Note: Descriptions are shown in the official language in which they were submitted.
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AZETIDINONE DERIVATIVES FOR THE TREATMENT OF ATHEROSCLEROSIS
The present invention relates to certain novel monocyclic ~-lactam compounds,
processes for their preparation, intprmçdi~tps useful in their p~ ;rtn,
5 ph~rm~çt:l.l;ç~l compositions co~ h~ g them and their use in therapy, in particular in
the tre~tment of atherosclerosis.
Lipoprotein Associated Phospholir~sP A2 (Lp-PLA2). The sequence of the
enzyme, the i.col~tion and purifi~tit)n thereof, i~ol~t~d nucleic acids çnroriing the
enzyme, recombin~nt host cells transformed with DNA enro i;"g the enzyme are
IlPsrrihed in patent ~pplir~ti,.n WO 95/00649 (.~mithRlinP P~eerh~m plc). Sug~Pst~d
thr. t~pc~"l ;~ uses for inhibitors of the enzyme inrllldPd atherosclelosis, ~ etPs~
rhrllm~toi~l arthritis, stroke, myocardial infarction"c;pelfu~ion injury and acute and
chronic infl~mm~tion A later patent applir~tion (WO 9S/09921, Icos Corporation)
and a related publication in Nature (TjoeL~er et al, vol 374, 6 April l99S, 549) desa-ibe
lS the same enzyme, ~lsholloh calling it by the name 'Platelet Activating Factor Acetyl
Hydrolase' (PAF acetyl hydrolase) and suggest that it may have potential as a
therapuetic protein for regulating pathological infl~mm~tnry events.
Lp-PLA2 is responsible for the conv~l~ion of phosph~titlyl~holinP to
lysophosphatidylcholinP during the conversion of low density lipoploleJ,~ (LDL) to its
oxidised form. The enzyme is known to hydrolyse the sn-2 ester of oxi-iioed
phosph~ti~ylcholine to give lysophosph~ti~iylcholine and an oxidatively morlifiPd fatty
acid. Both products of Lp-PLA2 action are biologically active with
lysophosph~ti~lylcholine, a component of oxidised LDL, known to be a potent
rhrmo~ttT~rt~nt for circ~ ting monocytes. As such, lysophosph~tiflylcholine is
thought play a signifir~nt role in atherosclerosis by being responsible for the
~cc~lmnl~tion of cells loaded with rholPst~rol ester in the arteries. Inhibition of the Lp-
PLA2 enzyme would the.ef~-~ be expected to stop the build up of these macrophageçnrirhçd lesions (by inhibition of the form~tion of lysophosrh~ti-lylrholinP- and oxi~;~Pd
free fatty acids) and so be useful in the tre~tmpnt of atherosclerosis.
The increased lysoph~-.crh~tirlylçhQlinP content of oxidatively modified LDL is
also thought to be responsible for the endothP~ dy~ nrtion observed in patients with
atherosclerosis. Tnhibitors of Lp-PLA2 could therefore prove bpnpfiri~l in the
tre~tmçnt of this phenomenon. A Lp-PLA2 inhibitor could also find utility in other
disease states that exhibit endothelial dysfunction inç~ ing diabetes, h~liel sion,
angina pectoris and after i.sch~Pmi~ and reperfucion
Lp-PLA2 inhibitors may also have a general application in any disorder that
involves activated monocytes, macrophages or lymphocytes, as all of these cell types
express Lp-PLA~. Examples of such disorders include psoriasis.
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Lp-PLA2 inhihitors may also have a general applir~tif)n in any disorder that
involves lipid pero~i-htinn in co~ ;on with Lp-PLA2 activity to produce the two
injurious products, lysophosphi~t1'lylch~ np and o~cidatively modified fatty acids. Such
conflition~~ include the aforPmPntinn~d con~ition~A ath~l~oscl~.usis, diabetes, rhPIIm~~~~id
S arthritis, stroke, infl~~mm~tnry con~iticm.~ of the brain such as ~l7hPin~Pr's Disease,
Illyoc~dial infarction, ~ r .~ injury, sepsis and acute and chronic inflA.. z~lion
Further such con~litinn~~ include various llt;ulop~yclliatric disorders such as
schizophrenia (see Psychorhi rn~.~ro1ogy Bulletin, 31, 159 165, 1995).
We have now it1entifiPd a series of compounds which have been found to act
10 as inhibitors of Lp-PLA2.
Accordingly, the present invention provides a compound of fo~n
R2 Z-R3
R'
o~N~cR4Rs_X--Y (I)
in which:
15 R1 and R2, which may be the same or different, is each ~lPcted from hydrogen, halogenorC(1 g)a1kyl;
R4 and R5 which may be the same or dirre~ is each ~l~cte~l from hydrogen, C(l
6)alkyl, C(2 6)alkenyl, aryl, aryl(Cl 4)alkyl and heteroaryl(C 1 4)alkyl each of which
may be optionally ~..b~ d or R4 and R5 may be linked together to form the
20 rçm~in-ler of a (C3 7)cycloalkyl ring;
X is a linker group;
Y is an optionally sllhstitl-t~ aryl group;
Z is oxygen and R3 is C(1 g)a]kyl, C(3 g)cycloaLkyl, C(3 g)cycloaL~cylC(l 6)alkyl,
heteroaryl, heteroaryl(C 1 ~)alkyl, aryl, or aryl(C 1 4)aLkyl, each of which may be
optionally substituted or Z is S(~)n in which n is 0, 1 or 2 and R3 is C(1 g)aLkyl, C(3
g)cycloaL~yl, C(3 g)cycloaLkylC(l 6)allyl, aryl, aryl(Cl 4)aLkyl, he~lualyl, or
heteroaryl(Cl 4)aLkyl, each of which may be optionally substi~llt~-d and
.oy~lnAing compounds in which:
X is a direct bond; a group Xl(CH2)m in which xl is CO, CONR6, COO,
CONR6CO, or CONR6O in which R6 and m are as hereinbefore (1~fin~tl or a C
12)alkylene chain optionally in~lu~Jtcd by Xl;
Z is S(~)n in which n is 0, 1 or 2 and R3 is C(1 g)aLkyl, C(3 g)cycloalkyl, C(3
g)cycloaLkylC(l 6)alkyl, aryl, or aryl(C 1 4)alkyl, each of which may be optionally
sllbstihlt~d; and
R4 and RS is each hydrogen.
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Suitably, X is a direct bond; a group X1(CH2)m in which xl is CO, CONR~j,
COO, CONR6CO, or CONR60 in which R6 is hydrogen or C(1 6)alkyl and m is 0 or
an integer from 1 to 12; a group (Xl)aX2 in which a is 0 or 1 and x2 is a C(l
12)aL~cylene chain illL~lu~L~d andtor tçrrnin~ted at the end ~ Pnt to Y by one or more
groups X3 sçlPct~pd from O, S(O)x, NR6, alkene or aL~cyne, in which ~c is 0, 1 or 2; or a
C(1 12)aL~cylene chain optionally ul~lup~d by Xl.
Suitable sub-sets of co l.p~u.lds within fom~ (I) include those in which:
(a) X is a direct bond; a group Xl(CH2)m as herçin~,fore ~efin~ a group (Xl)aX2
as hereinbefore ~lefinP~l or a C(1 12)alkylene cham optionally L~ u~Led by Xl;
Z is oxygen and R3 is C(1 g)alkyl, C(3 g)cycloaLkyl, C(3 g)cycloalkylC(l 6)alkyl,
hetelual yl, heteroaryl(Cl ,I)aL~yl, aryl, or aryl(Cl 4)alkyl, each of which may be
optionally substituted or Z is S(~)n in which n is 0, 1 or 2 and R3 is h~le...~l or
heteroaryl(C l 4)aL~yl, each of which may be optionally s~,b~
R4 and R5 are as hereinbefore defin~; or
15 (b) X is a direct bond; a group Xl(CH2)m as hereinbefore dPfinPd a group (Xl)aX2
as her~inhPfore ~lefin~tl or a C(1 12)alkylene chain optionally il.L~.upLed by Xl;
Z is S(~)n in which n is 0, 1 or 2 and R3 is C(1 g)aLkyl, C(3 g)cycloaL~cyl, C(3g)cycloaLlcylC(l 6)alkyl, aryl or aryl(Cl 4)aL~cyl, each of which may be optionally
~u~l;l..l~d;
R4 and R5 which may be the same or dirr~ is each sPl~ct~d from hydrogen, C(l
6)aLkyl, C(2 6)aL~enyl, aryl, aryl(Cl 4)alkyl and heteroaryl(Cl 4)alkyl each of which
may be optionally sub.stitllted or R4 and R~ may be linked together to form the
rPm~in(lPr of a (C3 7)cycloalkyl ring, with the proviso that R4 and R5 are not both
hydrogen; or
(c) X is a group (Xl)aX2 as hereinbefore cl~fin.~d:
Z is S(~)n in which n is 0, 1 or 2 and R3 is C(1 g)alkyl, C(3 g)cycloaLkyl, C(3
g)cycloalkylC( 1 6)alkyl, aryl or aryl(C 1 4)aL~yl, each of which may be optionally
substit~lt~d; and
R4 and R5 is each hydrogen.
Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expecled
to be of use in treating atherosclerosis and the other disease con~litionc noted above.
Representative eY~mples of R1 and R2 include hydrogen, bromo, methyl and
ethyl. Suitably, Rl and R2 is each hydrogen or one of R1 and R2 is hydrogen and the
other of R1 and R2 is methyl (to give a trans-methyl). Preferably, R1 and R2 is each
3~ hydrogen.
Reprçsent~tive values for when R3 is aryl(C 1 4)aL~yl include arylC(1 3)alkyl.
Within this, representative examples of the aryl group include phenyl and nap},Lhyl.
Suitable examples of R3 include benzyl, 2-phenylethyl and 3-phell~lplo~J~l in each of
which the phenyl ring may be optionally substituted by up to three sub~ e~
- 3 -
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Suitable ~ .e~ ; for a phenyl or nap}~ yl nng in R3 include halo, hy~uAy, C
6)aL~CYl~ C(l 6)alkoxy~ c(l-6)aL~l~Aycdlbonyl~ C(2 6)alkenyluAy~allJollyl~ Cal~Ay,
carboxyC(1 6)aLI~yl and C(1 6)aL~uAy~u~ ylc(l-6)alkyl- More pl~r~-~ hly~ R3 is
carboxybenzyl or a colle~onding C(1 6)alkyl or C(2 6)alkenyl ester thereof.
Repl~se~ ive eY~mrlPs of the aryl group for when R3 is aryl include phenyl
and naphthyl. Preferably, the aryl group is optin~ y ~ I;l-.e-l phenyl. Suitable.sllbstitnent~ for a phenyl or naphthyl ring include halo, hy~llo~y, C(1 6)aLkyl, C(l
6)aLk~XY~ C(1-6)aLh~Y~UI~OnYL C(2 6)a1kenY1~AY~~ Y1~ AY~ C~I~AY~(1-
6)aLkylandC(1 6)alh"~yc ~IYlc(l 6)aLkYL
ReprecPnt~tive eY~mplP-s for R3 when R3 is C(1 g)alkyl, C(3 g)cycloalkyl or
C(3 g)cycloa~ylC(l 6)aL~cyl include methyl, n-butyl, t-butyl and n-hexyl, cyclohexyl
and cyclohexyl methyl, suitably n-butyl, t-butyl or n-hexyl. .Suit~hlP subs~;l..el~ for
the aLIcyl or cycloaLkyl group in R3 include halo, hydroxy, C(1 6)aLkyl, C(1 6)aL~o~cy,
C(1 6)aLko~ycalbollyl, C(2 6)aL~enyloxycarbonyl, carboxy, carboxyC(1 6)aL~cyl and
C(1 6)a~ yc~l,onylc(l 6)alkyl.
Further lc~plesen~tive values for R3 include helel~ ylC(l 3)aLkyl, plt;re,~.bly
heteroarylmethyl. Representative PY~mrlps of the he~lo~ylaryl group for use in R3
include pyridyl, pyridyl N-oxide, furanyl, thienyl and thiazolyl. Suitable ~ubsl;~
for a heteroaryl ring in R3 include halo, hydroxy, C(1 6)aL~cyl, C(1 6)alkoxy, C6)alkoxycarbonyl, C(2 6)aL~enylo~y~l,onyl, c~l~ y, carboxyC(1 6)allyl and C
6)alk~ Y~ ol'ylc(1 6)aL~yl.
It will be appreciated that within R3, an optional ~,..'~,l;l..~..~ may be located in
the aLkyl, cycloaLkyl, aryl and/or h~loalrl por~ion. Preferably, the ~.u~ e~tiS
carboxy or a C(1 6)alkyl or C(2 6)alkenylester thereof.
Preferably, R3 is arylC(1 3)alkyl or heteroarylC(l 3)alkyl, more preferably
arylC(1 3)aLkyl, most preferably benzyl, whicn may be optionally ~ b~.l;lul~ in
particular by a carboxy group or a C(1 6)aLkyl or C(2 6)aL~cenylester thereof.
Preferably, Z is S(O)n. Preferably, n is 1 or 2, more preferably 1.
Preferably, S(o)nR3 is opdonally sllbstihled ben~y~ rhinyl7 more preferably
4-carboxybenzylclllphinyl or a C(1 6)aL~cyl or C(2 6)aL~enylester thereof.
Repl~selltative ex~mpl~s of R4 and R5 when an alkyl group include methyl,
ethyl and propyl. Representative P~mplps of a C(2 6)alkenyl group include allyl.Representadve e~c~mrlPs of a (C3 7)cycloalkyl ring include cyclopropyl.
Repres~nt~tive e~r~mplP~ of aryl(Cl 4)aL~yl and heteroaryl(Cl 4)a'~yl include benzyl
and furylmethyl, respectively. Replt;se--L~Liv~ eY~mple-s of R4 and R5 when aryl or
araLkyl include phenyl and benzyl. Suitably, R4 and R5 are both hydrogen or R4 is
hydrogen and R5 methyl.
Representative eY~mplPs of X include CO(CH2)m, CONH(CH2)m,
COO(CH2)m, CONHCO(CH2)m, CONHO(CH2)m and C(l 12)alkylene. Preferably,
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x1 is CO or CONR6, more preferably CONH. Preferably, m is 1, 2, 5, 6, 7 or 9,
prP.fP.r~bly 6.
Further ieplc;sel,L~tive ey~mplps of X include X4(CH2)pCH~H(CH2)q~
X4(CH2)pC_C(CH2)q or X4(CH2)p(0)r(CH2)q(0)S in which X4 is a direct bond or
S CONR6, p is an integer from 1 to 12, q is 0 or an integer from 1 to 12 such that p+q
12, suitably < 6, r is 0 or 1 and s is 1 or r is 1 and s is 0, with the proviso that if r ancl s
are both 1, then q 2 1. In preferred eY~mrlf~s in this subset of compounds, X isCONR6(CH2)4C=-C or (CH2)0(CH2)6-
Preferred e-Y~mplPsc of X include CONH(CH2)6, CONR6(CH2)4C=C and
(CH2)0(CH2)6
Suitably, Y is a benzene ring, optionally sub~ L~ d by up to three further
substitll~f~-nt.c. Suitable substitllent.c include halo, hydroxy, C(1 g)aLkyl and
C(1 g)aLkoxy. Preferably, Y is phenyl optionally s~bstit--tf~d by halo.
Useful combin~tiQnc of ~.ub~ e~ i for compounds of formula (I) which are
f~Yemrlifif~.d herein are sllmm~r~ in the following table:
R3 R4 R~ X
1 carboxy- hydrogen methyl CONH(CH2)6
benzylsulfinyl
5-carboxyfuran-2-hydrogenhydrogenCONH(CH2)6
methylsulfinyl
bel~ybulfinylhydrogenhydrogen(CH2)0(CH2)6
benzylsulfinylhydlugellhydlugellCONR6(CH2)4C=C
Compounds of formula (I) in which the group R3 incorporates a carboxy
substitllent are generally found to have illlpl~lved activity against the target enzyme in
20 in vivo models, in particular, a superior ability to inhibit plaque ~c.c~i~te~l Lp PLA2.
In such studies, it is however found that such compounds have better pharmacokinP.ti~
plupelLies if initially ~min.ctered as an aLkyl or alkenyl ester 'pro-drug'. The ester
grouping is then rapidly hydrolysed in the liver to release free carboxyl. Generally,
compounds with an a -methyl sul,~ ent that is those in which one of R4/R5 is
25 methyl are more potent than the corresponding des-methyl compounds.
It will be readily appleciat~d by the skilled person that C-4 of the ~-lactam ring
is a chiral centre which will give rise to the presence of stereoisomers. The present
invention en~)mp~c.cP,s all such stereQi.comers. An ~dtliti()n~1 chiral centre will be
introduced when R4 and R5 are not the same. This will give rise to the PYi.CtP.nf P of
30 extra stereoi.comf~.r.c. The present invention encr mp~cces all such stereoi.colnPr.c
It will be further readily appreciated by the skilled person that, in compounds of
formula (I) in which n is 1, that is sulphoxide compounds, the presence of the SO
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moiety will introduce an ~d~itinnAl chi~al centre into the molPclllp- and the.~Çore give
rise to the eYi.ctPn~e of extra stereoicomPrC. The present invention ç~ p~c~rs aU
such stereoisomers.
In ~l~fell~d compounds of formula (1), the ~bsolllte configllr~tio~c at C-4 and
S the SO moiety are R and S respectively. In pl~rell~d col-lpou-lds of formula (I) when
R4=H, R5=Me, the absolute configuration at the cL-carbon ~to which R5 is ~tt~chPd)
isS.
When used herein, the term '~kyl' and similar terms such as 'aL~oxy' i...'l..tlP~ all
straight chain and brAn~hPd isomers. Re~ e--l~Liv~ PYr~ thereof include methyl,
10 ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-he~cyl.
Snit~lP~b~ e~ foranaLkylgroupin~ le,for~Y~mrl~ hAlogçn cyano,
az~do, nitro, carboxy, (Cl 6)aLIcoxycarbonyl, carbamoyl, mono- or
di-(Cl 6)aLkylcarbamoyl, sulpho, slllrhAmQyl, mono- or di-(Cl 6)a1~yl...~ lA...oyl,
amino, mono- or di-(C l 6)aLkylamino, acylamino, ureido, (C l 6)aLhl~y~ l,o.ly~.ll"o,
15 2,2,2-trichloroetho~y~cubonylamino, aryl, heleio;yclyl, hydroxy, (Cl 6)aLt~oxy,
acyloxy, oxo, acyl, 2-thienoyl, (Cl 6)aLkylthio, (Cl 6)aLkyl~ h;~yl, (C
6)aL~cyl~lllph-nyl, hyd~u~yi~ihlo, (Cl 6)aL~,Ayi...i~lo, hydrazino, 11Y~ JnQ~
b~.~ol.ydlu~ oyl, gu~ni~lin~ Amitlino and iminr)AlkylaIrlino.
When used herein, the term 'aryl' in~ Ps, unless otherwise defin~-l phenyl or
naphthyl optionally ~lb~ d with up tO five, preferably up to three ~b~ ,~,.l~.
Suitable ~,bs~ ~ntc for an aryl group in~lllde~ for eYAmpl~, halogen, cyano,
(C1-6)aLcyl, (C3-7)cycloaLkyl, (Cl-6)aLkoxy, halo(Cl-6)aLkyl, hydroxy, amino, mono-
or di-(C1-6)aL~cylamino, acylamino, nitro, c~l~y, (Cl-6)aL~uAycd.l,onyl,
(C 1 -6)aL~enylu~y~,~ l~nyl, (C 1 -6)aL~coxycarbonyl(C 1 -6)aLkyl, (C 1 -6)aL~ylc~,.ylo~cy,
carboxy(C 1-6)aLkyloxy, (C 1 -6)aLkylcarbonyloxy, (C 1 -6)aLkylthio, (C 1 -6)aLkylclllrhinyl,
(C1-6)aL~cylc~llphonyl, slllrh~moyl~ mono- and di-(Cl-6)-aL~cyl.slllrh~moyl, carbamoyl,
mono- and di-(C 1-6)aLlcylcarbamoyl, and heterocyclyl.
When used herein, the term 'heteroaryl' includes single and fused rings, each
ring suitably compncing up to four, preferably 1 or 2, he~.uato.ns each sel~ctecl from
oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring
atoms. A fused heteroaryl ring may include carbocyclic rings and need include only
one heteroaryl ring. Suitable fused ht:L~ ua,yl rings include bicyclic systems.
When used herein, the term 'heterocyclyl' inclll~es aromatic and non-aromatic
single or fused Angs comprising up to four hetero-atoms in the ring ~l~ct~ from
oxygen, nitrogen and sulphur and optionally substituted with up to three substihllontc
Suitably the hc~-u-;yclic ring compri~Ps from 4 to 7, preferably 5 to 6, r ng atoms. A
fused heterocyclic ring system may include carbocyclic rings and need only include one
h~u~yclic ring.
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fused heterocyclic ring system may include carbocyclic rings and need only include one
hele~ ,lic ring.
When substitntP~ a heteroaryl or a heterocyclyl group may have up to thr~e
substihlpntc Suitable such s~s~ ent~ include those previously mPntionP(l for an aryl
5 group as well as oxo.
When used herein, the terms 'halogen' and halo' include fl~lorinP., chlrJrinP.
bromine and iodine and fluoro, chloro, bromo and iodo, l~specLi~ely.
Preferred compounds of formula (I) inr~ e
[6-(4-chl~ ph~..ylhexyl)]-2-[~benzyl.c~llrhinyl-2-oxo~7Ptirlin-l-yl]propion~mill~p~ in
10 particular diastereoisomers lb, 2a and 2b, çspeci~lly isomer 2b;
(a-5,4-R,SS)-N-[6-(4-Fluorophenyl)hexyl]-2-[4-carbo~yl,en~l.c~llrhinyl]-2-
oxoazetidin-l-ylpropion~mide- and the corresponding allyl ester;
(+/-)-N-(6-[4-Chlorophenyl]hex-l-yl)-4-(3-furylmethyl.culrhinyl)-2-oxo~7P.ti-lin-l-
yl~ret~mifle. (diastereomer 2);
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(5-metho~ycarbonyl-2-furylmethyl.clllrhinyl)-2-
oxoazetidin-1-yl~r.et~mi-le (diastereomer 2);
N-[6-(4-Fluorophenyl)hex- 1 -yl]-~(5-allylo~y ,~1~onylfuran-2-methylthio)-2-
oxo~7P.ti-iin-l-yl~ret~mi~le;
N-[6-(4-Fluorophenyl)hex- l-yl]-4-(5-carboAyrulal~-2-methylsulphinyl)-2-
20 oxoazetidin-l-yl~ret~mi~le (Diastereomer 2) and the corresponding allyl and methy1
esters thereof;
N-(6-{4-Chlorophenyl}hexyl)-4-(S-carbo~yrul~l-2-methyl.clllrhinyl-2-oxo~7P.ti~lin-l-
yl)~ret~mkhP. (Diastereomer 2) and the corresponding allyl and methyl esters thereof.
N-[6-(4-chlorophenyl)hexyl]-t4-(4-carboxymethylphP.noxy)-2-oxo-~7Pti~lin-l -yl]-25 ~cet~micle;
N-[6-(4 Chlorophenyl)hexyl]-[4-(2-fluorophenoxy 2-oxo ~7P.ti~lin-l yl) ~cet~mi~1e
N-(6-(4-Chlorophenyl)hexyl)-(4-(4-allyl~y~,~ 1,onyl-methylphenoxy)-2-oxo~ 7.otiflin-
l-yl)~ret~mitlp
1-(2-(6-(~Chlorophenyl)hexyloxy)ethyl)-4-benzyl.cnlrhinyl-2-oxoazetidine
30 (Diastereoisomer 2);
1 -(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)~(4-ethoxycarbonylbenzylsulphinyl)-2-
oxo~7Pti~linP (Diastereoisomer 2); and
1 -(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4-henzyl.clllphinyl-2-oxoazetidine
~ (Diastereoisomer 2).
More plc~felled compounds include:
N-[6-(4-chlorophenylhexyl)]-2-[4-benzyl.cnll hinyl-2-oxo~7~.ti~in-l-yl]propior~mille,
in particular diastereoisomers lb, 2a and 2b, especi~lly isomer 2b(1);
(~-5,4-R,SS)-N-[6-(4-~luorophenyl)hexyl]-2-[4-carboxybenzyl.c~llphinyl]-2-
oxoazetidin-l-ylpropion~mi~le and the corresponding allyl ester;
-- 7 --
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W O 97/02242 PCT~EP96/02765
N-16-(4-Fluorophenyl)hex- l-yl]-4-(5-carbo~yru~-2-methyl.clllrhinyl)-2-
o~n~7Pti~1in-l-ylAretAmirle (Diastereomer 2) and the c-,l,c;sp~,nding allyl and methyl
esters thereof;
N-(6-{4-Chlorophenyl}hexyl) 4 (5-carbo~-yfulal~-2-methylclllrhinyl-2-o~n~7Ptitlin
5 Y1)A~'et~m;~lP (Diastereomer 2) and the cc,lresponding allyl and methyl esters thereof;
1 -(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)~benzyl.c--lrhinyl-2-o~o~7P.titlin~,
(Diastereoisomer 2);
1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl) 4 (4-eth~-ywl,ol~yll~l.~l.~..lrhinyl)-2-oYo~7Pti~iinp (Diastereoicom~r 2); and
10 1-(2-(6-(4-Chlorophenyl)hexyloxy)ethyl)-4-benzyl.clllrhinyl-2-~ xo~7Ptitlin~. (Diastereoisomer 2).
Since the compounds of the present invention, in particular compounds of
formula (I), are intPn~ed for use in phArm~ Al compocitionc, it will be ~ Prst~od
that they are each provided in sl~bst~ntiAlly pure form, for PYAmrlP at least 50% pure,
15 more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt
basis). Irnpure l~lepA.,1l;onc of the compounds of formula (I) may be used for
pl~,Odlillg the more pure forms used in the ph~rmAreuti~l CGIllpoS;lionc Althol-gh the
purity of intermP~iAtP compounds of the present invention is less critical, it will be
readily untl~prstood that the substAnti~lly pure form is preferred as for the COml)GUll~lC
20 of formula (I). Preferably, whenever possible, the compounds of the present invention
are obtained in crystalline form.
When some of the compounds of this invention are allowed to crystallise or are
recrystAllic~-i from organic solvents, solvent of crystAllicAtion may be present in the
crystalline product. This illvenLion inrluriPs within iB scope such solvates. SimilArly,
25 some of the compounds of this invention may be cryst~llic~Pd or recrys~llicecl from
solvents COI-IA;~ ~ water. In such cases water of hydration may be formed. This
invention in~ln~Ps within its scope stoichiometric hydrates as well as compoundsCOI-IA;~ O variable amounts of water that may be produced by processes such as
lyophilisAtion. In Ad~lition, different cryst~llicAtion con-iitior c may lead to the
30 form~tinn of dirre~ polymorphic forms of crystalline products. This inventionincludes within its scope all polymorphic forms of the compounds of formula (I).Compounds of the present invention are inhibitors of the enzyme lipop.oL~in
associated phospholipAcP A2 (Lp-PLA2) and as such are expected to be of use in
therapy, in particular in the tre~tmpnt of atherosclerosis. In a further aspect thel~rult;
35 the present invention provides a compound of formlllA (I) for use in therapy.The compounds of formula (I) are inhibitors of lyso~ho.cph~tirlylcholinP
production by Lp-PLA2 and may therefore also have a general application in any
disorder that involves endothelial dysfunction, for exAml)lP atherosclerosis, ~liA-he
h~l~el~ cio~, an~ina pectoris and after icchAPmiA and l~pelfu:jion. In addition,- 8 -
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compounds of formula (I) may have a general ap~ ir,n in any disol.ler that involves
lipid peroxirl~tion in conju.,clion with enzyme activit,v, for e~..r.lr m ~d~1ition to
conrlitinne such as atherosclerosis and ~ hetpe~ other co~ such as rhPnm~t~
arthritis, stroke, infl~mm~tory cQnrlitionC of the brain such as ~l7hPimefs Disease,
myocardial infarction, ~ P. ~l~sion injury, sepsis, and acute and chronic infl~mm~tif~n
Further such con~litinne include various n~u.~ ycl~ ic disol~el~, such as
scnizophrenia (see Psychoph~ ology Bulletin, 31, 159-165, 1995).
