United States Patent
`Jiinsson et al.
`{-15} Date of Patent:
`Jan. 17, 1995
`
`
`[11] Patent Number:
`
`5,382,600
`
`lllllllllllllllllIllll||l|||l|||lll||lllllllllllllllllllillllllllllllllllll
`
`US005382600A
`
`[19]
`
`[54] 3,3-DIPHENYI..PROPYLAMlN'ES AND
`PHARMACEUTICAL COMPOSITIONS
`THEREOF
`
`[75]
`
`Inventors: Nils A. Jiinsson, Sodertiilje; Bengt A.
`Sparf, Tringsund; Lemhit Miltiver,
`Jiirna; Pincllas Muses, Saltsjii-Boo;
`Lishet Nilrebr-ant, Bromma; Gunilla
`Glas, Spinga, all of Sweden
`
`[73] Assignee:
`
`Pharmnein Aktiebolag, Uppsala,
`Swed
`
`[21] Appl. No.: 810,185
`
`[22] Filed:
`
`Dec. 19, 1991
`
`Related US. Application Data
`' Continuation of Ser. No. $43,767. Sep. 24. 1990. aban-
`doned.
`
`[63]
`
`Foreign Application Priority Date
`[30]
`Jan. 22, 1988 [SE]
`Sweden ............................. 8800207-6
`
`[51]
`
`Int. 0.5 ................. AGIK 31/135; A6lK 31/165;
`A6lK 31/18; C07C 217/62
`[52] US. Cl. .................................... 514/603; 514/620;
`SI4/648; 564/86; 564/165; 564/316
`[58] Field of Search ....................... .. 564/86, I65, 316;
`514/603, 620. 648
`
`[56]
`
`Refueueee Cited
`
`U.S. PATENT DOCUMENTS
`
`3,44-6,901
`
`5/I969 Joni: .................................. 424/330
`
`FOREIGN PATENT DOCUMENTS
`111894 3/1969 Denmark.
`1169944 ll/I969 United Kingdom .
`H69945 ll/I969 United Kingdom .
`
`OTHER PUBLICATIONS
`
`Markaryan et a.I.. Chemical Abstracts, vol. 97 (1982)
`l20l05n.
`
`Atwal et al., J. Med. Chem... vol. 30 (1987) pp. 627-365.
`Strehlke et al., Chemical Abstracts, vol. 91 (1979)
`10794-3r.
`
`Primary Examiner—Richard L. Raymond
`Attorney. Agent. or Fi'rm——Pollock, Vande Sande &
`Priddy
`
`[57]
`
`ABS'I'RAC.l'
`
`(0
`
`R2
`
`R3
`
`OR‘
`
`CI-l—Cl’~I1—C.H2'-'X
`
`R4
`
`Novel 3,3-diphenylpropylamines of formula (I) wherein
`R1 signifies hydrogen or methyl, R2. R3 and R‘ indepen-
`dtly signify hydrogen, methyl, methoxy, hydroxy,
`carbamoyl, sulphanoyl or halogen, and X represents a
`tertiary amino group -NR5, R5, wherein R5 and R5
`signify non-aromatic hydrocarbyl groups. which may
`be the same or difierent and which together contain at
`least three carbon atoms, and which may form a ring
`together with the amine nitrogen, their salts with physi-
`ologically acceptable acids and, when the compounds
`can be in the form of optical isomers, the racemic mix-
`ture nud the individual enantiomers, their use as drugs,
`especially as anticholinergic agents, their use for pre-
`paring an anticholinergic drug, pharmaceutical compo-
`sitions containing the novel amines. and methods for
`preparing the same.
`
`1Claims,NoDrawing
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2053 - 0001
`
`

`
`1
`
`5,382,600
`
`5
`
`IO
`
`&&D O AND
`PHARMACEUTICAL COMPOSITIONS THEREOF
`
`This is a continuation of Ser. No. 07/543,761, filed on
`Sep. 24. 1990, now abandoned.
`The present invention relates to novel 3,3-diphenyl-
`prcpylamino derivatives, to pharmaceutical composi-
`n'onsocntsiningtl1esame.sndsothenseoi'saidderiva-
`lives for preparing drugs.
`Swedish Pat. No. 215 499 discloses certain 3,3-
`diphenylpropylyamines having an advsntageom efi‘ect
`on the heart and circulation. These pharmecologically
`active 3,3-diphenylpropylamines are secondary amines.
`Said Swedish patent also discloses certain chemical
`intermediates which are tertiary amines carrying aro-
`matic snbstiruents on the amine nitrogen. Neither the
`endprodncts(secondsryamines)northeinter'mediates
`(tertiary airlines) have any hydroxy or methoxy groups
`sssubstituentsintheorthopositionsofthephenylrings,
`butonlymetsamdparasuhetituentsareapecifically
`- disclosed.
`
`Itirlmow-nthetterodillne,acommercinlly
`drughavingthechemicalfornrnla
`
`available
`
`25
`
`*.=*="
`Cl-I—CHz—CH—N\
`
`°‘°“”’
`
`0/
`
`35
`
`40
`
`has anti-cholinergic properties, and is well resorhed in
`thebody.I-Ioweventhisdrnghasaverylongbiological
`half-lifeanditisamnlii-efi‘ectdrugalsohavingother
`pharmacological properties such as Ca-antagonist, nor-
`adrenaline antagonist and anti-histamine properties as
`well as a pronounced effect on the heart.
`U.S. Pat. No. 3,446,901, GB-A-1.169.944 and GB-A-
`1.l69.945 disclose certain 3.3-diphenylprovylamlne de-
`rivatives and pharmaceutical compodtions having anti- 45
`depressant activity.
`in. N,N-dimethyl-3-(2-methoxr
`phenyl)-3-phenylpropylarnine, which '3 considaed to
`he the closest prior art as regards chemical structure
`(seealsothecornparativetesisreporlzedattheendofgo
`this specification). DK-A-111.894 discloses a special
`proeessforpreparingoertnindiphenylalkylamines hav-
`inganefi'eetonthehartnndcin':ulation.'I'heIpecifi-
`cally dscribed compounds are primary or secondary
`ammes,andnoneoftheinlnsanyhydroxyoralkoary5-5
`suhs1ituentinorthoposiIionofthephenylrings.C.A.
`Vol. 910982) 1201051: discloses certain N-arylak-
`Iyliscquinolinu which may have a hydroxy suhstituent
`inIheorthopositionofsphenylring.Thesecompcunds
`have sympatholytie activity and carry aromatic substit-
`uents on the nitrogen atom.
