to that de~cribed ln Example 8 but using 9 g. of crude 4'-hydroxy-2-~3-(4-methoxyphenyl)propyl~amino~-3'-(methylthio)acetophenohe 4'-acetate hydrochlorideg 600 mgO of sodium borohydrlde and 200 go of potassium hydroxide there wa~ obtalned 1.2 g, o~ 4-hydroxy-a- ~3-(4-methoxyphenyl)propyl]amino~methy~_3-(methylthio)benzenemethanol acetate salt, m.pO 123-125C.

Example 57 Followlng a procedure ~imilar to that described in Example 11 but using 1.2 gO (00003 mole) of 4-hydroxy-a ~ ~3-(4-methoxyphenyl)propyl]amino~methyI~-3-(methyl-thiO)benzenemethanol acetate salt and 0.44 mlO (00003 mola) of commercial 40% peracetic acid there was obtained lo 1 g~
o~ 4-hydroxy-a ~ {L3-(4-methoxyphenyl)propyl]amino~ ethy V~
3-(methylsul~inyl)benzenemethanol acetate salt as an amorphoUs tan ~olidO

~ 45 Example 58 A. A stlrred mlxture containing 64 g. (0~334 mole) o~ 5-t4-methoxyphenyl)-2-pentanone, 80 g~ 77 moles) of formamide and 6 mlO of formic acid waB 910wly he~ted to 165Co and tr~ated dropwise over 305 hour~ wlth 50 ml.
o~ ~ormlc acid while the water f'ormed during the reactlon was allowed to dl~till 810wly. Stirrlng at 165C. was contlnued an additlon~l 3 hoursO The reactlon mlxture was then cooled9 diluted wlth 1 liter of lce and w~ter and extracted with a mixture of ether and benzeneO The or~anic extract~ were evaporated and the resldual oll wa~
heated under reflux 1.5 hours in 130 mlO o~ 12N hydrochlorlc acidO The mixture was cooledJ dlluted with ~00 mlO Or water and washed with a mixture of ether and benzene. The aqueous layer was made baaic with 35~ aqueoua sodium hydroxlde and extracted with a mlxture o~ ether and benzene.
The organic layer wa~ extracted with lN hydrochloric acid, and the acidic aqueou~ layer made ba~ic wlth 35% aqueou~
sodium hydroxide and extracted with an ether-benzene mixture~ The extract~ were drled over anhydro~s sodium ~ulfate and the solvent evaporated in vacuo~ The residual oil was distilled under reduced pres~ure to glve 37 gO of 4-(4-methoxyphenyl)-1-methylbutylamine, b~po 163-166.5C./
18 mmO
Bo To a stlrred ~olution contalnlng 1505 gO (o~o8 mole) o~ 4-(4-methoxyphenyl)-1-methylbutylamlne in 80 ml.
Or N,N-dlmethylformamide at -60Co there was add~ed dropwlse over 0075 hour a aolution contalnlng 8.o g. (00027 mole) of 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4'-1, ., --90--. ~

__ ~ __ . . .. . .. ...... ..... .... . .. .. .. ....... . ............ .. .. .... . .. . .. . ..

acetate ln 25 ml. of N,~i-dimethyl~ormamlde. After the addltion was complete stlrrlng at -60 to -45C. wa~
contlnued an addltional hour. The reaction mixture 1qas then acldlfied with 48% hydrobromlc acid and extracted wlth chloroform. The chloroform solutlon was diluted with 20 5 volumes Or ether and cooled to -65Co ~he re-` sultlng preclpitate wa~ collectedg redlssolved ln chloro-form and the resultlng solution wa~hed thoroughly ~ith ~ater.
The chloroform solution was then drled over anhydrous sodlum sulfate and evaporated to dryness to glve 9 gO o~ I
crude 4'-hydroxy-2-~L4-(4-methoxyphenyl)-1-methylbutyl]-aminol-3'-(methylthio)acetophenone 4'-acetate hydrobromlde. - i Example ~9 i Following a procedure similar to that described ln Example 8 but using 9 gO of crude 4'-hydroxy-2-~[4-(4-methoxyphenyl)-1-methylbutyl]amino,}-~'-(methyl'Ghio)-acetophenone 4'-acetate hydrobromide, 500 mgO of aodlum borohydrlde and 1 gO o~ pota~ium hydroxide there was obtained 505 gO o~ 4-hydroxy-a-<f[4-(4-methoxyphenyl)-1-methylbutyl]amlno,}methyl~3-(methylthio)benzenemethanol acetate salt, mOpO 155-157Co Example 60 ',-, Followlng a procedure simllar to that described ln Example 11 but using 300 gO (00007 mole) of 4-hydroxy-a-~L4-(4-methoxyphenyl)-1-methylbutyl]amino,}methy:1~3-(methylthio)benzenemethanol acetate ~alt and 1004 ml.
(0.007 mole) Or commerclal 40% peracetlc acid there was obtalned 2.6 g. o~ 4-hydroxy-a-<~[4-(4-methoxyphenyl)-1-', .

1~S~2~S

methylbutyl]amlno~methy~~3-(methyl~ulfinyl)benzenemethanol acetate salt as an amorphous yellow solld~

Example 61 A. To a stirred mixture of 52~5 g~ (0.253 mole) of 4-(4-methoxyphenyl)-1,1-dimethylbutyl alcohol, and 44O5 g.
(oO685 mole) of powdered potasslum cyanide in 200 ml~ of n-butyl ether at 60Co was added dropwise over 1 hour 80 mlO of concentrated sulfuric acidu The tempera$ure wa~
maintained at 60-65Co throughout the addition and stlrring was continued at 50-55Co an additi~nal hour after the addition was complete~ The reaction mixture was then poured into 850 mlO of ice, made baslc wlth 35~ aqueous sodium hydroxide and extracted with ether~ The ethereal extracts were evaporated to dryness and the resldual oil heated under reflux 3 hours in 125 ml. of 12N hydrochloric acidO The resulting mixture was diluted wlth 300 mlO of water and washed with a mixture of ether and benzeneO The aqueous layer was made baslc with 35~ aqueous sodium hydroxide and e~tracted with a mixture of ether and benzeneO The organic layer was then extracted with lN
hydrochloric acid, the acldic aqueous layer made basic with 35~ aqueous sodlum hydroxide and extracted with an ether-benzene mixtureO The extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo afford-2~ ing 1202 gO of 4-(4-methoxyphenyl)~ dlmethyl.butylamine as a straw-colored oilO
Bo Following a procedure slmllar to that described ln Example 58~ but using 19 gO (0009 mole) of 4-(4-methoxy-phenyl)-131-dimethylbutylamine and lOoO gO (0.033 mole) of lQ~Z45 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4'-aceta~e and allowing the flnal product to crystallize from acetone in a refrigerator overnight, there wa~ obtalned 1005 gO
of cry~talline 4~-hydroxy-2-~[4-(4-methoxyphenyl)-191-dimethylbutyl]amino~-~'-(methylthio)acetophenone 4'-acetate hydrobromide9 mupO 180-181Co Example_ 2 Following a procedure similar to that descrlbed ln Example 8 but using lOo 5 gO (0~021 mole) of 4'-hydroxy-2-~4-(4-methoxyphenyl)-191-dimethylbutyl]amino~-3'-(methylthio)acetophenone 4'-acetate hydrobromide, 250 mgO
of sodlum borohydride and 1 gO of potasslum hydroxide, and recrystallizing the product rrom mekhanol-ether there was obtained 4 gO of 4-hydroxy-a ~ f[4-(4-methoxyphenyl)-1,1-dimethylbutyl3amino~ .methyl~ ~-(methylthio)benzenemethanol as the ~ree b~e mOpo 179-180Co Example 63 Following a procedure similar to that described in Example 42 but employing 2. 7 gO (00007 mole) of 4- :
hydroxy-a-~ [4-(4-methoxyphenyl)-1~1-dimethylbutyl~amlno~
methyr~3-(methylthio)benzenemethanol there ~as obtained 108 go Of 4-hydroxy-a-<{[4-~4-methoxyphenyl)-191-dimethyl-butyl]amino~methy~-3-(methylsulfinyl)benzenemethanol as an amorphous white powderO

Example 64 A stirred mixture containing 7 u 4 gO (00015 mole) of optlcally pure (+)-4'-hydroxy-2- ~3-(4-methoxyphenyl)-1-methylpropyl]amino~-3'-(methylthio)acetophenone 4'-benzoate hydrobromide and 100 ml. of 48~ hydrobromlc acid wa~ heated under reflux 1.5 hours. The reaction mlxture was then evaporated to drynes~ and the re~ldue trlturated wlth ethanol and i~opropyl acetate to glve 5.3 g. of (+)-4'-hydroxy-2-~[3-(4-hydroxyphenyl)-1-methylpropyl]amino~-3'-(methylthio)acetophenone hydrobromide.