Further applir~tionc include any dLso ~er that involves activated monocytes,
macrophages or lymphocytes, as all of these cell types express Lp-PLA2. F~mplps of
such disorders include psc-ri~cie
Accordingly, in a further aspect, the present invention provides for a method oftreating a disease state ~ceoei~tP~I with activity of the enzyme Lp-PLA2 which metha,d
involves treating a patient in need thereof with a thP.,.~ lly effective amount of an
inhibitor of the enzyme. The disease state may be associated with the il~leased
involvement of monocytes, macrophages or lymphocytes; with the form~ti~n of
lysophoerh~tidylchr,linP and oxitli~Pd free fatty acids; with lipid pero~ tirn in
con~unction with Lp PLA2 activity; or with endothelial dy~ru"~lion.
Compounds of the present invention may also be of use in treating the above
mrntif)nPd disease states in combination with anti-hy~.l;~ Pmir or anti-
atherosclerotic or anti-diabetic or anti-anginal or anti-infl~mm~ts~ry or anti-
llyl~t;l~nsion agents. Flc~mrlPs of the above include çhnlest~prol synthesis inhihitor.c
such as statins, anti-oxi-l~ntc such as ~l~ucol, insulin ~eeneiticpre~ c~lrillm ch~nnPl
antagonists, and anti-infl~mm~tory drugs such as NSAIDs.
~ thel~eulic use, the compounds of the present invention are usually
~ led in a standard ph~rm~celltir~l composition. The present invention
therefore provides, in a further aspect, a ph~rm~celltic~l composition compri.cing a
compound of formula (I) and a ph~rm~re~ltir~lly acceptable carrier.
Suitable ph~rm~reutir~l compositions include those which are adapted for OI
or pa,~nte,dl ~lministration or as a suppository.
~he compounds of forrnula (I) which are active when given orally can he
fnrm~ tP~ as liquids, for example syrups, ~ ~"cionc or Pmnlcione, tablets, c~rslllPs
and l~7~n~ps~
A liquid fol~nlll~tion will generally consist of a suspension or solution of thecompound or ph~rm~reutir~lly acceptable salt in a suitable liquid ca~rier(s) forexample, eth~nol, glycerine, non-aqueous solvent, for example polyethylene glycol,
~ oils, or water with a sll~pentling agent, pl~l v~tive, flavouling or colouring agent.
A composidon in the form of a tablet can be prepared using any suitable
ph~rm~reutir~l carrier(s) routinely used for p,~pa i"g solid ft~rmnl~tionc Fy~mplt~s of
such carriers include m~gnecillm stearate, starch, lactose, sucrose and cellnlnsP~
g
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A composition in the form of a capsule can be prepared using routine
enr~rsul~tion procedures. For eY~mrlP, pellets eo~ the active ingredient can be
prepared using standard carriers and then filled into a hard gelatin c~rsnlP
~1lP~ ;V~1Y~ a fli~pPnciQn or s~L,p~cion can be prepared using any suitable
S rh~rm~rel~tir~l carrier(s), for eY~mpkP aqueous gums, c~ll~ ses, .~ilir~tPs or oils and
the di~pf~n~ion or ~u.,~llsion then filled into a soft gelatin c~rslllP
Typical palell~ldl compositions consist of a sollltirn or sll~ren~ion of the
compound of formula a) in a sterile aqueous carrier or palc;nt~l~lly acceptable oil, for
eY~mrl~P polyethylene glycol, polyvinyl pyrroliAonP, lPcithin arachis oil or sesame oiL
10 ~ltprn~tively~ the sol~ tion can 'oe lyophili~PA and then recon~titntPd with a sllit~' lP
solvent just prior to ~A...;.~ ftic)n
A typical suppository formlllation c~-mpri.c~s a compound of forrnula (I) which
is active when ~r.~mini~tPred in this way, with a binding andl'or l~.h. ;.~I;..g agent such as
polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synt'netic
waxes or fats.
Preferably the composition is in unit dose form such as a tablet or c~psl~1P
Each dosage unit for oral ~Amini~tration cont~inC preferably from 1 to 500 mg
(and for pZ~ t~.a~ minictration contains preferably from 0.1 to 25 mg) of a
compound of the formula (I).
The daily dosage regimen for an adult patient may be, for eY~mrlP, an oral dose
of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an
avf_nous, subcutaneous, or intramllcclllar dose of between 0.1 mg and 100 mg,
preferably between 0.1 mg and 25 mg, of the compound of the formula a), the
compound being ~f1,.,;.~ f~-~ed 1 to 4 times per day. Suitably t'ne compounds will be
~fAminictered for a period of continuous therapy, for eY~mplP for a week or more.
Compounds of fcrmlll~ a) may be prepared from co-lv~nient starting m~tPri~
by adapting synthetic procedures well known in t'ne arL A suitable process compri~P,s
treating an azetidone of formula (II!:
R l ZR3
o~ H
(II)
in which:
n, R1, R2 and R3 are as hereinbefore dPfinPf ,';
with an aLkylating agent of the formula (IlI):
LlCR4R5xy
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in which Ll is a snit~hlp- leaving group such as halogen or triflate; and
R4, R5, X and Y are as he~l~;nh~-ro, e ~lPfinrd,
in the presence of a s~it~hlP base such as sodium hydride or ~ hydroxide
5 optionaly with a 4~ y ~mmoninm salt such tetrabutyl ~mmonillm bromide, in a
suitable a71~ylating solvent such as tetrahyd-uful~n ( I~;), and at a ~ in t"e:
range -10 tO 0~C
For compounds of formula a) in which Z is S(O)n, the preceding a7kylation
re~rtion is collvenielllly t~-ffPcte~7 on compounds of formula (~) in which n is 0.
Compounds of form-ll~ (I) in which one of R4 and R5 is a7kyl may a7so be
prepared from corresponding compounds of formula (I) where both R4 and R5 are
hydrogen by tre~tmPnt thereof with an aL~ylating agent under the contlitit~ns t7çsr7 ihed
above. Such compounds may be obtained by treating a compound of formula (~) withan a7kylating agent of formula (lII) in which both of R4 and R5 is hydrogen, under
15 aL~ylating connitit ns as hereinbrfnre described.
A second aLkyl group for R4/R5 may be introduced by treating a first obtained
compound of formula (I) in which one of R4 and R5 is hydrogen, with an a71cylating
agent in the presence of a suitable base such as sodium hydride, pot~C~il7m hydroxide
or lithium hry~mpthyll7icil~7it7e in a suitable aLkylating solvent such as ~y~ Çu~u
20 (THF), and at a ~ç.--pel~tl-re in the range -80 to 10~C.
Compounds of formula (~) in which Z is S(O)n and n is 1 or 2 can be readily
prepared from cc,l,es~onding compounds of formula (I) in which n is 0 by tre~tmPnt
thereof with a s~it~hlP oxiflicin~ agent such as m-chlolopell~nzoic acid. Use of chiral
~xi~licing agents such as (+)- or (~ -bi-2-n~rhth- l / til;...;~ isopropoxide (N~nm~tsu et al, J Org Chem, 1993, 58, 7624-7626) can give diastereoi.comrnc
selectivity, if not chirally pure compounds.
Compounds of formula (rl) in which in which Z is S(~)n and n is 0 may be
obtained by treating 4-aceto~y;-7PI ;tlinonr~ 4-benzoyloxy~7~ti-1innnP or 4-
phenylsulfonyl~7Pti~linone with a thiol R3SH in the presence of a base such as sodium
ethoxide, in a suitable solvent such as ethanol at a tempelat~ in the range 0 to 5~C.
When this displ~remçnt is con~lucted in the prespnre of a chiral base, such as
~hinrhc~ni~linP or cinchonine, çn~ntiomerir~lly PnrichPd compounds (II) can be obtained
(J Chem Soc, Chem Commun, 1982, 1324-5).
Compounds of formula (~) in which Z is O may be obtained by treating
4-acetoxy~7Pti~linQnr 4-benzoyloxy~7pti~inrJnp or4-phenylsulfonyl-~7Pti-~inonP with a
phenol/alcohol R30H in the presence of a base such as pot~ccillm t-butoxi~lP~ in a
suitable solvent such as THF at a temperature in the range O to 5~C
Compounds of formula (m) may be readily prepared by ~ pting known
synthetic procedures, according to the specific value of X. A convenient starting
- 11 -
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m~tP.ri~l is an applupliately sukstitllt~Pd aryl compound which may then be elaborated
to introduce the side chain LlCR4RSX-.
Compounds of formula (I) in which X denotes a group CONR6(CH2)m,
CONR6X2, CONR60(CH2)m or CONR60X2 may be cc.llvt;niell~y plc~ cd by
S treating an acid of the formula (IV):
R2
R'+~",ZR3
~N
O CR4R5--CO2H
(IV)
in which:
10 Z, Rl, R2, R3, R4 and RS are as hereinbefore ~lpfinpd
with an amine of the formula (V):
NHR6x5y
(V)
15 or a hydroxylarnine of the forrnula (VI):
NH20XSY
(VI)
in which XS is (CH2)m or x2 and m, R6, Y and x2 are as hereinbefore tlefin~
20 in the presence of an activating agent such as ethyl chloroformate or
dicyclohexylcarbodiirnide (DCC), in a suitable solvent such as chlo-ofc",l, or dirnethyl
form~mirl~P~ at a temperature in the range -10 to 20~C.
An acid of formula aV) in which one of R4 and RS is hydrogen may be
obtained by treating a compound of forrnula (II) with a co~ ,pollding 2-bromo ester,
25 for inct~n~e a (Cl 7) ~lk~no~tP. ester, under aLkylating conditions as hereinbefore
~losrrihe~ followed by the hydrolysis of the thus formed intp~n~ te ester using
standard confii~if)nc A second group, for in.ctqsln-~e an aLtcyl group, may then be
introduced by aLkylating of the first formed mono~lkyl ester.
Compounds of formula (I) in which X denotes a group COO(CH2)m or
30 COOX2 may be conveniently prepared by a tr~n.cestP.rifi~tion reaction from another
ester, in particular the methyl ester of forrnula (VII):
R2 3
~f ZR
~ \CR~R5--CO2CH3
CA 02225627 1997-12-23
WO 97/02242 PCTIEP96/02765
(VII)
in which:
Z Rl- R2, R3 R4 and R5 are as h~ ;..r~fore clP.finP.-l
using con~litionC well known in the art for such rP~ction.C, for ~ e heating in
S toluene in the presence of a catalytic amount of sodium mP.th~xi~1P and an ~lt'oh~l
A compound of formula (VII) in which one of R4 and R5 is hydrogen may be
obtained by treating a compound of fonn~ (I[) with a methyl 2-bromo(Cl 7)
k~no~te under aLkylating con~itio~c as hP.~ hç~ ~lç~nhe~
.~ltP.rn~tively a compound of fonnlll~ (I) in which X denotes a group
10 COO(CH2)m or COOX2 may be prepared by treating a compound of formula (IV)
with an alcohol YX50H or an activated derivative thP~eof, for inst~nre- a tosyla~e.
Compounds of formula (I) in which the linker group X contains an ether
function may be prepared by a suitable ether coupling reaction, for inct~n~e treating a
compound of formula (Vm):
R~ ZR3
~~ \CR4R~--X2(CH2)pL2
(VIII)
in which Z Rl R2 R3 R4 R5 and x2 are as here~nbefore ~IP.finP.d
20 with a compound of formula (lX):
L3(CH2)qY
(r~
in which one of L2 and L3 is a halogen or other sllit~hhP- leaving group such as triflate
25 or tosylate and the other is OH or a suitable salt therof and p and q are as he,cil~fc,,~
dP-finP.~; under standard ether forming coll~itionc
Compounds of formula (I) in which Z is S(~)n and n is 0 may also be prepared
by a process which cnmpri.ces treating a compound of formula (X):
R2 _~SAg
O CR4Rs-x y
(X)
in which Rl R2 R4, R5 X and Y are as hereinbefore defined;
with an aL~cylating agent of the formula (XI):
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W O 97/02242 PCT~EP96/02765
R3Ll
~ )in which R3 and Ll are as hereinbefore definPd;
5 under snit~khP aLkylating con~liticmc~ for inct~n~P, in a solvent such ~ ~elu..;~ P, at a
...pe~i.tllre in the region 25~C.
Compounds of formul~ (X) may be obtained from the corresponding ~
acetylthioa7Pti(linone by trÇ~tn Pnt with silver nitrate and a b~e in a suitable solvent
such as mPth~nnl
Mixtures of diastereoisomeric compounds of formula (I) may be resolved, if so
ecire~l according to procedures well known in the a~ For ~ nce slllpho~i.1P,s
(n=l) may be separated by chromatography and/or cryst~llic~tion. Chirally pure
compounds may be prepared by chiral chromatography, from chirally pure
intPrmP11iatPS or by chiral syll~lesis using chiral reagents or catalysis. S-litahlp chiral
15 intern~p~ tp~s may be obtained by resolution or chiral in~uction or by using chiral
re~g~ntc, in particular natural chiral molecules, according to methods well known to
those skilled in the art. For chiral synthesis, a convenient chiral starting m~tPri~l is a
pPni~illin derivative which has the pl~Çellr d confi~llration at C~ of the ,B-lactam ring.
This is illllctr~t~d in the following scheme for the preparation of suitable intPrmPrliat~s
Br S~O P(OiPr)3, Ac~O ~SAc (fl ~3. EtOAc~ -70~ Br"~c
~ ~ MB ~ (iii) aq acid O ~
Br _SAg Br ,SCH2Ph Br ,SCH2Ph
NEt3. AgN03 '~~ PhCH2Br "~ (i) KOH/MeOH. 0~ '~
MeOH ~N~Coo-pMB MeCN ~N~CO~pMB (ii) HCI 0~ \~COOH
DCuHogt Br~scH2ph mCPBA, CH2C12 Br~SCH2Ph Zr~AcOHJCH2C12 F~SCH2Ph
Ph(cH2)6NH2 0 N~coNH(CH2)1~Ph O N~CONH(CH2)~Ph N ,coNH(cH2)~,Ph
The preparation of the starting material (4-methoxyben_yl-6-bromopenicillin~tP-1-
oxide) is descr~bed by J. Chem. Soc., Perkin Trans. 1, 1994, 179-188. An alkyl
sllbsSituent (R4/R5) may be introduced at a late stage in the sequence. using alkylating
25 conditions hereinbefore described.
The present invention will now be illustrated by the following PY~mpl~Ps The
relative confign~tinnc of the centre at the C4 position in the ~7Pti~linone and the centre
alpha to the N of the azetidinone are unknown in the two diastereoisomers (a and b)
described below but are thought to be R,R/S,S (diastereoisomer a) and R,S/S,R
- 14-
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W O 97/02242 PCT~EP96/027C5
ctPrçoicomPr b). The relative conf~ r~tionc of the C4 and snlfo~ P centres ar~
also unknown, but are thought to be R,R/S,S (tlia~tereoi~com~r 1) or R,S/S,R
(~iactPreni~(!rnp~r 2). Such config~ tinnc were obtained initially by x-ray analysis of a
limited number of colllpuu~lds and then eYsr~r)olatp-cl to the rçm~ining cc~ ds an
S the basis of their lH NMR spectra Unless o~erwise speçifiP~l (e.g. isomer (-)b2) ~11
compounds are racPmir (e.g. diastereoicomPr b2). All cc,lllpollnds are pre~ y
the (diastereo)isomer descAbed. All compounds are c 1 ~~- a~ ~. ;.ced by NMR and most
by microanalysis and mass spec,. Melting points are uncorrected. T.comPrc and
çn~ntirJmPrs are l~hPllPd as de~crrihed above to farilitatP des ,~i~lion of the s,~ leses
10 and to in~licatP prefprred collll)ounds.
- 15-
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W O 97/02242 PCT~EP96/0276S
lions
4(5-AllyloAy~ .ylru~ 2-~ lU,io~ 2 one
a Meffiyl5-(chlo.~ 2-rulo~l~
A stiIIing mixture of p~ rO.. ~ltiehyde (25.22 g, 0.84 mol), anllydr~us zinc çhlr)ri~p~
(108.06 g), and methyl 2-furoate (100 g, 0.793 mol) were cooled to 15 ~C (ice bath)
and a stream of HCl gas bubbled through with .stirring- The Ir~ e wa~s allowed
to rise to 25-30 ~C, and after 1 hr the ll~A~ULC~ was poured onto ice-water. Theorganic layer was sep~ d off and the ~queolls layer further e~trActPd with
10 dichloromPth~np-~ The comhinP-d eytrArtC were dried (MgS04) and t;vapc,ld~d to a
dark brown oil. Di.ctill~tion under reduced ~ ,ule gave the product as a pale yellow
solid (72.5g, 52% yield ), b.p.( 88~C/0.8 mm Hg). lH NMR ~ (DMSO-d6) 3.82 (3H,
s, CH3), 4.90 (2H, s, CH7), 6.75, 7.29 (each lH, d, furan-H)
b. Methyl5-(ac~lylll.iomethyl)-2-lu~o~te
Methyl (5-chloromethyl)-2-furoate (50 g, 0.286 mol) was dissolved in dry
dimethylform~mi~lP (300 ml) and pot~ lm thin~et~tP ( 32.68 g, 0,286 mol) added
with stirrino The initial exotherm was controlled by cooling ( ice bath), then the
reaction was stood at room Lelllpt:,ature for 2 hr. The solvent was evaporated and the
residue treated with water and thoroughly e~trA~tP-d with ether. The combinPd
extracts were dried (MgSO4), evaporated and purified by flash chromatography (silica,
ethyl acetate/petroleum ether) to give the product as an oil (40.9g, 67% yield). lH
NMR ~ (CDC13) 2.36 (3H, s, CH3CO), 3.88 (3H, s, CH30), 4.16 (2H, SCH7), 6.36,
7.09 (each lH, d, furan-H)
~ 4(~-(AIIYIOA~1,onyl)furan-2-~nLU.~lll~iop~ 2-one
Potassium t-butoxide (12.77 g, 0.114 mol) was stirred in allyl alcohol ( 60 ml) until
complPtP sol~ltio~ was obtained. Methyl 5-(acetylthiomethyl) furoate (22.17 g, 0.104
mol) in allyl alcohol (60 ml) was then added, and after 2 hr the mixture was cooled (ice
bath) and a solution of 4-acelo~y~7~ 1in-2-one (13.36 g, 0.104 mol) in dry
tetrahydrofuran (100 ml) added dropwise over 20 min. After a further 30 min, thecooling bath was removed, then the mixture stirred for 3 hr at room tempel~lLulc~. The
solvent was evaporated and the residue treated with brine and e~ttr~ctPd with ethyl
acetate. The combined extracts were dried (MgSO4) and evaporated to give the
product as a pale yellow oil (22.5g, 81% yield). lH NMR ~ (CDCl3) 2.87 (lH, m,
--3a)~ 3-43 (lH, m, H3b), 3.89 (2H, m, SCH2), 4.79 (2H, m, CH20), 4.94 (lH, m, ~4),
5.38 (2H, m, CH7CH-), 6.01 (lH, m, C_CH2), 6.33, 7.13 (each lH, d, furan-H), 6.74
(lH, N~)
4(2-Fluoroph~noxy)~7eff~1in-2-one
A solution of 2-fluorophenol (4.5g, 40mmol) and 18-crown-6 (5 mg) in dry THF
(lOOml) was treated with potassium t-butoxide (4.5g, 40mmol) and a solution of 4-
benzoylo,.y;17P!i~lin-2-one (7.7g, 40mmol) in dry THF added. The mixture was stirred
for 1 h and quçnrhP(i with aqueous citric acid and ethyl acetate. The organic layer was
sPp~r~ltP(l, washed with brine, dried (Na2SO4) and evaporated. On trituration under
ether/excess n-hexane and filtration the title compound was obtained as a solid (5.8g,
80%) m.p. 95-6~
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WO 97/02242 PCT/EP96/02765
lH NMR ~ (CDCl3) 3.17 (lH, dd), 3.34 (IH, m), 5.66 (lH, m), 6.59 (lH, bs), 6.93-7.18 (4H, m)
The following were prepared from 4aceto~ non~ (or ~acetoxy-3-
5 methyl~7Ptit1in-2-one) and the required phenol in a similar manner
4(Phenoxy)~7~ in-2-one m.p. 107-8~C
1 (2-Methylr~ nnxy)~ one m.p.105-6~C
~ 4(2-Ben_yloAy~ ,(,A~ e~ 2~onem.p. 86-7~C
4(2-MeU.ylU~iophenn~y)~ one m.p. 131-2~C
4(4Allyl~ ~Lonylrhpnnyy)h~ onem.p. 51-2~
4~4-Chlor.,~lleJ,.,~)~7PhA;n- one m.p. 115-6~C
4(4Methoxyph~n.>Yy)~7e1i~lin-~one m.p. 96-7~C
4(4Mell,~lll.iophenoxy)~ ~Dne m.p. 118-20~C
~rans-3-Methyl~(phenoxy) ~7~ffrlin_~one lH NMR o (CDC13) 1.35 (3H, d,7.6E[z),
3.55 (lH, m), 5.63 (lH, d, 4.0Hz), 6.83-7.38 (6H,m)
N-(6-phenylhexyl)br~.l..o~e~ ide
A cooled solution of 6-phenylhexylamine (26.6 g) (Morse M. A. et al., Cancer
Research, 1991, 1846) and Hunig's base (19.5 g) in dry dichl~ J...~Ih~ne (300 ml) was
treated with bromo~cetylchl- n~l~ (23.38g) in dichlorom~th~nP (50 ml) at 0-5 ~C.20 After aqueous workup and chromatog;aphy N-(~phenylhexyl)-l-bromo~ret~mi-1e was
obtained as a colourless solid, 35.4 g (83%), m.p. 29-32~C.
N-(6-(4-chlorophenyl)hexyl)~ v.~ c~ ~ide
~(~Chlorophenyl)hexylamine (T ~m~ttin~ J. L. EP 138464 A2 850424 (CA
103: 142000)) was treated with bromoacetylbromide in a similar manner to give the
title compound as a colourless solid, m.p 67-8~C, (93%).
4(Bc..~,~lll.io)~7Pti~in-2-one
Sodium (8.1g, 0.35mol) was dissolved in ethanol (250ml) and ben_yl melca~La l
(45.2g, 0.37mol) added dropwise over 20 minllt~s k~eping the Lt~lllpel~ beLweel~ 20
~C - 25~C whilst bubbling nitrogen through the mixture. After 15 ~ r-s~ the
reaction was cooled to 5~C and a solution of 4-aceto~y~7Ptitlin-2-one (45.0g, 0.35mol)
in ethanol (50ml) was added dropwise over 15 min~tPs whilst m~ ;ni-~g the
temperature at 5~C. The mixture was stirred at room tempel~lu~e for 60 ..~ and
evaporated to dryness under reduced pressure. Water (400ml) was added, the mixture
eYtr~rtPd with dichlorometh~np (2x300ml), the extracts dried (MgS04) and
evaporated under reduced pressure to an oil. The oil WâS cooled to -20~C and
tir~lr~tP-d with ether (400ml) to give a white solid which was i.col~tP.cl by filtration
(50.2g, 79%), mp 50-51.0~C.
Methyl-(4-bel.~yltllio-2-oxo~7~ n-l-yl) acetate
To a solution of ~(benzylthio)~7Ptidin-2-one (5.0g, 25mmol), methyl bromo~re
(4.6g, 30mmol) and tetrabutylammonium bromide (0.9g, 0.28mmol ) in dry THF
(lSOml) was added powdered potassium hydroxide (1.7g, 30mmol). The res~llting
n~ ule was stirred for two hours at room tempelalu,f before water (50 ml) was
added. The solution was extracted with ethyl acetate (3xl50ml portions) and the
combinP~ extracts dried (MgS04) and evapol~d. The residue was purified by flash
CA 02225627 1997-12-23
W O 97/02242 PCTAEP96tO2765
chromatography on silica gel eluted with petroleum ether 60~-80~:ethyl acetate 4:1 to
give methyl (4-ben~ylll~o-2-oYo~7Ptillin-l-yl)acetate as a yellow oil (Sg, 70%).lH NMR ~ (CDC13) 2.96(1H, dd, J=2.5, 16 H_ H3a)~ 3.24,3.99 (each lH, d, J=18.00
H_, NCH2), 3.4 (lH, dd, J=5,12.5 Hz H3b), 3.70 (3H, s, OCH3), 3.77 (2H, s, SCH2),
4.92 (lH, m, ~4), 7.28 (SH, m, Ph-_)
(4-Be.~llll;O 2-Q~ Iidin-l~yl)ace'dc acid
To a solution of methyl (4-benzylthio-2-oxo-~7Pti~lin-l-yl)acetate (2.5g, g.4mmol) in
methanol (80ml) was added, dropwise at 0~C, a soll~ti~n of 1 N sodium hydro~cide(9.9ml, 9.9mmol). The reaction was stirred for 1 hr and eva~ulà~d to dryness. Water
(50 ml) was added and the soluti~n ~Ci~lifipd to pH 3 with dilute hydrochloric acid and
extracted with ethyl acetate (3xlOOml) . The combinPd eYtr~rtc were dried (MgS04),
evaporated and the residue pu~ified by lt ~;ly~ li.~tinn (hexane/ether) to give (4-
benzylthio-2-oxo-~7Ptitlin-l-yl)acetic acid as a white solid (1.3g, 55%), mp 110-111~
C. lH NMR ~ (CDC13) 2.99 (lH, dd, J=6.87,17.5 Hz, H3a)~ 3.27, 4.06 (each lH, d,
J=18.40 Hz, NCH2), 3.39 (lH, dd, J=5,15.4 Hz, H3b), 3.77 (2H, s, SC_2)~ 4.91 (lH,
m, H1), 7.27 (SH, m, Ph-_).
l-(Am~no)-6-(3-chlorophenyl)hex-1-yne
a 6-(3-chlorophenyl)hexyn-1-ol
A surred mixture of 3-chloroiodoben~ne (14.3g, 60mmol),
tetrakis(triphel.ylrhosrhinP) p~ flinm (2.1g, 1.8mmol) and 5-hexyn-1-ol (5.9g,
60mmol) in triethylamine (120ml) was stirred at 25~C for 3h and partitioned b~n
water and ether. The ether layer was ~s~p~r~tPd and the aqueous extracted with ether.