`It isobject ofthepresent invention to provideanove!
`class of 3,3-diphenylpropylamina having improved
`anti-chohnergicproperties,especiallyinrelafiontothe 55
`efi'ectsontheseothersysternsandecutetoxicity.
`Inafimaspecttheinventionprovidesnovel 3,3-
`diphenylpnopylamines of formula I
`
`60
`
`'
`
`R3
`
`I
`
`CH-CHz"'CH1—X
`
`R4
`
`wherein R1 signifies hydrogen or methyl. R’. R3 and R4
`independently signify hydrogen. methyl, mothoxy. hy-
`droxy, carbamoyl, snlphsnoyl or halogen, and X repre-
`senlsstertiaryaminogroupofformnlsn
`
`/
`—N
`
`15
`
`R6
`
`wherein R5 and R5 signifky non-aromatic hydrocsrhol
`groups,whiehmaybetl1esameordifi'e:-entandwhlch
`to3etl1erconteinatleastthreecarbonntorns,preferahly
`atleatfourcarhonasonuuespeciallyntleastfiveearhon
`atoms,andwhereR5andR‘mayformeringtogether
`withtheaminenitrogen,saidringpre.fetablyhavingno
`otherheteroatomthattheamineniuogen.
`Thecomponndsoffoumnlnlcanformsaleswith
`physiologically accepnble-cidaorsamioandinors-nic.
`andtheinvenfioncomprisesthefreebasesaswellssthe
`saltsthereol'.Examplesofsuehacidsdditionsaluin-
`cludethehyt|rochloride,hydrohromide,hydrogenfi:-
`maramandthelilce.
`
`Whenthenovelcompoundscanbeinthefonnof
`optical isomers, the invention comprises the racemlc
`mimnreesweflutheindividnalenantiomemassuch.
`Apreferredsub-classofcompolmdsaccordingtothe
`invention comprises tertiary mines of formula I,
`whereineeehofR5andR‘independentlysignifiesC;.;-
`alkyl. wpecially C|.¢-alkyl. or sdamantyl. R5 and R5
`togethetcomprisingatleastthreepreferablyat least
`t'onrearbonatorns.R.5andR‘-maycarryoneormcre
`hydroxygruglpsmndtheymnybejoinedtoformsring
`togetherwiththesnainenitrogenatorn.
`Presentlyprei’erredtertiaryanaino-gronpsXinfor-
`nmlslincludethefollowinggronpsa)-i),eschof
`whiohmsycarryonecrmcrehydmxygronps.
`
`/CHCCHJJ2
`a} --N\
`.
`Cl'HCHs)1
`
`II) —N
`
`CR3
`
`.
`G(CI’l3)3
`
`CH3
`
`o) -N/
`\
`C(CHJ}zC|'!2C'-H3
`
`,
`
`°’{’c:‘i"..3.,.
`u) —N/
`\
`/CTCH2
`CH3
`CH3
`
`.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2053 - 0002
`
`

`
`3
`
`-continued
`
`_
`CI? /cl]!
`/ :
`CI‘?
`9) ‘'N\
`/CH;.
`/°‘\_—°"‘?
`CH3
`CH3
`
`‘'13:
`I) -N
`
`4
`
`(ml
`
`cu-cu,-oo-x
`
`R‘
`
`R2
`
`R
`
`5
`
`:0
`
`V
`
`whereinkl-R“andXareasdefinedaboveandauy
`hydroxy groups may be protected. preferably using a
`15 complex metal hydride,
`c) N-methylnling a secondary 3,3-diphenylpropylm
`"in VI
`
`go
`
`35
`
`1;:
`
`OR:
`
`VI
`
`CH-cu:-cuz—NH~—z
`
`R,
`
`I
`3° ;”,°";’_ff“m‘:;',§e‘"°”‘°fi=m;°g ="°"° mgfgguwmv
`.
`"‘°‘°°‘°“'.
`“""““‘.
`“'3'
`';::“"§];“Rf “‘:’;:y“'h ‘h’ ]‘‘°°P“°‘'°:1“‘‘?‘3.‘V'' :
`“nub,
`smug . mung
`as apoms, the N-methyleuon preferably
`beingcarnedoutuangformnldehydeorformicacid,or
`d) reducing a 3.3-diphenylpropylamine of formula
`Vna or VIII:
`R;
`
`vu.
`
`The following are examples of presently preferred
`specific compounds of formula I:
`N-N-diisopropyl-3-(2-hydroxy~s-me:hy1pheny1)-3-
`phenylproprlamine and its (+)-isomer.
`N-methyl-N_-tn-Lbuty1-3-(2-hyaroxypheny1)-a.pheny1-
`propylamme.
`N-methyl-N-tert.buty1-3-(2.4-dil:ydroxyphenyl)-3-
`phelaylprolwl-mine.
`N-methyl-N_-tert.hntyl-3.3-bia-(2-hydmxy'phenyl)-
`Prolfylnmne.
`N.N_-dansopropyl-3.3-his-(2-hvdroxvphenynpropyla.
`name.
`N-N-d5i5°Pr0Pvl-3-(2.5-dih1rd:oXYphenyl)-3-Phenyl-
`pmpyiamine.
`N-nnethyl-N-ta-Lbutyl-3-(2.5-dihydroxypheuy1).3.
`I:
`l
`'
`Nll:I°|}_YW
`ha I
`-
`'d"9°P"°P_ '
`"M50-‘KYP
`V)-3'PhflI?1-
`P1'°P3'1l|1lm°-
`N'(3-(9»-mI‘-;lll_0XYl11}EflY1)-3-Phfl1Ylpropyl)-1-?.5.6-tet-
`“nah? IflP¢|'ld?1|¢
`Inasec_onda.specttheinven1ionpIovidesmethods4o
`forprepenugtheoompoundsofformuln Lespeciany
`the following methods:
`I) Nactillz a reactively esterified 3,3-di.phenyl-
`propane] offormula III
`1:1
`
`45
`
`III
`
`‘
`
`'33‘
`
`c_cH_c":_x
`
`R4
`
`onl
`
`C<C'l-lg-C1Hz'-K
`w
`
`no
`
`R,
`
`R2
`
`R
`
`VIII!