Example 65 Following a procedure slmilar to that de~cribed in Example 41 but employing 500 g. (00012 mole) of (+)-4'-hydroxy-2-~[3-(4-hydroxyphenyl~-1-methylpropyl~amino~-3'-~methylthio)acetophenone hydrobromide and 0.455 g~ of sodlum borohydrlde, there was obtained 4.2 g. of 4-hydroxy-a ~ ~3-(4-hydroxyphenyl)-1-methylpropyl]amlno~-methyl~3-(methylthio)benzenemethanol acetate salt, [a~25 -+5.

Example 66 Followlng a procedure similar to that described ln Example 22 but employing 402 g~ (OoOl mole) of crude 4-hydroxy-a ~ [3-(4-hydroxyphenyl)-1-methylpropyl]amlno3-methy~-3-(methylthio)benzenemethanol acetate salt and eluting the oxidation product from a short (1.5 m.) column cf sillca gel followed by conversion to the cyclo-hexylsulfamate salt afforded 203 gO o~ dextrorotatory 4-hydroxy-a-~{[4-(hydroxyphenyl)-1-methylpropyl]amino3methyr~-3-(methylsulfinyl)benzenemethanol cyclohexylsulfamate salt, m.p~ 149-151Co ~ [a]25 - ~2.1~

" ,.

~ xample 67 A. To a'stirred solutlon contalning 100 g. (0.55 mole) of 4'-hydroxy-3~-(methylthio)acetophenone in 650 ml. of dioxane and 3~0 ml. of ether was added dropwise over 4 hours a ~olution containing 14~ g. of dioxane dibromide ln 1050 ml. o~
dioxane-ether. Wl~en the addition was complete the reaction mixture was diluted wlth 500 ml. o~ ether and washed with water.
The organic layer was separated, washed with saturated aqueou~ ;
sodium chloride~ filtered through cotton and the solvents evaporated under vacuum. The residue wa~ twice ~lurried in benzene and the benzene evaporated. The final re~idue was crystalllzed from benzene-ether to give after drying, 107.5 g.
Or 2-bromo-4'-hydroxy-3'-(methyl~hlo)acetophenone.
B. To a stirred solutlon containing 50 g. (0.28 mole) of )3-(4-methoxyphenyl)-1-methylpropylamine(optical purity ~ 94%
in 150 ml. o~ N,N-dimethylformamide at -6~C. wa~ added dropwise over 0.5 hr. a solution containlng 30 g. (0.12 mole) of 2-bromo-4~-hydroxy-3'-(methylthio)acetophenone in 8~ ml. Or N,N-dimethyl-formamide. Arter addition was compIete, stirrlng at -60c. to -40C. was continued an additional 5.5 ho~rs. The reaction mixture was then acidified with 6~ ml. of 48~ hydrobromic acid, diluted with 150 ml. of water and washed with ether. The aqueou~
solution was evaporated to dryness under vacuum. The residue was dissolved in dichloromethane and the resulting solution was washed wlth water and saturated aqueous sodium chloride'. The dichloromethane wa~ evaporated and the residue was diluted wlth 2-propanol and cooled to ~C. The solid which precipitated was collected to give 9.5 g. Or white crystalline ~lydrobromide salt.
Concentration of the filtrate provided arl additional 2.9 g.
which was converted to the hydrochloride salt in conventional fashion affording 2.5 g. o~ 4'-hydroxy-2- ~[3-(4-methoxy-ph~nyl)-l-methylpropyllamln ~ -3'-(methylthio)acetophenone hydrochloride, m.p. 195-197 C.,[a]D5= -11.4~.
-95~

, Z9~S

Rxample 68 Following a procedure slmilar to that described in Example 23 ~ but employlng 25 g. of 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4~-benzoate and 32 g. 0~
(4-methoxyphenyl)-1-methylpropylamine (optical purity ~ 94~), there was obtalned 29.6 g. or (- ~-4'-hydroxy-2- ~ [3-(4-methoxy-phenyl)-l-methylpropyl]amino~ -3'-(methylthio)acetophenone 4'-benzoate hydrobromlde.
Exam~le 6~
Following a procedure similar to that descrlbed in Example 41 but employing 9.~ g. of (-)-4'-hydroxy-2-~'~3-(4-methoxyphenyl)-l-methylpropyl]amino~ -~'-(methylthio)a,cetophenone hydrobromide and 1 g. of sodium borohydride; and preclpitating the hydrochlorlde salt directly from the ethyl acetate extracts, ' there was obtained 3.4 g. or 4-hydroxy-a-<~'[3-(4-methoxyphenyl)-l-methylpropyl]amino~ -methyl> -3-(methylthio)benzenemethanol hydrochlorideJ m.p.l56-157C., [a]25 = -9.3 as a mixture o~
two diastereomers, Exam~le 70 ' 20 Following a procedure similar to that described in Example 10 but employing 29.6 g. (0.055 mole) o~ 4'-hydroxy-2-~ [3-(4-methoxyphenyl)-1-methylpropyl]amino~ -3'-(methylthio) acetophenone 4'-benzoate hydrobromide, 1.55 g. (~.041 mole) o~ -, sodium borohydride and 30 ml. of 35 percent aqueous sodium hydro-xide: and isolating the product as the hydrochlor'ide salt there was obtained 18.6',g. of 4-hydroxy-a-<~ [3-(4-methoxyphenyl)~
methylpropyl'~amlno~ methyl ~ -3-( methylthio)benzenemethanol hydrochloride.

Z~S

Example 71 Following a procedure s imilar ~o that described in ~xample 11 but employing 17.6 g. (0.044 mole) Or 4-hydroxy-2-~
-~ ~3-(4-methoxyphenyl)-1-methylpropyl~amlno~ methyl~
(methylthlo)benzenemethanOl hydrochloride prepared according to the method of Example 70 and 3.36 g. (~.o44 mole) of commercial 50~ peracetic acid, there was obtained 12.5 g. Or 4-hydroxy-2-~ ~ ~3-(4-methoxyphenyl)-l-methylpropyllamlnO~
methyl ~ -3-(methylsulfinyl)benzenemethanol hydrochloride, m.p. 107-117C., [~]25 = +7.6, as a mixture of ~our diastereomers.
Example 72 .
A chloroform solution containing 10 g. tO.0185 mole) o~ (+)-4'-hydroxy-2- ~ [3-(4-methoxyphenyl)-1-methylpropyl]amino~ -3'-(methylthio) acetophenone 4'-benzoate hydrobromlde wa~ washed thoroughly with saturated aqueous sodium bicarbonate. The chloroform ~olution was then acldified with acetic acid and evaporated to dryness. The residue was oxidized with 2.2 ml.
of commercial 50% peracetic acld in trifluoroacetic acid according to the method descrlbed ln Example 25 to give 5.4 g.
o~ 4'-hydroxy-2- ~ ~3-(4-methoxyphenyl)-1-methylpropyl~amino~
(methylsulfinyl)acetophenone 4'-benzoate hydrochloride as a mixture Or diastereomeric sul~oxides,m.p. 158-159C.
Example 73 A mixture containing 15 g. o~ (+)-4~-hydroxy-2-(4-methoxyphenyl)-1-methylpropyl]amino ~ -3'-(methylthio) acetophenone 4'-benzoate hydrobromide, 140 ml. or acetonitrile and 40 ml. o~ concentrated aqueous ammonia was stlrred ~ minute~
whereupon a solid began to precipitate. The mixture was cooled to 0C. and the precipitated product was collected and washed 3o with ether. Drying at 60~. caused the product to turn to a black gum. The latter was di~solved in methanol-ethyl acetate and riltered through 3ilica gel. The filtrate was evaporated - - -- - . . ...
,~ , .. . .

J O9i~Z45 to dryness and t~e residue was dissolved ln ethyl acetate.
Ac~dirication of the re~ulting solutlon wlth ethanollc hydrogen cllloride afrorded 2.5 g. of pale yellow crystalline (+)-4~-hydroxy-2- ~ [3-(4-methoxyphenyl)-1-methylpropyl~-amino~ -3~-(methylthio)acetophenone hydrochloride.
Example 74 Following a procedure similar to that descrlbed in Example 25 but employing 2.46 ml. (0.016 mole) of commerclal 50~ peracetic acid and 5.7 g. (0.016 mole) of (+)-4'-hydroxy-2- ~ [~-(4-met~oxyphenyl)-1-methylpropyl]amino~ (methylthlo) acetophenone which was prepared as the free base according to the method o~ Example 73 and used lmmedlately after drying 4 hrs.
under vacuum at 45C., there was obtained arter precipltatlon with ethanolic hydrogen chloride ~rom acetone/2-propanol, 2.5 g. of 4'-hydroxy-2- ~ [3-(4-methoxyphenyl)-1 methylpropyl]amino ~ -3'-(methylsulflnyl)-acetophenone hydrochloride as a mixture Or diastereomeric sulfoxides, m.p. 192-194C. (dec.), [a325= +19.2.
In addition to antihypertensive and antiarrhythmic activlty this compound has also been ~ound to posses~ cardlotonic activity when tes'ced according to the procedures described in Example 20 hereinabove. In the in vi o test this compound at doses of 10, 30 and lOC~/ml. caused increases in rlght atrial rate of 0,3 and 8 percent respectively; in rlght atrial force of 1,5 and 6 percent respectlvely; and in papillary muscle force f 7,23 and 38 percent respectlvely. In the in vltro test, at doses of 1.0~ 3.0 and 10.0 mg/kg., the compound caused lncrea~es in cardiac contractlle force o~ 22, 25 and 59 percent respectlvely.
In a second, slmilar series of in vitro tests, increa~es ln cardlac ccntractile force of 4, 12 and 50 percent were observed.