The combined ether extracts were washed with lN HCl and dried (Na2S04). The
ether was evaporated and the residue purified by flash chromatography on silica using
dichlorometh~n~ as eluant. Evaporation of the applu~,liate fraction~ gave the product
as an oil (l l.Sg, 92%)
b. 1~ o)-6-(3-chlorophenyl)hex-1-yne
A solution of 6-(3-chlorophenyl)hexyn-1-ol (ll.Sg, SSmmol), triphenylphosphin~
(14.5g, 55mol) and phth~limidP (8.1g, 55mol) in dry THF (l lOml) was treated with a
solution of DEAD (9.6g, 5~mmol) in THF (20ml) over several minllt~s- After 16h,
volatiles were removed in vacuo and the residue treated with ether. The precir)it~ted
solid was removed, the filtrate evaporated and the residue purified by flash
chromatography on silica using dichloromp-th~nlo as eluant. Evaporation of the
applopliate fractions gave l-(phth~limil10)-6-(3-chlorophenyl)hex-l-yne as a solid
(16.5g, 89%)
c 1-(An~ino)-6-(3-chlorophenyl)hex-1-yne
A mixture of l-(phth~limitlQ)-6-(3-chlorophenyl)hex-1-yne (6.6 g) and hydrazine
hydrate (2.24 g) in ethanol (100 ml) was heated at reflux temperature for 18 h. After
cooling and filtPrin, the solvent was evaporated to give an oil which was dissolved in
diethyl ether and washed with brine, dried and evaporated to give 1-(amino)-6-(3-
chlorophenyl)hex-l-yne as a brown oil (3.1 g, 77%).
The following 2 amines were prepared in an analogous manner:
1-(Amino)-6-(2-chlorophenyl)hex-1-yne
l~(Arnino)-6-(1-naphthyl)hex-1-yne
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~phenyl-3-heA,~
a N-(6-phenyl 3 1,~
A ~ Lulc: of phth~limi~p (8.78 g), 6-phenyl-3-hexynol (J.Dijkink, N.Sye~;~
S Tetr~hPllron~ Vol.34, 173-178, 1978) (8.0 g) and triphenylrh~).crhinP (12.04 g) in dly
THF (75 ml) was cooled to 5~C u~der nitrogen. A soluti~n of diethyl
~7o~lir~rboxylate (8.0 g) in dry THF (20 ml) was added over 10 minutes m~i.~ .;..;.~p
~ the tPmrPr~tllre at 10~C. The reaction was stirred at room tP~re~,.tllre for 20h,
evilpoldted to dryness, dissolved in CHC13 (250 ml) and washed with lN NaOH, brine,
10 2N HCl, saL NaHCO3, brine, dried (MgS04) and ev~ol~d to a cream solid (28. l
g). pllrifir~tion by flash column chrom~to~o~r~rhy eluted with 10:1 to 2:1 petroleum
etherethyl acetate and recryst~lliC~t~n from ethanol gave N-(6-phenyl-3-
h~yllyl)rhth~limiti~ as a cnlol-rlPcc solid (8.25 g, 59%) m.p. 95-96~C.
b. 6-phenyl-3-heAy ~ ~
15 N-(6-phenyl-3-he~yllyl)rhth~limi~l~p (3.0 g) in ethanol (150 ml) was treated with
hydld~e monohydrate (0.96ml) and st~red at reflux for 4h. The reaction was coo]~ed,
evaporated to dryness and azeotroped with water. The residue was treated with lMNaOH and P~tr~ctPd with diethyl ether (x2). The organic extracts were combined a~nd
e~LIa~;L~d with 2N HCl (x2). The aqueous extracts were combined and b~cifiPd with
20 NaOH(aq) and extracted with diethyl ether (x2). The organic extracts were combined,
washed with water, dried (MgSO4), evaporated to give 6-phenyl-3-h~y,ld.l.il~e as ~In
oil (1.52 g, 89%).
Z~phenyl-3-h~At:l.yl~...~.e
a Z-N-(~phenyl-3-hexenyl)phth~
25 N-(6-Phenyl-3-hexynyl)phth~limi~i~P (4.4 g) in ethanol (140 ml) was hydrogenated at
40psi/20~C with Lindlar's cayalyst (60 mg) for 105 minlltPs The reaction was filtered
and ~vapoldted to a yellow oil (4.51 g). Pl-nfi~tion by flash colurnn chromatography
eluted with 6: 1 to 4: 1 petroleum ether: ethyl acetate gave ZN-(6-phenyl-3-
hexenyl)phth~limi~l~P as a colourless oil (4.15g, 94%). v c=c 1656 cm~l; nmr
30 hom-)n~clP~r decoupling gives 3JH3 H4 (alkene) = 10.8Hz.
b. Z-6-phenyl-3-heA~:--yl~--~i~-e
Z-N-(6-phenyl-3-hexenyl)phth~limirle (1.95 g) in ethanol (100 ml) was treated with
hydrazine monohydrate (0.64 g) and the mixture was stirred at reflux for 4.5 h and
stirred at room tempela~ule for 22 h. The reaction was evaporated to dryness and35 azeotroped with water. The residue was mixed with lN NaOH and eYtr~rtPd with
diethyl ether (x2). The organic extracts were combined, washed with brine, dried(MgSO4) and evaporated to dryness. pll~ifir~tion by Kugelrohr ~ till~tion at 185-
200~C/0.2mmHg gave Z-6-phenyl-3-hexenylamine as a colourless oil (collLa~ns 6-
phenylhexylamine 10%) (0.89g, 80%).
40 E-6-phenyl-3-hexenylan~ine
a, E-N-(6-phenyl-3-hexenyl)phth ~lim;~l~
A I~ Lulc~ of E-6-Phenyl-3-hexenol (J.Dijkimc, N.Spec~mp, Tetrahedron, Vol.34,
173-178, 1978) (6.35 g), phth~limicle (6.89 g) and triphenylphospin~ (9.45 g) in dry
THF (50 ml) was cooled under nitrogen. Diethyl azodic~l~ylate (6.27g) in dry I~IF
45 was added over 10 minutPs m~int~inino t'ne temperature at 10~C. The reaction was
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W O 97/02242 PCT~EPg6/02765
stirred at room ~ lprl"hlre for 20 h and evaporated to dryness. The residue was
rnixed with CH2C12 (100 ml) and washed with lN NaOH, brine, lN HCl, brine, dried(MgS04) and evaporated to dryness. pll.;r~ on by flach column chromatography
eluted with 8:1 to 4:1 petroleum ethel..,Lhyl acetate gave trans-N-(6-phenyl-3-
hexenyl)phth~limi~P as a colourless solid (6.96 g, 63%) m.p. 75~C. v ~=~ 1670 cm~
and nmr homrm~ P~r ~lecollpling gives 3JH3 H4 (alkene) = l5Hz.
b. E-6-phenyl-3-h-:At~ ,e
E-N-(6-phenyl-3-hexenyl)phth~limitle (4.79 g) and propylamine (5 g) in ethanol (200
ml) were stirred at reflux for 2h and then at 70~C for 18h. The reaction mL~t; was
evaporated to dryness and azeotroped with eth~nol The residue was mi~ed with lN
NaOH and extracted with diethyl ether (x2). The organic eAtracts were combinP-I
washed wit-h- 2N HCl (x2). The aqueous ç~tr~tc were combined, washed with diethyl
ether and then basified with NaOH(aq) and eYtr~tp-d with diethyl ether (x2). Theorganic extractc were combined, wached with brine, dried (MgSO4) and eva~o,a~d to
an oil. Purification by Kugelrohr rlictill~tion at 180~C/0.5mmHg gave E-6-phenyl-3-
hexenylamine as a colourless oil (0.98g, 36%).
5-PhenoA~ e
a S-Chlor~l-phenoA~pent~
A mixture of phenol (2.67 g, 0.028mol), 1,5-dichlolopenta~le (20 g, 0.148mol) and
K2C03 (20 g, 0.144mol) in methyl ethyl ketone (300ml) was refluxed for 24 hourc.After cooling, the reaction mixture wac filtered, and evaporated to a yellow oil (37.8
g). This was purified by flash chromatography on silica gel eluted with hexane/ethyl
acetate 15:1 to give a yellow oil (18 g). This was evapo,ated using a high va~;uu~l
with a water bath temperature >80OC to remove the excess 1,5-dichlc~,~n~e (b.p.
63-65~C) to give a yellow oil (5.8g). The oil was further purified by flash
chromatography on silica gel eluted with hexane to give 5-chloro- l-pheno~Lyl,e..~e as
a yellow oil (2.50 g, 44%).
b. N-5-Ph~ Ay~ lyl ph~
5-Chloro-l-pheno~ypentane (2.50 g,l2.6mmol) was dissolved in DMF (75 ml) and
pot~ m phthsllimi~iP (4.65 g, 25.13mmol) was added and the mixture stirred at
100oC overnight for 18 hours. The DMF was evaporated and the solid was
partitioned between ethyl acetate (75 ml) and water (50 ml). The organic layer was
washed with H2O (50ml3, dried (MgS04) and evaporated to yellow solid. The yellowsolid was purified by re cryst~llic~tiQ~ from ether/pet ether to give a white solid. The
white solid was re cryst~lliced again from ether to give N-5-phenoxypentyl phth~limide
as a white solid (2.50 g, 64%), m.p. 62-64~C.
c 5-Pl~ Ay~entylarl~ine
N-(phenoxy)-5-pentyl phth~limidp- (2.50 g, 8.08mmol) in ethanol (200ml) and
hydrazine monohydrate (1.21 g, 24.17mmol) was refluxed for 18 hours overnight.
Then filtered and evaporated, then evaporated from water a few times then evaporated
from ethanol. 2M NaOH (500 ml) was added and extracted with ether (200 ml x2).
The organic layer was washed with water several times until pH of solution was
neutral, then dried (MgS04) and evaporated to give 5-phenoxypentylamine as a a
yellow oil (1.13 g, 78%).
2-(2-phenoAy~:ll,ylox~)ethylamine
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Se~uential tre~tm~nt of 2,2'-dichlorodiethylether with phenol/K2CO3/2-l,.~ o..P arld
pot~ccillm phth~limi-WDMF as ~esr,ribed m the previous Plr~p;l~n~ (at a and b)
above gave N-(2-(2-pheno~-yt:~-yloxy)ethyl)rhth~limitle as a colourless solid.
Tre~tment of this phth~limi~P (2.99 g) with hyd~azine hydrate (1.44 g) in ethanol (2130
5 ml) by the procedure in the previous Prep~tinn (at c) gave the title amine as a yellow
oil (0.81 g, 47%)/
2-(3-phr~ r~ yloxy)~ u~-e
~ FSh~nQ1~minP (1.53 g) was added to NaH (1.0 g) in di-nethyl sulfoxide (DMSO) (10
rnl) at room tompr~ , followed by l-bromo-3-ph~nylt,lo~alle (5 g) and the mi~nlre
10 stirred at room temperature for 0.5 h. After aqueous work-up the title col--poulld u~as
obtained as a yellow oil (1.6 g, 36%).
~Phenylhexy~loxy~ triflate
a 2-(6-Pht~ oxy)e~
6-Phenylhexyl bromide (6.10 g) and ethylene glycol (15.5g) were added tO a solution
15 of sodium hydroxide (1.08 g) in water (1.1 ml) and the mixture heated at 100~C for
30hrs. Ether (75 ml) and water (75 ml) were added, sep~aled and the ether layer was
washed with water then brine, dried over MgSO4 and evaporated to an orange oil.
This was purified by Kugelrohr ~lictill~tion (225~C/0.2mm) followed by
chromatography on silica gel (40-60 petroleum ether/ethyl acetate) to give a colourless
20 oil (3.04g; 54%)
b. 2-(~Phenylhexyloxy)ethyl triflate
2-(6-Phenylhexyloxy)ethanol (2.88g ), pyridine (1.23 g) and DMAP (20 mg) were
dissolved in dry CH2C12 (lSml), cooled to -5~C and triflic anhydride(4.37 g) in
CH2C12 (10 ml) was added over 5 mins kPeping temp ~0~C. The mixture was stirr~d
25 at 0~C for 1 hr then washed with water, bnne, dried over MgSO4 and evaporated to a
colourless oil (4.54g, 99%).
The following 2 triflates were prepared in an analogous manner.
2-(6-(4-Chlorophenyl)hexyloxy)ethyl triflate
30 2-(6-(4Fluorophenyl)hexyloxy)ethyl trinate
3-Phenoxy-1-trifluo,o..~ .lrhollyll"o~!a~-e
A mixture of 3-phenoxypropan-1-ol (2.38 g), pyridine (1.19 g) and 4-
dimethylaminopyridine (DMAP) (0.10 g) was cooled to -5~C under a N2 atrnosphere.35 TrifluoromPth~nP sulfonic anhydride (4.4 g) dissolved in dry dichloromPth~n.- (15 ml)
was added dropwise over 30 mimltps between 0~C to -5~C, then stirred for 2 hours at
0~C. The mixture was poured into water and the organic layer was sep~r~tp-~l washed
with water (x2), dried (MgSO4), evaporated under reduced pressure to a dark brown
oil which was purified by silica gel flash chromatography, eluted with petroleum ether
40 40~C - 60~C/ethyl acetate 2:1, to give the title compound as a clear oil pale brown/orange oil (3.22g, 73%).
2-Phenoxy-1-trifluororn~Pth~nPe-llphonyleth~nP was prepared in an analogous
manner from the corresponding alcohol.
(4-(4-ethoxycarbonyl)ben_ylthio)~7eff~lin-2-one
45 a. Ethyl 4(bromompthyl)ben7o~t~p
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1 (Bromom~Athyl)benzoic acid (25.75g, 0.1197moles) was s~lspentled in thionyl
~hlori~le (50ml) and dimethylr~ e (0.25ml) was added. The lll~ALuLt~ was heated
under reflux for 25 mimlt~s until clear, eva~u~ d and a~e~ ,ped with toluene (~c2).
The rç~ ting oil was dissolved in dichlorometh~n~A- (75ml) and added dlo~ ise over 10
S minutps to a soll~tinn of absolute alcohol (8.6ml, 0.1465moles), pyridine (lO.~ml,
0.1298moles) in dry dichlorom~-th~n~ (SOml), cooled to 10~C. The ice bath was
removed and the re~Atif)n was stirred for 45 minllt~s, then washed with water, 2NHCl,
water, sodium hydrogen carbonate solutic ~ and brine. The organic sol~ltif ~ was dried
(MgS04) and evapola~ed to give a mixture of 60:40 ethyl 4-(bromollle~lyl,~ ~n -~LtA
ethyl 4-(chloromethyl)ben70~t~o- as an oil (25.6g, 94%)
lH nmr ~ (CDC13) 1.40 (3H, m, CH3), 4.40 (2H, m, CH20), 4.50, 4.61 (2H, 2~s,
CH2Cl/Br), 7.45 (2H, m, Ar-H), 8.01 (2H, m, Ar-H)
b. Ethyl 4(a~1y! ' ~
60:40 Ethyl 4-(bromQm~thyl)b~n70~te ethyl 4-(chloromethyl)be~ ~ (25.0g,
0.11 lmoles) in dry dimethylfnrm~mi~ie (lSOml), cooled to 5~C, was treated with
potassium thio~ret~t~-- (13.3g, O.117moles) and the temperature rose to 20~C. The
reaction was stirred at room ~ e,~1t~lre for 2 hours, poured into water (250ml) and
extracted with diethyl ether (3xlOOml). The organic extracts were combined, washed
with water, dried (MgS04), charcoaled and evaporated to give ethyl 4-
(acetylthiom~thyl)~-n70~t~- as a brown soild (26.0g, 99%), m.p. 36-37~C.
lH nmr ~ (CDC13) 1.38 (3H, t. J=7. lHz, C_3), 2.36 (3H, s, COC_3), 4.14 (2H, s,
CH2S), 4.36 (2H, q, CH20), 7.35 (2H, d, J = 8.2Hz, Ar-H), 7.97 (2H, d, J= 8.2Hz,Ar-H)
~ 4-(4-(Ethoxy~ l,onyl)~ io)~ -~one
A soluti~ n of sodium (1.87g, 0.0813moles) in absolute alcohol (300ml) was treated
with a sol~lti~ n of ethyl 1 (acetylthiomethyl)ben7o~tP- (19.4g, 0.0814moles) in absolute
alcohol (75ml) over 3 mimltes The reaction was stirred at room t~mpe.~--f~ for 30
minut~S, cooled to -5~C and treated with a snlllti- n of 4-acetoA~ in-2-one (lO.Og,
0.07745moles) over S min~lt~s The cooling bath was removed and reaction was
stirred for 2 hours, evaporated to dryness and treated with brine (200ml) and ~t-~etecl
with ethyl acetate (200ml, lOOml). The organic extracts were combined washed with
brine, dried (MgS04) and evaporated to a red oil. Purified by flash column
chromatography on silica gel eluted with 3:1 to 1:2 petroleum ether40-60~C:ethylacetate to give 4-(4-(ethoxycarbonyl)benzylthio)~7ptil1in-2-one as an orange oil(18.64g, 91%).
lH nmr ~ (CDC13) 1.38 (3H, t, J=7. lHz, C_3), 2.82, 2.89 (lH, 2xm, _3), 3.29, 3.35
(lH, 2xm,_3), 3.88 (2H, s, CH2S), 4.37 (2H, q, C 2~)~ 4.70 (lH, m,_4), 5.70
(lH,bs, N_), 7.40 (2H, d, J = 8.3Hz, Ar-_), 8.00 (2H, m, Ar-H)
CA 02225627 1997-12-23
WO 97/02242 PCT/EP96102765
F,~
7~Y~7rr7p~ 1 N-t6-(4-chloro~ "~ exyl)~ t1 b~ lU,io~ idin-1.
yl]propionz77n~ n~ b)
a Methyl 2.~be,~ylll~io~ in-l-yl)propionate
A mixture of 4-bel~y~ o~7ptirlin-2-one (1.93 g, 0.01 mol), methyl DL-2-
bromopropionate (1.23 ml, 0.011 mol) and tetra-n-buty1~7mmQni-7m bromide (0.32 ~"
0.001 mol) in dry tetrahydluru~n (50 ml) was treated with freshly powdered
po!~c~ l hydroxide (0.62 g, 0.011 mol) and stirred at ~mhi~nt ~ ; for 1
10 hour. Following trP~tmPnt with ethyl acetate and water, an in.col~lble yellow solid ~as
removed by fillr~tion and discarded, and the filtrate sep~ 7 The aqueous layer ~vas
extracted again with ethyl acetate and the c~ mhined PY~,7-~t~ dried (MgSO4) andevaporated to a brown oil. p~lrifir~tion by flash chromatography (silica, ethyl
acetate/petrol) gave the title co,~ nd as a mixture of diastereoicom~rs (coloorless
15 oil), 0.5 g, 18% yield.
lH NMR o (CDC13) 1.55 (2x3H, d), 2.93 (2xlH, m), 3.29(2xlH, m), 3.74 and 3.7'5
(each 3H, s), 3.80 and 3.84 (each 2H, s), 3.91 and 4.41 (each lH, q), 4.70 and 4 96
(each lH, m), 7.30 (2x'5H, m)
b. 2-(4.B~yla~io~ o~ ;..-l-yl)~ acid
A st7rred solution of methyl 2-(4-ben~ylLhio-2-o~o~7Pt~ n-l-yl)propionate (1.39 g,
0.005 mol) in m~.th~nol (12 ml) was treated with 1 molar pol~c~ .. hydroxide (5.4'7
ml). After 2 hours, the mçth~nol was evaporated and the residue diluted with water
and extracted twice with ether. The aqueous layer was ~ ih~Cl with cooling (ice
bath) and the oil which precipitated was eYt~ ted into ether. The combined extracts
were dried (MgS04) and evaporated to give the title compound as a white solid
(mixture of diastereoi.~omers), m.p. 78-82~C, 0.98 g, 74% yield.
lH NMR o (CDC13) 1.58 (2x3H. d), 2.94 (2xlH, m), 3.29(2xlH, m), 3.80 and 3.83
(each 2H, s), 3.80 and 4.39 (each lH, q), 4.73 and 4.95 (each lH, m), 6.94 (2xlH, s),
7.30 (2x~H, m)
c N-[6-(~chlorophenylhexyl)]-~t~be~ la,io-~oxo~7~ff~lin-l-yl]propionamlide
(dia~, ~;somer b)
A mixture of 6-(4-chlorophenyl)hexylamine (0.54 g,0.00256 mo1 r ~m~ttin~ J. L. El?
138464 A2 850424 (CA 103:142000)), 1-hyd~o~yben7ofri~7ole hydrate (0.35 g,
0.00256 mol), 2-(4-benzylthio-2-oxo~7Ptitlin-l-yl) -propionic acid (0.68 g, 0.00256
mol) and dicyclohexylcarbodiimide (0.53 g, 0.00256 mol) in dimethylÇ~ e (1()
ml) was stirred for 16 h at ambient tempe~tllre. The solvent was ~vapul~Led and the
residue treated with ethyl acetate. The insoluble dicyclohexylurea was filtered off and
discarded, and the filtrate washed with saturated sodium hydrogen carbonate solution,
dried (MgSO4) and evaporated tû an oil. The diastereomeric mixture was separatedby flash chromatography (silica, tert. butyl methyl ether/petrol) and fractions
c-",~ -ing the more slowly eluting diastereoisomer were combined and evapoldLed to
give the title compound as an oil (0.14 g, 11.8% yield)
1H NMR ~ (CDCl3) 1.32 (4H, m), 1.51 (3H, d), 1.53 (4H, m), 2.55 (2H,t), 2.87 (lH,
dd), 3.24 (3H, m), 3.82 (2H, s), 4.06 (lH, q), 4.69(1H, dd), 6.51 (lH, m), 7.06-7.33
(9H, m)-
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W O 97/02242 PCTAEP96/02765
F ~ ? 2 N-[6-(4chlo.o~ lhe~1)]-2-t41~-~
yl~lù, ~ sl~ - a)
Evaporation of the fractions CO~IA;~ the faster eluting ~ ct~reoi~compr in the above
eY~mrlP gave the other diastereoi.~P~ as a colourless oil (0.54g, 46% yield)
S lH NMR ~ (CDC13) 1.33 (4H, m), 1.53 (3 H, d), 1.57 (4H, m), 2.55 (2H, t), 2.83 (lH,
dd), 3.26 (3H, m), 3.84 (2H, s), 3.92( lH, q~, 4.77 (lH, dd), 6.58(1H, m), 7.05-7.36(9H, m).
EY~nple 3 N-t6-(4chlorophenylhexyl)l-2-t4l~e~ bul}~hinyl-? ~~ Un-l-
yl]~lu, '~ lel~oisomers bl &b2)
A solution of N-[6-(4-chlon~phel,ylhexyl)]-2-[4 bel~ylll~io-2-0~0~7Pti~lin-l-
yl]propic)n~mi-l~P ((li~ctPreoicomPr b) (0.96 g, 0.0021 mol) in di.,llo~o.-.Pth~nP (25 ml)
was cooled to -65 to -70~C and a solution of m-chlo,u~ll,el~oic acid (0.43 g, 0.0025
mol) in dichloromPth~nP- (10 ml) added dropwise over 15 min. After 45 min the
ule was washed with a mixture of saturated sodium hydrogen carbonate and
.c~tllr~tPd sodium s~llrhitP, dried (MgSO4) and evapolated to an oil. Cryst~lli.c~tion
from ethyl acetate - ether gave the title compound as a 40:60 mixture of
dia_tereoisomers bl:b2, m.p. 70-73~C
F.Y~mp~e 4 N-t6-(4-chlorophenylhexyl)]-2-t4b~ y~;nyl_~
yl]propiQn~m;~l~ (isomer (-)b2)
The solid was purified by chromatography (HPLC, Ch~ PIl OJ column,
ethanol/hexane), followed by silica, ethanol/hexane) to give the title compound, a
white solid, as a single enantiomer.
[a]D20 = -41.6~ (c 0.11, ethanol)
lH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m),l.61 (3H, d), 2.56 (2H, t), 2.76 (lH,
dd), 3.12 (lH, dd), 3.23 (2H, m), 3.96, 4.09 (each lH, d), 4.45 (lH, q), 4.58 (lH, dd),
7.07-7.39 (9H, m)
The other 3 components of the mixture (FY~mrl~s 5-7) were obtained by the same
chromatographic procedure.
F.Y~lmp~e S N-[6-(4-chlorophenylhexyl)]-2-t4bt:~r~ k~ 2--J~
yl]propion~mi-le (isomer (+)b2)
[a]D20 = +345~ (c 0.112, ethanol); 99.2% pure.
lH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m),l.61 (3H, d), 2.56 (2H, t), 2.76 (lH,
dd), 3.12 (lH, dd), 3.23 (2H, m), 3.96, 4.09 (each lH, d), 4.45 (lH, q), 4.58 (lH,
dd), 7.07-7.39 (9H, m)
F.Y~mrle 6 N-t6-(4-chlorophenylhexyl)]-2-t4-~ yh~ 2 ~ ;Air 1-
yl]propior ~mi~le (isomer (+)bl)
[a]D20 = +80.7~ (c 0.03, ethanol); 96.2% pure.
lH NMR ~ (CDC13) 1.32 (4H,m), 1.42 (3H, d), 1.55 (4H, m), 2.55 (2H, t), 2.90 (lH,
dd), 3.20 (2H, m), 3.45 (lH, dd), 3.88, 4.06 ( each lH, d), 4.34 ( lH, q), 4.48 (lH,
dd), 6.g5 ( lH, m), 7.08-7.41 ( 9H, m)
F.Y~mrle 7 N-t6-(4-chlorophenylhe~y~yl)~-2-t4-b~ h;nyl-2~ n
yl]prorio~mi~l~ (isomer (-)bl)
[a]D20 = -95 5~ (c 0.11, ethanol); 99.4% pure.