`
`on1
`
`cH_Cflz_a.h_Y
`
`no
`
`I
`
`so
`
`55
`
`wherein R‘-R‘ an: as defined above, and any hydroxy
`sfollpsunybepronectedsuchasbymetlrylationor
`benzylatIon.nndwheteinYisnleavinggmoup,pa-efen- so
`my man °r'n'lkyl°’”y'3“1ph°nV1°"V 5"°“P~
`withanamineofformulalv
`,.,_x
`wherein x is as defined above. or
`B) ‘fiucillfl 3 3.3-diphaenylpropionamide Of formula V
`
`W
`
`wherein R1-R‘andXu'easdefined;bovean¢|my
`hydmxygmnpsmaybepm 'imdw .
`.5
`a
`hvdroxygu-ouporahalogenawm.prefenblybymeans
`ofcaulytiehydrogenetiomand
`6‘ i)
`‘§_f":";f"“ “’““5"‘l of ."3""°Hf‘Vi P.'°‘°°“"3
`mono or fi.m] of-‘one or both ofthe phcnyl _
`ringx,and/or
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2053 - 0003
`
`

`
`5,382,600
`5
`ii)ifdesired convertingohtninedhasesofformulalinto
`salts thereofwith physiologically acceptable acids. or
`V103 W138. and/or
`
`iii) ifdesiredseparalinganohtained mixture ofoptical 5
`isomer: into the individual ennntiomen, and/or
`iv) if desired methylating an ottho-hydmxy group in an
`obtainedccmpoundofformulnI,whercinR1'mhy-
`drogen and/or R4 is hydroxy.
`Theabovegencralmethodscanbecarriedoutina
`mannerlmownpersennd/orinaccordanccwiththe
`
`1°
`
`6
`mmm
`R:
`
`3‘
`
`R’
`
`Vm
`
`R1
`
`OR‘
`
`;r=;,";a,..°*="..i.==%=*,.e.d°*°".,...,*:* °°:°‘*;.“:.**:;:".:....°°~°'.;..;.; :5 mmmmmccnmaccc
`oath:
`_
`3””
`tionoftheccnesponding3,3-diphenylpropionicacids,
`h°“°°° ‘"93’
`preferably using complex metal hydrides.
`The removal ofhydroxy protecting groups according
`The 3,3-diphenylpropanola vm can convoniently be
`toi)abovecanc.g.bedonebytreatmentwitl1hydro-
`ccnvertedintothecorrespondlngxeactivelyestetified
`bro:nicacid.borontrb:omideorbyeetelyIichydmge-
`derivaliveslllinamnnnerlmownperaebydisplacing
`mfion,
`thehydtoxygroupswithe.g.aha1ogenntomoranalkyl
`Tbesepa1'ationofIIIixtnresofopticaliIomen.acoord-
`°' "7}“lPh;°”V1°‘3'
`_
`ingtoii)aho‘ve.intotl1eindividualenantiomerscene.g. 25
`Th?3l’3:'phmIyhmfiuwauoigzghvuwgmgng
`beachievedbyfxacticnalcrystallintionofsaltswith
`the
`.
`as .
`l.l.
`.
`.5
`_
`_
`_
`above mentioned , -dzphenylpropncmc acids with
`chmlacidsorbychromatographicsepnraticnonchirnl
`uammpfinaflm
`°°'“"""-
`Thetcccndaryuminesusedasstnrflngmaterialsin
`Nove1cornpo1:ndsofformulaVlII
`gomethoddcanoonvenimtlybepreparedbyreactinga
`.
`primaryamincl-!2N-Z(whcreinZisadeflncdabovc)
`withscorresponding reectivelyataified 3,3-diphenyk
`m pmpnnolinanalcgywithmethoda)ahove,orbyreduc-
`35 ticn of the corresponding secondary 3.3-cliphenylpto
`pion|midesinanalogywithmethodb)above.'I‘hesec-
`oudaryeminescanalsobepreparedbyreducdcnof
`unsaturatcdhydrcxyamlnesxl
`
`CH
`
`c“_
`
`CH1
`
`on
`
`spcndmg protected compounds (e.g. ccmpnmg pro- 43
`tectcdhydrcxygmups),areusefnlccchcnncalmterme-
`dmtesfortheptepanfimcfegthecompmndsof
`foI'mulaI,andtheycanbcpreparedbyu:eInIofseveral
`difi'ercntmefl:odswhichareknownperu=,suchasby50
`addition of ethylene oxide (X) no a y whcreinkl-R‘nndZnrcasdefincdabove,eithcrinone
`mbfljmmd ° hmyimethme
`inmepreaemeofa
`stepbycatalyfichydmgemfiomorbyreducfiontoflie
`corresponding saturated hydmxyamine, preferably
`
`C‘-CI-lz—(‘.'l-I-N—2
`\OH
`E4
`
`R3
`
`R3
`
`OR.
`
`'
`
`O
`/ \
`+caz-—-cnzfi->
`
`55 mingacomplexmculhydridesuchaalithiu:nnlnmin-
`inn: hydride, followed by removal of the hydxoxy
`groupbycatalyticrednction.Asmaltemartive,the
`hydnoxygroupmnyfintbesplitofi'aswater,followcd
`byreductionoftheformednnsatmatedamine.
`The unsaturated hydroxy amines XI can conve-
`nientlyhepreparcdbytheaddifionofaschiffbaseof
`formulaxll
`
`5°
`
`65
`
`('.'.fl3—CH=N—Z
`
`XII
`
`Ix
`
`X
`
`whereinzisasdefmedabcvenoabenzophenoneof
`formulaxlll
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2053 - 0004
`
`

`
`XIII
`
`R2
`
`1!
`
`onl
`
`CIIIO
`
`R4
`
`wherein R‘--R4areasdefned above. inthepresenceof
`a_bese.prefenblyalithiurnorganicbueenchaslithinm
`lamide.
`
`thes1artingrnaterlaBVIIa,VIIbforprocered)
`eanbepreparedbyn1ethodal:nownperse,suchasby
`adclitionofanorganometalliccornpoundXIVaor
`XIVb
`
`R1
`
`R3
`
`Me
`XIV:
`
`I.‘
`XIVI:
`
`toaketoan:ineXVaorXVbreapeetivelyroforn1a
`correspondinghydroxyaminexw
`
`R1
`
`XVI
`
`5,382,600
`
`8
`tion, suchaetablets, capsules, powders, syrups. elixir:
`andtheIike,inthefonnofster'ileao1utions,anspensiona
`oremulsiomforpannteraladminisuafiomandtheiike
`The compounds and compositions according to the
`inventioncanbeaaedfortreatingcholin~mediateddis-
`orderasuchasurinar-yincontine-nce.Asiswelllcnown,
`tl1edoeagedependaanseveralfactor:aucha.sthepo-
`tencyoi'theseleetcdspeoifiecompo1Ind,theInodeof
`adn1inistrafion,thea9eandweightofthepau'ent,the
`sever-ityofthecondition1:obeu'eated.andthelil:e.The
`daiIydougernay,l‘orexample,befromabout0.05rng
`toabout4n:gperlci1oofbodyweight.admiuisteredin
`cneormoredoees,e.g. containingfi"on1ebout0.05to
`abontzllomgeach.