.

.. . .

.: . -~xample 75 2-~romo-4'-hydroxy-3~-(methylthlo)acetophenone (26.1 g., 0.1 mole) lYas reacted with ~,4-di~ethoxyphenethylamlne (45 g.~ ~.25 mole) essentially accordlng to the method described in Fxample f~7B. The product initially obtained upon evaporation of the aqueous solution was treated wi.tn hot methanol and the .insoluble N,N-bls-[4-hydroxy-3-(methylthio)phenacyl]-3,4-dimethoxyphenethylamine wa9 filtered orf. The riltrate was concentrated, diluted wlth 2-propanol and cooled~ The.resultlng ~olld was recrystallized from water, again filtering orr insoluble by-product. The product t~lus obtalned was recrystallized from aqueous ethanol, and a 5.5 gram sample was converted to the hydrochloride salt i.n conventional ra3hlon a~ording 4.6 g.
of 2-~ [2-(3,4-dimethoxyphenyl)ethyl]amino~ -4'-hydroxy-3~- .
(methylthio)acetophenone hydrochloride, m.p. 208-212C.
Example 76 F~llowlng a procedure similar to that described in Example 41 but employing 13.1 g. (0.033 mole) or 2- ~ [2-(3,4- .;
dimethoxyphenyl)ethYl~amlno ~ -4'-hydroxy-3'-(methylthio) acetophenone hydrochloride and 2.0 g. (0.053 mole) or so~ium borohydride; acid~fying the reaction mixture wlth 6N hydrochloric acid and isolating the hydrochloride ~alt ar~orded 11.5 g. or a- ~ ~ ~ ?- (3J4-dimethoxyphenyl)ethyl~amino~ met~yl> -4-hydroxy-3-(methylthio)benzenemethanol hydrochloride, m.p. 124-126C.
Example 77 F~llowing a procedure ~imilar to that described in Example 11 but employing 5.6 g. (0.014 mole) Or -<{ [2-(3,4- .
dlmethoxyphenyl)ethyl]amino ~ methyl > -4-hydroxy-3-(methylthio) benzenemethanol hydrochloride and 2.13 ml. Or commercial 50%
peracetic acid there wa~ obtained upon crystallizatlon ~rom 2-propanol, 4.9 g. Or a-< ~.2-(3,4-dimethoxyphenyl)ethyl]amlno~
- methyl> -4-hydroxy-3-(methylsulfinyl)benzenemethanol hydrochlorlde m. r . 173-17~C.

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

Example 78 To a stirred solution containing 72.~ g. (0.4 mole) of 3,4-di~ethoxyphenethyl amine in 275 ~1. o~ N,N-dimethylformamlde at -50C. was added over 2.25 hr~. a solution containing 39.3 g.
(0.133 mole) of 2-bromo-4'-hydroxy-3'-(me~hylsulronyl)acetophenone in 275 ml. Or N,~-dlmethylformamide, Ar~er the addition was complete, ~tirring wa continued 1 hr. at -40C. to -45C., then 1.5 hrs. at ~30C to -40C., and finally 0.5 hr. at -~0C to -5C. The reactlon mixture was cooled to -20C. and acidi~led with 45 ml. Or 48% hydrobromic acid, The solvents were evaporated under vacuum and the residual syrup was washed with ' ether. The syrup was dissolved in 200 ml. of water and allowed to crystallize over a weekend. The precipitated solid was collected, washed with water and ether and recrystal'lized from 95~ ethanol afford~ng 32.31 g. of 2- ~ ~2-(3,4-dimethoxyphenyl) ethyl~amino3 -4'-hydroxy-3'-(methylsulronyl)acetophenone hydro-bromide9 m.p. 220-227C. A 10 gram sample was converted to the free base which was crystallized from aqueous methanol and then converted to the hydrochloride; m.p. 227-233C. (de^.) Example 79 A mixture c~ntaining 14.3 g. (0.03 mole) of 2- ~ [2-(3,4-dimethoxyphenyl)ethyl]amino~ -4~-hydroxy-3'-(methylsulfonyl) acetophenone hydrobromide and 1 g. of 10~ palladium-on-carbon hydrogenation catalyst in 200 ml. of N,N-dimethylformamide wa~
shaken under an initial hydrogen pressure of 50 psi until the absorption of hydrogen ceased. The catalyst was removed by ~iltration and the filtrate was evaporated under vacuum. The residual oil was treated with 1~0 ml. of 5 percent aqueous potasslum bicarbonate, 20 ml. of 10~ aqueous sodium carbonate and 4~ ml. of ether. The solid which precipitated was collect and dissolved in 100 ml. of methanol containing 10 ml. of ethanolic ., .. . . : : .

~ , .

hydrogen chloride. The solutlon was treated with decolorlzing carbon and evaporated to dryness. The residue was dlssolved in 2~5 ml. of hot methanol and the resultlng ~olution was diluted with ~Z5 ml. o~ acetonitrile and concentrated to a volume of 125 ml. On standing a first crop Or product crystallized and was collected by ~iltration. Further concentratlon o~ the filtrate a~rorded a second and third crop of product. The crop~
were combined to glve ll.2 g. of ~-C ~L2-(3,4-dimethoxYPhenYl) ethyl~amino~ methyl> -4-hydroxy-~-(methylsulfonyl~benzenemethanol hydrochloride, m.p. 209-210C.

~xample ~0 ~ollowing a procedure s~mllar to th~t de~cribed in Example 67B, 13.5 g. (0.05 mole) of 2-bromo-4'-hydroxy-3~-(methylthlo)acetophenone was reacted with ?2 g. (0.134 mole) of 1-methyl-3-phenylpropylamine. The product lnitially obtained upon evaporation of the aqueous solution was converted to the hydrochloride salt in conventional fashion.
Recry~tallization o~ the latter from aqueouR methanol af~orded 7.1 g. o~ 4'-hydroxy 2-~ methyl-3-phenylpropyl?amino]-3'-(methylthio)acetophenone hydrochloride, m.p. 205-208C.

,, .

lS!)5~LZ~5 ~xa mp 1 e ~31 To a ~olution containing 14.6 g. (0.05 mole~ of 2-bromo-4~-hydroxy-~-(methylsulfonyl)acetophenone ln 100 ml.
of N,N-dlmethylformamide at -40 to -50C. was added a solution containlng 22.6 g. (0.15 mole) o~ 1-methyl-3-phenylpropylamlne in 100 ml. of N,N-dimethylformamide. After approximately ~0 percent of the solution had been added over 1 hr. the remainlng solution was added rapidly over 10 minutes. Stlrring was continued 1.25 hr. at -40C. and then 1 hr at -10C. The reaction mixture was acldified with 21 ml. of concentrated hydrochlorio acld and diluted wlth 25 ml. of water and 175 ml. o~ satura~ed aqueous sodium chloride. After stirrine 0.5 hr. in the cold the precipitated solld was collected, washed with saturated aqueous sodlum chloride and ether and recrystallized from ~50 ml. of water containing 20 ml. of 6N hydrochloric acid. The product was colledted by flltration and washed with water and acetone. On standlng 2 days the filtrate afforded a second crop or product and a~ter standing one month a third crop was obtained. The final filtrate was evaporated to dryness and the resldue recrystalllzed from water to give a fourth crop of product.

Each oI t},e rour crops was recrystallized ~rom methanol-ethanol and the resultln~ product~ combined to yield 10.0 g. o~ l~'-hydroxy-2-[(1-methyl-3-phenylpropyl)amlno]-~'-(methylsulfonyl)acetophenone hydrochloride, m.p. 21~-215C.
Example 82 A mixture cor.taining 1~ g. (~.0327 mole) of 4'-hydroxy-2-[(1-methyl-3-phenylpropyl)amino~-3'-(methylsulfonyl)acetophenOne ~Iydrocllloride and 0 9 g. Or ]~ percent palladium-on-carbon hydrogenation catalyst in 180 ml. of ~ I-dimethylformamlde and 2~ ml. o~ water was shaken under an initlal hydrogen pres~ure of ~ psi until the absorption of hydrogen ceased. The catalyst ~as removed by flltration and the filtrate was evaporated under vacuum. The residue was parti~ioned between ethyl acetate and