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CA 02225627 1997-12-23
W O 97/02242 PCT/~1f.S/~2765
lH NMR ~ (CDC13) 1.32 (4H,m), 1.42 (3H, d), 1.55 (4H, m), 2.55 (2H, t), 2.90 ( IH,
dd), 3.20 (2H, m), 3.45 (lH, dd), 3.88, 4.06 ( each lH, d), 4.34 ( lH, q), 4.48 (lH,
dd), 6.95 ( lH, m), 7.08-7.41 ( 9H, m)
FY~, le 8 N-~6-(4~orophenylheYyl)] 2 [~1 ~n7y~ finy
5 yl]~rv~ m~ al)
Tr~-~tmP-nf of N-[~(4-chlw ~ hellylhexyl)]-2-[4-bel~ylll~,o-2~o~7Pti~in- 1 -
yl]propion~mi~P (diastereoic-)mpr a) with mCPBA as rlPs~rihecl m Fy~mrle 3 gave the
title colllpouIld as a mixture of diastere~ nmPn~ Recryst~lli~ti-)n of this mL~ture from
ethyl acetate gave N-t6-(4-chlorophenylhexyl)]-2-[~b~l~yl~ulfmyl-2-o~o~
yl]prorion~mitl~ (diastereoicomPr al) as cQIo-lrlPss crystals, m.p. 168-170~C.
lH NMR ~ (CDC13) 1.32 (4H, m), 1.49 (2H, m), 1.55 (3 H, d), 1.60 (2H, m), 2.56 (2
H, t), 2.83 (lH, dd), 3.20 (2H, m), 3.38 (lH, dd), 3.88, 3.97 (each lH, d), 4.08 (ll:I,
q), 4.67 (lH, dd), 6.38 (lH, m), 7.08-7.40 (9H, m)
Example 9 N-[6-(4chlorophenylhexyl)~-2-[4-b~ ulrl~ ~n~o~ lin-l-
15 yl]propinr ~m~ (di~le~
Tre~tmPnt of the mother liquors form the above le~cly~l~lli.~tion with petroleum ether
(b. p. 40-60) gave the title compound as a white cryst lline solid, m.p. 79-81~C.
lH NM~ ~ (CDC13) 1.33 (4H, m), 1.52 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.77( lH,
dd), 3.15 (lH, dd), 3.24 (2H, m), 4.01 (lH, q), 4.01. 4.12 (each lH, d), 4.58 (lH, dd),
20 7.08-7.41 (9H, m)
FY~n-ple 10 N-~6-(4-nuorophenylhexyl)l-2-~ io-2-nYn~7~t; 1in.
yl]propiQn~ liaslt:l ~isomer b)
a Methyl-~benzylthio-2-o~ ..-1-yl)acetate
To a solution of 4-(benzylthio)~7~tir~in-2-one (S.Og, ~Smmol), methyl brom~ce
25 (4.6g, 30mmol) and tetrabutylammonium bromide (0.9g, 0.28mmol ) in dry'l'~'
(lSOml) was added powdered potassium hydroxide (1.7g, 30mmol). The resnlting
mixture was stirred for two hours at room temperature before water (50 ml) was
added. The solution was extracted with ethyl acetate (3xlSOml portions) and the
combined extracts dried (MgS04) and evaporated. The residue was purified by flash
30 chromatography on silica gel eluted with petroleum ether 60~-80~:ethyl acetate 4: 1 to
give methyl (4-benzylthio-2-oxo~7Pti~in-l-yl)acetate as a yellow oil (Sg,70%).
lH NMR ~ (CDC13) 2.96(1H, dd, J=2.5, 16 Hz _ 3a)~ 3.24,3.99 (each lH, d, J=18.00Hz, NCH2), 3.4 (lH, dd, J=5,12.5 Hz H3b), 3.70 (3H, s, OC_3), 3.77 (2H, s, SCH[2),
4.92 (lH, m, H1), 7.28 (SH, m, Ph-H)
35 b. Methyl 2-(1 benzylthio-2-o~o~t~Ain-l-yl)propionate
A stirring solution of methyl (4-benzylthio-2-oxo~7p-ti~lin-l-yl) acetate (13.27 g, 0.05
mol) in dry tetrahydrofuran was cooled to -70~C (acetone-cardice bath) and a 1 molar
srlution of lithium bis(trirnethylsilyl)amide (60 ml) was added under nitrogen over 15
min, followed by 1~3-dimethyl-2-im~ 7olone (33 ml). After 30 min, iodompth~n~ (5.6
~ 40 ml, 0.09 mol) was added dropwise. After a further hour, the reaction temperature was
allowed to Ase to -20~C, then the mixture recooled to -70~C and glacial acetic acid
(5.6 ml) added dropwise. The reaction was qllench~d with water and e,~ d three
times with ether. The combined extracts were dAed (MgS04) and evaporated to an oil
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which was purified by flash çhromatography (fine silica~ ethyl acetatetlight petrol) to
give the product as a mixture of diastereoisomers, co~ tecl with 9% of the
dimethylated product, as a yellow oil, 13.7 g, 89% yield
lH NMR ~ (CDC13) 1.55 (2x3H, d), 2.93 (2xlH, m), 3.29(2xlH, m), 3.74 and 3.75
(each 3H, s), 3.80 and 3.84 (each 2H, s), 3.91 and 4.41 (each lH, q), 4.70 and 4.96
(each lH, m), 7.30 (2x5H, m)
c. 2-(4Be-~ylll,io-2-oxfi~ yl)propionic acid
A stirred solntion of methyl 2-(4-b~l~yllllio-2-oxo~7Pti~lin-l-yl)propionate (1.39 g,
0.005 mol) in m~th~nol (12 ml) was treated with 1 molar pol~ hyd~ ide (5.47
ml). After 2 hours, the mPth~nt)l was evaporated and the residue diluted with water
and extracted twice with ether. The aqueous layer was ~ ih~ci with cooling (ice
bath) and the oil which plC;~ ;ril~tPd was eYtr~ct~od into ether. The combined es~ctc
were dried (MgSO4) and evaporated to give the title compound as a white solid
(mixture of diastereoicomPr.~), m.p. 78-82~C, 0.98 g, 74% yield.
1H NMR q (CDC13) 1.58 (2x3H, d), 2.94 (2xlH, m), 3.29(2xlH, m), 3.80 and 3.83
(each 2H, s), 3.80 and 4.39 (each lH, q), 4.73 and 4.95 (each lH, m), 6.94 (2xlH, s),
7.30 (2xSH, m)
d. N-[6-(4-fluorophenylhexyl)~-2-t4-1 e~ ylll~io~ e~ -l-yl]l"~r ~ ~ ude
,...o;c~ . b)
A mixture of 6-(4-~luoll~phenyl)hexylamine (3.0 g, 0.0154 mol,), 1-
hydroxybenzotriazole hydrate (2.08 g, 0.0154 mol), 2-(4-benzylthio-2-oxo~7Pti-lin-l-
yl)-propionic acid (4.08 g, 0.0154 mol) and dicyclohexylcarbo~liimi-le (3.17 g, 0.0154
mol) in dimethylfonn~mi-le (60 ml) was stirred for 16 h at ambient temrer~tl-re The
solvent was evaporated and the residue treated with ethyl acetate. The in~Qhlbledicyclohexylurea was filtered off and d~c~ded, and the filtrate washed with s~t~lr~ted
sodium hydrogen carbonate soll~tion, dried (MgSO4) and evaporated to an oil. Thediastereomeric mixture was sepala~d by flash chromatography (fine silica, ter~ butyl
methyl etherlpetrol) and fraction~ corl~inin~ the more slowly eluting diastereoisomer
were combined and evaporated to give the title compound as an oil, yield 1.89 g (28%)
lH NMR (CDC13) ~ 1.33 (4H, m), 1.51 (3H, d), 1.53 (4H. m), 2.55 (2H,t), 2.87 (lH,
dd), 3.24 (3H, m), 3.82 (2H, s), 4.06 (lH, q), 4.69(1H, dd), 6.51 (lH, m), 6.91-7.33
(9H, m).
F,Y~ r 11 N-[6-(4-nuorophenylhexyl)]-2-[1 ben_ylthio-2-oY~7el;~1; -1-
yl]propio~n~: le (~ co~ a)
The more rapidly eluting diastereoisomer was also obtained from the above columnchromatography as an oil, yield 2.8 g (41%)
1H NMR ~ (CDC13) 1.33 (4H, m), 1.53 (3 H, d), 1.57 (4H, m), 2.55 (2H, t), 2.83
(lH, dd), 3.26 (3H, m), 3.84 (2H, s), 3.92( lH, q), 4.77 (lH, dd), 6.58(1H, m), 6.91-
7.36(9H, m).
F.Y~mrle 12 N-[6-(4-fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-o~
yl]propiq~r: le (.lia~h,~vicc~ bl+b2)
A sollltion of N-[6-(4-fluorophenylhexyl)]-2-[4-benzylthio-2-oxo~7Ptidin-l-
yl]propionamide (diastereoisomer b) (Fx~mrl~ 11) (1.82 g, 0.0041 mol) in
dichoromethane (30 ml) was cooled to -65 to -70~C and a solution of m-
chlolup~.l~llzoic acid (0.85 g, 0.0049 mol) in dichlorometh~nt- (30 ml) added
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dropwise over 30 min. After 2 h the mixture was washed with a mixture of .ca
sodium hydrogen carbonate and s~t~lr~qted sodium slllphitP, dried (MgSO4) and
e~vapoldL~:d to an oil. Crysf~ c~tirm from ethyl acetate - light petrol gave a mi-Atun~ of
diastereomers (1.18 g) (bl:b2, 1:3), m.p. 75-78~C.
S FY~r~rl~P 13 N-t6-(4fluoroph~lyll-~A~1)]-? [4~~ 1-2 ~ idin~
yl3~1V~ P (~ (-)b2)
The above mixfure of diacfereoi.cnm~r.C bl + b2 wac sep~ Pd by HPLC (Dynama~;
silica col~nn, ethanol/hexane) into bl and b2. Di~tP.e.oi.comPrb2 was then .CI~y~ tP(
into its co.llyonent çn~nti~mPrs by ciral HPLC (C~hir:llr~l OD column,
10 etnanoVhexane) to give the title coll,pouud as a white solid, 0.06 g
lH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m),l.61 (3H, d), 2.56 (2H, t), 2.75(1H,dd), 3.11(1H, dd), 3.23 (2H, m), 3.96, 4.09 (each lH, d), 4.45 (lH, q), 4.58 (lH, dd),
6.92-7.40 (9H, m)
[a]D20 = -36.2 (c 0.46, ethanol)
FY~mrle 14 N-[6-(4-fluorophenylhexyl)]-2-14-~.. ~.yl~ inyl-2
yl~prop:or- '?(~ ~so~ (+)b2)
ALco obtained was the (+) en~ntiomP-r as a white solid, yield 0.06 g.
lH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.75(1H,
dd), 3.11(1H, dd), 3.23 (2H, m), 3.96, 4.09 (each lH, d), 4.45 (lH, q), 4.58 (lH, dd),
6.92-7.40 (9H, m)
[a] D20 = +32.7 (c 0.42, ethanol)
Tre~tmen~ of N-[6-(4-fluorophenylhexyl)]-2-[~ber~zyllllio-2--)xo~7Pti~in-l-
yl]propionamide (1.15 g) (diactereoicomP-r a, FY~mplP 10) with mCPBA (0.54 g) bythe procedure ~le-s~ribed in Fy~mrle 12 gave the following two dia~ coic4---Prc after
chromatography (Examples 15, 16)
FY~mrle 15 N-t6-(4-fluorophenylhexyl)]-2-[4~ JAua~lidin l-
yl]l~ù~i<J .~m ~lP (~ Q;~ .Pr al)
0.5 g, white solid, m.p. 165-7~C, lH NMR d (CDC13) (selPcf~d tli~gnosti- peaks) 4.11
(lH, q, a-H), 4.70 (lH, m, H4); Found: C, 65.2; H, 6.7; N, 5.8% C2sH31FN2O3S
requires: C,65.5; H,6.8; N,6.1%
F~ le 16 N-~6-(4-fluorophenylhexyl)]-2-t4b~ ..ll,hinyl 2-~n~ffA n..l-
yl]propion~ e (~ ~oico~
0.28 g, white solid, m.p. 73-5~C, lH NMR d (CDC13) (sPlPcted ~ gnosti~ peaks) 400
(lH, q, a-H), 4.58 (lH, m, H4); Found: C, 65.3; H, 6.65; N, 5.7% C2sH21FN2O3S
requires: C, 65.5; H, 6.8; N, 6.1%
F~Y~mrle 17 N-[6-(4-fluorophenylhexyl)]-2-[4-b~ honyl-2-o~o~ in~-l-
yl]propion~m~ ,eoiso~-~er a)
Tre~tmPnt of N-t6-(~fluorophenylhexyl)]-2-t4-benzylthio-2-oxo~7Pti~lin-l-
yl]propionamide (2.7 g) (diastereoisomer a, Example 10) with mCPBA (2.43 g) at
room t~mpçr~tllre gave the title compound as a white solid (2.43 g), m.p. 85-7~C; lH
NMR d (CDC13) (selected diagnostic peaks) 3.96 (lH, q, a-H), 4.75 (lH, m, H4);
Found: C, 63.2; H, 6.45; N, 5.9% C2sH31FN2O4S requires: C, 63.3; H, 6.6; N,
5.9%
F.Y~rle 18 N-l6-(4-Fluorophenylhexyl)]-2-t4~ y~ o~yl-2-o~o~ ;m-l-
45 yl]propion~mi-le (dia~le~ ~isomer b)
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W O 97/02242 PCT/~r,''~765
Tre~tmPnt of N-[6-(4-fluo~,phe,.ylhexyl)]-2-t4-be,~yllllio-2-o~o~7Pt~ n-l-
yl]propion~mi~l~P (0.39 g) (diasterenicomPr b, FY~mrl~. 113 with mCPBA (0.22 g) at
room Ir-IIpP.I~ gave the title compound as a white solid (0.29 g), m.p. 90-2~C; lH
NMR d (CDC13) (SPlP-ctpd fli~gnnstir- peaks) 4.27 (lH, q, a-H), 4.64 (lH, m, H4);
Found: C, 63.0; H, 6.4; N, 5.85% C2sH31PN2O4S l~Ui~ C, 63.3; H, 6.6; N,
5.9%
Example 19 N-(Benzyl)-2-[41~,~11hio-~ .,~ yl]propionamide
(did~ oi~~ r a)
Tre~tmPnt of 2-(4-benzylthio-2-oxo~7Ptitlin-l-yl)p~opionic acid (F~mple lOb) with
benzylamine under the cnnrlitinnc ~lese~ibP-~l in FY~mplP lOc gave the title compound as
the higher rf product after chromatog.aphy: 1.19 g, clear oil; lH NMR d (CDC13)
(SPlPctP-d fli~gnostic peaks) 4.27 (lH, q, a-H), 4.80 (lH, m, H4);
FY~n~P'~ 20 N-(Benzyl)-2-[41~ io-2~ yl]propionan~ide
From the above chromatographic sep~r~tion the lower rf fT~ctionc were combined to
give the title compound as a colourless solid, m.p. 70-2~C, 1.44 g; lH NMR d
(CDC13) (SPhPCtpd rli~onnstiC peaks) 4.10 (lH, q, a-H), 4.69 (lH, m, H4);
Example 21 N-[6-(4Fluorophenylhexyl)]-2-r4(allyloA~ l,v~ e ~L~lll~io~-2-
,~"~ .- l yl]prv~ lia~ - a)
a Allyl4(~v~.~o~thyl)b~ o~lt
~(BromomPthyl)benzoic acid (103 g, 0.48 moles) was sncpPnt1P~ in thionyl chln~ P(200 ml) and dimethylform~mi-lP- (1 ml) was added. The ~ t; was heated under
reflux until clear, evaporated and azeotroped with toluene (2 x 150 ml). The res~lltin~
oil was dissolved in dichloromPth~nP and added d~ wise to a cooled solution of
pyridine (42 ml) and allyl alcohol (40 ml) in dichlolo~ nP. The mixture was stirred
at room temperature for 1 hour, then washed with water, 2M hydrochloric acid,
sodium hydrogen carbonafe solufion and brine. The organic solution was dried andevaporated to give allyl 4-(bromomethyl)be-n70~tP as a clear oil (98g, 84% yield). lH
NMR d (CDC13) 4.61 (2H, s, CH2), 4.82 (2H, m, C_2~)~ 5.34 (2H, m, C_2CH-),
6.05 (lH, m, CHCH2), 7.45 (2H, d, Ph-H), 8.03 (2H, d, Ph-H).
b. Allyl 4-(aeelylll~iol~eu~yl)~ o~fe
Allyl 4-(bromomethyl)ben7o~t~p (98 g, 0.4 moles) in dry dimethylf~-rm~mi~e (100 ml)
was added dropwise to a cooled suspension of potassium thio~-~et~tP (46 g, 0.4 moles)
in dry dirnethylform~midP- (200 ml). The cooling bath was removed and the mixture
was sfirred overnight. The rection mixture was poured into water and extracted with
efhyl acetate (x3). The combined extracts were washed with water and brine. The
mixture was dried and evaporated to give allyl 4-(aceLyl~l.iomethyl)~.~o~ as an
orange oil (lOOg, 100% yield). lH NMR d (CDC13) 2.36 (3H, s, COCH3), 4.13 (2H,
s, CH2), 4.82 (2H, m, C_2~)~ 5 32 (2H, m, CH2CH-), 6.05 (lH, m, CHCH2), 7.35
(2H, d, Ph-H), 7.98 (2H, d, Ph-H).
c. 4-~4-(Allyloxycarbonyl)be,~yl~llio)~ ;..-2-one
Allyl alcohol (27 ml) in dry tetrahydloîulan (50 ml) was added dropwise to a solution
of pot~c~ m tert-butoxide (4.93 g, O.W4 moles) in dry tetrahydrofuran (100 ml).
After stirring for S mimltPs a solution of allyl 4-(acetylthiomPthyl)bç..7.0~tP (10.1 g,
0.04 moles) in dry tetrahydrofuran (100 ml) was added dropwise. After stirring for 15
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W O 97/02242 PCT~EP96/0276S
...;...,I~s a sohltion of 4-aceto~y~ in-2-one (5.16 g, 0.04 moles) was added
dropwise. The ~ was stirred for 1 hour and ev~pol~d. The residue was
partitioned be~wt;en ethyl acetate and water and the a~luevu~, was ~ d w~th ethyl
acetate. The c~)mbinPd extracts were washed with brine, dried and ev~o,~t~d. Flash
5 chromatography (silica gel, ethyl acetate-petrol) gave 4-(4-
Allylo~ye~bonylbel~yllllio)~7P-ti~in-2-one as an oil (9.lg, 82% yield). lH NMR d(CDC13) 2.84 (lH, dd, H3a), 4.31 (lH, dd, H3b), 3.88 (2H, s, S-CH2), 4.68 (lH, dd,
~ H4), 4.78 (2H, m, CH2O), 5.35 (2H, m, C_2CH-), 6.05 (lH, m, CHCH2), 6.07 (lH,
br. singlet, N-H), 7.40 (2H, d, Ph-H), 8.03 (2H, d, Ph-H).
10 d. Methyl 4~1 (Allyl~ ~bonyl)l~,~ltl..o)~ r l-
~To a stirring solution of 4-(4-(allylo~-yc~l,ollyl)l~llzylll~~o)~7P~;A;i.-2-one (2.55 g, 9.:~
mmol), tetrabutyl~mmoni-lm bromide (0.33 g, 1.02 mmol) and methyl br mo~r~et~tP
(1.06 ml, 11.2 mmol) in dry tetrah~ .r~ (40 ml) was added powdered pol ~
hydroxide (0.63 g, 11.2 mmol) kP.epin~ the reacdon tPml~..,,l...c~ below 30 by means of
a cold water bath. After 2 h, the mixture was diluted with water and çxt~ctP~ three
times with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated
and the residue chromatogr~rhpd (fine silica, ethyl acetate-petrol) to give the title
compound as a clear oil, yield 2.66 g (83%).
lH NMR o (CDC13) 2.97 (lH, dd, H3a), 3.26. 4.07 (each lH, C_2CO, d). 3.42 (lH~.
dd, H3b), 3.70 (3H. s, C_3O), 3.81 (2H. s, SC_2)~ 4.83 (2H, m, C_2~)~ 4-93 (lH,
dd, H4), 5.35 (2H, m, C_2CH), 6.03 (lH, m, C_CH2), 7.39 (2H, d, Ph-H), 8.02 (2H,d, Ph-H)
e. Methyl 4(4(allylo~eal1,onyl)bel~y' ' ~)-2-o~ r~, ~nate
Methyl 4(4(allyloxycarbonyl)benzylthio)-2-oxo~7ptitlin-l-ylacetate (23.8 g, 68
mmolps) was stirred at -65~C in dry tretahy~orul~ under nitrogen and treated with
lithium bis(trimethylsilyl)amide (81.6 ml of a 1.0 molar solution in hexane), lrPepin~ Ithe
temperature to -65~C. The mixture was stirred for 5 minlltP~, then treated with 173-
dimethylimi-l~7olitiinonP (44.6 ml) dropwise Pn~nrin~ the ~l,lpelaLult: did not nse.
This m~lul~ was stirred for 30 mimltPs then methyl iodide (7.6 ml) was added
dropwise. The llli~ was stirred for a further 1 hour then allowed to warm to -20~C.
After re-cooling, the mixture was treated with acetic acid (7 ml), poured into water
and extracted with ethyl acetate (x6). The combined extracts were dried and
ev~polated to an orange oil. Flash chromatography (fine silica, 20% ethyl acetate in
petrol) gave the required methyl ~(4-(allyloAy~;~bonyl)bel-~ylLhio)-2-oxo~7Pti(lin-2-
ylpropionate as a yellow oil as a mixture of diastereoisomers (15.2 g, 62%).
lH NMR o (CDC13) 1.56 (3H, d), 2.85-2.96 (2H, m, diastereomer A and B, H3a)~
3.24-3.35 (2H, m, diastereomer A and B, H3b), 3.74 (3H, s), 3.76 (3H, s), 3.87 (2H,
d), 3.97 (lH, q, diastereomer B, N-C_), 4.43 (lH, q, diastereomer A, N-C_), 4.71(lH, m, diastereomer B, H4), 4.82 (2H, m), 4.97 (lH, m, diastereomer A, H4), 5.27-
5.46 (2H, m), 5.96-6.10 (lH, m), 7.39 (2H, d), 8.02 (2H, d).
f. 4-(4-(Allyloxy~l l,onyl)~ ylll~,o)-2-v~ 2~ acid
29.7 ml of 1 M potassium hydroxide solution was added dropwise over 20 mimltes IO
a sol-lti-)n of methyl 4-(4-(allyloxycarbonyl)benzylthio)-2-oxo~7Pti~lin-2-~ pi~(9.0 g, 0.0248 moles) in te~ahydrofuran (100 ml), keeping the temperature to 0-5~C.
The ~ Lul~ was stirred for a further 20 minut,qs then diluted with water and e~rart~
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with ether (x2). The aqueous so1~ltion was recoolP-d and ~ri~ifiPd with dilute
lly~lloel~loric acid then PYtr~e~d with ether (x2). The comhinPd ex~acts were dried
and eva~O~atedtO give the title compound as a yellow oil, 8.5g, 98% yield
lH NMR ~ (CDC13) 1.50-1.6 (3H, m), 2.86-2.98 (2H, m, di~lGlco,~er A and B, H3a)~3.24-3.35 (2H, m, diastereomer A and B, H3b), 3.87 (2H, d), 395 (lH, q,
diastereomer B, N-CH), 4.45 (lH, q, diastereomer A, N~_), 4.75 (lH, m,
diastereomer B, H4), 4.82 (2H, m), 4.98 (lH, m, diastereomer A, H4), 5.27-5.46 (2H,
m), 5.96-6.10 (lH, m), 7.39 (2H, d), 8.02 (2H, d).
g. (+/-)-N-t6-(4-Fluorophe~ Yyl)~- 2-t4(allylo~ bo...~lbel~;l'h,~)-2-
10 ~Yo~ ;.- l-yl]~"u~ , a)
Dicyclohexylcarbo-liimidP (4.75 g, 23 mmol~~) in dry dimG~IylÇ~ e (50 ml) was
added dropwise to a cooled sol-ltio~ of 4-(4-(allylu~y~l,onyl)l,el~yl~lio~2-
oxo~7etidin-2-ylpropionic acid (8.0 g, 23 mmnlPs), l-hydro~y~ 7~ 7o1P hydrate
(3.11 g, 23 mmoles) and 6-(4-fluorophenyl)hexylamine (4.5 g, 23 mmoles) in dry
15 dimethylformamide (S0 ml). Cooling was removed and the mixture was stirred
overnight. The dimethylf~3rm~midP was evaporated and the residue was purified byflash chromatography (fine silica, ter~-butylmethyl ether then ethyl acetate) to provide
samples which were predo...i..~ y diastereoisomer a (4.6 g), d~a~,eoicomP~ b (2.7 g)
and mixed fr~rtionc
Diastereoisomer a: yellow oil, 4.6 g, 38% yield
lH NMR o (CDC13) 1.23-1.63 (llH, m), 2.55 (2H, t), 2.81 (lH, dd, H3a)~ 3.20-3.30(3H, m, CH2 and H3b), 3.90 (2H, d), 4.04 (lH, q, N-CH), 4.78-4.84 (3H, m, C_2 and
H4), 5.27-5.45 (2H, m), 5.95-6.09 (lH, m), 6.50 (lH, br. triplet, NH), 6.90-6.98 (2H,
m), 7.06-7.26 (2H, m), 7.40 (2H, d), 8.02 (2H, m).
F-Y~ 22 (+/ ) N t~(4FI -= ol,henylheYyl)]-2-[4(a~lylo~ onyl-
l~l~ylll~io)-2--~Yo~ in-l-yl]propionamide (di~h.~.30mer b)
From the above chromatography diastereoicomP-r b was obtained as a yellow oil, 2.7 g,
~% yield
lH NMR ~ (CDC13) 1.23-1.63 (llH. m), 2.55 (2H, t), 2.85 (lH, dd, H3a)~ 3.19-3.23(2H, m), 3.28(1H, dd, H3b), 3.91 (2H, s)t 4.09 (lH, q, N-C_), 4.69 (lH, dd, H4),4.82 (2H, d), 5.25-5.45 (2H, m), 5.95-6.09 (lH, m), 6.43 (lH, br. triplet, NH), 6.90-
6.98 (2H, m), 7.06-7.26 (2H, m), 7.40 (2H, d), 8.02 (2H, m).
FY~mrl~q 23 (+/-)-N-t6-(4-Fluorophenylhey-yl)]- 2-14-(4-
allyl~l~onyl)~ y~ rhinyl)- 2-oy~7~ n-l-yl]~lr~)~ ~n~ide
(diasterec icO~ b2+bl 3:2)
A solution of (+I-)-N-[6-(4-fluorophenylhexyl)]- 2-[4-(allylo~y~ l~uIlylbel~yllllio)- 2-
oxo~7Pti~lin-l-yl]propion~mirle (diastereoisomer b) (2.5 g,4.75 mmoles) in
dichloromPth~nP (50 ml) was stirred at -65~C and treated with a solution of m-
chlorope~l,en~oic acid (1.0 g, 5.7 mmoles) in dichloromP-th~nP (30 ml). The mixture
was stirred for 1 hour, poured into a solution of sodium hydrogen carbonate and
sodium s~llphi~p7 separated and the a~ueous eytr~ctp~l with dichlorome-th~nP. The
combined extracts were washed with brine, dried and evà~Jo~ated to an oil which was
purified by flash chromato~raphy (fine silica, ethyl acetate) to give the title compound
as a yellow oil, 1.3 g, 50% yield as a 3:2 mixture of sulfoxide diastereoisomers 2 and 1.
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F~ '- 24 (+/-)-N-[~(4Fluo.(i~,henylhexyl)]- 2 t4(4
allylc,~ 2 c~ 1-yl3~ de
(~lia~h.~ , b2)
The sulfoxide diastereoi~omPr~ above were sep~rated by HPLC to give the ~dtle
- S compound as a yellow oil, 100 mg
lH NMR ~ (CDCl3) 1.32-1.34 (4H, m), 1.4~1.63 (4H, m), 1.61 (3H, d), 2.55 (2H, t),
2.84 (lH, dd, H3a)~ 3.15-3.31 (3H, m, H3b and CH2), 4.01 and 4.09 (lH each, d),
4.50 (lH, q, N-CH), 4.61 (lH, dd, H4), 4.83 (2H, d), 5.29-5.45 (2H, m), 5.95-6.0S'
(lH, m), 6.90-6.98 (2H, m), 7.06-7.26 (2H, m), 7.37 (2H, d), 8.08 (2H, m).