`The invention will be furtherillustrated by the fol-
`lowingnon-limitingexamples.
`General
`
`25
`
`20
`
`1H—N'MR.spectrawereruninCDCl3usingaJEOL
`PMX60 spectrometa-. In some cues, only a limited
`number ofspectral peaks, useful for characterization
`purpooes.arerep°rwd-
`Reported yields mostly refer to crude material of
`sufiicientpuritytobetakmtothenextstase.
`Solventsare abbreviated as follows:
`IPE=dii.sopropyleIher
`PBT=petroleurne'ther
`Ether=diethylethu'
`Aminesareabbreviatedasfollows:
`30 IPA=d.iisopropyi amine
`TBA==tert.butylamine
`Meltingpointsweretaltencnelioeflerbench.
`Tempentureserein'C.
`Waterisusedforthewnshingstaepsnrnlessotherwiae
`stated.
`
`C-CI‘I:—Cl'l1—X
`\
`OH
`
`EXAMPLE 1
`
`40
`
`R4
`
`R
`
`Preparation of 4-phenyl-3,4-dihydroooumarins
`a) 4-(2-Methoxy-5-methylphenyl)-6-methyl-3,4-dihy-
`drocounmin (I)
`A rnixture consisting of 2-methoxy-5-methyicinnarnic
`and,ifderired.aplittingofi'water£mmcompoundXVl.
`acid (96.0 3. 0.5 mol). p-creeol (108 g, 1.0 mol), teu-aline
`In formulae xlva. Xlvb, Xva. Xvh, XVI, RLR4
`(200n:I),andconc.aulphm'ieaeid(20g)washeared
`aree.sdefinedabove,andMesi3nifieanmetaluueha.s 45 31°WlY3°f°fl||Iil181¢1flP¢‘3Wf°(145'-150')-M39?“-2
`rnagnesiumorlithiunn.
`h,then:ixturewascooled.tal:enupinether,washed
`lnaccondancewiththeinventionthecounpoundsof
`with water and sodium carbonate, dried and evapo-
`formulal,intheformofl’neebaeeaor:altswithphy:io-
`rated, giving 138 g(9'I%)ctudeoil. Two -
`logically acceptable acids, can be brought inm suitable
`tionsfmmaeetonegave whiteorystalsofthedesired
`gelenicforms,suchas
`eompoain'onsfororaluae,for50
`intone, mp. l26'—I21'.
`iniection.orthelike.inaccordancewithacceptedphar-
`CnH1gO3 (282.3) requires: C. 16.37; H. 6.43; O. 17.00,
`n:aceuticalprocedures.Suc.hpharn:aceuu'caicomposi-
`Found: C, 76.9; H, 6.44; O, 11.0.
`tiona according to the invention comprise the com-
`b) 6-I-[ydroxy—4-phenyl-3,4-dihydrocournarin (II) was
`pounds of formula I in uaodafion with compatible
`prepared in a similar way in 97% yield from cinnanaic
`pharrnaceutiealiy acceptable carrier materials. or diiu- 55
`acid and hydroquinonne. M.p. 138’ (II-‘B-Ether).
`en13,asiawel1knownintheart.'l'hecan'iersmaybe
`015111203 (240.3) requires: C, 14.99; H, 5.04; O. 19.98,
`anyinertma!erial.organicorinorganic.snitablefor
`Found: C, 75.0; H, 5.00, O, 19.6.
`en1:enl,percuteneonsorparenteralad:ninirt1-etionsuch
`c) 4-(2-Methoxy4-|nethylphenyl)-7-methyl~3.4-dihy-
`as:water,gelatin,gun1arabieun:,lectoee.microerystal-
`drooomnerin was obtained in a similar way from 2:
`iineeellulose,siar¢:h.aodiun1sta.rchglycoiate,caleiInn60
`nrethoxydl-methyleinnarnic acid and n:-cresol in 58%
`hydrogen phosphate, magnesium stearate, talcum, col-
`yield. M.p. I47‘-148‘ (IPE-acetone).
`loidalsilicondioxide.andthelike.Suchcon:poaitions
`CISHIIOJ (282.3) requires: C, 76.51; H, 6.43; O, 11.00,
`rnayalsocontainotherpharmaeeuficallyactiveagents,
`Found: C, 76.4; H, 6.3!; O, 17.2.
`nmiconvenl:ionaladditivesmchasstabilizel'5,wetting
`Tbeabovel.ectone(90g.0.32n1oi)inn1ethylene
`w.e1nulsifiers,flavonringagents,bufl'ers.andthe65
`chloride (500 ml) was refluxed with B313 (115 g, 0.46
`rnol)for24h,thesolutionwasconcentrated,thereaidue
`Thecmnpcnsitionsaccordingaotheinvenfioncaneg.
`wastakennpinethenthesolntionwaswashedwith
`bemedeupinsolidorliquidI‘ormforora1administra-
`sodium carbonate and water. dried and evaporated,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2053 - 0005
`
`

`
`5,382,600
`
`-
`I0
`yield fromthe1ectone(II) ofExan1p1e1b)a.ndbenzy
`chloride.
`
`NMR: 8 6.8-7.4 (in 18H), 5.0 (s 4H. t 11-1), 3.7 (s 3H),
`3.1 (d 214).
`1:) Methyl 3,3-his-(2-benzyloxy-4-methylph.enyl)prc>
`pionate(X1I1)waaobrainedinasi:ni!arwayin95%
`yieldi'romthelnctone(lII)ofExantple id) nndbenzyl
`chloride. By GLC the product is homogenons, and by
`MS it has the correct M.W.
`i) Ethyl 3-(2.4-dimetlioxyphenyl)-3-phenylpropionete
`
`5
`
`10
`
`9
`giving 80 g (93%) of a syrup which crystallized on
`standing. Crystallization from IPE-PET gave white
`crystals of
`cl) 4-(2-hydroxy-4-methylphenyl)-7-methyl-3,4-dihy
`drocoumarin (III), nip. 137'.
`C17H:s03 (268.3) requires: C. 76.10; H. 6.01; O, 17.89,
`Found: C, 76.2; H. 6.30; O, 17.0.