5 percent aqueous potassium blcarbonate. The aqueous phase was saturated with sodium chloride and re-extracted wlth ethyl acetate.
The organic extracts were combined, washed with saturated aqueous sodium chloride~ drled over anhydrous sodium sulfate and evaporated under vacuum. The residual oil was dissolved in 50 ml.
of warm ethanol and the resulting solution was acldi~led with ethanollc hydrogen chlorlde. The solvent was evaporated and the residue was crystallized from acetonitrlle. The product was converted to the free base which crystallized from aqueous methanol. Reconversion to the hydrochloride and crystalllzatlon of the latter from acetonitrile afforded 8.95 g. of 4-hydroxy-a- ~[(1-methyl-3-phenylpropyl)amlno]methyl ~ -3-(methylsulfonyl) benzenemethanol hydrochloride, m.p. 178-13~C.
E mple 8~
Following a procedure similar to that descrlbed in Exa~ple ~0 but employing 13 g. (0.05 mole) of 2-bromo-4'-hydroxy-z~s 3'-(methyltllio)acetophenone and 22 g. (0.1~5 mole) of 1,1-dimethyl-3-phenylpropylamine, and stirring the reaction mixture 1.5 hrs. at -10C., there was obtained 7.8 g. o~ 2-[(1,1-dimethyl-3-phenylpropyl)amino~-4'-hydroxy~ (methylthio)acetophenone hydrochloride, m.p. 215-220C.
Example ~4 T~ a stirred solution containing 44.5 g. (0.23 mole) Or ~-(4-methoxyphenyl)-1,1-d~methylpropylamine in 185 ml. of N~T-dimethylrormamide at -50C. was added over 2.25 hrs. a solution containing 27 g. (0.092 mole) of 2-bromo-4'-hydroxy-3'-(methylsulfonyl)acetophenone ln 185 ml. of N,N-dimethylformamide.
After the additlon was complete, stirring was continued an additional 3 hrs. as the reaction mixture was allowed to warm to room temperature. The mixture was then acidified with 23 ml. of 48 percent hydrobromic acid and evaporated under vacuum.
The residual oil was washed with ether and then slurried in 200 ml.
of acetone whereupon 3-(4-methoxyphenyl)-1,1-dimethylpropylamine hydrobromide precipitated. The solid was separated by filtration and the ~iltrate was dlluted with ether to precipitate the desired product. The solld so-obtained was slurried in 500 ml.
o~ hot acetonitrile, cooled and collected by filtration. This material wa~ slurried in 200 ml. of hot chloroform, cooled and filtered to give 21.9 g. of 4'-hydroxy-2- ~ [3-(4-methoxyphenyl)-l,l-dlmethylpropyl~amino} -3'-(methylsulfonyl)acetophenone hydrobromide, m.p. 220-224C (dec.). A 10 gram sample wa~
converted to the free base by dissolving in methanol; basifying with 10 percent aqueous sodium carbonate; evaporatlng the methanol;
diluting with water; and allowing the base to cry~tallize giving 5.4 g.~ m.p. 159-165C., which was then converted to 2.93 g. Or the hydrochloride, m.p. 222-232C. (dec.) '' ' ' Example 8~
F~llowing a procedure similar to that described in Example 79 but employlng 11.3 g. (~.023 mole) Or 4'-hydroxy-2-~ [3-(4-methoxyphenyl)-1,1-dimethylpropyl]amlno~ -3'-(methyl-sulfonyl)acetophenone hydrobromide there was obtalned 9.66 g.
of 4-hydroxy-a<~3-(4-methoxyphenyl)-1,1-dimethylpropyl~amino~
methyl~ -3-(methylsulfonyl)benzenemethanol hydrochloride, m.p.
; 202-2~4C.
Example 86 ; 10 2-Bromo-41-hydroxy-3l-(methylthio)acetophenone (25.4 g., O.C97 mole) was reacted with 3-(4-methoxyphenyl)propylamine (40 g., 0.242 mole) es~entially according to the method described in Example 67B. The product lnltlally obtained upon evaporation Or the aqueous solution was treated with aqueous ethanol. The N,N-bi~-[4-hydroxy-3-(methylthio)phenacyl]-3-(4-methoxyphenyl) propylamine whlch preclpitated was flltered off. The ~iltrate was evaporated to dryness and the resldue was crystallized from 2-propanol/ethyl acetate. The product so-obtained was trlturated with hot water and the residue was crystalllzed ~rom ethanol-ethyl acetate to give 6.5 g. of 4'-hydroxy-2- ~[3-(4-methoxyphenyl) propyllamino~ -3'-(methylthlo)acetophenone hydrobromlde.
Example 87 Following a procedure similar to that described ln Example 76 but employing 6.5 g. (~.015~ mole) Or 4'-hydroxy-2-~ ~3-(4-methoxyphenyl)propyl~amino~ -3'-(methylthio)acetophenone hydrobromide and 1.2 g. of sodium borohydride, there was obtained 5.1 g. of 4-hydroxy-a- ~3-(4-methox~phenyl)propyl]
amlno~ methyl> -3-(methylthio)benzenemethanol hydrochlorlde, m.p. 151-152C.

. .

Example 88 To stirred suspen~ion of 31.6 g. (~.14 mole) of N-benzyl-~phenylpropylamlne ln 280 ml. of methanol at -40 to -45C.

was added ln one portion 2~.5 g. (0.07 mole) of 2-bromo-4'-hydroxy-3~-(methylsulfonyl)acetophenone. After ~tirrlng 2.5 hrs. the reaction mixture was allowed to warm to room temperature over 1.5 hr Evaporation under vacuum afforded a gummy residue which was ~lurried in 40~ ml. of boiling ethyl acetate to give a solld precipitate of N-benzyl-3-phenylpropylamine hydrobromide. The solid was separated by filtration and the filtrate was evaporated to dryness under vacuum. The residue was dissolved in ab~olute ethanol and the resulting solution acidified with 35 ml. cf 6.8 N ~thanolic hydr~-gen chloride. Evaporation Or the acidic solution and crystallizatlon Or the residue from ethanol afforded 18.3 g. of 2-[N-benzyl-3-(phenylpropyl)amino~-4'-hydroxy-3'(methylsulfonyl)acetophenone hydrochloride, m.p. 190 - 191C. The latter was combined with the product~ of several other runs and~recrystallized from absolute ethanol to give material with m.p. 193.5-195C.

F~ample ~9 A mixture containing 4.74 g. (0.01 mole) of 2-[N-benzyl-3-(phenylpropyl)amino~-4'-hydroxy-3'-(methylsulfonyl) acetophenone hydrochloride and 250 ~g. Or '0 percent palladium-on-carbon hydrogenation catalyst in 100 ml. Or 95 percent ethanol was shaken under an inltial hydrogen pressure o~ 51.5 pBi until the theoretical quantity Or hydrogen had been absorbed.

It was necessary to dllute the reaction mixture wlth 200 ml. of 95 percent ethanol and 50 ml. o~ N,N-dimeth~lformamide in order to di~solve the solid which had prec~pltated. The catalyst was then removed by filtration and the filtrate was evaporated to dryness under vacuum. The residue was triturated with 25 ml. of hot ethanol, cooled and the solid collected by flltratlon. This material was comblned with the products Or other run~ and re-crystallized ~rom aqueous methanol to give l2.0 g. of 4'-hydroxy-3'-(methylsul~onyl)-2-[(~-phenylpropyl)amlno]acetophenone hydrochloride m.p. 241--242C. (dec.) Example 90 `
Followin a procedure similar to that described in Exam~le ~7B b~t employing 61 g. (~.29 mole) of mescaline and 28 g. (~.107 rnole) or 2-bromo-4 -hydroxy-3 -(methylthlo) acetophenone there was obtained 33 g. of crystalline product contaminated with a small amount of N,N-bls-[4-hydroxy-3-~methylthio)phenacyl~-3,4,5-trimethoxyphenethylamine. The s product was talen up in boiling water and the insoluble by-product was ~iltered off. ConcentratiDn Or the filtrate to a small volume produced 1~.2 g. of 4 -hydroxy-3 -(methylthio) -2- ~ [2-(3,4,5-trimethoxyphenyl)ethyl]amino~acetophenone hydro-bromide. The hydrochloride isolated as the monohydate had m.p.193-195 C. Example 91 Following a procedure similar to that descrlbed in Fxample 41 but employing 16 g. of 4 -hydroxy-3 -(methylthlo~-2-~ [2-(3,4,5-trimethoxyphenyl)ethyl~amino acetophenone hydro-bromide and 2.5 g. of sodlum borohydride; and isolating the product as tne hydrochloride there was obtained 14.6 g. of 4-hydroxy-3-(methylthio)-a-~[2-(3,4,5-trlmethoxyphenyl)ethyl-amino~ methyl > benzenemethanol hydrochlorlde, m.p. 168-169.5C.
Example ~
Following a procedure similar to that described in Example 11 bu~ employing 7.7 g. (0.0175 mole) of 4-hydroxy-3-(methylthio)-a~ 2-(3,4,5-trimethoxyphenyl)ethyl~amlno~ -methyl> benæ~nemethanol hydrochloride and 2.66 ml. (0.0175 mole) of commercial 50 percent peracetic acid; and crystallizing the product from methanol-ether there was obtained 6.~ g. of 4-hydroxy-3-(methylsulfinyl)-x~ ~[2- (3,4,5-trimethoxyphenyl) ethyl]amino~ methyl> benzenemethanol hydrochloride, m.p.
164-16GC. -10~-.