FY~mr~ 25 (+/-~N-t6~(4-Eluo~v~l~e~ h~A~ _t~4
allyloA~LonYl)bw~ Yl)-2 Q~ l-yllpropionamide
(~5isl~n ;o~ . bl)
The above chromatography also gave ~e title col,.~und as an oil, 50 mg
lH NMR ~ (CDC13) 1.32-1.34 (4H, m), 1 4~1.63 (4H, m), 1.45 (3H, d), 2.54 (2H, t),
lS 2.90 (lH, dd, H3a)~ 3.18-3.22 (2H, m, CH2), 3.43 (lH, dd, H3b) 3.94 and 4.02 (lH
each, d), 4.34 (lH, q, N-CH), 4.53 (lH, dd, H4), 4.83 (2H, d), 5.29-5.45 (2H, m),
5.95-6.09 (lH, m), 6.80 (lH, br. triplet, NH), 6.90-6.98 (2H, m), 7.06-7.26 (2H, m),
7.37 (2H, d), 8.08 (2H, m).
FY~mrle26 (+/-)-N-[6-(4-fluorophenylhexyl)~ 2 t4 (4
(allyloxy~l,onyl)bel~Ly~ hinyl)-2-o~ lir l-yl]propionamide
(~li~l~.eo;30mer al)
TrP~tmPnt of N-t~(1 fluorophenylhexyl)]- 2-~4-(allylu~y~l,o"ylben_yl~lllrhinyl)- 2-
oxo~7~Pti(1in-l-yl]propion~mi-le (diastereoisomer a, FYZImpl'' 21) with mCPBA by th~e
method (~çscrihed in Example 23 gave the title compound as white crystals after
chromatography and le~,y~ s~tiQ~ from ethyl acetate, m.p. 175-177~C, 27% yiel~
lH NMR ~ (CDC13) 1.32-1.34 (4H, m), 1.38-1.65 (4H, m), 1.54 (3H, d), 2.55 (2H, t),
2.82 (lH, dd, H3a)~ 3.20 (2H, dt, CH2), 3.35 (lH, dd, H3b) 3.94 (2H, d), 4.17 (lH[, q,
N-CH), 4.78 (lH, dd, H4), 4.83 (2H, d), 5.29-5.45 (2H, m), 5.95-6.09 (lH, m), 6.35
(lH, br. triplet, NH), 6.90-6.98 (2H, m), 7.06-7.26 (2H, m), 7.37 (2H, d), 8.08 (2H[,
m)-
FY~rl~P 27 (+/-)-N-t6-(4-ilu~l u~JhenylheYyl)~ 2-[4-(4-
(ally~ du~onyl)be~l~..l~hinyl)-2-n~A~ _yl]~ ?
(~li&~h. ~;so...er a2)
From the above reaction (Example 26) the title compound was obtained as off-white
crystals after chromatography and recryst~ nn from diethyl ether, m.p. 75-76~C,
22% yield
lH NMR ~ (CDC13) 1.32-1.34 (4H, m), 1.38-1.65 (4H, m), 1.62 (3H, d), 2.56 (2H, t),
2.82 (lH, dd, H3a)~ 3.17-3.30 (3H, m, CH2 and H3b), 4.00-4.15 (3H, m, CH2 and N-- CH), 4.63 (lH, dd, H4), 4.83 (2H, d), 5.29-5.45 (2H, m), 5.95-6.09 (lH, m), 6.90-
6.98 (2H, m), 7.06-7.26 (3H, m), 7.37 (2H, d), 8.08 (2H, m).
F~y~mple 28 (+/-)-N-[6-(4-fluorophenylheYyl)]- 2-[4-(4-
(carboxy)be..~ h nyl)_2_oYn~7Pff~lin-l_yl]propiQn~m;~le (lli&l~:leu~ nPrs
b2+bl 3:2)
Trç~t~nPnt of (~/-)-N-[6-(4-fluorophenylhexyl)]- 2-[4-(4-allyloxycarbonyl)-
45 benzyl.~ rhinyl)-2-oxoazetidin-1-yl]propionamide as the mixture of diastereoisomers
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W O 97/02242 PCT~EP96/0276
produced in FY~mrlP 23 (b2+bl 3:2) (0.32 g) with triphenylrhosphin~ (0.165 g),
pyrrolidine (0.045 g) and tetrakis triphellylphocp~ p~ m(o) (0.02 g) in
dichlor~mP-th~nP (40 ml) under nitrogen for 16 h, followed by aqueous work-up gave
the title compound as a white solid, m.p. 122-150~C, 0.155 g, 51 % yield as a 3:2
S mixture of diastereoi.com~rs b2 and bl.
lH NMR - some rii~gnostio peaks: ~ (CDC13) 4.7 (m, H4 of dia b2) 4.6 (m, H4 of dia
bl).
Example29 (+/-)-N-[6-(4Fluo.~ l)heY~yl]-2-(4-be~ lll.io~2-oYn~7~tidin-l-
yl-3-(3-furyl)~ c n~m;~le (~l~a~ eGi~mers a and b)
10 a 4-(Benzylthio~ ;..-2-one
Sodium (8.1g, 0.35mol) was dissolved in ethanol (250ml) and benzyl mel-;d~l
(45.2g, 0.37mol) added dropwise over 20 minlltos k~epin~ the ~Ill~la~ belwe~ll 20
~C - 25~C whilst bubbling nitrogen through the .~ After 15 Ill;lllll~S, thereaction was cooled to 5~C and a solution of ~acetoxy~7P~ti~iin-2-one (45.0g, 0.35mol)
15 in ethanol (50ml) was added d.~.p~ise over 15 minntPs whilst m~ g the
temrer~tllre at 5~C. The mixture was stirred at room l~lll~ldlUlt~ for 60 minntes and
evaporated to dryness under reduced pl~S~ c;. Water (400ml) was added, the
ç~rtr~etPd with dichlor mPth~nP (2x300ml), the eYt~c'tc dried (MgSO4) and
evapo.a~d under reduced p.~s~u,e to an oil. The oil was cooled to -20~C and
~o titnr~t-~d with ether (400ml) to give a white solid which was isolated by filtration
(50.2g, 79%), mp 50-51.0~C.
lH NMR ~ (CDC13) 2.86(1H, m, H3a)~ 3.30 (lH, m, H3b), 3.85 (2H, s, SCH2), 4.68
(lH, m, H,l), 7.31 (SH, m, Ph-H).
b. Methyl-(4-benzylthio-2-o~ ;..-l-yl) acetate
To a solution of 4-(bel"ylLhio)~7~ti~1in-2-one (5.0g, 25mmol), methyl bromo~cet~to
(4.6g, 30mmol) and tetrabutylammonium bromide (0.9g, 0.28mmol ) in dry THF
(150ml) was added powdered pot~c~jnm hydroxide (1.7g, 30mmol). The res~llting
ule was stirred for two hours at room te~r pPr~tllre before water (50 ml) was
added. The solution was extracted with ethyl acetate (3xl50ml portions) and the
combined extracts dried (MgS04) and evaporated. The residue was purified by flash
chromatography on silica gel eluted with petroleum ether 60~-80~:ethyl acetate 4: 1 to
give methyl (4-benzylthio-2-o~o~7P-ti~in-l-yl)acetate as a yellow oil (5g, 70%).lH NMR ~ (CDC13) 2.96(1H, dd, J=2.5, 16 Hz H3a)~ 3.24,3.99 (each lH, d, J=18.00
Hz, NCH2), 3.4 (lH, dd, J=5,12.5 Hz H3b), 3.70 (3H, s, OCH3), 3.77 (2H, s, SCH2),
4.92 (lH, m,_4), 7.28 (SH, m, Ph-H)
c 3-Bro~ -yllu~d~-
A solution of triphenylphosphine (8.45g, 0.0322moles) and 3-(llyd~u~yl~lethyl)-furan
(2.93g. 0.02987moles) in dry dichloromethane (30ml) at 0~C was treated with N-
br~!mosurrinimi-l~P (5.74g, 0.03225moles) in solid portions over 10 minlltes Thereaction was stirred at 0~C for 30 minutes and the allowed to warm to 15~C over 1.5
hours. The reaction was then purified by flash column chromatography on silica gel
eluted with petroleum ether 40-60~C to give 3-bromomPthylfuran as a pale yellow oil
(3.25g, 68%).
d. Methyl 2-(4be~ o-2-oyo~7~ffAin-l-yl)-3-(3-furyl)propionate)~
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W O 97/02242 PCT~EP96/02765
A solution of methyl-(4-benzylll-io-2~ o~7Pt~ n-l-yl)~et~t~P (3.0g, 0.01131moles) in
dry tetra~ly~ ,Çu~an (60ml) at-78~C under r~itrogen was treated with a lM s~ tion of
lithium bis(tnmethylsilyl)amide in 1~ (13.8ml, 0.0186moles) over 10 mimlte~
kPepin~ the temr~Pr~ lre below-74~C. 1,3-Dim~ yl~ 7~ in-2~ne (7.5mL
0.0687moles) was added kpeping the ~ below -74~C. The r~snltin~
s~ cion was stirred at -78~C for 30 .--i----l~s and then treated with a solution of 3-
bromomethylfuran (3.0g, 0.0186moles) in dry THF (lOml) over 10 ~ s k~Ppi~
the le~ tnre below -73~C. The reaction was stirred at -78~C for 1 hour and then
allowed to warm to -20~C over 30 mim~tPs The r~tion was cooled to -75~C and
q~len~h~od with glacial acetic acid (l.~ml), partititionp~ ~Lw~,. brine (150ml) and
ethyl acetate (lSOml). The organic layer was washed with water, dned (MgS04) arld
evaporated to a coloured oil (7.81g). Purified by flash column chromatography onsilica gel eluted with 2:1 petroleum e~er 40-60~C:ethyl acetate to give methyl 2-(4-
be ,zyl~.io-2-oxo~7Pti~lin-1-yl)-3-(3-~uryl)propionate as yellow oil (2.35g, 60%, 85: 15
d.~L~lGoicom~r A:B)
lH NMR ~ (CDC13) 2.83, 2.90 (dd, J=2.4, lS.S Hz, 1 Of _3A)~ 3.17 (m, CH2-furyl,
--3B 3A)~ 3.54, 3.80 (2H, 2xs, SCH2A+g), 3.77 (3H, s, C02CH3), 3.95,4.26 (lH,
2xm, C_A+B), 4.60, 4.64 (lH, 2xm, H,lA+g), 6.30 (lH, m, furyl-H), 7.30 (6H, m,
Ph-_, furfyl-H)
e. 2-(4-be.. ~ylU~io-2~Yo~7~ in-1-yl~3-(3-furyl)~ acid
A sol--tinn of methyl 2-(4-benzyl~.io-2-o~ro~7Pti~lin-l-yl)-3-(3-furyl)propionate (2.93g,
0.00848 moles) in meth~nQl (SOml) at 10~C was treated with a lN sodium hydroxidesolution (8.5ml, 0.0085moles) over 30 ...;.~ es The cooling bath was removed andthe reaction was stirred for 1 hour. lN NaOH (l.Oml) was added and the reaction was
stirred for 30 minut~s~ diluted with water (SOml) and evaporated to remove m-oth~nt)l
The residue was mixed with water (SOml) and extracted with diethyl ether (SOml). The
aqueous was ~ ifiPd with dilute Hcl and e~t~r-t~-d with diethyl ether (2x75ml). The
organic extracts were combined, washed with brine, dried (MgS04), and t;vapOl~d
to give 2-(4-benzylthio-2-oxo~7~ti~1in-1-yl)-3-(3-furyl)propionic acid as a cream soliid
m.p. 77-80~C (2.73g, 97%, 50:50 distereoi~omt~r A:B)
lH NMR o (CDC13) 2.86, 2.92 (dd, J=2.3, 15.4 Hz, H3), 3.10 (m, CH2-furyl, H3),
3.54, 3.79 (2H, m+s, SCH2A+g), 3.89 (m, C_B)~ 4.19 (m, C_A)~ 4.23 (lH, bs,
C~2_), 4.57, 4.64 (lH, 2xm, H4A+g), 6.30, 6.37 (lH, 2xbs, furyl-HA+g), 7.30 (6H,m, Ph-H, furfyl-_)
f. N-t6-(4Fluorophenyl)hexyl]-2-(1 bel~ylll-io~2-oYo~e~ l-yl-~(~
furyl)propi~ e (dia~ rs a and b)
6-(4-Fluorophenyl)hexylamine (l.S9," 0.00814moles) in dry DMF (75ml) was added
to a mixture of 2-(4-benzylthio-2-oxo~7~t~ n-l-yl)-3-(3-furyl)propionic acid (2.7g,
0.00814 moles), 1-hydroxybenzotriazole (l.lg, 0.00814moles), 1-cyclohexyl-3-(2-
morpholinoethyl)carbodiimide metho-p-toluene sulfonate (3.5g, 0.00826moles) and the
r~snlting solution was stirred at room IP~ tllre for l9h. The ~ cicn was
partitioned between aq.NaHC03 (175ml) and diethyl ether (75ml). The layers were
sep~r~t~d and the aqueous layer was washed with diethyl ether (75ml). The organic:
extracts were combined and washed with brine (x2), dried (MgS04) and evaporated to
an orange oil (3.76g). Purified by flash column chromatography on silica gel eluted
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W O 97/02242 PCT~EP96/02765
with 2:1 petroleum ether 40-60~C:ethyl acetate to give the title compounds as
colourless oils.
Diastereoi.eomer a, 1.17g, 28% (coll~ins 20% dia~etereoi~eo-mpr b)
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xC_2)~ 2.55 (2H, t, J=7.9 Hz, CH2Ph), 2.75,
2.80 (dd, H3), 3.15 (m, C_2-furyl, H3), 3.75 (3H, m, CH, SC_2)~ 4-30 (lH, m, H1),
6.23 (lH, bs, furyl-_), 6.85 (lH, m, N_), 6.9-7.4 (1 lH, m, pF-Ph-H, Ph-H, furyl-H)
Diastereoieomer b, 1.36g, 33% (cont~ine 20% diastereoieompr a)
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.55 (2H, t, J=7.9 Hz, CH2Ph), 2.81,
2.87 (dd, _3), 3.15 (m, C_2-furyl, H3), 3.70 (2H, s, SC_2)~ 4.12 (lH, m, C~),
4.57 (lH, m, Hl), 6.25 (lH, bs, furyl-_), 6.4 (lH, m, NH), 6.9-7.4 (1 lH, m, pF-Ph-_,
Ph-_, furyl-H)
Example 30 (+/-)-N-[6-(4Fluorophenyl)hexyl]-~ (4~,~
oY~P~ yl-3-(3-furyl)~ ude
A sQllltinn of (+/-)-N-[6-~fluorophenyl)hexyl]-2-(4-bell~ylthio)-2-oxo~7ptirlin-l-yl-3
(3-furyl)propio~mi~lP (80% diastereoisomer b) (0.30g, 0.00256moles) in
dichlorometh~nP (25ml), cooled to -70~C, wae treated with a solution of 3-
chloroperoxy benzoic acid (0.80g, 0.00255moles) in dichloromp~th~np (25ml) over 1
hour m~int~ining the ~Illl e~ature at -70~C. The cooling bath was removed and the
reaction mixture was stirred for 1 hour giving a colourless solution. The reaction
mixture was diluted with dichlorompth~np (SOml) and washed with 10% aq sodium
slllI-hitP solution, sodium hydrogen carbonate solution, water, dried (MgS04), and
evapoldted to a colourless oil which cnnt~inP-d a mixture of diastereoieomPre bl+b2.
~lrific~tion by repeated flash column chromatography on silica gel eluted with 1:1 to
3:1 petroleum ether 40-60~C: ethyl acetate followed by recry~st~llie~tion from ethyl
acetatelpetroleum ether 40-60~C gave (+/-)-N-[6-(4-fluorophenyl)hexyl]-2-[4-
benzylelllrhinyl]-2-oxo~7Pti~lin-l-yl-3-(3-furyl)propionamide (di~l~oisomer b2) as
colourless solid. (0.38g, 28%) m.p. 90-91~C.
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.57 (2H, t, J=7.6Hz, C_2Ph), 2.67,
2.73 (lH, dd, J=2.5, 15.4Hz,_3), 2.94, 3.01 (lH, dd, J=5.5, 15.4Hz,_3), 3.22 (4H,
m, C_2-furyl, CH2NH), 3.92, 4.05 (each lH, 2xd, J=13.1Hz, SOC_2)~ 4.41 (lH, m,
H1), 4.58 (lH, dd, J=6, 10 Hz, C_), 6.29 (lH, d, J=0.77Hz, furyl-_), 6.9-7.4 (12H,
m, pF-Ph-_, furyl-H, Ph-H, N_)
F~y~mple 31 N-[6~ Fluorophenyl)hexyl]~ l b~ ~oY~ idin-l-
yl-3-(3-furyl)pr~
A solution of N-[~(4-fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxo~7pti(lin-l-yl-3-(3
furyl)propio~-mitle (80% diastereoisomer a) (1.13g, 0.00222moles) in
dichlorometh~nP (25ml), cooled to -70~C, was treated with a solution of 3-
chlolupelu,.y benzoic acid (0.70g, 0.00223moles) in dichlorompth~np (25ml) over 1
hour m~int~ining the temperature at -70~C. The cooling bath was removed and the
reaction was stirred for 1 hour giving a colourless sollltion The rP~ctinn mixture was
diluted with dichloromPth~ne (SOml), washed with 10% aq sodium sulphite solution,
sodium hydrogen carbonate solution, water, dried (MgS04), and evaporated to a
colourless oil which ct nt~inPd a mixture of diastereoisomers. pnrific~tion by flash
column chromatography on silica gel eluted with 1:1 to 4:1 petroleum ether 40-
60~C:ethyl acetate gave (+J-)-N-[6-(4-fluorophenyl)hexyl]-2-(4-benzylqllrhinyl)-2
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CA 02225627 1997-12-23
W 0 97/02242 PCT~EP96/02765
oxc ~7Pti~in- l-yl-3-(3-furyl)propion~mi~lp (dliastereoisomer a2) as colourless oiL
(0.31g, 26%).
lH NMR o (CDCl3) 1.2-1.6 (8H, m, 4xCH2), 2.57 (2H, t, J=7.6Hz, CH2Ph), 2.76,
2.79 (lH, dd, J=2, 15.2Hz, H3), 3.00, 3.04 (lH, dd, J=5.2, 15.2Hz, H3), 3.30 (4H, m,
S CH2-furyl, CH2NH), 3.93, 4.08 (4H, 2xm, CH, H4, SOC_2)~ 6.29 (lH, s, furyl-H)D
6.9-7.4 (llH, m, pF-Ph-_, furyl-H, Ph-H), 7.88 (lH, m, N~
F.Y~mpl~ 32 (+/-)-N-[6-(4-Fluorophenyl)heYyl]-2~ lll.io}2~Y~ idin-l-
Yl-3-phenyl)pr~ (9S% ~lia~ r a
a Methyl 2-(1 be~ l,io-~-)Y~>~7~t;~in 1-yl) 3 ~
A solution of methyl-(4-be,l~ylt~lio-2-oYr~7pti~1in-l-yl) acetate (2.03g, 0.00765moles)
in dry tetrahydrofuran (40ml) at -75~C under nitrogen was treated with a lM sol~ltion
of lithium bis(trimethylsilyl)amide in hP~ ~n~-s (9.2ml, 0.0092moles) over 5 ...i~
keeping the temperature below-68~C. 1,3-Dimethylimi~l~7~ n-2-one (5.0ml,
0.0457moles) was added keeping the te.mpr..~ below -70~C. The resnltin~
snCI~çn.cion was stirred at -75~C for 30 min-ltPs and then treated with a solution of
benzyl bromide (2.36g, 0.0138moles ) over 5 min-ltes kPeping the ~ below -
70~C. The reaction was stirred for l.S hours during which time it reached -20~C.The reaction was cooled to -75~C and quenrh~cl with glacial acetic acid (l.Oml),partititionPd beLween brine (lOOml) and ethyl acetate (lOOml). The organic layer was
washed with water, dried (MgS04), and evaporated to a coloured oil. pllrifi~tion by
flash column chromatography on silica gel eluted with 2: 1 petroleum ether 40-
60~C:ethyl acetate gave methyl 2-(4-benzylthio-2-oYo~7Pti~in-l-yl)-3-
phe"yl~ )ionate as yellow soild (1.78g, 65%, 9:1 diastereoi.~omPr a:b) m.p. 66-67~C.
lH NMR o (CDCl3) 2.83 (lH, m, H3), 3.12 (lH, m, H3), 3.35 (2H, m, CH2Ph),3.76
(5H, m, OCH3, SC--2)~ 4.06 (m, CHg), 4.75 ( m, H/l, C_A)~ 7.23 (lOH, m, 2xPh-H)
b. 2-(4-benzylthio-2-oY.~ in-l-yl)-3-pl~ r~ io. ic acid
A solllti-~n of methyl 2-(4-benzylthio-2-oxo~7Ptiflin-l-yl)-3-phenylpropionate (1.75~,
0.00492 moles) in mPth~nol (75ml) at 10~C was treated with a lN sodium hydroxidesolution (4.92ml, 0.00492moles) over 40 minll~Ps The cooling bath was removed ;md
the reaction was stirred for 2 hour. lN NaOH (0.2ml) was added and the reaction was
stirred for 60 minlltps~ diluted with water (SOml) and evaporated to remove mPth~nol
The residue was mixed with water (75ml) and extracted with ethyl acetate (SOml). The
aqueous was ~ri~lifipd with lNHCl and extracted with ethyl acetate (2x75ml). Theorganic extracts were combined washed with brine, dried (MgS04), and evaporatedl to
give 2-(4-benzylthio-2-oxo~7Ptitlin-l-yl)-3-phenyl)propionic acid as a cream solid m.p.
125-131~C (1.37g, 82%, 40:60 distereoisomer a:b)
lH NMR ~ (CDC13) 2.8 (lH,m, H3), 3.15, 3.35 (3H, 2xm, CH2-furyl, H3), 3.53 (m,
SCH2g), 3.73 (s, SCH2A), 4.0, 4.15 (lH, 2xm, C_A+B)~ 4-07. 4.59 (lH, 2xm, ~,1),
5.47 (lH, bs, C02H), 7.08-7.37 (lOH, m, 2xPh-H)
c. (+/-)-N-t6-(4-Fluorophenyl)hexyl]-2-(4-b~-~yllllio~2 ~ 1-yl-3-
phenyl)propi~ A~
~(4-Fluorophenyl)hexylamine (0.76g, 0.00389moles) in dry DMF (40ml) was added
to a mixture of 2-(4-benzylthio-2-o7~o~7ptillin-l-yl)-3-phellylpl~3pionic acid (1.33g,
0.00389moles), l-hydroxybenzotriazole (0.52g, 0.00385moles), N,N'-
dicyclohexylcarbodiimide (0.8g, 0.00388moles) and was stirred at room Lelnpel~L~ Le
- 35 -
CA 02225627 1997-12-23
W O 97/02242 PCT~EP96/02765
for 4h. The ~"s~en~ion was diluted with ethyl acetate (lOOml) and filtered to remove
urea The hltrate was evaporated to remove ethyl acetate and the residue was miAed
with aq.NaHC03 (125ml) and washed with diethyl ether (2x75ml). The organic
extracts were combinP~i and washed with brine, dried (MgS04), and evapo ~d to anoil. This was com~inP~ with product from sep~ rÇS7~tionC (from 0.33g, 0.96g of 2-
(4-b~l~yl~lio-2-oxozt7Pti~lin-l-yl)-3-phellyl~opionic acid) and purified by repeat flash
column chrom~togr~rhy on silica gel eluted with 3:1 P.E.:ethyl acetate to give the title
compound as a waxy colourless solid, 0.79g, 20% (conts7inc 5% ~ oi~...Pr b),
nmr for a:
lH NMR o (CDC13) 1.2-1.6 (8H, m, 4xC_2)~ 2.56 (2H, t, J=7.8 Hz, C_2Ph), 2.68,
2.74 (lH, dd, J=2.3, 15.4Hz, H3), 2.99, 3.05 (lH, dd, J=5.2, 15.4Hz, H3), 3.26 (4H,
m, NHCH2, CH2Ph), 3.70 (2H, s, SC_2)~ 3.81 (2H, m, C_, H,,), 6.9-7.4 (lSH, m,
pF-Ph-H, 2xPh-_,N_)
FY~7mple 33 (+/-)-N-[6-(4-7~uJlo~henyl)hexyl]-2-(47De~ ;o)-2~ lin-l-
15 yl-3-phenyl)~ , A~P (98% ~li;~cl~eo~ .-. b)
The above chromatography gave the title compound as a colonrlP-ss soi d, l.Olg, m.p.
78-80~C, 25% yield (cont~inc 2% diastereoisomer a)
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.8 Hz, C_2Ph), 2.76,
2.80 (lH, dd, J=2.4, 15.6Hz, H3), 3.06, 3.10 (lH, dd, J=5.2, 15.6Hz,_3), 3.24, 3.34
(4H, m, NHCH2, CH2Ph), 3.51 (2H, s, SC_2). 4.16 (lH, dd, J=5.6, 10.4 Hz, C_),
4.54(lH,m,H1),6.35(1H,m,N_),6.9-7.4(14H,m,p.~-Ph-_,2xPh-_)
l~Y~77~rlP 34 N-t6-(4-Fluorophenyl)heAyl]-2-(4-benzy sulphinyl)-2-~A )a~lidin-l-yl-3-phenyl)~ P (lia~
A soltltion of N-[6-(4-fluorophenyl)hexyl]-2-(4-ben~ylthio)-2-oxozt7Ptil1in-l-yl-3-
phenylpropion~mi~le (0.76g, 0.00147moles) in dichlorornPthztnP (25ml), cooled to-70~C, was treated with a solution of 3-chl(Jlu~luAy benzoic acid (0.46g,
0.00147moles) in dichlorornP-th~nP- (25ml) over 1 hour ...~i.-t~ o the te~ llle at-
70~C. The cooling bath was removed and the reaction was stirred for 2 hour giving a
colourless solution. The reaction was washed with 10% aq sodium s~llrhitp solution,
sodium hydrogen carbonate ~olntion, water, dried (MgS04), and evaporated to a
colourless oil (0.89g). Purification by repeat flash column chromatography on silica
gel eluted with 1: 1 to 2:3 petroleum ether 40~-60~C:ethyl acetate followed by
recyst~lli ~ti-)n from diethyl ether / pelroleum ether gave N-r6-(4-fluorophenyl)hexyl]-
2-(4-benzylc-llrhinyl)-2-o~ 7Pti~lin- l-yl-3-phenylpropion~mi-le (diastereoisomer a2)
as colonrl~s solid. (0.26g, 33%) m.p. 62-63~C.
lH NMR o (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.57 (2H, t, J=7.6Hz, CH2Ph), 2.77,
2.87 (lH, dd, J=2.2, 15.3Hz, 3~, 2.88, 2.93 (lH, dd, J=5.2, 15.3Hz, _3), 3.38 (4H,
m, CH2Ph, C_2NH), 3.61 (lH, m, Hl), 3.83, 4.05 (each lH, 2xd, J=13Hz, SOC_2)~
3.99 (lH, m, C_), 6.9-7.4 (14H, m, pF-Ph-H, 2x Ph-_), 8.06 (lH, m, NH)
v ~=0 1785 cm~l; Found: C, 69.3; H, 6.5; N, 5.3%; C31H3sFN203S requires: C,
69.6; H, 6.6; N, 5.2%
F~ lc 35 N-t6-(4-Fluorophenyl)hexyl]-2-(4-l,e~ L~ f~p~ ..f;~
yl-3-phenyl)propio~ e (79% dia~ - al)
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CA 02225627 1997-12-23
W O 97/02242 PCTAEP96tO276S
Evaporation of column fractions from the above chrnm~to~r~rhy gave the title
compound as a colourless foam, 0.21g, 27% yield, (Cont~in~ 22% clia~ i.c~mPr a2);
nmr for al:
lH NMR o (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.57 (2H, t, J--7.8 Hz, CH2Ph), 2.62,
2.68 (lH, dd, J--~1.7, 14.8Hz, H3), 3.3 (5H, m, H3, CH2-Ph, CH2NH), 3.80 (4H, m,H1, SOCH2, CH), 6.60 (lH, m, N~), 6.9-7.4 (14H, m, pF-Ph-H, 2xPh-H)
F.Y~mpl e 36 (+/-)-N-t~(4Flu~vl.henyl)hexyll-~ (4benzyl~ h;~yl)-2-
oYo~ -yl-3-pht~ io~ ~ somer bl)
A sol~ltio~ of (+J-)-N-[6-(4-fluoluphe.,yl)hexyl]-2-{4-bG.~ylll.~o]-2-oxo~7~titlin-l-yl-
3-phenyl)propio~mi~iP (diastere~ omPr b) (0.95g, 0.00183mnlPs) in dichloromPth~nP
(25ml), cooled to -70~C, was treated with a solntion of 3-chlo,upel~o~y bel~oic acid
(0.57g, 0.00182moles) in dichloromp-th~np (25ml) over 45 ~ -~ m~ the
tPmpçr~tllre at -70~C. The cooling bath was removed and the reaction was stirred for
2 hour giving a colourless soh~tio~ The reaction was washed with 10% aq sodium
sulphite solution, sodium hydrogen carbonate solution, water, dned (MgS04), and
evaporated to a colourless oil (0.89g). Purified by repeat flash column
chromatography on silica gel eluted with 1:1 to 1:3 petroleum ether 40-60~C: ethyl
acetate lo separate the diasterenic~ mPr products. Cooling the higher running isomer
in diethyl ether gave N-t6-(4-nuoluphenyl)hexyl]-2-(4 benzylcnlrhinyl)-2-
oxo~7~ti~in-l-yl-3-phenyl)propion~m~ (diactereoisomer bl)ascolo~lrl~-ccsolid.