`6) 8-Hydroxy-4-phenyi-3.4-dihydrocoumarin (IV)
`was
`in a similar way from cinnamie acid and
`catechol in 18% yield. M.p. 136‘ (IPE).
`CisHt20: (140.2) requires: C, 74.99; 1-1, 5.04; O, 19.98,
`Found: C, 75.0; H, 5.0I; O, 19.9.
`(V)
`f) 4-(2-Methoxyphenyl}-3,4-dihydrocoinnarin
`wesobteinedinasin:|ilnrwnyin45% yieldfronunethyl
`2-methoxycinnamate and phenol. The crude reaction
`mixture was contaminated with methyl 3-(4-hydroxy-
`phenyl)-3-(2-methoxyphenyl)-propionete. After
`re-
`moval of this by-product with ice-cold N103. the title
`ootnpoundwasohtainedasanoilofsufficientpurityto
`be taken to the next step.
`
`I5
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`A mixture of ethyl cinnamate (88 3, 0.5 mol), di-
`methyl reeorcinol (276 g, 2.0 mol) md canc. sulphuric
`acid(50g)wasstirredonaboilingwater-bathforzh,
`whereafietallthevoletilematerinlwasdistilledoffin
`vacuum. The residual oil was dissolved in ether, the
`
`evapomtedgiving101g(64%)ofthe titleeeterinthe
`form of a vbcous oil.
`
`NMR: 8 6.4-7.2 (in 8H), 4.9 (t 11-1), 4.0 (q 21-1), 3.7 (s
`6H), 3.0 (at 21-1.’). 1.l_ (t 31-I).
`‘
`j) Methyl 3,3-his-(2,4-din1ethoxyphenyl)propionate
`(XV)wnsobtai.nedinaaimilarweyl'rommethyl2,4-
`diniethoxycinnamate and dimethyl
`resorcinol. The
`productthutobtainedoontain:edebout23%ofdin1ethyl
`resorcino1.Itwasta1:entothenextstepwithoutfnrther
`
`k) Methyl-3-(5~chlom-2-methoxyphenyl)-3-phenyl-
`propaonue
`6-Chloro-4-phenyl-3,4-dihydrocoumnrin (435 g, 1.68
`:no1.Preperntion:T.Maninnran&:V.T.lhmakrish-
`nan,Ind.J.Chem.Bl8(1979)328)isaddedtoahot
`solutionofsodiumhydroxide(140g.3.5mol)inwa£er
`(500rnl).'I'hesolutionischilledto25'C.anddimethyl
`sulphnte(442g,3.5mol)isnddeddropwised1ninglh
`withstirringandooolingat25'-35‘C.Themixtureis
`stirredforannclditionalzhwhereuponasolntionoflm
`gofeodinmhydroxidein500mlofwaterisaddedend
`theinixtureiestirreduntilaclearsolntionisobtained.
`Anexceesofconoentretedhydrochloricacidisadded
`toprecipim:ethemethoxyacid,which:e-preteeuan
`oi1whichalowlycryste1lizes.Itisfiltetedofi',washed
`with water and dried. Crystallization fioan 2-propenol
`gives eolourlesa crystals of 3-(5-chloro-2-methoxy-
`phenyl)-3-phenyl propionic: acid. mp. 144‘ C. Yield 455
`8-
`
`‘I'heaboveo.cid(29l g. l.0:nol)in lliterrnethanol
`oonuiningiogconcuiuuedsnlphuficacidwasre
`fiuxedfor8h.Thesolventwasdis1illedoff,theresidue
`wastakennpinether,washedv.rithwnI:erandsodiu:n
`cerbonat solution. dried and evaporated giving 300 g
`(100%) crude oil. Recrystallization from IPE gave
`white crystals of thetitle compound, rn.p. 65‘—66'.
`C11H11Cl03 (304.3) 1'=¢Ifli1’€-5: C. 57-0; H» 5-52; Cl.
`11.63, Found: C, 68.1; H. 5.82; CI, 11.7.
`EXAMPLE 3
`
`Pmepernfion of 3.3-diphenylpropanols
`
`60
`
`3) 3-(2-Metltoxy-4-methylphaiyl)-3-phenylpropnnol
`
`65
`
`'I‘heester(V'l)ol'Example2n)(84g.0.295rnoI)in!50
`mldryetherwasndded
`’
`toasuspemionof
`LiAlH4(11.3g,0.295n1ol)in300|nld.ryether.The
`mixmrewassfirredovanighgthendeconaposedbythe
`carefuladditioni'mtof1lgofwater,thenofl5%
`Naofluntilnwhitegranularprecipitatewasformed.
`'I'hemixturewasfiltered,thefiltntewaswashedwith
`
`EXAMPLE 2
`
`Preparation of 3,3-diphenylpropiouie acid enters
`1) Methyl 3-(2-methoxy-4-methylphenyl)-3-phenyl-
`proiaio-me (VI)
`7-Methyl-4-phenyl-3.4-diliydmoouinarin (78 g. 0.327
`mol)in150mlmethnnolnnd lsomlacetnnecontaining
`methyl iodide (101) g. 0.7 mol) and IQO03 (55 g. 0.4
`n1oI)wesreflm:edfor24h. filteredmndthenolventwu
`evaporeted.'l'heresiduewasdi:so1vedinethe.r.the
`solutlonwaswaehedwithwatendriedandevaporated
`giving86g(92%)ofnviseonsoil.
`NMR: 8 6.6-7.2 (in SE), 4.9 (t 11-1), 3.8 (s 3H), 3.5 (s
`3H), 3.0 (:1 2H), 22 (5 31-1).
`la) Methyl
`3.3-bis-(2-methoxyphenyl)-pnopionnte
`(Vl1)wasobtninedintheean1ewayin96%yieldfron:
`thelactone(V)ofExnn1ple1t),n:.p. 84-'-
`' (IPE).
`C|sH2o04 (300.4) requires: C. 71.98; H. 6.71; O. 21.3,
`Found: C, 71.4; H, 6.67; O, 21.6.
`c) Methyl 3-(1.3-dI'benzyIoxyphenyl)-3-phenyiprm
`pionete(VlII)wuobtainedinasin:ilarwayinqumIita-
`tiveyieldfi'ointhelIctone(IV)ofExample le)and
`be-nzyl chloride in n:ethanoL In addition to K2003 the
`(r:aetionmixmrealsoeontainedsomeNal.M.p.72'
`PE).