~xa~le 97 To a ~tirred sollltion containing 76.o g. (0.~6 mole) o~ me~callne in 250 ml. o~ N~-dimethylrormamide at -65C. was added over 3.5 hrs. a solution containing 35.2 g. (o.l? mole) of 2-bromo-4'-hydroxy-3'-(methylsul~onyl)acetophenone in 250 ml.

o~ N,N-dimethylformamide. Arter the addition was complete~

~tirring was continued at -40 to -30C. for lhr. and then at ;
-30 to -5C. for 0.75 hr. The mixture wa~ cooled to -20C., acldiried wlth 32 ml. of 48 percent hydro~romic acid and evaporated under vacuum. The residual syrup was wa~hed thoroughly with ether and crystalllzed rrom 2-propanol. The solld product was collected in several fractions the first ~ew of which contalned slgniricant amountsof mescaline hydrobromide. The later ~ractions contained the deslred product essentlally ~ree o~

mescaline hydrobromide. A 15-gram sample of the later rraction~

wa~ converted to the free base and then to the hydrochloride to give 5.52 g. o~ 4'-hydroxy-2- ~[2-(3,4,5-trlmethoxyphenyl)ethyl]amln~ _ ; 3'-(methylsulfonyl)acetophenone hydrochloride, m.p. 230-234C. (dec.) Example ~4 ~ mixture Or 16.47 g. (0.0357 mole) of 4~-hydroxy-3'-(methylsulfonyl-2- ~ [2-(3,4,5-trimethoxyphenyl)ethyl~amlno ~
acetophenone hydrochloride and 1.2 g. of lO percent palladium-on-carbon hydrogenation catalyst in 180 ml. o~ N,N-dimethyl~ormamide and 2~ ml. Or water was shaken under an initial hydrogen pressure;
of 4~ psi until thc absorption of hydro~en ceased. The catalyst was removed hy ~iltration and the filtrate was evaporated under vacuum. The residual oil was cry~tallized from methanol-ether and recrystallized from methanol. The resulting product was converted ~lith aqueous ammania to the ~ree base which crystalllzed from water. Conversion to the hydrochloride afforded 12.56 g. of 4-hydroxy-~-(methylsul~onyl)-a-~ [2-(3,4,5-trlmethoxyphenyl)ethyl~
amino~ met~yl >benzenemethanol hydrochloride, m.p. 192-194C.
' ~x_m~e_~
To a st'~rrcd solution containing 12 g. of 4-hydroxy-a-<~[3-(4-met~loxyphenyl)-l-methylpropyl~amino~ met'nyl> -3-(methylthio)benzenemethanol prepared accordlng to Example l9C in 50 ml. of chloroform at 50C. was added 2~ ml. of thionyl chloride.
The temperature was maintained at 50C. and after stirring a short time the product began to crystallize. After stirring 2 hrs. the mixture was cooled and the precipitated product was collected and washed with benzene to give after drying, 11 g.

F~ Or 4-hydroxy-a- ~[~-~4-metho~yp henyl)-l-methylpropyl]amino~
~e 7~ ~ ~f ~ ~ 0) methyl> benzyl chloride hydrochloride.

:' ' ;24S

Example 96 To a stirred solution containlng 9.6 g. (~.0226 mole) r~ - 3~ o) 43~ ~ of 4-hydroxy-~<~L3-(4-methoxyphenyl)-l-methylpropyl~aminO~ methyl> -benzyl chloride hydrochloride in ~0 ml. of ~,N-dlmethyl~ormamide at O to 10C. under nltrogen was added portionwise over 0.25 hr.
].9 g. (0.05 mole) of sodium borohydride. After stirring an additional hour the reaction mixture was neutralized wlth glacial acetic acid, diluted wit~ chloro~orm and washed with saturated aqueous sodium bicar~onate. The chloroform so]ution was dried over anhydrous sodium sulfate and evaporated to dryness.
The residue was d~ssolved in 9:] 2-propanol-methanol and the resultin~ solukion was acidified Wit~l ethereal hydrogen chloride.
On concentration and cooling there was obtained 5.5 g. of -(+)-4-~ 2- ~ [3-(4-methoxyphenyl)-1-methy1propyl]amino~ ethyl> -2-(methylthio)phenol hydrochloride, m.p. 1~4-185DC.
Example 97 To a stirred solution containing 5.0 g. (0.0135 mole) of (+)-4- < 2-~ [3-(4-methoxyphenylj-l-methylpropyl]amino~ ethyl>-; 2-(methylthio)phenol hydrochloride in 50 ml. of methanol wasadded lO ml. of commercial 50~ peracetic acid. The reaction mixture was then cooled to 0-5C. and treated with an additional lO ml. of peracetic acid. After the addition was complete the - reaction mixture was concentrated to 20 ml. and diluted with~ 50 ml. of 2-propanol. On standing at 5C. overnight the product ; 25 crystallized. It was collected and dried to give 4.5 g. of 4- <
2- ~ [3-(4-methoxyphenyl)-l-methylpropyl]amino~ ethyl> -2-(methyl-sulfinyl)phenol hydrochloride, m.p. 205-208~C.
.

l Q~ S

Example 9~
A ~lxture of 50 g. (0.925 mole) of (~)-4'-hydroxy-2-~ [3-(4-methoxyphenyl)-1-methylpropyl~amino~ -3~-tmethylthio)-acetophenone 4'-benzoate hydrobromide and 500 ml. of 48 percent hydrobromic acid was stirred and heated under reflux 1 hr. On coollng the product crystallized. It was collected and recrystallized from ethanol-lsopropyl acetate to glve ,26.7 g.
of (+)-4'-hydroxy-2- ~ [~-(4-hydroxyphenyl)-1-~ethylpropyl]amino~
-3'-(methylthio)acetophenonè hydrobromide.
~xample Following a procedure similar to that described in Example 76 but employing 3~ g. (0.0765 mole) of (+)-4'-hydroxy-2-~ [3-(4-hydroxyphenyl)-1-methylpropyl~amino~ -3'-(methylthio) acetophenone hydrobromide and 3.3 g. of sodium borohydrlde there was obtained 4-hydroxy-a-<~ [3-(4-hydroxyphenyl)-1-methylpropyl3 amino ~ -methyl> -3-(methylthio)benzenemethanol which was used dlre'ctly in a ~urther reaction.
Example 100 A stirred solutlon containing 0.075 mole of crude 4-hydroxy-~-< ~ [3-(4-hydroxyphenyl)-1-methylpropyl]amino~
methyl> -~-(methylthio)benzenemethanol ln 50 ml. of dry dloxane was saturated with hydroge,n chloride o~er 1.5 hrs. After stirrlng overnight the reaction mlxture was dlluted wlth ether, filtered through cotton and then concentrated to a ,25 volume of 150 ml. The concentrate was cooled and the precipltated product was collected and dried to glve 27.8 g. of 4-hydroxy-a-<{~-(4-hydroxyphenyl)-1-methylpropyl]amlno~ methyl~ -~-(methylthlo) benzyl chloride hydrochloride.

. ; , :

, Example 101 To a ~tlrred solution containlng 27.8 g~ (~.0685 mole) of 4-hydroxy~ [3-(4-hydroxyphenyl)-1-methylpropyl]amino~ methy~>
3-(methylthio)benzyl chloride hydrochlorlde ln 150 ml. o~
N,N-dlmethyl~ormamide at 0C,was added portlonwi~e over 0.25 hr.
4 g. Or sodium borohydride. Arter stirrlng an additional 0.5 hr. th~
reaction mixture was acidified with 6N hydrochloric acid, concentrated to near dryness, diluted with saturated aqueous sodium bicarbonate and extracted thoroughly with ethyl acetate. The extracts were washed with saturated aqueous sodlum chlorlde, drled over anhydrous sodium sulfate and evaporated to dryness under vacuum. T~le residue was dissolved in a mlxture o~ ether and ethyl acetate and the resulting solution was acidified with ethanollc hydrogen chlorlde and cooled. The solld whlch crystalllzed was collected and recrystallized from acetone-methanol-ether to give 15.0 g. o~ (+)-4- ~ 2- ~ ~3-(4-hydroxyphenyl)-1-methylpropyl~
amlno~ ethyl > -2-(methylthio)phenol hydrochloride. Recry~talll-zation of a sample from methanol-acetone-ether and then ~rom 2-propanol-ether followed by drying 4 hrs. under vacuum at 100-115C.
afforded a material havlng m.p. 150-151C.