(0.071g, 7%) m.p. 128~C. (contains 4.8% diactereoisomer b2)
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.8 Hz, CH2Ph), 2.62,
2.68 (lH, dd, J-1.9, 14.7Hz, H3), 2.85 (lH, m), 3.25 (2H, m, C_2NH), 3.36, 3.42
(lH, dd, J=2.2, 14.7Hz, H3), 3.52 (lH, m, 1 of CHC_2)~ 3.70. 4.05 (each lH, 2xd,J=lOHz, SOC_2)~ 4.20 (lH, m, H4), 4.67 (lH, dd, J=S, 1 lHz, CH), 6.7-7.4 (lSH, m,
pF-Ph, 2xPh-H, NH)
Found: C, 68.9; H, 6.5; N, 5.1%; C31H3sFN203S requires: C, 69.6; H, 6.6; N, 5.2%Example37 (+/-)-N-t6-(4-Fluorophenyl)hexyl]-2-(4-bt~ nyl)-2-
oY~7P~in-l-yl-3-phenylpropio~miAp(~ia~ ~nic~ rb2)
The lower lunning isomer fr~rtio~ from the above chromatography were ~ d
from ethyl acetate/diethyl ether to give N-[6-(4-fluorophenyl)hexyl]-2-(4-
benzyl.clllrhinyl~-2-o~o~7P~itlin-l-yl-3-phenyl)propion~mi-le (diastereoisomer b2) as
colourless solid. (0.328g, 33%) m.p.84-85~C.
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.8 Hz, CH2Ph), 2.60,
2.65 (IH, dd, J=2.4, 15.6Hz,_3), 2.84, 2.87 (lH, dd, J=5.6, 15.6Hz,_3), 3.21 (3H,
m, 1 of PhCH2CH), 3.53, 3.59 (lH, dd, J=6.4,14.9Hz, 1 of PhC_2CH ), 3.91, 4.02
(each lH, 2xd, J-13.1Hz, SOC_2)~ 4.34 (lH, m, Hl), 4.70, 4.74 (lH, dd, J=6.4, 10,
CH), 6.9-7.4 (lSH, m, pF-Ph-H, 2xPh-H, N_)
Found: C, 69.0; H, 6.5; N, 5.1%; C3lH3sFN203S.1.0%H20 requires: C, 68.9; H,
6.6; N, 5.2%
FY~mple 38 (+)-N-[6-(4-Fluorophenyl)heYyll-2-(4l*~ rhinyl)-2
oY~7eff~lin-l-yl-3-ph~ ;on~m ~ ~r~~ r (+)-b2)
The above b2 diastereoisomer was se~a~d by chiral HPLC to give the title
compound as a Oum
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xC_2)~ 2.56 (2H, t, J=7.8 Hz, CH2Ph), 2.60,
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CA 02225627 1997-12-23
W O 97/02242 PCT~EP96/02765
2.65 (lH, dd, J=2.4, 15.6Hz, H3), 2.84, 2.87 (lH, dd, J=5.6, 15.6Hz, H3), 3.21 (3H,
m, 1 of CH2NH), 3.53, 3.59 (lH, dd, J=6.4,14.9Hz, 1 of C_2Ph), 3.91, 4.02 (each
lH, 2xd, J=13. lHz, SOCH2), 4.34 (lH, m, H1), 4.70, 4.74 (lH, dd, J=6.4, 10, C~),
6.9-7.4 (lSH, m, pF-Ph-H, 2xPh-H, N_)
S aD = +35.8~ (c=0.4%w/v ethanol) at 20~C
FY~mrl~ 39 (-)-N-t6~(4-Fluorophenyl)he~y-yl~-~ (4~ ~
;..-l-yl-3-~ (dia~l~.eoisomer (-)-b2)
The title compound was a so obtained from the b2 diastereoicomPr by chiral HPLC and
was icol~tPd a gum
lH NMR o (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.8 Hz, C_2Ph), 2.60,
2.65 (lH, dd, J=2.4, 15.6Hz, H3), 2.84, 2.87 (lH, dd, J=5.6, 15.6Hz,_3), 3.21 (3H,
m, 1 of CH2NH), 3.53, 3.59 (lH, dd, J=6.4,14.9Hz, 1 of CH2Ph), 3.91, 4.02 (each
lH, 2xd, J=13. lHz, SOCH2), 4.34 (lH, m, H1), 4.70, 4.74 (lH, dd, J=6.4, 10, C_),
6.9-7.4 (15H, m, pF-Ph-H, 2xPh-_, NH)
lS aD = -43.7~ (c=0.3%w/v ethanol) at 20~C
FY~mp'~40 (+/-)-N~[6-(4-Flu~ enyl)heYyl]-2-(4-l)e~ lU~io~2~ idin-1-
yl-2-all~lac~.~ide (diactere~ico-n~r a)
a Methyl 2-(4-l~el~ylU~io-2-~ in-l-yl)-2-allyl~
A solution of methyl-(4-benzylthio-2-oyr~7pti~lin-l-yl) acetate (5.0g, 0.01884moles)
in dry tetrahy l~oru~ (lOOml) at -75~C under nitrogen was treated with a lM
sol~lti()n of lithium bis(trimethylsilyl)amide in THF (23.0ml, 0 02~molPs) over 10
mimltPs keeping the tPmpPr~tllre below -68~C. 1,3-Dime~lyli...;~ in-2-one
(12.5ml, 0.1143moles) was added keeping the tPmrer~tllre below -70~C. The
resnlting suspension was stirred at -75~C for 30 Illil.lllPS and then treated with aUyl
iodide (3.1ml, 0.0339moles) over 5 minlltPs . The tempeialule rose to -65~C. Thereaction was stirred at -78~C for 30 ...i....~Ps and then aUowed to warm to -20~C over
30 mimltPc The reaction was cooled to -75~C and ~llen~hPd with glacial acetic acid
(Sml), par~ititionpcl between brine (lSOml) and ethyl acetate (175ml). The organic
layer was washed with brine, dried (MgS04), and evaporated to a coloured oil.
30 pnrifi~tiQn by flash column chromatography on silica gel eluted with 4:1 petroleum
ether 40-60~C:ethyl acetate gave methyl 2-(4-benzylthio-2-oxo~7Pti~in-l-yl)-2-
allylacetate as yellow oil (4.48g, 78%, 85:15 diasterPoicQmP- a:b)
lH NMR ~ (CDC13) 2.7 (2H, m, C_2)~ 2.90 (lH, m, _3), 3.27 (lH, m, H3), 3.80 (SH,m, C02C_3,SCH2), 3.92, 4.23 (lH, 2xm ,C_A~C B)~ 4.55, 4.90 (lH, 2xm, H1),
5.16 (2H, m, CH=C_2)~ 5.80 (lH, m, CH=CH2), 7.31 (SH, m, Ph-_,)
b. 2-(~be..~y~ io-2-o~Q~7~H~l:n-l-yl)-2-allyl acetic acid
A solutio~ of methyl 2-(4-benzylthio-2-oxo~7~ti~lin-l-yl)-2-allyl acetate (4.38g,
0.01434 moles) in methanol (lOOml) at 10~C was treated with a lN sodium hydroxide
solution (14.3ml, 0.0143moles) over lS minut~Ps The cooling bath was removed and40 the reaction was stirred for l.S hour. lN NaOH (2.0ml) was added and the reaction
was stirred for 30 mimltes, diluted with water (lOOml) and evaporated to remove
meth~nol. The residue was extracted with diethyl ether (lOOml). The aquous was
aei~lifi.od with dilute HCl, and extracted with diethyl ether (lOOml, SOml). The extracts
were combined, washed with brine, dried (MgS04), and evaporated to give 2-(~
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WO 97/02242 pcTlEps6lo2765
l~n~yl~~~o-2-o~o~7pt~ n-l-yl)-2-allylacetic acid as a yellow oil (3.97g, 95%) 60:40
distereoi.~omPr a:b
lH NMR o (CDC13) 2.7 (2H, m, CH2), 2.90 (lH, m, H3), 3.27 (lH, m, H3), 3.80 (m,
CHg, C02CH3,SCH2), 4.12 ( m ,CHA), 4.65, 4.85 (lH, 2~cm, H1), 5.16 (2H, m,
CH=CH2), 5.80 (lH, m, CH=CH2), 7.31 (5H, m, Ph-H,)
G (+/-)-N-~(4Fluorophenyl)hexy1]-2-(4 bt~ llluo)-~ yl-2-
allylAr~ ude (90% ~ a)
6-(4-Fluorophenyl)hexylamine (2.5g, 0.0128moles) m dry DMF (75ml) was added ItO a
u~i~LLul~ of 2-(4 benzylthio-2-o~oA7~ n-l-yl)-2-allylacetic acid (3.73g, O Ol'~gmol~s),
0 l-hydl~yl~e~.0~ 7.Clf' (1.75g, 0.0129moles), 1-cyclohe~yl-3-(2-
morphnlin~thyl)carbo~liimi-l~ metho-p-toluene sulfonate (5.42g, 0.0128moles) andwas stirred at room temperature for 19h. The ~sl~,nc~ was partitioned between
sodium hydogen carbonate sollltion (300ml) and diethyl ether (lSOml). The layerswere se~ d and the aqueous was washed with diethyl ether (lOOml). The organic
~ ;ls were combined washed with water, dried (MgS04), and evaporated to an oil
(5.92g). Purified by repeat flash column chrom~togr~phy on silica gel eluted with :2:1
petroleum ether 40-60~C:ethyl acetate to give the title colllpol"ld as a colourless oil,
1.27g, 21 %yield
lH NMR ~ (CDC13) 1.35-1.6 (8H, m, 4xC_2)~ 2.56 (2H, t, J=7Hz, CH2Ph), 2.65
(2H, m, CH2), 2.79, 2.85 (lH, dd, J=2.4, 15.4Hz, _3), 3.25 (3H, m, _3, NHCH2)9
3.71 (lH, dd, J=6Hz, CH), 3.82 (2H, s, SCH2), 4.65 (lH, m, ~4), 5.15 (2H, m,
CH=C_2)~
5.72 (lH, m, CH=CH2), 6.85 (lH, m, N_), 6.9-7.3 (9H, m, Ph-_, Ar-H)
Example41 (+/-)-N-[6-(4-Fluo~ l)hexyl]-2-('1 be~ io~2
yl-2-allyl~f ~ P (80% .lia~ b)
From the above chromatography the title compound was isolated as a colourless oil,
1.1 lg, 19% yield
lH NMR ~ (CDC13) 1.25- 1.6 (8H, m, 4xC_2)~ 2.56 (2H, t, J=7Hz, C_2Ph), 2.78
(2H, m, C_2)~ 2.84, 2.91 (lH, dd, J=2.3, 15.3Hz, H3), 3.25 (3H, m, H3, NHCH2),
3.82 (2H, s, SC_2)~ 4.03 (lH, dd, J=6Hz, C_), 4.65 (lH, m, ~4), 5.08 (2H, m,
CH=CH2)~
5.72 (lH, m, C_=CH2), 6.51 (lH, m, N_), 6.9-7.3 (9H, m, Ph-_, Ar-H)
F ~ e 42 (+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(41~~
~Y ~7~ n-l yl-2-ally~ *~ ?(~ oiSO~ a2+al)
Tre~tmPnt of 1.2g (0.00256moles) of (+/-)-N-[6-(4-Fluolophellyl)hexyl]-2-(4-
benzylthio)-2-oxo~7Pt~ n-l-yl-2-allyl~Rt~mi~lP (90% diastereoisomer a) with mCPBA
using the procedure described in F~mr)l~ 34 gave, after similar work-up and
chromatography the title compound as a colourless oil, 0.41g, 33% yield
lH NMR (diastereoisomer a2) ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t,
J=7Hz, CH2Ph), 2.7-3.3 (6H, m, CHCH2,_3, NHC_2)~ 3.80-4.20 (3H, m, SOCEI2,
CH), 4.48 (lH, m, _4), 5.13 (2H, m, CH=CH2), 5.72 (lH, m, CH=CH2), 6.9-7.4
(lOH,m,Ph-_,Ar-H),7.46(1H,m,N~
FY~nP'e 43 (+/-)-N-[6-(4-FIUOrOPhenYI)heXYI]-2-(4-b~ UIPhinYI)-2
o~ -yl- 2-ally~ et~
- 39 -
CA 02225627 1997-12-23
W O 97/02242 PCT~EP96/02765
Tre~tmPnt of l.O5g of (+/-)-N-[6-(4-Fluorophenyl)he~cyl]-2-(4-bel~ylll~io)-2-
oxo~7pt~ n-l-yl-2-ally~ e~ A~p (80% diastere~icomp-r b) with mCPBA using the
procedure ~P-sr~ihed in FY~mrlP 34 gave, after similar work-up and ~ 1Q~ Y
the title co~ ol.lld as a pale yellow oil, 0.38g, 35% yield
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7Hz, C_2Ph), 2.6-3.3
(6H, m, CHCH2,_3, NHCH2), 3.95, 4.09 (each lH, 2xd, J=11.6 Hz, SOCH2), 4.47
(lH, m, C_), 4.57 (lH, m, H4), 5.11 (2H, m, CH=C_2)~ 5.72 (lH, m, CH=CH2),
6.9-7.4 (lOH, m, N_, Ph-H, Ar-H)
F~ e 44 (+/-)-N-[6-~1 Fluor~ lhexyl)]-2 [4L~
~ n~l-yl]l~ul,~ ~ide
a Methyl 2-(4-l>~ lll,io-2-~ l-yl)butanoate
A mixture of methyl 2-(4-bel~yll~io-2-r,Y~)~7Pti~lin-l-yl)~et~tP(l~2 g, 0.0045 mol) in
dry tel.~hydloru.di~ (20 ml) was treated with lithium hP~mPthyl-licil~AP sollltil-n
(1 Mol solution in hPY~n~ ~ 4 ml, 0.0054 mol) and stirred at -78~C for 30 ~ s
forming a pl~ci~ te which was broken up with vigorous stirring. Following tre~tmPns
with ethyl iodide (0.64 ml,O.008 mol) at -78~C, the incoln~lP yellow solid dissolved
forming a yellow sollltion The reaction ~ was then left 16 hours at -20~C.
After cooling to -78~C the sollltion was treated with acetic acid (0.5 ml) followed by
partitiong belween ethyl acetate and water. The aqueous layer was e~ P~ again
with ethyl acetate and the combinP-d extracts dried (MgS04) and ~val.olaL~d to abrown oil. pnrifir~tion by flash chrom~tography (silica, ethyl acetate/petrol) gave the
title componn-l as a miYture of diastereoicom~rs (colourless oil), 0.3 g, 23% yield.
lH NMR ~ (CDC13) 1.02 (3H, d of d, CH_C~), 2.07 (2H, m, SCH2), 2.92 and 3.25
(each lH, m, H4s), 3.76 (2H, d, CH2), 3.83 (2H, d, C_2)~ 3.67, 4.16 (lH, m, CH),4.64 and 4.94 (lH, m, H3), 7.28 (2xSH, m, Ph)
b. 2-(~B~ l.io-2-oYo~eti~' l-yl)L~ -o:~ acid
A stirred solution of methyl 2-('1 bel~yl~io-2-oxo~7p-ti~lin-l-yl)but~no~tp (1.40 g,
0.0047 mol) in meth~nol (12 ml) was treated with 1 molar pot~ccinm hydroxide (5.47
ml). After 16 hours, the meth~nol was evaporated and the residue diluted with water.
The aqueous layer was ~ci~lifi~d with cooling (ice bath) and the oil which pl~eipi~d
was eYtr~rtPd into ethyl acetate. The combined extracts were dried (MgS04) and
evaporated to give the title compound as a white oily solid (Uli~ t; of
diastereoicomPr.c), 1.36g, 100% yield.
lH NMR ~ (CDC13) 1.02 (3H, m, CH_C~), 2.07 (2H, m, SCH2), 2.92 and 3.35
(each lH, m, H4s), 3.74 (2H, s, CH2), 3.84 (2H, s, CH2), 3.53, 4.10 (lH, m, CH),4.71 and 4.94 (lH, m, H3),6.99, ~lH,bs, OH), 7.28 (2xSH, m, PhH)
c N-~6-(4-Fluorophenylhexyl)]-2-t4-be~ io-2-oYo~ff~lin-l-yl]b~ ide
ixlul.: of ~lia~le~;com~rc a + b)
A mixture of 6-(4-fluorophenyl)hexylamine (0.9Sg,0.0048 mol,T ~m~ttin~ J. L. EP
138464 A2 850424 (CA 103:142000)), l-hydroxybenzotriazole hydrate (0.56g,
0.0042 mol), 2-(4-benzylthio-2-oxo~7ptitlin-l-yl)-butanoic acid (1.2 g, 0.0043 mol)
and dicyclohexylcarbo-iiimi-ie (0.89 g, 0.0043 mol) in dim~Lhylr~ mi-le (50 ml) was
stirred for 16 h at ambient temperature. The solvent was evaporated and the residue
treated with ethyl acetate. The insoluble dicyclohexylurea was filtered off and
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WO 97/02242 PCT/EP96/02765
discarded, and the filtrate washed with ~tnr~t~d sodium hydrogen c~ul,onatP sol~ltir~n
dned (MgS04) and evaporated to an oil. This w~ pnrified by flash chrom~t~ ~rh y
(silica, ethyl acetatelpetrol) to give the title compound as an oil (1.47 g, 75% yield)
lH NMR ~ (CDC13) 0.83-.98,(3~,m C-H3),1.1-17(~T~,m ~'~2),1.8-2.15(4~,m,~
2.55 (2H, t,CH2),2.88 (l~,m ~'H2), 2.99,(~,m ~ 2), 3.46,(1~,q,C~2), 3.85,
4.12(1~,q ~), 3.85 (2H,s,C_2)~ 3.86 (lH,d,CH2), 4.65(1~,m,~4), 6.5(1H,t,NH~,
6.75(1H, t,N_), 6.9-7.33(9H, m,Ph ).
F.~ r 45 N-[6-(4-Fluorophenyl)heAyl]-2-[41~b~ ,hinyl~2~Aoa2L~din-1-
yl]l~ ide,
A solnti~n of N-[6-(4-fluoluphenylhexyl)]-2-~beliLyllli~o-2-o~ 7~ti-1in-l-
yl]bulyl~llide (diastere~ i.comt~rs a &b) (1.27 g, 0.0028 mol) in dicholo..~ h~nP. (50 1~)
was cooled to -65 to -70~C and a solution of m-chlc~l-)pe~ Loic acid (0.58 g, 0.0033
mol) in dichlorom~-th~n~ (20 ml) added dropwise over 15 m~n. After 3 hours the
mixture was washed with a mixture of saturated sodium hydrogen carbonate and
1~ c~nlr~t~d sodium SnlIlhit~ dried (MgSO4) and evaporation gave the title co-llpoulld as
a mixture of diastereoi.com~rs al, a2, bl. b2 as an oil, 1.47g 100% yield.
lH NMR ~ (CDCl3) 0.93-1.04,(3H,m,CH2C_3),1.1-1.7(6H,bm,-CH2),1.8-
2.25(~,m -'H3CH2) 2.55 (2H, t,CH2Ar),2.6-3.0 (l~,m,~H), 3.05-3.55
(3H,m,CH2,_3),3.7 (lH,q,CH),3.85,4.12(1H,q,C_),3.85-4.25(2H,m,SCH2), 4.5-
4.85(1H,m,H4),6.45(1H,t,N_), 6.85(1H, t,N_), 6.9-8.1(9H, m,PhH).
0.8g of the above oil was purified by chrom~to~r~I)hy (HPLC, Re~l~m~n silica column,
ethanol/hexane), to give the i.corn~rs described in F~m~ s 4~48.
F~ .'e 46 (+/-)-N-t6-(4-Fluorophenyl)hexyl]-2-[4be-~yl~
oyn~ ; l;.. 1 yl]~ le(Isomeral)
Isomer al, oil, (0.05g)
lH NMR ~ (CDC13) 0.83-.98,(3H,t,C 3),1.2-1.7~(6H,m,C_2)~ 1.99 (2H,
q,CH3C_2),2.56 (2H,m,C 2Ar) 2.78,3.34,(2H,m,_3)3.21,(2H,m,NHC_2)~ 3.87
(3H,m,CH,PhCH2), 4.71(1H,m,H4),6.25(1H,t,NH), 6.9-7.39(9H, m,PhH).
FY~mple 47 (+l-)-N-t6-(4-Fluorophenylhexyl)]-2-t4be.~ h;~ 1-2-
oY~ -1-yl]l~ P (isomer bl and b2, 1:3)
The above procedure yielded 0.05g of the title compounds (bl:b2, 1:3) as an oil
lH NMR ~ (CDC13) 0.93,(3H,t,C_3),1.01,(3H,t,C_3),1.22-1.38(6H,m,C_2)~ 1.99-
2.1 (2H, m,CH3C_2)~ 2.1-2.25 (2H, m,CH3CH2), 2.56 (2H,m,C_2Ar),
2.55,3.08,(2H,m,_3) 2.68,3.55,(2H,m,_3),3.18,3.25,(~ ~ym,NHC_2j, 3.87-4.25
(3H,m,C_,PhCH2), 4.45,4.51(1:3)(1H ~ym~H4)~6~7s(lH~t~N_), 6.9-7.40(9H,
m,PhH).
Example48 N-t6-(4-Fluorophenyl)hexyl]-2-t4-bel~yl~
yl]~ P (isomer a2)
The above procedure yielded 0.05g of the title compound as an oil
lH NMR ~ (CDC13) 098,(3H,t,C_3),1.3-1.61(6H,m,C_2)~ 2.08 (2H,
q,CH3CH2),2.56 (2H,m,C_2Ar),2.75,3.19 (each lH,m,_3),3.26 (2H,m,NHC_2)~
3.85 (lH,m,CH,), 4.05 (lH,d of d,ArCH2), 4.54(1H,m,H4), 6.92-7.40(9H, m,PhH).
FY~mp'e 49 (+/-)-N-t6-(4-Fluorophenylhexyl)]-2-t41,e-~ l-2-
~Y~ l-yl]pe~ P
a Meffiyl 2-(4-benzylthio-2-- Yo~7e~lin-l-yl)p~p~ Q~te
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Sub~ g propyl iodide (4g, 0.023 mol) for ethyl iodide and using the collG~ g
amounts of the other lta~gell~ in FY~mrlP 44a gave after pllrifir~tion by flash
chromatography (silica, ethyl acetate/petrol) the title ccllu~oul-d as a ll~i~ G of
dia~lGl~oico.~.Pr.s (colollrlPss oil), 1.05 g, 25.3% yield.
S lH NMR ~ (CDC13) 0.96 (3H, d of d, CH2C~), 1.36 (2H, m, CH3CH2),1.96 (2H,
m, CH2CH2),2.90,3.29 (each lH, m,_3s), 3.74 (3H, d, OCH3,), 3.79 (2H, d, SCH2),
4.27 (lH, m, CH), 4.64 and 4.94 (lH, m, H4), 7.29 (SH, m, Ph)
b. 2-(4Be~lll 'o ~ o~.~a~ yl)pentanoicacid
.SIlbs~ g methyl 2-(4-bGll~ylLl~iO-2-o~ Pl;l1in-l-yvppnt~nn~tp (1.04g, 0.0033
mol) for methyl 2-(4-ben~yllllio-2-oxo~7Pti~lin-l-yl)b~ r and using the
corresponding ~mountc of the other l~agen~ in FY~mrlP- 44b gave the tide CO-ll~Ou ld
as a mixture of diastereoisomers (colourless oil), 0.8 g, 82% yield.
lH NMR ~ (CDC13) 0.96 (3H, d of d, CH_C 3), 1.40 (2H, m, CH3CH2),1.91 (2H,
m, CH2CH2),2.90,3.29 (each lH, m, _3s), 3.64 (lH, m, OC_3,), 3.84 (2H, d,
lS SCH2), 4.24 (lH, m, CH), 4.64, 4.94 (lH, m, H4),6.4(1H,bs,OH),7.29 (SH, m, Ph)
~ (+/-)-N-[6-(4-Fluoroph~:..;lht:A,~1)]-2-[1 1~t~ n-l-
yl]y. u~.~l~ide
S~stitllting 2-(1 bel~yllllio-2-oxn~7pti~lin-l-yl)propanoic acid (0.8g, 0.0027 mol.) for
2-(4-ben~ylLl~io-2-oxo~7pti(lin-l-yl)butanoic acid and using corresponding 4~n~ s of
20 the other reagents in FY~mrlP 44c gave the title compound as an oil, 1.4g 100%yield
lH NMR (complPY spectrum) ~ (CDC13) 0.93,(3H,m,CH3),1.2-1.6(4H,m,CH2),1.8-
2.15(4H,m,CH2)
2.55 (2H, t,CH2),2.88 (1H,m,CH2) 2.8,3.3 (lH,d of d,3_) 2.9,(~ ,CH2)
2.95,(2H,s,CH2)3-28.(~ m,C~2)~ 3.85
25 (~ m,CH2),4.62(1H,q,C_),4.74(1H,m,_4),6.5(1H,t,NH), 6.76(1H, t,NH), 6.9-7.3
(9H, m,Ph_).