`C3oHza04(452.5) requires: C, 79.63; H. 6.24; O, 14.14,
`Found: C, 79.9; H, 6.15; O. 14.1.
`:1) Methyl 3-(2-benzyloxypheny1)-3-pheny1ptopion-
`nte(IX)wasobtainedinasi:ni1nrwayaeaviscousoi1in
`81% yield from 4-phenyl-3,4-dihydrocomneiin end
`henzyl chloride.
`.
`21-Nhgk: 8 7.2 (In 141'-I), 4.9 (5 2H, t 1H), 3.5 (3 3H), 3.0
`.
`1:) Methyl 3-(2-methoxy-5-niethylphenyl)-3-phenyh
`propionate(X)wasobtninedinasimilarwayfrom6-
`methyl-4-phenyl-3,4-dihydrocoumarin in 96% yield.
`NMR: 8 7.4 (in 81-1), 5.0 (t 11-1), 3.9 (s 3H), 3.7 (s 3H),
`3.2 (d 2H), 2.4 (3 31-1).
`
`(t
`
`NMR: 15 &6-1.1 an 51-1), 5.1 (1: 11-1.), 3.1 (3 61-1), 3.5 (s
`3_I-I), 3.0 (d 21!), 2.2 (3 61!).
`g) Methyl 3-(2,5-dihenzyloxyphenyl}~3-phenylpro-
`pionnte(XII)wasobtainedinnsimi1nrwayin90%
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2053 - 0006
`
`

`
`11
`water. dried. and evaporated giving 71 3 (91%) of an oil
`which crystallized on standing. Recrystallization from
`IPE-PET gave white crystals, mp. 83'.
`Cr.-I-1:001 (256.4) requires: C, 79.65; 1-1, 7.88; O, 12.48,
`Found: C. 79.4; H. 7.89; O. 12.7.
`b) 3,3-Bis-(2-tnethoxyphenyl)propanol (XVII) was
`obtainedinasianilarmannerinquantitativeyieldasa
`viseousoi1£romtheester(VII)ofExample2b).
`c)
`3-(2.3-Dibenzyloxyphenyl)-3-phenylpropano!
`(XVIII)wasobtainedinasimi1arwayasavisoousoilin
`96% yield from the ester (VII) offixample 2e).
`(XIX)
`d) 3-(2-Benzyloxyphenyl)-3~phenylpropanol
`wasohtainedinasimilarwasmanoilin78% yieldfrom
`the ester (IX) of Example 2d).
`e) 3-(2-Methoxy-5-methylphenyl)-3-phenylpropanol
`()G()wasohtained inaslmilarwayssan oilinquantila-
`tive yield from the ester (X) of Example 2e).
`NMR: 8 6.8-7.4 (1.11 71-1), 4.7 (t 1H), 3.8 (5 31-1), 3.7 (m
`21-1), 2.3 (s 3H), 2.0-2.3 (a: 21-1).
`1)
`3.3-Bis-(2-methoxy-5-methylphenynpropanol
`(XXI)wasobtainedinasin1i1arwayin98% yieldfrom
`theester (XI) offixample 20. M.p. 89‘(IPE).
`C19Hz-I03 (300.4) requires: C, 75.97; H, 8.05; 0. 15.98,
`Found: C, 75.9; H. 8.02; O, 16.1.
`3)
`3-(2.5-Dihenzyloxyphenyl)-3-phenylpropanol
`(XXII)wasobtah1edina|imilarwayin88% yieldfrom
`the ester (XII) of'Eaamp1e 2g). M.p. 78' (IP13).
`C2sH2s03 (424.5) requires: C, 82.05; H, 6.65; O, 11.31,
`Found: C, 82.0; H, 6.62; O, 11.2.
`11)
`3,3-Bis-(2-benzyloxy-¢-1nethylphenyl)propano1
`(XXI.ll)wasobtainedinasimila:‘\vayasanoilin93%
`yieldfromtheester(XIII)oi'Examp1e2h).
`i)
`3-(2,4-Dimethoxyphenyl)-3-phenylpropanol
`(XXIV)wasolmineduagoladenoilin92%yieldfrom
`the star (XIV) of Example 2:’).
`NMR: 8 6.5-7.2 (m 811). 4.5 (t 11-1). 3.8 (s 6H), 3.6 (m
`211), 2.0-2.6 (in 31-1).
`(XXV)
`j)
`3,3-Bis-(2,4-dimethoxyphenyl)propanol
`wasobtainedinaaimilarwayfromtheimpureester
`(XV)ofE.u.mp1e2j).ByNMR,theprodnctcontains
`about 20% of dimethyl resorcinol.
`1:) 3-(4-Flnorphyl)-3-(2-niethoxypheuybpropanol
`
`5
`
`I0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`A Grisnard reagent was prepared in the usual man-
`nerfromo-brounoanisole (93.5g.O.5:no1) andma3ne-
`um(I2g,0.5n1o1)inl00mldryether. Aaolniionof
`p-lluorobenzaldehyde (62 g, 0.5 mol) in III) In! ether
`wasaddeddropwisetothisao1ut:ion.Afierabout1h,
`themixturewasdecomposedwithNI-Igclandworked
`up, giving 100.6 3 (87%) of 4-l'luoro-2’-metl1oxy-
`dipheuylmethanol. Recrystallization from IPE-PET
`gave white crystals, 111.1). 88'.
`Cu!-1131302 (232.3) requires: C. 72.40; H, 5.64, Found:
`C, 72.9; 1-1. 5.75.
`'I'heohtainedcarbinol(46.2g,0.2mol)in6C0Inl
`ethann1washydrogenatedinthepreaeneeof4gof5%
`Pd/Ccatalyst. A.fierahout5-6h,thereactionwaseom-
`pIeteandthemixtu.rewasworl:edupgivh1g40g(93%)
`of 4-fluorc>2'-methoxy-diphenylmethane as a clear oil.
`NMIR: 6.8-7.2 (in 8H), 4.0 (s 2H), 3.8 (s 31-1).
`The obtained methane derivative (71 3. 0.33 mol) in
`l0Omletherwasaddedtoaso|utionofNa.N1-Izpa-e-
`paredinaitufromsodium (8.5 g,0.37moI)inabont3(.'0
`mlofhll-I3. Afterabont I h,asolntionofethy1encoxide
`(17.5 g. 0.395 mol) in 75 ml ether was added dropwise.