To a stlrred solution contalning 4.2 g. (0.0114 mole) Or (~)-4- < 2- ~3-(4-hydroxyphenyl)-1-nsethylpropyl]amino~ ethyl> -2-(~ethylthLo~phenol hydrochloride in 75 ml. of methanol at oC.
was added over 20 min. 1.73 ml. o~ commercial 5~% peracetic acid in 5 ml. o~ methanol. W~len the addition was complete the reaction mixture was evaporated to dryness and t,he residue was crystallized B ~rom acetonitrile/2-propanol to give a~ter drying ~ hrs. under vacuum at 1~C.~ 5,7 g, or 4-< 2-~ [3-(~ydroxyphenyl)-1-methyl-propyl]amino~ ethyl~-2-(met})ylsulfinyl)phenol hydrochloride.
m.p. 2~4-205~C.
Additional examples of benzenemethanols and amino ketones having respe'ctively Formulas I and II hereinabove and ~hich, lt is contemplated, can be obtained in accordance with the above-described procedures are presented in Table A hereinbelow.
Additional examples Or haloketone~ and the corresponding parent phenyl ketones havlng respectively Formu1as V and VII
hereinabove wllich are useful intermediates in the preparation of the amino ketones of Formula II (Table A) and which) it i~
contemplated, can be prepared in accordance with the above-de~crib-ed proceduree are presented hereinbelow in Tables B and C. The phenyl ketones of Table C can in turn be obtained in accordance with the a'bove-described procedures by acylating the generally known o-(lower alkylthio)phenols with an appropriate acyl halide under Friedel-Crafts condit1ons follo~ed by esterirication Or the resulting 3-(lo~rer alkylthio)~4-hydroxyphenyl ketones with an appropriate.lower alk~noyl or aroyl halide according to conventional esteri~lcation procedures, Addit~onal examples o~ 2-phenylethyla~ines and 2-halo-2-3o phenylethylamines having re'.',pectively l~ormulas III and IV herein-above and which,it is conte~lplated, can be obtained in accordance with the above-described procedures are presented in Table D herein-below. -114-...... ,. .. . ~ ... ..

4~
T ~LE A

YO ~ -cH-NH-c-(cH2)n-Ar benzeneme~hanol~ of Formula I. Z ls CHOH
amlno ketones Or Formul~ IIs Z 18 C~O

Q y ¦ Rl ¦R2 - n Ar ~ __ _ _ 3 H C2H5 H CH3 2~-CH30C6H4 CH3S H C2H~ H CH3 2~-CH30C6H4 CH3S~-CH3C~H4CO H H CH~ 2~~CH3c6H4 CH3S(CH3)3CCO H H CH3 2. ~-CH30C6H4 CH~SO(CH3)3CCO H H CH3 2~-CH30C6H4 C2H5S2HCO H H C2H5 1 C6H~
CH3SC~HllC H H H 1 C6H5 C2H5S H H H ~H3 2 P 3 6 4 C2H~SO . H H H CH3 2p-CN3C6H4 n~C4H9S H H H CH3 1 _ 3 6 4 CH3S H H HCH(CH3)2 1 C6H5 CH3S H n-C4Hg HH 1 ~-(CH3)3CC6~4 CH3S H H ~H3CH3 1 2,5-~CH3)2 C6N3 CH3S02 H H H H 1 ~_(CH3)2cHcH2~c6H4 CH3S H n-C3H? H C4Hg 1 C6H5 CH3S H H H c~3 1 3,4-(Ho)2-C6H3.

3 H H. H H 1 ~J4J5-(Ho)~-c6H2 CH3SO H H H CH3 2 3-Br-4-HO-C~

CH3S H H ~H3 CH3 1 4-Br-C6H4 25 CH3SO H . H H CH3 1 2,5-(Cl)2-G6H3 : CH3S H . ~ H H 1 3~ J5 ( )3 6 2 3 2 H . ~ H H H 1 2,4,6-(CH3)3-C6H2 CH3S H .H H CH3 1 2-(C4Hg~)-3-CHjoLC

~ABIE B

Y~,3 C-CR-X

Q Y Rl X
- . , CH3S H C2Hs ~r CH ~S E!- CH ~jC6H4co H Br CH~jS ( CH~ ) 3C Co H Br .: C2H5 2 HGO H Cl CH~S C5HllC H Br C 2H5S H H Br n C4HgS 3 H Cl C~3S H n-C4Hg Br CH3S H n~C3H7 :~r . ~ . .

,, .

.,. ~.
., .

~i , i~ ~

~j . .
, . .

;

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

TABLE C

~ li YO ~ C-CH2-R

_ . , R
__ CH3S p-CH3C~H4Co H
3 (CX~)3CCO H

CH3 C5HllC H
C2H5S CH~CO H
n-C4H95 CH3CO H
CH3S 3 n-C4Hg CH3S 3 0 n-c3H7 ... .. _ . __.. _. ... _ .. .... ~. ,. ~., , _. _. __ .. ____._ _ ... .. ,_ _ . _ -TABLE D
Q~ -yo . ~ 3--CH- CH- NH- ~- ( CH2 ) n~ A r R;3 a-phenylethylamines of Formula III: B 13 hydro~;en 2-Halo-2-ph~nylethylamlnes of Formula IV: B is chloro~ bromo or iodo.

Rl R2 R r Ar ...
. . ~ _ CH3S H H H CH3 ¦ p-CH30C6H4 CH3S CH3C0 H C~ CH3 1 C6H5 CH3S0 H CH3 H CH3 1 ~-CH30C6.~4 ; 10CH3S H H H H 2 6 5 CH3S0 H H H CH3 1 3,4-(CH30)2-C6H3 CH3S H H H CH3 3 p~CH3C6H4 CH3S0 C6H5C0 H H CH3 2 3-Br-4-CH30-C6H3 15CH3S H H H H 1 3~4~5-(CH30)3-C6H2 CH3S0 H C2H5 H CH3 2 ~-CH30C6H4 `' CH3S C2H5 H CH3 2 P 3 6 4 3 p-CH3C~H4C0 H H CH3- 2 p~CH3C6H4 CH3S (CH3)3CC0 H H CH3 2 ~~CH3c6H4 ...
20CH3S0(CH3)3CC0 H H CH3 2 ~ CH3C6 4 C2H5S2 HC0 H H C2H5 1 C6H~
CH3S C5HllC H H H 1 6 5 H H H CH3 2 ~-CH3C6H4 C2H~S0 . H H H CH3 ~ p-CH3C6H4 25n-C4HgS H H H CH3 1 m-CH30C6H4 CH3S H H H CH(CH3 3 2 1 C6H5 ~, H n-C4H9 H H 1 p~(CH3)3CC6H4 CH3S H H CH3 CH3 1 2,5-(CH3)2 C6 3 3 2 H H H H 1 ~-(CH3)2CHCH20C6H4 CH3S H n~C3H7 H C4H9 1 C6H5 CH3S H H H CH~ 1 3,4-(Ho)2-C6H3 ~: : ., .

lZ~
TABLE D

~ Hl R2 r ~

C~13~ùc .Il H H H 1 3 J 4, 5- ~HO )3- C6H2 CH3 SO H H H CH3 2 3- Br- 4- HO- C6H3 : 5 CH3S H H H H 1 3 6 4 CH3S H HnH3 CH3 1 4- Br- C6HI~
CH3SO H H H CH3 1 ~5 ( )2 6 3 CH3S H H H H 1 3,4~5- (Cl)3 C6H2 3 2 H H H H 1 2,4,6- (CH3)3-C6H2 10 CH35 H H H CH3 ~1 2- (C4Hg)-3- ~30-C6H3 ' .. .
... .

~ ' ' ' `.
., .

.

:- .
' :

Y~ ~ ~ :

The compounds Or this invention having Formula I
have been shown to have userul antihyperten~lve, va~odllator and ~-adrenergic blocking activity as can be seen from the result~ of standard pharm~cologlcal test~ carrled out on representative examples as described below~
Antihypertensive activity was determined on the basis of the observed reduction in systolic blood pre~sure measured according to the method of Ho Ker~ten et alO, J.
LabO and ClinO Med. ~2, 1090 (1947) followlng a ~ingle oral medlcation in the unanesthetized spontaneous hyperten-sive rat de~cribed by Okamato et al. 9 Japan Circulation JO
` 27~ ~82 (1963)o , Antihypertensive activity was also ~udged on the,;J' basis of sustained reduction of blood pressure ob~erved in the unanesthetized tralned renal hypertensive dog ~ following repeated oral medication according to the pro-i:~ cedure described by Lape et aLg Arch. intO PharmacodynO
- 160~ 342 ( 1966 ) o Vasodilator activity was ~udged on the basis of observed reduction in perfusion pressure in the hind limb vasculature of the anesthetized dog determined according to the procedure described by Jandhyala et alO,European J.
Pharm. 17~ 357 (1972)~ and also on the basls of percent reduction in perfusion pressure as measured in the i~olated `' rabbit ear artery according to the method described by De La Lande et al~9 Austo JO Expo BiolO ~edO Scio 43~ 639 ( 1965 ) o i, The ~-adrenergic blocking activity was determined in the pentobarbitalized dog as ~udged by the ability of the test compound to inhibit the elevation in heart rate elicited by a 0.5 mg./kg. i.v. in~ection of isoproterenol.
"

~ . .