Example ~0 (+/-~N-[6-(4chlol~op~~~ylhexyl)]-~ t1 ~ ..lyh;~.,~1-2-
~o~ ,._t~ - l-yl]y~
A ~solllti-~n of N-t~(4-fluorophenylhexyl)]-2-[4-benzylthio-2-oxo~7Pti~lin- 1 -
yl]pçnt~n~mi~e (diastere~isompr~s a &b) (0.2g, 0.00042 mol) in dichoromPth~nP (S ml)
was cooled to -65 to -70~C and a solution of m-chloropelbenzoic acid (0.09 g,
0.00051 mol) in dichloromethane (5 ml) added dropwise over 15 min. After 1 hour
the mL~ was washed with a mixture of ~rnr~tP~1 sodium hydrogen carbonate and
saturated sodium snlrhitp~ dried (MgS04) and t;vapolation gave the title compound as
a mi~ of diastereoicomprs al, a2, bl, b2 as an oil, 0.2g 100% yield.
H NMR (complex spectrum) ~ (DMSO d6) 0.83-0.95,(3H,m,CH2CH3), 1.1-
1.7(6H,bm,-C_2) 2.7 (2H, s,CH2Ar), 2.9 (2H, s,CH2Ar), 3.05-3.55 (3H,m,CH2,H3),
3.7 (lH,q,CH), 3.85, 4.12 (lH,q,CH), 3.70-4.25 (2H,m,SC_2)~ 4.6-S.lS (lH,m's,H4),
7.0-8.2 (9H, m,PhH).
Example ~1 N-(Ben_yl)-2-[4-be~ l-2~o~ n-1-yl]propionamide
(dia~l~.. ~o;coln~- bl&b2 l:l.S)
Tre~tmPnt of N-(benzyl)-2-[4-benzylthio-2-oYo~7Pti-lin-l-yl]propton~mi~lP
(diastere-)icc-mPr b, FY~mrlP 20) (1.31 g) with mCPBA under the Con~litiQn~ described
in FY~mrlP 12 gave the title compound as a mixture of diastereoisomers (b 1 :b2 1: l.S)
1.14 g, colourless solid, m.p. 110-3~C
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F~ample52 N-(Benzyl)-2-[4 b~ lphfnyl-2~ idfn-l-yllpropionamide
(89% ~ ~.~ eo~ . al)
T~ç~l.nP.I~ of N-(benzyl)-2-[4-bel~y~ o-2~o~7p-t~ n-l-yl]~ P
(diastereoi.somPr a, FY~mplP. 19) (1.31 g) with mCPBA under the con-lition.c des~ ed
- ~ in F.Y~mrlP. 12 gave the title compound a,, a mi~cture of ~ cte~o~ which were
sP,p~r~tP~ by cryst~lli.c~tion to give pred~ hlly diastereoic~mpr al as a colollrlpcc:
solid, m.p. 150-3~C
FY~rle 53 N-(Benzyl)-_-['l benzylsulphinyl-? ~ lidin-l-yllpropiona nfde
(82% li~ ~n' ~ a2)
10 The mother liquors from the above ~ ,lya~lli.c~tion were ~ p~ (l and l~
to give the title conlpound a_ pre(lc,...;.-~..lly the dia~t~,eoi.cl mP!r a2, 0.67 g, m.p. 134-
~~C.
F,Y~ple S4 R-Me~yl~[(4-allyloAy~bv~l)bel~y~ i
15 a (-)-(R)-4-(4-(Allylo~y~l,onyl)bt~ y' ' ~)-2-o~oa~- ~idfn-l-;lzc&~cacid
4-(4-(Allyloxycarbonyl)benzylthio)-2-oxo~7Pti~lin-l-ylacetic acid ( 3.41 g, 10.2mmol) and cin~ho~ nP (2.99 g, 10.2 mmol) in ethanol (40 ml) were heated to
boiling when a clear sollltion was obtamed. On st~n~in~ for 90 mm, the crystalline
salt which had precipit~ted was fltered off, and lG~ 71~lli~,~ from ethanol (20 ml).
20 The solid obtained was s~irred vigorously with ether and water whilst acidify~ng with
dil. hydrochloric acid, and when complete solution was obtained the layers were
sep~d and the aqueous layer further ~ rtPd with ether. The cornhinP~ extracts
were dried (MgS04) and evaporated to an oil which crystallised on tritllr~tion wit'r
light petrol to give the title compound as white crystals, m.p. 74-6~C, 6.7 g, 50%
25 yield
~ D25 = -24.2 (c. 0.7 w/v CHCl3, 25~C)
'H NMR ~ (CDC13) 2.97 (lH, dd, H3a), 3.26, 4.07 (each lH, CH2CO, d), 3.42 (lH,
dd, H3b), 3.70 (3H, s, CH30), 3.81 (2H, s, SCH2), 4.83 (2H, m, CH20), 4.93 (lHl,dd, H4), 5.35 (2H, m, CH2CH), 6.03 (lH, m, CHCH2), 7.39 (2H, d, Ph-H), 8.02 (2H,30 d, Ph-H)
b. R-methyl-4[(4-allylox~c~l,onyl)b~ 111,io] 2~ r~ r ~ t~
A sn~pencion of anhydrous potassium carbonate (8.88g), R-4-[(4-
allylo,~y~ onyl)bell~yl~lio~-2-oxo~7p-titlin-l-ylacetic acid (21.55g) in N-
metllyl~.yl.,lli~linonP (lOOml) was t eated with methyl iodide (10.94g) and stir~ed at
35 room ~p~ t; for 2 hours. After a further (l.Og) methyl iodide was added the
reaction was stirred for 30 minl~tP~, partitioned between brine (SOOml) and diethyl
ether (SOOml). The aqueous layer was washed with diethyl ether (SOOml) and the
organic extracts were combined, washed with water (x2), brine, dried (MgS04),andevaporated to an orange oil (22. lg). Purified by flash column chromatography on40 silica gel eluted with [1:1] P.E. 40-60~C: ethyl acetate to give R-methyl-4-[(~
allyloxycarbonyl)benzylthio]-2-oxoazetidin-1-yl~-et~te as a yellow oil (20.0g, 89'~).
lH NMR ~ (CDC13) 2.94, 3.01 (lH, dd, J=2.2, 15.3Hz, H3), 3.26 (lH, d, J=18.1Hz, 1
of NCH2), 3.39, 3.46 (lH, dd, J=S.1, 15.3Hz, H3), 3.7 (3H, s, C02CH3), 3.81 (2]H,
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W O 97/02242 PCT~EP96/02765
S7 SC~2), 4.03 (lH, d, J=18.1Hz, 1 of NCE~2), 4.83 (2H, m, C02C~I2), 4.93 (lH, m,
), 5.37 (2H, m, C~12=CH), 6.04 (lH, m, CH2=C~D, 7.39 (2H, m, Ar-~D, 8.02 (2H,
m, Ar-~)
~ R,R.Methyl-2-(4-t(4allylox~c~Lonyl)b~ lll,-o]-2 o~ idin-l-
y~ r~ and S,R- Methyl-2-(4[(4-allylox~rl,onyl)be ~ylll~;o]-2- -
u~Q~ -l-yl)t,.o~:Qn~t~ solnt~ of R-methyl~[(4
allylc~yc~l onyl)benzylthio]-2-o~c0~7Ptitlin-l-yl~et~t~p (13.2g) in anhydlous
tetrahydrofuran (250ml), cooled to -75~C under nitrogen, was treated with a lM
solution of lithium bis(trimethylsilyl)amide in THF (46.3ml) over 10 ...;.~ s keeping
the temperature below -70~C. The red sollltion was cooled back to -75~C and 1,3-dimethyl-imi~oli~linonP (30.5ml) was added kPPping the t ~"~ below -70~C.
The r~-sulting snsl-çn~ion was stirred at -75~C for 30 ~ e-s and then treated with
methyl iodide (4.3ml) over 1 minute and the ~m l.e. ~ t; rose to -68~C. The reaction
was stirred at -75~C for 1.5 hours and ~hen allowed to warm to -20~C over 30
minlltps- The reaction was cooled to -75~C and quen~hPd with glacial acetic acid(3.5ml), partititio~pd between water (300ml) and diethyl ether (250ml). The ~queou~
was washed with ether (250ml) and the organic extracts were combined washed withbrine (x3), dried (MgSO4) and evaporated to a coloured oil (7.81g).1H nmr inr~ tP~
- a ratio of al)plv~ ately 50% R,R (diastereoi~()mPr a): 35% S,R (diastereoisomer b):
15% starting m~ttori~l Purified by repeat flash column chromatography on silica gel
eluted with [2:1] petroleum ether 40-60~C:ethyl acetate to give the products as
various mixtures (12.06g, 88%).
d. R,R-2-{4-[(4-allyloxycarbonyl)be:J.Lylll.io]-~o~ yl}propionic acid
and S,R-2-{4-[(4-allyloAycal l,onyl~e~ ;o]-~oy~7~HAin l -yl}propionic
acidA solution of methyl-2- {4-[(4-allylo~ycdll,onyl)bell~yl~lio]-2-ox- ~7Pti~lin-l-
yl}propionate (2.65g) in tetrahydrofuran (50ml) was cooled to 3~C and treated with
lN sodium hydroxide solution (7.5ml) over 1 hour. The cooling bath was removed
and reaction mixture was stirred for 30 ~ P-S and a further l.Oml of lN sodium
hydroxide solution was added. The reaction was stirred for 30 minllt~s~ brine (75ml)
was added and the reaction mixture was extr~ct~d with diethyl ether (75ml). The
aqueous was ~ ifiPd with 2NHCl and extr~ct~d with diethyl ether (2x75ml). the
extracts were combined, washed with water, dried (MgS04), and evaporated to give a
Lule of (R,4-R) and (S,4-li~)-2-~4-[(4-allyloxycarbonyl)bel-~yl~-io]-2-
oxo~7Ptil1in-l-yl}propionic acid and des a-methyl analogue as an orange oil (2.50g,
98%).e. (S,4-R~N-[6-~4-Fluorophenyl)hexy1]-2-t(4 allyo~ l~--yl)~e,~yl ' ~]-
2~ ;n-l-yl~ ion~
A mixture of 6-(4-fluorophenyl)hexylamine (1.38g), 2-~4-[(4-
allylo~yca~l ol~yl)benzylthio]-2-oxo~7ptirlin-l-yl~propionic acid (mixture of
diasteroisomers) (2.47g), 1-hydroxybenzotriazole (0.95g) and
dicyclohexylcarbodiimide(1.46g) in dimetl-ylÇo, ~ mi(le (50ml) was stirred at room
L~-l-~el~tult: for 4 hours. The reaction mixture was treated with diethyl ether (lOOml)
and filtered to remove dicyclohexylurea. The filtrate was washed with saturated
sodium hydro_en carbonate solution, brine, dried (MgS04) and evaporated to dryness.
Purified by flash column chromatography on silica gel eluted with [2: 1] P.E. 40-60~C
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W O 97/02242 PCT~EPg6/0276S
-
to give S,R-N-t6-(~fluolophenyl)hexyl]-2-~(1 ally~Ay-,~L.ollyl)be-~ylll~o]-2-
o~u~ ;..-l-ylplu~;o~ P, (~lis ~tPreoieo~ b) as a yellow oil (0.479g, 13.4%)lH NMR ~ (CDCl3) 1.32-1.6 (13H, m, CEI3. 4xC~12), 2.56 (2H, t, J=7.6Hz, CH2Ph)~
2.8~, 2.87 (lH, dd, J=2.3, 15.3Hz, 1~3). 3.1-3.3 (3H, m, NHC~2, ~13), 3.86 (2H, s,
- S SCH2), 4.10 (lH, q, C~CH3), 4.69(1H, m, 314), 4.83 (2H, m, C02C~I2), 5.37 (2H,
m, C_2=CH), 6.02 (lH, m, CH2=C~), 6.43 (lH, m, N~D, 6.94 (2H, m, p-F-Ph-~),
7.10 (2H, m, p-F-Ph-~), 7.37 (2H, m, Ar-~), 8.09 (2H, m, Ar-~)
FY~mplc ~ S,4-R,SS,~N-t6-(4Fluo..~ yl~heYyl]-'~ t(4
allylu~,~ul,onyl)l~L.~.~l~-.lrh;nyl]-2~ a, ~ lyr~
10 A sollltion of S,R-N-[6-(~Fluol~phenyl)heAyl]-2-[(~ally-3Ay-,dLbonyl)l>el~ylll.io]-2-
v~n~7~ in-l-ylplupiot.,....i-l~ (1.20g) in dichloromPthstnP (25ml), cooled to -75~C,
was treated with a sollltion of mcpba (0.7lg, 1Pq~ in dichloromP-thS~n~P (25ml) d~0~. ise
over 1 hour. The cooling bath w~ removed and the reaction .~ w~ stirred for 2
hours, diluted with dichloromPthS,nP- (25ml) and washed with 10% aqueous sodium
15 s~llphite (SOml), saturated sodium hydrogen carbonate ~olntion (SOml), water. dried
~MgS04) and evaporated to an orange oil. Intially purified by flash column
chromatography on silica gel eluted with ethyl acetate and then by IJlGpaldLiV~ hplc to
give S7R~s-N-[6-(4-fluorophenyl)hexyl]-2-t(~allylu~y~ lyl)benzylclllphinyl]-2
tl~o~7pti~iin-l-ylpropion~mirlp (diastereni~omp-r b2) as colourless oil. Soli~lifips on
20 st~n-ling (0.24g, 19.4%).
lH NMR o (CDCl3) 1.32-1.6 (13H, m, C~3, 4xCE12), 2.56 (2H, t, J=7.6Hz, C~I2Ph)
2.83, 2.87 (lH, dd. J=2.4, 15.3Hz, ~3), 3.1-3.3 (3H. m, NHC~2, H3), 3.96, 4.08 (2H,
2xd, J=13Hz, SOCH2), 4.4 (lH, q, CHCH3), 4.60 (lH, m, ~4), 4.84 (2H, m,
C02CH2), 5.,37 (2H, m, CH2=CH), 6.04 (lH, m, CH2=C~), 6.94 (3H, m, NH, p-F-
25 Ph-~), 7.10 (2H, m, p-F-Ph-~), 7.37 (2H, m, Ar-~), 8.09 (2H, m, Ar-~)
F-Y~ ,'~ S6~ S~4-R~SS)-N-t6-(4~FIUOIU~h~ I)heXYI]-2~4
carb~yl.~,~y~ l]-2~ ;Ain-l-yl~lul i~nan~ide
A solntion of (oc-S, 4-R, SS)-N-t6-(4-Fluorophenyl)hexyl]-2-t(4-
allyoxycarbonyl)benzyl~nlrhinyl]-2-07co~7Pti~in-l-yipropionamide (FY~mrlP 55, dia
30 b2) (0.24g), terakis(triphenylphosphinP)p~ rn (O) (lSmg) and
triphenylphosphine (6mg)i in dry dichloromp-th~np (Sml) was treated with pyrollidille
(0.039ml) and the reaction was stiired at room temperat~lre for 20 hours. The
rP~etion mi~Lulc~w~s treated with dichlorompth~np (50ml) and water (25ml) and
lifiPd with 2NHCl. Brine (75ml) was added to the emnlci~n the layers were
35 separated and the aqueous was washed with dichloromPth~nP (2x50ml). The organic
extracts were dried (MgS04) and evaporated to a yellow gum (0.22g) and purified lby
flash column chromatography on silica gel eluted with 50:50: 1
dichlorom~Pth~nP:~retonP ~eetic acid to give (oc-S, 4-R, SS)-N-[6-(4-
fluorophenyl)hexyl]-2-[(4- allyoxycarbonyl)7~ll~yllllio]-2-oxo~7pti~lin
40 ylpropion~mi~le as a brown foam (0.123g, 56%).
lH NMR o (CDC13) 1.32-1.6 (13H, m, CH3, 4xCH2), 2.55 (2H, t, J=7.6Hz, CH2Ph),
2.84, 2.88 (lH, dd, J=2.4, 15.2Hz, H3), 3.1-3.3 (3H, m, NHCH2, H3), 4.04, 4.10 (2H,
2xd, J=13Hz, SOCH2), 4.4 (lH, q, CHCH3), 4.68 (lH, m, Hl), 6.94 (3H, m. NH, p-
F-Ph-~), 7.10 (2H, m, p-F-Ph-H), 7.39 (2H, m, Ar-H), 8.06 (2H, m, Ar-~)
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Example 101 - (+/-)-4(Pyrid-2 yl~ )-1-(4phenyl-2
one
a) (+/-)-4(Pyrid-2~ ..eU.~ .o)azetidin-2-one
Sodium (0.935 g, 40 mmol) was dissolved in etnanol (100 ml), then 2-
S (m~L.lo~Pthyl)pyridine (5.0 g, 40 mmol) was added and stirred 10 min at room
~ ela~u~~ A solution of 4-ac~tu~yi~7~ n-2-one in ethanol (50 ml) was added
dropwise, and stirring contimlP~d for a further 30 min. The solvent was evaporated,
water was added, and the product eY I . ~ d into ethyl acetate. Drying and ~apolalion
gave an oil which slowly cryst~lli.cP~ and was l~ -d with petroleum ether to give
the title compound (5.3 g), m.p. 99-100~C. IH NMR (CDC13) ~ 2.84 (lH, dd), 3.34
(lH, dd), 3.95 (2H, s), 4.86 (lH, dd), 6.58 (lH, br s), 7.17-7.34 (2H, m), 7.65-7.72
(lH, m), 8.50-8.53 (lH, m).
b) (+/-)-4(Pyrid-2-yl~ ll.ylll~io)-1-(4-phenyl- oxobutyl)~7~ti~1ir 2 one
A mixture of (+/-)~(pyrid-2-ylmethylthio)~7pti~lin-2-one (5.3 g, 27 mmol), l-bromo-
4-phenyl-2-bnt~nonP (6.8 g, 30 mmol), tetrabutyl~mmoninm bromide (0.87 g, 2.7
mmol), finely powdered KOH (1.7 g, 30 mmol) and dry THF (100 ml) was stirred at
room temperature for 2 hours, then poured into water and extracted with ether.
Chromatography (silica, dichloromPth~n~) of the organic extracts and cry.~t~lli.~tion
from ether gave the desired product (2.5 g), m.p. 56-58~C. 'H NMR (CDC13) o 2.70(2H, t), 2.90 (2H, t), 3.01 (lH, dd), 3.43 (lH, dd), 3.57 (lH, d), 4.11 (lH, d), 3.84 (
2H, s), 4.98 (lH, dd), 7.15-7.32 (7H, m), 7.60-7.67 (lH, m), 8.48-8.51 (lH, m).
Example 102 - (+/-) 1-(Pyrid-2-ylmell~ hinyl)-1-(4phenyl-2-
oxobutyl)~Pti-l;n-2-one (diastereomer 1)
A sol~ltion of (+/-) 1 (pyrid-2-ylmethylthio)-1-(4-phenyl-2-oxobutyl)~7Pti~iin-2-one
(2.4 g, 7 mmol) in dichlorometh~n~o (50 ml) was cooled to -60~C and a solution of m-
chlo,o~lo~ybenzoic acid (1.46 g, 8.4 mmol) in dichloromPth~ne (50 ml) was added
dropwise. Stirring was continued at this tPmrPr~mre for 1 hour, then the ~ Lulc: was
poured into an aqueous solution of sodium sulphite and sodium bicarbonate. The
organic layer was dried and evaporated, and the residue trinlratPd with ethyl acetate.
Recryst~lli.c~ti~n from ethyl acetate gave a single diastereomer (0.66 g), m.p. 123-
125~C. IH NMR ~ (CDC13) 2.74 (2H, t), 2.92 (2H, t), 3.01 (lH, dd), 3.33 (lH, dd),
3.84 (lH, d), 3.98 (lH, d), 4.13 (lH, d), 4.40 (lH, d), 4.92 (lH, dd), 7.15-7.35 (7H,
m), 7.70-7.80 (lH, m), 8.56 (lH, m). v~=O 1785 cm~l (CCL)
Found: C, 63.63; H, 5.62; N, 7.97%
ClgH20N203S requires: C, 64.02; H, 5.66; N, 7.86%
F.Y~mple 103 - (+/-)~(Pyrid-2-ylmell~ yl)-1-(4phenyl-2-
oxobutyl)~-7Pt--l;n 2-one (diastereomer 2)
The mother liquors from the ethyl acetate trihl~tinn in e~mrlP 102 were
y~ ced twice from ethyl acetate/ether to obtain a sample of the second
diastereomer, cont~min~t~-d with 20% of diastereomer 1 (0.34 g), m.p. 70-72~C. IH
NMR o (CDC13) 2.69-2.77 (2H, m), 2.77 (lH, dd), 2.90 (2H, t), 3.26 (lH, dd), 4.17
(2H, s), 4.22 (lh, d), 4.37 (lH, d), 4.79 (lH, dd), 7.14-7.34 (7H, m), 7.69-7.74 (lH,
m), 8.56-8.57 (lH, m).
vc=O1785cm~l(CC14)
Found: C, 64.07; H, 5.65; N, 8.22%
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CA 02225627 1997-12-23
W O 97102242 PCT~EP96/0276S
ClgH20N2O3S req~ s: C, 64.02; H,5.66; N,7.86%
Exa nple 104 - (+/-)-N-(6-Phenylhex-l-yl)- 4 (~ ylm~ lU~.o)-2
l yls.~
a) (+/-)~(Pyrid-~ .,t;ll,rlUIio)~7~ 2-one
S The synthesis was carried OUt as in e-~mrlP la, using 20 mmol each of 4 (a~lyl~o-
methyl)pyridine and 4 act;Lo~yi17~ in-2-one~ Chromatography (silica,0~% MeOH in
CH2Ck) gave the title compound as an oil (2.7 g). lH NMR ~ (CDC13) 2.87 (lH, dd~,
3.34 (lH, dd),3.g0 (2H, s),4.70 (lH, dd),7.03 (lH br. singlet),7.26-7.30 (2H, m),
8.51-8.59 (2H, m).
10 b) (+/-)-N-(~Pht ,.~' -l-yl)~(~ tl.r! ' ~ !idin-l-
~ylac~,l~-lide
The syn~esis was carried out as in eY~mrlp 101b, using 8.5 mmol of (+/-) 4 (pyrid-2-
ylmethylthio)~7Pti-lin-2-one (8.5 mmol), N-(6-phenylhex-1-yl~2-brnmo~.~e~ P (9 4
mmol), tetrabutylammonium bromide (0.94 mmol) and powdered KOH (9.4 mmol) in
dry 1~ (50 ml). Chromatography (silica,0-2% MeOH in EtOAc) gave the tide
compound as an oil (2.2 g). IH NMR ~ (CDCl3) 1.27 (4H, m), 1.46-1.66 (4H, m),
2.59 (2H, t), 2.91 (lH, dd),3.22 (2H, m), 3.39 (lH, dd), 3.47, (lH, d), 3.72-3.89 (31H,
m), 4.91 (lH, dd), 6.23 (lH, br. triplet), 7.14-7.30 (7H, m), 8.53-857 (2H, m).
F - ~'e 105- (+/-~N-(6-Phenylhex-l~yl) 1 (~ yll~eû~yl~,ulphinyl)-2-
~~Yn~ .-l-yl~ ~ t ~ eomer 1)
The synthesis was carried out as in pY~mr)lP 102, using (~-)-N-(6-phenylhex-1-yl) 4
(pyrid-4-ylm~ yl~,io)-2-oxo~7rli~1in-l-yl~ret~mitlP (2.1 g, S.1 mmol).
Recryst~llic~tion of the crude product from ethyl acetate/ether gave a single
diastereomer (0.55 g), m.p. 126-127~C. 'H NMR ~ (CDC13) 1.31-1.35 (4H, m), 1.48-1.64 (4H, m), 2.59 (2H, t), 3.01 (lH, dd), 3.23 (2H, dt), 3.46 (lH, dd), 3.82-3.90 (3H,
m), 4.03 (lH, d), 4.70 (lH, dd), 6.36 (lH, br triplet), 7.15-7.29 (7H, m), 8.64 6.66
(2H, 7m). vC=O 1794, 1745cm~l (CC14)
Found: C, 64.37; H, 6.74; N, 9.75%
C23H2sN3O3S requires: C, 64.61; H, 6.84; N, 9.83%
Example 106 - (+/-~N-(6-Phenylhex-l-yl)~(pyrid 1 yl~ l)-2,
in_1_y~ ...;A~(~L~ omer2)
The mother liquors from eY~mplP- 105 cry~st~ ce~ from ethyl acetate/ether to give a
sample col-t~ g 86% of the second diastereomer (0.5 g), m.p. 89-91~C. IH NMR o
(CDC13) 1.33-1.37 (4H, m) 1.50-1.60 (4H, m) 2.60 (2H, t), 3.00 (lH, dd), 3.21-3.33
(3H, m), 3.95-4.03 (3H, m), 4.18 (lH, d), 4.71 (lH, dd), 6.70 (lH, br. triplet), 7.15-
7.29 (8H, m), 8.64-8.66 (2H, m). n~O (CCl~) 1795, 1766.
Found: C, 64.53; H, 6.72; N, 9.84%
C23H29N3O3S requires: C, 64.61; H, 6.84; N, 9.83%
Example 107 - (+/-)-N-(6-Phenylhex-l-yl~4-(1-ox ~ 1-4~ U~yl:,ull~honyl)-2'-
~ n l yl~r~
A solution of (+/-)-N-(6-phenylhex-1-yl)-4-(pyrid 4 ylmethyls--lrhinyl)-2-0~0~7Ptitlirl-
l-yl~et~mi~le (0.2 g, 0.47 mmol) and m-chlol~Jpelo~y-henzoic acid (exces~s) in
dichlorom~th~nP (30 ml) was stirred at room ~~ dture for 2 hours, then worked upas in e~mplP 102. Chromatography (silica, 0-5% MeOH in CH2Ck) gave the title
compound (0.17 g), m.p. 72-74~C. 'H NMR ~ (CDC13) 1.33-1.37 (4H, m), 1.'50-1.6'5
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CA 02225627 1997-12-23
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(4H,m).2.60(2H, t), 3.24-3.30(2H,m),3.38(lH, dd), 3.86(lH, d), 4.06(lH,d),
4.30(lH,d),4.54(IH, d), 5.00 (lH, dd), 5.76(lH, br. ~plet), 7.15-7.20(3H,m)
7.26-7.30(2H,m),7.40(2H, d), 8.22(2H, d). vc~ 1780cm~l (KBr)
Found: C 59.41;H6.18;N9.05
C23H29N3O5S;0.2H20 requires: C 59.64;H6.41;N9.07
FY~plel08-(+/-)-N-(6-Pheny~ex-l-yl)1(~ru~ -ylU-io~ ;Un-l-
y~ce~de
a) (+/-)-(~F~ .io)~-F~ one
The synthesis was carried out as in eY~mrl~ 101a, using furfuryl me~ (42.5
10 mmol) and 4-ace~oAy~P~ n-2-one(38 mmol). Chromatography (silica, 1:1 pet.
ether/CH2Ck) gave the title compound as an oil (5.5 g). 'H NMR ~ (CDC13) 2.86(lH,
dd), 3.36(lH, dd), 3.86(2H,s),4.79(lH, dd), 6.06(lH, br. singlet), 6.21-6.23(lH,m), 6.33-6.35(1lH, m), 7.37-7.39(lH,m).
b) (+/-)-N-(6-Phenylhex-l-yl)-1 (2-lu~ U~ylU~io)-2
15 yl~ Pt~m;~lP
The synthesis was carried out as in eY~mplP 101b, using (+/-)~(2-fulyl~ ylLhio)-~7pti~lin-2-one (10 mmol), N-(6-phenylhex-1-yl)-2-bromo~-et~mitle (10 mmol), tetra-
butylammonium bromide (1 mmol), and powdered KOH(ll mmol) in dry- THF (150
ml). Chromatography (silica, EtOAclpet. ether) gave the title compound as an oil (3.4
g). lH NMR~(CDC13) 1.31-1.40(2H, m), 2.60(2H, t), 2.97(lH, dd), 3.19-3.28
(2H, m), 3.43(lH,dd),3.65(lH,d),3.83 (lH, d), 3.84(2H, d), 4.91 (lH, dd), 6.13
(lH, br. triplet), 6.22(lH, m), 6.31(lH, m), 7.14-7.36(6H, m).