`'I'hen1iJ:tnrewasstin'edfor2h.and:nostofthea:nn1o-
`niawasthenreanoved withastreamofair. So1idNH4Cl
`wasthenadded, followedbytheaddition oi'water.'I'he
`
`45
`
`50
`
`55
`
`- so
`
`65
`
`5,382,600
`
`12
`organic phase was separated, washed with water and
`2N I-1C1. dried and evaporated, giving 81.5 g (95%) of
`the title compound. M.p. 61' (IP12-3-PEI‘).
`C|6H:1FOz (260.3) requires: C, 73.82; H. 6.58. Found:
`C, 74.1; H, 6.77.
`l) 3-(5-Chloro-2-tnethoxyphenyl)-3-phmylpropanol
`The ester from Example 21:) (91.5 g. 0.3 nml) in 500
`mldryetherwasaddeddropwiseundernitrogento
`LiA1H4(ll.4g.0.3 mol) in 200mld1-yether. Themix-
`turewasstirredatroomtemperanireovemightnhen
`decomposed with 11g water and 11 g 15% NaOH
`solution. Work up gave 72.5 g (87.5%) colourless oil.
`Recrystal1izaIion&omIPEgavewhitecrystalsofthe
`title compound, mp. 80'.
`CI6Hl7C101 (276.8) requires: C, 69.43; H, 6.19; CI,
`12.81, Found: C, 70.1; 1-1, 6.44; CI, 12.9.
` 4
`
`Preparation of 3.3-diphenylpmpyl-p-toluene
`snlphonaies
`
`a) 3,3-Bis-(2-methoxyphenyl)pmpyl-p-toluene sul-
`phonate (XXVII)
`The propane! (XVII) offixample 3b) (35 3. 0.128
`mol)in10Dmlch1orofoa-mconlainingiioml pyridine
`wasoooledtoabont -10’ andthentrea:tedwithp-tol-
`uene sulphonyl chloride (29 3, 0.15 mol). After standing
`inthecoole:-(about +5‘ C.)overnight.the:ni:xturewa
`poured into ice-water, the organic phase was washed
`withwaterandoold2N1-1C1,d|-iedmndthesolventwas
`distilledoffat <50‘C.,givingacrndeoi1inquantita-
`dveyie1d.Rec.rystalliution from IPE3ave white crys-
`tals of low and indefinite m.p.
`Cz4Has0sS (426.5) requires: c, 67.58; H, 6.14; s, 7.52,
`Found: C, 66.8; H, 6.22; S, 7.76.
`b) 3(2-Meth9xv4-methylphenvl)-3_-pheny!pmpyl-p-
`toluene anlphunate (XXX!) was obtained in quantitative
`yidd from the propane] (XVI) of Example 3a).
`c) 3-€2.3-Dibenz3*loxyph=1v!)-3-phenv1:!ropy1-p-to1-
`uene sulphonate (XZXVIII) was obtained in a similar
`wayasathiel:oilin88%yieldfromthepropanol
`(XVIII) of Example 3c).
`d) 3-(2»Benzy1oxvpheny|)-3-phenylproprl-p-toluene
`sulphonate(XX1X)wasobtainedinisimilarwayin
`98% yield from the propane! (XIX) of Example 3d).
`e) 3(2-Methoxy-5-mcthylphwyb-3-phenvlpropvl-r
`to1uenesulphonate(XXX)w-asobtainedinquan'
`'
`yield ftomthepropanol (JD!) ofExa:np1e3e). M.p. 64'
`(IPE-PET).
`C231-114048 (396.5) requires: C. 69.67; I-I, 6.10; S. 8.09,
`Found: C. 69.8; H, 6.20; S. 7.85.
`1) 3,3-Bis-(2-methoxy-5-methylphenyi)-propyl-p-to1-
`uene sulphonate (XXXII) was obtained in quantitative
`yield from the propane] (XXI) of Example 31). M.p.
`117' (acetone-PET).
`Cz6H300sS (454.5) requires: C, 68.7; H, 6.65; S. 7.05,
`Found: C, 68.8; H, 6.66; S, 7.11.
`s) 3-(2.s-D:1:enzy1oxyphenyl)-3-phenyIpro:>vl-p-to1-
`uene sulphonate (XXXIII) was obtained in a similar
`mannerinquantitativeyieldfrom thepropanol (XXII)
`of Example 33).
`h)
`3.3-Bis-(2-benzy1o:y-4-metlIy1phenyl)-propyl-p-
`toluene sulphouate (XXXIV) was obtained in a similar
`\v.lra33il::)86% yield fromthepropanol(XXIII)ofExam-
`p e
`.
`i)
`3-(2.4-Dimethoxyphen:rl)-3-pheny|pcropyl-p-tol-
`nenesulphonate(XXXV)wasinthesan1eway obtained
`in96%yie1dl‘romthepropanol (XXIV')ofExamp1e 3i).
`
`' Patent Owner, UCB Pharma GmbH — Exhibit 2053 - 0007
`
`

`
`5,382,600
`
`'
`14
`NMR: 6.9-7.2 (11: 181-1). 5.0 (s 4H), 0.9 (d 12H).
`c) N,N-Diisopropyl-3-(2-methoxy-5-methylphenyl)-
`3-phenylpropylamine (XL), hy
`'1'11efreebascwasobIainedin69%yie1dfromthe
`tosylate(XXX)ofE.xample4e).Itwasconver1aedtothe
`fumaricacidaaltintheusualmanner. M.p. 176' (ace-
`tone).
`C211-I3-;NO5 (455.7) requires: C, 71.17; H, 8.20; N,
`3.07; O, 17.6, Found: C, 71.3; H. 8.27; N, 3.04; 0. 17.9.
`d) N,N-Diiaopropyl-3-(2-Inethoxy-4-methylphenyl)-
`3-phenylpropylalnine (XL1), hydrogenfmnarate
`'I'hefreebasewasobtainedin25% yicldfiromthe
`tosy1ate(X.‘XXl) ofExample4b). Thefumaric acid salt
`had m.p. 147'-148' (acetone).
`C2-,-I-I3-;N0s (455.7) requires: C, 71.17; H, 8.20; N,
`3.07; O, 17.6, Found: C, 71.3; H. 8.14; N, 3.1!); O, 17.6.
`e)
`N,N- "
`1-3,3-bis-(2-methoxy-5-methyl-
`phenyl)p1-opylamiue (XLII). hydrochloride
`'I'hefreebasewaaobtainedin78%yieldfromthe
`tcsylate (XXXI1) of Example 41). It wu converted to
`thehydroehloridewithedierealHClintheususalman-
`ner. M.p. 163'-164' (acetone-ether).