_ . , 1~9~Z45 Acute intravenous and oral toxiclty in mice wa~
determined for the compound of Example llA as follows~ The compound was diæsolved in distilled water and administered as the base at a volume of lO ml./kg. ~or the l.v. ALD50 or 10-40 ml./kg. for the p.o. ALD50. The compound was admlnistered in graded doses to groups of three mice each (Swis~-Webster strain males welghing 20 ~ 2 g.)0 Mortality - occurred within 1 minute after i~Vo admlnistratlon and within lO minutes aftér oral administ~ationO Symptoms of acute intoxication for the fatalities included atoxia, loss of righting reflux, clonic convulsions and dyspnea followed by respiratory arrestO There were no untoward symptom observed for up to 7 days for the ~urvivor~0 The ioV~
ALD50 was 75 mgO/kgO and the p.o. ALD50 was 1500 mgO/kgO
The 7-day oral LD50 in rats wa~ determlned for two separate batches of the compound of Example 20B and was found to be 1850 and 1940 mgO/kgO re3pectively~ No changes ln body welght and no gross tissue change~ were observed in animals sacrlficed 7 days post-medication.
The results of the above-described phramacological tests are pre~ented in Table E hereinbelow. ~r As noted hereinabove certain of the compounds of this invention also have antiarrhythmic activity. The latter was determined in vivo and efficacy was judged on the ability of the test compound to convert to normal rhythm the arrhythmia ~; induced by barium ion or ouabain intoxication. The test pro-cedures were carried out as follows:

,:

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

~++-induced arrh~thmia A~Ult rabbits or either sex, weighing between 1.7 and -~ 2.~ kg, were anesthetlzed wlth 30 to 35 mg/kg Na-pentobarbital i.v. via a marginal ear vein. Monopolar ECG pin electrode~
were lnserted ~or a lead II display on a Model 5 Grass Polygraph `using standard electrocardiographic procedures. A 23 ga.
hypodermic needle, attached via a polyethylene catheter to a 10 cc syringe, was inserted into tlle ~ame vein as was used for anesthesia. A BaC12.2H20 solution in saline was then infused at a constant volume o~ 0.2 cc/min from a Harvard Apparatus Model . .
600 infusion pump. This infusion was ilOt stopped until .
termination of the experiment. In some studies barium chloride ln distilled water was used without detectable di~ferences. The ....
standard rate o~ BaC12.2H20 infu~lon was established at 0.3 mg/kg/
min (1.2X10 6M/kg/min)~ and the concentration was ad~usted ~`~ appropriately in each case to accomodate the weight o~ the rabbit.s When the desired arrhythmia was established, the test ; compound was lntroduced as a water or saline solution into the marginal ear vein of the unused ear. The volume used was , : .
~- 20 between 0.5 and 2.0 cc/kg and was injected as a bolus over approximately 30 seconds. Deviations from standard vehicle, rate of in~ection, and total volume administered were at the , . .
discretion of the operator. ~he standard initial does o~ an unknown .:~ .
~ compound on-the ~irst rabbit was 5X10 5M/kg In general two to ;`~j three rabbits were used to determine anti-arrhythmic actlvity and the do~e range of activity; multiple doses were administered~
Once activity and dose was indicated, two additional rabbits were employed to confirm antl-arrhythmlc activity against a ; multifocal tachycardla.
.,~ . .

, ~ , ; .
.. . . .

Ouabain-induced arrhythmia ~dult mongrel dogs of either sex, after fa~tlng for 16 to 2~ hours~ were anesthetlzed with 35 mg/kg Na-pentobarbital i.v. and tied supine on an operating table. ~ patent airway was provided by inserting an endotracheal cannulaj and the anlmal respired spontaneously. A femoral vein was double cannulated with one cannula for in~ection and the other as a site for ouabain infusion. The ipsilateral renloral ar~ery was cannu]ated 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 Vl) i; were taken with monopolar pin electrodes. Both parameters were r.
printed out on a C-rass polygraph. Each dog was given ~6 mcg/kg ouabain i.v. over 1 minute (the solution contained 50 mcg/ml ouabain in lsotonic saline) followed by a constant ouabain inlusion (0.6mcg~kg/min) starting 5 minutes later. The in~usion solution was prepared so that the appropriate do~e per-minute was del~vered in 0.5 ml.
When the predominant rhythm Or the ensuing arrhythmia was a ventricular tachycardia (or sometimes nodal) an attempt was `i made to convert this arrhythmia with the test compound. Up to 10 4 M/kg o~ test drug was delivered in a volume Or 1 ml ~ g over a 5 min. infusion period. If a conversion or cardiotoxic e~fect was seen before 10 4 M/kg was delivere~, the dose was noted and repeated on a second dog.

,: , :

, ,. , ~ . . .

2~5 ; The te3t Wa8 routinely conducted using palrs of dogs wlth a 15 minute dlr~erence in startlng tlme. All EC~l interval and duratlon measurement~ were made on lead I~
wtth a chart speed of lOo ~m/~ec. Hear~ rates were made on -: 5 lead II wlth a chart speed or 100 mrn/sec. Heart rate~ ~-were taken ~rom l~ad II QRS complex~s a~ 25 nun/sec. Blood pressure was measured using a ~ensitivi~ Or 10 mm Hg/~n pen derlection.
T~le results of the abovç-described tes~ are . .
pre~ented ln Table F hereinbelow. The test compounds are indicated to be active (A) or inactive (I) at the dose tes~ed :expressed in r~/k~.
.
.... .

"

.
.. . .

. . .
.,., ' ' . i .

`/ ` :
.
~ .

~ --124.
, .

. -TABLE E
Pharmacologlcal Propertle~

Antlhypertenslve . Adrenerglc Actlv' ty Va~odilat ~r Activlty Activity Renal Hyperten- .
Cpd SH Ra~ MEDlo Per~us~on Rabbit ~-bloc~de , 10 Exo ~ .40 - mg. /kgo 50 vasodilation 5o r~ NoO mg~/kg, P.OO tid mg./kgo (molar conc.) mg./ke-_ . . . ~
~; 2lOoO 0.5 50% c~o(6 . (lxlO 5M) 32000 0.5 56~ 0.1 . (2xlO 5M) 4 2~O ` 1~25 O~25 5~9~ O~04 . (6.25xlo 5M) ~500 O( -26 )f~l O~ 5 90j~ <1~ 0(700 : (lxlo M) . 20 815.0 >2,5(0)g 0.5 55~ 0.1 (lxlO M) llA2.0 0.0316 0.5 50% 0.025 . (5xlO 5M) ' llB9.0 0.5 20~ 00025 (5xlO 5M) 13>5000(-20) ~-5() -5 50~ 0.1 (305x~o 5M) 17~20~0(-33) 0.5 (lxlo ~M) CaO. 5 l9B ~ ~ 0.1(45~) 20A3.o 0.0316 0.5 49~ o.125 . (5xlO 5M) .' 20C 4.0 50% ~0.25(70%) . (5xlO 5M) : -125--Z~5 TABLE E
Pharmacological Propertie~

Antlhypertensive . Adrenerglc ~. Activlty Va~odilator Actlvity Activity : 5 . Renal .
. Hyperten-~i SH Ra~ MEDlob Per~us~on Rabbit-bloc~ade Ex. AHD40 mgO~kgo AED50 va~odllatlonED50 NoO mgO/kgO P0OO tid mgO/kg. (molar conc.) mg./kg.
,~ .
t 20D400 71%
lxlO 4M) 20E 64 j15 s 15 ( lx10-41q) 21A 0.5 >0.1(14%) ~,j 21B .5 0.1 22A15.0 ~0.025( ?5~) 58% 0.25 ( ~xlO 5M) ~I~ 20 23A~ 50.0 ( - 22) '6 24A> 5 00 ( - 10) ', 25 30 29A20.0 >0.025 (25% ) 61,~ O,0125 (5xlO 5M ) 30~16.0( -17) ~ >oO 5(8O 50~ >0.10(23O
(2xlO M ) ~16.0 ( - 14) ~0.5 (14% ) 384~ 0.25 32 5 ~0.5(14%) 50~ 0.05 (2xlO M) 33 3 <o 5 (17~ ) (1 10-4%M ) 0.0125 .~

. ~ . . . , __ .

l~g~Z45 TABLE E
Pharmacological Propertle~

, :
;.
Antihyperten~lve Adrenergic -. Actlvity Vasodllator Actlvlty ~ctivity ~' _ Renal Hyperten-CpdoSH Rat MEDlob Per~u~on Ear ArterY d ~-bloc~de Ex.AHD40 mgv/kgO AED50 vasodll~tlon 5o No. mgO/kg. POOO tld mg./kg. (mol~r conc.) mg./kg.
36Ca50.0 0~5 71~ ~100(56~) . (lxlO 5M) ;, 38 35.0 0.5 33~ <l.o~60%) (2xlO 5M) 39 20.0 0.5 29~ ~lo o(870 (1~10 M) 41~ 20.0(-23) 42~ 2000(-25) 45 1500 005 75% ~ 8~) ;' . (5x10-5~) :~
:~ 47 CalO.O 0.5 70~ Cl. o( lOO~) . (5xlO 5M) :: 48~ 2000(-37) 005 50~ 0.05 (5xlO 5M) ,~ 50 20.0 0.5 095 50% Cl.0(72~) ; . (9xlO 5M) .` 51~ 20.0(-2~) ~0.125(0) 0.5 42~ ~1.0(100%) . (lxlO M) 53 5.0 005 81% Oo l .~ (5xlO 5M) . 54 2000 ~00125(0) 0.5 50% ~0.025(~7%) .~ (5xlO 5M) .