`Cz$H38N02Cl (420.1) requires: C, 71.49; H. 9.12; N.
`3.33; O, 7.61; Cl, 8.44, Found: C. 71.6; H, 9.08; N. 3.27;
`O. 7.93; CI, 8.36.
`1)
`N,N-Diifi0P1’°PYl-3-(2,5-dibenzy1oxyphenyl)-3-
`phenvlpropylamine (XL!!!)
`The free base was obtained in 70% yield from the
`tosylate (XXXIII) of Example 4;).
`NMR: 8 5.6-1.2 (:1: 181-1). 5.0 (a 41-1), 4.5 (1: 1H), 1.0 (:1
`121-1)
`g) N.N-Diisopropyl-3,3-bis-(2-benzyloxy-4-n:ethy1—
`phenmpropylamine (xLlV)
`Thefreehaaewasobtainedin62% yieldfromthe
`toaylate (XXXIV) of Example 411).
`
`r~1)'1t1R:6r6.]‘8q-7.2(nr161-I),l3..I3'a4I-I,tIH), 0.9£1“3:13).-
`
`I
`
`I.
`
`13
`3,3-Bis-(2,4-dimethoxyphenyl)-propyl-p-toluene
`j)
`sulphonate (XXXVI) was obtained in the same manner
`from the propanol (XXV) of Example 3j). The product
`was contaminated with dimethyl reaorcinol.
`1:) 3-(4-Fluorphenyl)-3-(2-methoxypheuyl)-propy1-p-
`toluene sulphonate
`was obtained in a similar
`way in 88% yield from the propano1(XXVI)ofExam-
`pl: 31:). 111.1). 67' (IPE).
`C23H23FO45 (414.5) requires: C. 66.65; 1-1. 5.59; S.
`7.74. Foimd: C, 67.1; I-1, 5.69; S, 7.78.
`I)
`3-(2-Methoxyphenyl)-3-phenylpropyl-p-toluene
`sulphonate (XLVIII)
`A mixture of amiaole (1080 3, 10 mol), benzyl alcohol
`(216g,2mol)andp-tc1nenesulphonicaca‘d(40g)was
`refluxedforzhinanapparatnsequipped withawater
`separator. Bxceaofaniaolewasthendistilledollithe
`oilyresidue wasdissolved in ether, washed withwatcr
`and sodium carbonate, dried and fractionated. giving
`304 g (77%) of a pale yellow oil. b.p. 115'-113'/0.4
`'I‘orr.ByN1\¢IR,itisa1:1mixtureofo-methoxyand3°
`p-methcaydipheuylmethane.1'hismaterialwasc¢m-
`vu'te_dtoa_nn:un'eofthe_correspoudingpropano1sby
`reacuonw1thethyleceondae,asinthepreparationof
`thepropanol(XXVI)ofExample3k).Thiamixtureof
`. propanolswasthenconvertedasdeacrihedabovetoa
`mixture of p-toluene sulphonates from which the title-
`compoimdcou1dbeiso1atedin35%yie1dafhertwo
`recrystallimtions from IPE. M.p. 108°.
`C23Hu0a5 (3965) requires: C, 69.67; H. 6.10; s, s.o9,
`Found: C, 69.3; H, 6.00; S. 8.17.
`m) 3-(5-C1:loro-2-mcthoxypheny1)-3-pheny1propyl-p-
`toluene sulphouate
`'I11ealcoho1l'romExample3l)(66g,0.24mol)in300
`ml chloroform containing 75 ml pyridine was treated
`porfionswiaeinthecoldwhhp-mlueneeulphmylchlo
`ride(55g.0.29moI).'I'hemixturewaskeptat5'C.for
`l8h.aolventwaaevaporatedundervaemunat <50‘,
`theresiduewastakenupinethenwaahedwithwater
`and2NHC1,driedandevaporatedgiving100g(97%)
`of a straw-yellow syrup.
`'
`' n from IPE
`ave the title compound, in.p. 89'-90’.
`Cz3!iz;<C1O4S (430.96) requires: C, 64.10; H, 5.38; S,
`7.44; Cl, 8.23, Found: C, 64.4; H, 5.45; S, 7.04; CI, 8.17.
`EXAMPLE 5
`
`5
`
`25
`
`30
`
`35
`
`40
`
`45
`
`I
`
`y
`' _n..
`h
`Phenvlnromrlamine (XI-V)
`The free base was obtained in 56% yield firm: the
`toaylate (xxxv) of Example 4;)
`NMR: 6.5-7.3 (m 8H), 4.4 (t 11-1), 3.8 (5 61-1), 1.0 (d
`12H).
`1) N.l‘i-Diiaopropyl-3,3-his-(2.4-dimethoxyphenyl}
`proprlmmne (XI-V1)
`'I'hefreehasewasobtainedin34%yie1dfromthe
`toaylate (XXXVI) of Example 4j).
`NMR: 8 6.5-7.3 (in EH), 4.6 (t 1H), 3.9 (3 121-1), 1.0 (cl
`121-1).
`1') N.N-DiiIoprv9py|-3-(4—flnorophenyD-3-(2-methox1r-
`phenynpropylamme XLVII)
`Thefreebaaewaaobtainedin71%y'le1dfnomthe
`tosylate (XXXV11) of Example 41:).
`1:) N,1tI-Di'uopropyl-3-(2-methoxypheny1)-3-phenyl-
`propylamme (XLIX), hydrogen firmarate
`The free base was obtained in 86% yield from the
`tosy1ate(XLVIII)ofEr.1unple4l)andwasconvertedto
`the thmaric acid salt in the usual way. M.p. 134‘-136'
`(acetone-IPE) or 163'-164' (methanol).
`C26H36N0s (441-5) T009513: C. 70-72: H. 7-99; N.
`3.28; O, 18.11 Found: C, 70.8; H, 7.93; N, 3.28; O, 18.1.
`1) N-(3Q-M=}h0xYn|wn¥|)-3-PhfiIY|Pr0P¥l)-2.2.6.6-
`tetrainethylpipendine (LXIV)
`Thiscompoundwaaobtainedintheaamewayin54%
`y'leldfi'omthetosy|ate(XLVIll)ofExample4l)and
`2.2.6.6-telzramethylpiperidine. M.p. III)’ (IPE).
`C25H3$NO (355.6) require: C, 82.14; H, 9.65; N, 3.83,
`Found: C, 82.0; 1-1, 9.62; N, 3.57.
`
`Preparation oftertiary 3,3-diphenylpropylamiues
`_ N.N—