:, lOS1~45 TABL~ ~ I
Pharmacologlcal Propertles .

. Antihypertensive . Adrenerglc . Actlvlty Vasodilator Actlvlty Actlvlty _ Renal . .
. Hyperten-Cpd~ D ~ MEDlob Perrus~on Rabbit Dog Ex. AH 4o mg./kg. ED50 vasodllatlon 50 No. mg./kg. PØ tld mg./kg. (molar c~nc,) mg~/kg.
~.
.~ 57 . 7.0 >0.125(0) 5 (constrlctor) ~ 0.1(67~) ~`~ 59 > 50.0(-17) .
:, ~0 ~0. 0 . ~0,~ ' . . (lxlO 3M) 63 > 50.0(-12) ~
66 40.0 . . < 0.025(80O
l9D . . ca.O. 10 23B ~ 50(^17) ~ 1.0(0~) 24B > 50(-31) ~ OdØ50 67B > 50(-14) . . ~ 1.0(10%) 68 Ca.10 > 1.0(33%) > 50(-12) . . caØ50 72 ~ 50(-la) .
74 ca.40.0 ~ 20(0)J . . > 1.0(18~) > 50(-22) . > 1.0(~%) 76 > 50(-13) - . . ca.l.0 77 > 50(-26) . caØ10 78 > 50(-20) . . > 1.0(0%) 79 ~ 50(-22) caØ10 > 50(-22) ~ 1.0(17%) 81 ~ 50(-~1) . . .~ 1.0(~%) 82 ? 50(-12) ca,o,oS

2~S

TA~LE ~ -~harraco~o~lc~l Pronertle~
. _ Antlhypertenslve Adrenergic Activlty Vasodllator Actlvity Actlvity _ Renal Hyperten-C pd o D ~ MEDlO Perfus~on Ear ArterY d ~-blocekade E~. AH 40 mg-/kg- 50 vasodllation 5o No. mg./kg. PØ tid mg./kg. (molar conc.) mg./kg.
_ ~, 83 ~ 50(~9) ~1.0(11%) '~ 84 ~? 50(-18) ~1.0(0%) - 85 > 50(-18) . ca,o.50 87 ~ 50(-1~) < 1.0(67O
89 ~ 50(-11) `
91 C 50(-51) ` 92 ~ 50(-1:5) 93 ca.50.0 96 ca . 50 .0 > 1. o ( 14% ) 97 C20(-54) > 40~ >1.0(43,~) 01 ~50(-8) 102 ~ 50 (-3 ) ca . 3 . 50 .

~ -129-: ' .';:

(a) AHD40 = single oral do~e required to induce a 40 mm average reduction in systollc blood pressure ln the un-anesthetlzed spontaneous hypertensive ratO
i, .
(b) MEDlo = mlnlmum repeated oral dally dose requlred to e~fect a sustained lowering Or blood pressure Or 10~ or greater ln the unanesthetized trained renal hyper-tenslve dog.
(c) AED = approximate lntraarterlal dose required to cause a 5 50~ reduction ln perfuslon pressure ln the hind limb o~ the anesthetized dog.
` (d) Vasodilatlon is expressed as the percentage redùctlon ln perruslon pressure from the contro~ level at the indicated molar dose.
(e) AED 0 = approxlmate lntravenous dose requlred to cause 50 inhlbition Or thè heart rate increase ellcited by ~^j lsoproterenol ln the pentobarbitslized dog.
~j~ (f) Actual reductlon ln blood pressure (ln mm Hg) observed at .',;5 the indlcated dose.
}j, (g) Actual percentage reduc~tlon ln blood pressure observed i~ at the lndlcated dose.
~,:, . .
(h) Actual percentage reduction ln perfusion pressure ob-served at the indicated~dose.
(1) Actual percentage lnhlbltlon Or heart rate lncrease above control level observed at the lndlcated dose.
(~) Admlnl~t~d-On~e per d~y.
:

,, ! .
"~
~ ' `~' ~ .~

.,.`~
, 130-,~
- . . . . . .

, : .

TA ~ i F

Antiarrhythmlc Actlvlty _ Cpd. of Convers~on of Converslon of Ba -Ouai~tl in - induc ed indllced a rrhyt}lmla 5 Ex. No. arrh.ythnii.a ~ . , ---~

a .

6 A ~ 5XlO 5 A ~ 5XlO 5 ., 19D A ~ 2 . 5XlO 5 A, 5X10 6 20E,F A, 5XlO 6 A, lXlO 5 23B . A, lXlO 5 51 A, 5xlO 6 A, 5X10 6 54 A, 5X10 5 A, 2. 5X10 6 67B A, 2. 5XlO 5 .
: 63 I 2,5XlO-5 A~ 5XlO 6 - 15 87 I 2. 5X10- 5 A, lX10 5 -- 101 A, 5X10 6 :. 102 A, lX10 5 A, 2X10 5 ' '.
.'.'.
'' ~
.: ~ (a ) M/kg, (b ) Toxic at 2 . 5XlO 5; inac tive below 2 . 5XlO 5 '~.
1.
. .
.
. , .
I
.. . ~
, .~ . ,

Claims (19)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for producing a compound having in the free base form the Formula I

wherein R1, R2 and R3 are independently hydrogen or lower alkyl;
n is an integer from 1 to 3;
Ar is phenyl or phenyl having from one to three halo, lower alkyl, hydroxy or lower alkoxy substituents;
Q is lower alkylthio, lower alkylsulfinyl or lower alkyl-sulfonyl: and Y is hydrogen, lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl;
or an acid addition salt thereof, which comprises reducing a compound having in the free base form the Formula II

or an acid addition salt thereof, wherein in the event that Y in the starting compound is lower alkanoyl or aroyl and the reduc-tion is carried out with a reducing agent capable of reducing both ketone and carboxylic ester functions, Y in the resulting compound is hydrogen.

2. A process according to claim 1, which includes hydrolyz-ing a compound obtained wherein Y is lower-alkanoyl or aroyl to obtain the corresponding compound wherein Y is H.

3. A process according to claim 1, which includes esterify-ing a compound obtained where Y is hydrogen to obtain the corre-sponding compound where Y is lower alkanoyl or aroyl.

4. A process according to claim 1, which includes oxidiz-ing a compound obtained wherein Q is lower alkylthio to obtain the corresponding compound wherein Q is lower alkylsulfinyl.

5. A process according to claim 1, which includes convert-ing a free base compound obtained to an acid addition salt thereof or forming a basic salt of a compound obtained wherein Y is hydrogen.

6. A process according to claim 1, wherein Ar is phenyl or phenyl having one or two lower alkyl, hydroxy or lower alkoxy sub-stituents.

7. A process according to claim 6, wherein R1 is hydrogen and Q is methylthio, methylsulfinyl or methylsulfonyl.

8. A process according to claim 7, wherein Y is hydrogen, lower alkanoyl or aroyl.

9. A process according to claim 7, wherein Ar is 4-methoxy-phenyl.

10. A process according to claim 6, wherein R1 is methyl, Q
is methylthio, methylsulfinyl or methylsulfonyl, Ar is lower alkoxyphenyl and Y is hydrogen.

ll. A process according to claim 1, for preparing 4-hydroxy-.alpha.-<{[3-(4-methoxyphenyl)-1-methyl-propyl]amino}-methyl>-3-(methyl-sulfinyl)benzenemethanol or an acid addition salt thereof, which comprises reducing (+)-4'-hydroxy-2{[3-(4-methoxyphenyl)-1-methyl-propyl]amino}-3'-(methylthio)-acetophenone and oxidizing the re-sulting compound.

12. A process according to claim 1, which includes converting a compound obtained to the hydrochloride salt thereof.

13. A process according to claim 12, which includes separat-ing a diastereomer from the diasteriomeric mixture produced.

14. A compound of Formula I as defined in any one of claims 1, 2 and 3, when prepared by the process according to claims 1, 2 or 3, respectively, or by an obvious chemical equivalent thereof.

15. A compound of the Formula I as defined in any one of claîms 4, 5 and 6, when prepared by the proces according to claims 4, 5 or 6, respectively, or by an obvious chemical equivalent thereof.

16. A compound of the Formula I as defined in any one of claims 6, 7 and 8, when prepared by the process according to claims 6, 7 or 8, respectively, or by an obvious chemical equivalent thereof.

17. A compound of the Formula I as defined in claim 9 or 10, when prepared by the process according to claim 9 or 10, respec-tively, or by an obvious chemical equivalent thereof.

18. 4-Hydroxy-.alpha.-<{[3-(4-methoxyphenyl)-1-methyl-propyl]amino}-methyl>-3-(methylsulfinyl)benzenemethanol or an acid addition salt thereof, when prepared by the process according to claim 11 or by an obvious chemical equivalent thereof.

19. The hydrochloride of 4-hydroxy-.alpha.-<{[3-(4-methoxyphenyl)-1-methyl-propyl]amino}-methyl>-3-(methylsulfinyl)benzenemethanol or an acid addition salt thereof or a separated diasteraomer there-of when prepared by the process according to claim 12 or 13, re-spectively or by an obvious chemical equivalent thereof.