F~y~plelO~-(+/-)-N-(6-Pheny~ex-l-yl)1(2-~ e~
o~ e~ ;..-l-ykc '~ omerl)
The synthesis was carried out as in PY~mrl~lo2~ using (tJ-)-N-(6-phellyll.c;A-l-yl)~
(2-furylme~,yl~lio)-2-oxo~7Pti~in-l-yl~et~mide(2.9 g, 7.2 mmol). Recryst~lli~ti~n
of the crude product from ethyl acetate gave a sample cont~inin~ about 99% of
diastereomer 1 (0.2 g), m.p. 160-161~C.'H NMR~(CDC13)1.32-1.36(4H, m) 1.50-
1.63(4H, m), 2.60(2H, t), 3.01(lH,dd),3.18-3.30(2H, m), 3.42(lH,dd),3.76(lH,
d),4.00(lH,d),4.10-4.16(2H, m), 4.60(lH, dd), 6.42(2H, m), 6.55(lH, br.
triplet), 7.16-7.19(3H, m), 7.25-7.29(2H,m),7.43(lH, m). n~ 1748,1791cm~
(CC14)
Found: C, 63.18;H,6.59;N,6.77%
C22H28N2O4S requires: C, 63.44;H,6.78;N,6.73%
FY~mpl~ 110~ N-(6-Phenylhex-l-yl)~ e~
n l ~ ide (.li~c~ -er2)
The mother liquors from ex~mpl~- 109 were purified by chromatography (silica, 0-2%
MeOH in CH2C17) and recryst~llic~ti-~n from ether/ethyl acetate to give a sample of
diastereomer 2 cont~ining 5% of diastereomer 1 (1.08 g), m.p. 61-62~C. IH NMR ~ -
(CDC13) 1.33-1.37 (4H, m), 1.51-1.63 (4H, m), 2.60 (2H, t), 3.00 (lH, dd), 3.23-3.30
(3H, m), 3.98 (lH, d), 4.29 (lH, d), 4.12 (lH, d), 4.24 (lH, d), 4.61 (lH,dd), 6.42
(2H, m), 7.15-7.18 (3H, m), 7.25-7.31 (3H, m), 7.44-7.45 (lH, m). vc~01793cm~
(CC14)
Found: C, 63.41; H, 6.63; N, 6.80%
C22H28N2O4S requires: C, 63.44; H, 6.78; N, 6.73%
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W O 97/02242 PCT/EP96/02765
F~ (+/-)-N-(6-Ph~ lh~-1-yl) 1(2~ruu~ 2
lin l_~ t---~ide
The synthesis was carried out as in eY~mrlP 107, using N-(6-P1Ie~IY1I1GA-1-Y1) 4 (2-
furylmethylsulrhinyl)-2-oxo~7Pti~1in-l-yl~fet~mirl~ (0.10 g). Tri~ration vith ether
S gave the title compound (0.065 g), m.p. 102-104~C. 'H NMR ~ (CDC13) 1.32-1.36(4H, m), 1.49-1.64 (4H, m), 2.60 (2H, t), 3.12 (lH, dd), 3.22-3.29 (3H, m), 3.94 (l~i[,
d), 4.03 (lH, d), 4.38 (lH, d), 4.45 (lH, d), 4.89 (lH, dd), 6.00 (lH, br. triplet), 6.4
6.46 (lH, m), 6.55-6.56 (lH, m), 7.1~7.19 (3H, m), 7.25-7.29 (2H, m), 7.4~7.47
(lH, m). vOO 1797 cm~l (CCI4)
10 Found: C, 60.15; H, 6.32; N, 6.50%
C22HzgN2O5S Ø3H20 ~c;~luil ;:s. C, 60.34; H, 6.58; N, 6.40%
Example 112- (+/-)-N-(6-[4 Fluorophenyl]hex-l-yl)~ fu~ U~ )-2-
~Yo~7-~ti~1in.l.yl~ret~ni~1P
The synthesis was carried out as in PY~mphp 101b, using (+I-) 4 (2-ru~ hyllLio)-
~7Pti~lin-2-one (15 mmol), N-(6-~fluorophenyl)hex-1-yl)-2-bromo~ce~ P* (15
mmol), f~-tr~blltylammonium bromide (1.5 mmol), and powdered KOH (16.5 mmol) im
dry THF (100 ml). Chromalography (silica, 0-2% MeOH in CH2Ck) gave the title
compound as an oil (3.4 g). 'H NMR o (CDC13) 1.25-1.64 (8H, m), 2.~7 (2H, t), 2.9~8
(lH, dd), 3.23 (2H, dt), 3.43 (lH, dd), 3.67-(lH, d), 3.76-3.91 (3H, m), 4.90 (lH, dcl),
6.10 (lH, br. tr~plet), 6.22 (lH, d), 6.31 (lH, dd), 6.90-6.98 (2H, m), 7.08-7.18
(2H,m), 7.36 (lH, m).
*obtained by treating of 6-(4-fluo~ophe-lyl)hexylamine (2.0g) and Hunig's base (1.33g~)
in dry dichloromP,th~ne (2~ ml) with bromoacetylbromide (2.07g) in dichloromPth~nP
(10 ml) at 0-5 ~C.
F ~'e 113 - (+/-)-N-(6-t4-Fluorophenyl]hex-l-yl)-4(2-r~ ~ lphinyl)-2-
~Y~7et~ n-l-yl~r~t~m~ t omer 1)
The synthesis was carried out as ~n eY~mI~lp 102, using ~+l-)-N-(6-(4-fluorophenyl)-
hex-l-yl) 1 (2-furyl~ yllllio)-2-oxo~7pt~ n-l-yl~et~mi~l~(2~og~4~8mmol)~
Recryst~ ation of the crude product from ethyl acetate gave a sample Cc--~t~
about 93% of diastereomer 1 (0.3~ g), m.p. 157-8~C. 'H NMR ~ (CDC13) 1.31-1.3~
(4H, m), 1.~0-1.~8 (4H, m), 2.56 (2H, t), 3.02 (lH, dd), 3.20-3.26 (2H, m), 3.42 (lH,
dd), 3.74 (lH, d), 4.00 (lH, d), 4.10-4.17 (2H, m), 4.59 (lH, dd), 6.42 (2H, m), 6.65
(lH, br. triplet), 6.92-6.97 (2H, m),7.09-7.13 (2H, m), 7.43-7.44 (lH, m). n~=~, 1791
cm~l
Found: C, 58.85; H, 6.00; N, 6.36%
C22H27FN2O4S Ø68H20 requires:C, 59.14; H, 6.40; N, 6.27%
Example 114 - (+/-)-N-[6-(4-Fluorophenyl)hexy]~(2-furylmell-yl~ nyl)-2-
oY- ~et~ n-l-yl~cet~mide (~ eomer 2)
Evaporation of the mother liquors from e~r~mpl~ 113 and cryst~llic~tion from ethyl
acetate/ether gave a sample c~ nt~inin~ 97% of diasteromer 2 (0.62 g), m.p. 100-101~C. tH NMR ~ (CDC13) 1.33-1.35 (4H, m), 1.50-1.60 (4H, m), 2.56 (2H, t), 3.01(lH, dd), 3.22-3.31 (3H, m), 3.98 (lH, d), 4.11 (lH, d), 4.23 (lH, d), 4.29 (lH, d),
4.60 (lH, dd), 6.41-6.42 (2H, m), 6.92-6.96 (2H, m), 7.09-7.13 (2H, m) 7.26 (lH, br.
triplet), 7.44-7.45 (lH, m). nc=O 1794 cm~l
Found: C, 60.70; H, 6.22; N, 6.44%
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W O 97/02242 PcTr~l~Gl~2765
C2~H27FN204S requires: C, 60.81; H, 6.26; N, 6.45%
Example 115- (+/-)-N~(6-[4Eluorophenyllhex-l-yl}4~ r~u,~ ulphonyl)-
The synthesis was carried out as in ey~mrlp 107, using N-(~(4-fluolvpht;l",l)he~-l-
S yl) 1 (2-rulyl~ yl~lllrhinyl)-2-oYn~7ptitlin-l-yl~ icle (1.0 g). Tnt~lr~tion of the
crude product with ether and ~t;e~ c~ti~n from ethyl acetate/pet. ether gave ~e
title compound (0.29 g), m.p. 114-115~C. IH NMR ~ (CDC13) 1.31-1.35 (4H, m),
1.4~-1.60 (4H, m), 2.57 (2H, t), 3.12 (lH, dd), 3.22-3.29 (3H, m), 3.95 (lH, d), 4.03
(lH, d), 4.38 (lH, d), 4.45 (lH, d), 4.88 (lH, dd), 6.01 (lH, br. triplet), 6.446.45
(lH, m), 6.55-6.56 (lH, m), 6.93-6.97 (2H, m), 7.09-7.13 (2H, m), 7.46-7.47 (lH, m).
nOO 1797 cm~l
Found: C, 58.27; H, 5.96; N, 6.20%
C~2H~7~205S requires: C, SX.65; H, 6.04; N, 6.22%
F~ 116- (+1-)-N-(6-t4-Chlorophenyl]hex-l-yl) 1 ('~ fur~ ylU~io).~-
The synthesis was carried out as in e~r~mrle 101b, using (+/-)~(2-~u~yl~ ylthio)-
in-2-one (12 mmol), N-(6-(~chlorophenyl)hex-1-yl)-2-bromoE~t~ e (12
mmol), tetrabutyl~mmonillm bromide (1.2 mmol), and powdered KOH (13.2 mmol) m
dry TH~ (100 ml). Chromatography (silica, 50-100% EtOAc in pet. ether) gave the
title compound as an oil (3.9 g). 'H NMR ~ (CDC13) 1.23-1.61 (8H, m), 2.56 (2H, t),
2.g7 (lH, dd), 3.23 (2H, dt), 4.05 (lH, dd), 3.62-3.91 (4H, m), 4.91 (lH, dd), 6.18
(lH, br. triplet), 6.22 (lH, d), 6.30 (lH, dd), 7.08 (2H, d), 7.20-7.26 (2H, m), 7.36
(lH, d).
F~ 117- (+/-)-N-(6-[4 Chlorophenyl]hex-l-yl)-4(2-ru}~lJ~ y' ~ nyl)-
25 2~o~ ;-l-y~ ,e- 1)
The synthesis was carried out as in exarnple 102, using (+/-)-N-(~(4-chlorophenyl)-
hex-1-yl)~(2-furylmethylthio)-2-oxo~7Pti~in-1-yl~et~mi~e (3.8 g, 8.7 mmol).
Tritnration of the crude product with ether gave a sample of diastereomer 1 (0.4g g),
m.p. 171-2~C. IH NMR ~ (CDCl3) 1.31-1.34 (4H, m), 1.49-1.61 (4H, m), 2.56 (2H,
t), 3.02 (lH, dd), 3.20-3.26 (2H, m), 3.42 (lH, dd), 3.75 (lH, d), 4.00 (lH, d), 4.10-
4.17 (2H, m), 4.60 (lH, dd), 6.42 (2H, m), 6.60 (lH, br. triplet), 7.08-7.10 (2H, m),
7.22-7.26 (2H, m), 7.43-7.44 (lH, m). n~=O 1791 cm~l
Found: C, 58.16; H, 5.91; N, 6.25%
C22H27ClN204S requires: C, 58.59; H, 6.03; N, 6.21%
FY~ 118 - (+/-)-N-(6-[4-Chlorophenyl~hex-l-yl)~ U~ e~ }~
2~o~q~tiA;n-l-yl~rPt ~ el~omer 2)
The mother liquors from e~mple 117 were evaporated and cryst~lli.~ec~ from ether to
give a sample of diastereomer 2 (1.2 g), m.p. 92-3~C. IH NMR ~ (CDCl3) 1.32-1.34(4H, m), 1.50-l.S9 (4H, m), 2.56 (2H, t), 3.01 (lH, dd), 3.24-3.31 (3H, m), 3.98 (lH,
d), 4.11 (lH, d), 4.25 (lH, d), 4.27 (lH, d), 4.60 (lH, dd), 6.41-6.42 (2H, m), 7.08-
7.10 (2H, m), 7.21-7.26 (2H, m), 7.35 (lH, ~r. triplet), 7.44-7.45 (lH, m). nOO 1794
cm~l
Found: C, 58.32; H, 5.95; N, 6.23%
C22H27ClN204S requires: C, 58.59; H, 6.03; N, 6.21%
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.
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F.Y~mr~ 119 - (+/-)-N-(6-[4 C~ I)hex-l-yl)~(2-r.,. ~ lphonyll)-
-yl~'Pt~ ?
The synthesis was carned out as in eY~mrle 107, using N-(6-(4-ch~ol.)phe..yl)he~yl)~(2-furylmethyl.~ r)hinyl)-2-oxQ~7Pti~in-l-yl~ret~mitle T.;I...,.t;.~n ofthecmde
product with etner gave the title compound (0.6 g), m.p. 107-8~C. 'H NMR ~
(CDC13) 1.31-1.35 (4H, m), 1.49-1.60 (4H, m), 2.57 (2H, t), 3.12 (lH, dd~, 3.22-3.29
(3H, m), 3.95 (lH, d), 4.03 (lH, d), 4.38 (lH, d), 4.45 (lH,d), 4.88 (lH, dd), 6.03
(lH, br triplet), 6.44 6.46 (lH, m), 6.55-6.56 (lH, m), 7.08-7.11 (2H, m) 7.21-7.26
(2H, m), 7.45-7.47 (lH, m). n~=O 1797 cm~l
Found: C, 56.54; H, 5.74; N, 6.02%
C22H27ClN2OsS requires: C, 56.58; H, 5.83; N, 6.00%
FY~mpl? 120- (+/-)-N-(6-14-Chlorophenyl]hex-l-yl) 1 (3-rur,~ .eU-g~ 2
~y~7~h'- 1-yl~
a) (+/-)-4(3-Fu~ -e~ io)~7et~ n-~one
The synthesis was ca~,Tied out as in ~Y~mple 101a, using 3-(acetylthi()mPthyl)furan (64
mrnol) and 4-accL~y,.7Pti~lin-2-one (64 mmol). Cyst~1li.~tion from ell-cJI,cL ethLer
gave tne title compound (10 g), m.p. 60-61~C. IH NMR o (CDC13) 2.90 (lH, dd),
3.35 (lH, dd), 3.68 (2H, d), 4.70 (lH, dd), 6.14 (lH. br s), 6.42 (lH, m), 7.38-7.42
(2H,m).
b) (+~-)-N-(6-[4-Chlorophenyllhex-l-yl)-4(3-fu~ ' ~C ~ 7- ~;din-
1-yl-- ?
The synthesis was CalTiedOUt as in e7c~mplP 101b, using (+/-)~(3-ru~ io)-
~7Pti ~in-2-one (13.6 mmol), N-(6-(4-chlorophenyl)hex- 1 -yl)-2-bromo~ret~mi(~e (13.6
mmol), tetrabutylammonium bromide (1.36 mmol), and powde,cd KOH (14 mmol) iin
dry THF (100 ml). Chromatography (si'lLica, 50-100% EtOAc in pet. e~Ler) gave the
title compound as an oil (4.0 g). IH NMR ~ (CDCl3) 1.25-1.36 (4H, m), 1.40-1.68
(4H, m), 2.56 (2H, t), 2.96 (lH, dd), 3.20-3.28 (2H, m), 3.41 (lH, dd), 3.61-3.73
(3H, m), 3.85 (lH, d), 4.84 (lH, dd), 6.12 (lH, dd), 6.39 (lH, m), 7.06-7.10 (2H, m),
7.21-7.26 (2H, m), 7.37-7.39 (2H, m).
FY~mrle 121 ~ (+/-)-N-(6-t4L-Ch~orophenyl]hex-l-yl)-4-(3-lu, ~ll-,etl.~l~.ullJhLinyl'~
7~ n-l yl~et~m~ (dia~.l~.~...~ 1)
The synthesis was carried out as in ex~mple 102, using (+/-)-N-(6-(4~hlol.,phel.yl)-
hex-l-yl)~(3-furylmethylthio)-2-oxo~7.~ti-1in-l-yl~et~mitle (2.5 g, 5.7 mmol).
Cryst~llis~tion of the crude product from ethyl aceLate gave a sample ~ont;~ 98
of diastereomer 1 (0.6 g), m.p. 162-163~C. IH NMR ~ (CDC13) 1.30-1.34 (4H, m),
1.49-1.59 (4H, m), 2.55 (2H, t), 3.04 (lH, dd), 3.20-3.26 (2H, m), 3.55 (lH, dd),
3.7~3.78 (2H, m), 3.86 (lH, d), 4.13 (lH, d), 4.59 (lH, dd), 6.37-6.38 (lH, m), 6.l50
(lH, br. triplet), 7.08-7.10 (lH, m), 7.21-7.26 (2H, m), 7.46-7.47 (2H, m). n~=O 17~92
cm~l
Found: C, 58.52; H, 5.94; N, 6.20%
C22H2,ClN204S requires: C, 58.59; H, 6.03; N, 6.21%
FY~mrle 122- (+/-)-N-(6-[4-Chlorophenyl]hex-l-yl) 4 (3 ~u,,~l~"~ll,yl Ip~;nyl?-
2-~ e~ n-l-y~ et~mi~l~ (diastereomer 2)
The mother liquors from example 121 were evaporated, L~ ated with ether, and
45 recryst~ e~ from ethyl acetate to give a sample cont~ining 98% of diastereomer 2
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CA 02225627 1997-12-23
W O 97/02242 PCT~EP96/0276
(0.7 g), m.p. 95-96~C. IH NMR ~ (CDC13) 1.32-1.34 (4H, m), 1.50-1.60 (4H, m),
2.56 (2H, t), 3.03 (lH, dd), 3.20-3.32 (3H, m), 3.86-3.98 (3H, m), 4.24 (lH, d), 4.66
(lH, dd), 6.38-6.39 (lH, m), 7.08-7.10 (2H, m), 7.14 (lH, br. triplet), 7.21-7.26 (2H,
m), 7.46-7.48 (2H, m). n~=O 1794 cm~l
S Found: C, 58.53; H, 5.94; N, 6.20%
C22H27CIN2O4S requires: C, 58.59; H, 6.03; N, 6.21%
FY~mp'e 123- (+/-)-N-(6-14-Chlorophenyl]hex-l-yl)-4(3-ru~ ls~ onyl)-
~ Y~ 7 ~;rl;n l_yl5~c~t~ ide
The synthesis was carried out as in eY~mplp 107, using N-(6-(4-chl~,loplle..yl)he~
10 yl)~(3-furylrnethyl~nlrhinyl)-2-ol~o~7~ti~in-l-yl~ P. Tritl-~tion of the crude
product with ether gave the tide co.~poul-d, m.p. 95-96~C. IH NMR ~ (CDC13) 1.31-
1.35 (4H, m), 1.48-1.61 (4H, m), 2.56 (2H, t), 3.20-3.27 (4H, m), 3.87 (lH, d), 4.02
(lH, d), 4.18 (lH, d), 4.25 (lH, d), 4.91 (lH, dd), 5.98 (lH, br. triplet), 6.53-6.54
(lH, m), 7.08-7.11 (2H, m), 7.21-7.26 (2H, m), 7.47-7.48 (lH, m), 7.57 (lH, d). n~=O
lS 1795 cm~l
Found: C,55.41;H,5.61;N,5.83%
C22H27ClN2O5S ØSH20 requires:C, 55.51; H, 5.93; N, 5.89%
F ,~.e 124 - (+/-)-N-[6-(~Chlorophenylhexyl)] 1 (~Illi~"~ llh;o~2-
-yl~c~t ' ~e
20 a) (+/-)-4-(2-Thienylm~ ylU.io)azetidin-2-one
The synthesis was carried out as in example 101a, using 2-(acetylthio...~l~.yl)thiophene
(71 mmol) and 4-acetoxy~7Pti~lin-2-one (71 mmol). Chromatography (silica, 50-70%EtOAc in pet. ether) gave the title colllp~3und as an oil (9.1 g). lH NMR ~ (CDC13)
2.88 (lH, m), 3.35 (lH, m), 4.06 (2H, m), 4.75 (lH, m), 5.82 (lH, m), 6.96 (2H, m),
7.24 (lH, m)
b) (+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(~thi~ Ilhio~
1-ylacetamide
The synthesis was ca~rried out as in eY~mplP 101b, using (+/-)-4-(2-~ie.lyhllell,yl~.io)-
~7p-titlin-2-one (5 mmol), N-(6-(4-chlolophenyl)hex-1-yl)-2-bromo~ce~ le (S.S
mmol), tetrabutylammonium bromide (0.5 mmol), and powdered KOH (5.25 mmol) in
d.~ THF (25 ml). Chromatography (silica, 30-80% EtOAc in pe~ ether) and
trituration with ether/pet. ether gave the title compound (0.66 g), rri.p. SS-7~C. IH
NMR ~ (CDC13) 1.33 (4H, m), l.SS (4H, m), 2.56 (2H, t), 2.97 (lH, dd), 3.23 (2H,m), 3.41 (lH, dd), 3.63 (lH, d), 3.79 (lH, d), 4.05 (2H, m), 4.88 (lH, m), 6.05 (lH,
m), 6.89-7.26 (7H, m).
F~Y~mp~? 12~- (+J-)-N-t6-(4Chlor~ yll._A~1)]-~(2-thi~ -etl~yl~ hinyl)-~
The synthesis was carried out as in eY~mple 102, using (+I-)-N-(~(4-chlorophenyl)-
hex-l-yl)-4-(2-thienylmethylthio)-2-oxo~7P-ti~lin-l-yl~ret~mi~e (3.0 g, 6.65 mmol).
Cryst~ ti~)n of the crude product from ethyl acetate and recryst~llic~tion from
acetonitrile gave a sample cont~ining 97% of diastereomer 1 (0.73 g), m.p. 161-2~C.
IH NMR ~ (CDC13) 1.33 (4H, m), 1.51-1.61 (4H, m), 2.56 (2H, t), 3.01 (lH, dd),
3.23 (2H, m), 3.4~ (lH, dd), 3 74 (lH, d), 4.13 (lH, d), 4.13 (lH, dd), 4.25 (lH, dd),
4.57 (lH, dd), 6.59 (IH, m), 7.03-7.35 (7H, m). nOO 1791 cm~
Found: C, 56.51; H, 5.71; N, 6.06%
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C22H27ClN2~3S2 requires: C, 56.58; H, 5.83; N, 6.00%
F , '~ 126 - (+/-)-N-[6-(4-Chl~ ~y'' yl)] 1 ('~ thie~ yl)-2-
The ethyl acetate mother liquors from pY~mrl~ 125 gave further crystals on ~t~nrlin~,
S wnich cQnt~inP~ g8% of diastereomer 2 (0.57 g), m.p. 93-5~C. IH NMR ~ (CDC13)
1.34 (4H, m), l.SS (4H, m), 2.56 (2H, t), 2.98 (lH, dd), 3.25 (3H, m), 3.89 (lH, d),
4.25 (lH, d), 4.25 (lH, d), 4.33 (lH, d), 4.65 (lH, dd), 7.04-7.35 (7H, m). n~=O 17!33
cm~l
Found: C, 56.41; H, 5.72; N, 5.99%
C22Hz7ClN2O3S2 requires: C, 56.58; H, 5.83; N, 6.00%
FY~mple 127 - (+/-)-N-[6~ h~ ylhexyl)]-4('~ ie~h~-ell~ylsulphonyl) '~
f,y,~7.c~;~lin_~
The synthesis was carried out as in eY~mpl~ 107, using N-(6-(4-chlo.~,l)l~llyl)he~c-1-
yl) 4 (2-thienylmethylsulphinyl)-2-oxo~7P.ti-lin-l-yl~P.t~mirie (1.1 g). Cyst~lli.~titm
lS from ethyl acetate/pet. ether gave the title compound (0.9 g), m.p. 108-110~C. IH
NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H. m), 2.57 (2H, t), 3.09-3.28 (4H, m), 3.88
(lH, d), 3.97 (lH, d), 4.53 (lH, d), 4.60 (lH, d), 4.91 (lH, dd), 5.98 (lH, m), 7.05-
7.41 (7H, m). n~=O 1795 cm~l
Found: C, 54.59; H, 5.52; N, 5.80%
C22H27ClN2O4S2 requires: C, 54.70; H, 5.63; N, 5.80%
FY~mple 128 ~ (+/-)-N-[6~(4-ChlorophenylheYyl)]~(3-U,it~ l",ell,ylU~io)-2-
~Y~ yl~c~et~mirl~
a) (+1-)-'1 (3-thienylmeU~ylU,io)~7~ti~;n-2-one
The synthesis was carried out as in eY~mrllo 101a, using 3-(acetylthiom~-thyl)thiophene
(85 mmol) and 4-ace~u~yi~et~ n-2-one (85 mmol). Chrom~tography (silica7 50-70%
EtOAc in pet. ether) and trituration with pet. ether gave the title compound (8.65 g),
m.p. 41-45~C. ~H NMR ~ (CDC13) 2.85 (lH, m), 3.32 (lH, m), 3.88 (2H, m), 4.68
(lH, m), 5.72 (lH, s), 7.01-7.15 (2H, m), 7.33 (lH, m)
b) (+I-)-N-[6-(4-Chlorophenylhexyl)] 1 (~tlhie,-yl,~ U-ylU.io)-2-oYo~7~ffdirl-
l-y~
The synthesis was carried out as in ey~mrle 101b, using (+/-)-4-(3-thie..yllllelhyl~lio)-
~7~oti~lin-2-one (5 mmol), N-(6-(4-chlorophenyl)hex-1-yl)-2-bromo~eet~mi~o- (5.5mmol), tetrabutylammonium bromide (0.5 mmol), and powdered KOH (5.25 mmol) in
dry THF (25 ml). Chromatography (silica, 40-90% EtOAc in pet. ether) and
trituration with pet. ether gave the title compound (0.85 g), m.p.54-57~C. IH NMR.
(CDCl3) 1.32 (4H, m), 1.53 (4H, m), 2.56 (2H, t), 2.93 (lH, dd), 3.22 (2H, m), 3.38
(lH, dd), 3.56 (lH, d), 3.76 (lH, d), 3.84 (2H, m), 4.81 (lH, m), 6.07 (1 H, m), 7.0
7.82 (7 H, m)
FY~mple 129- (+/-)-N-t6-(4ChlorophenylheYyl)]-4(3-thie,~h,.eLI,~
oYn~7~ti~lin l~yl~et~m;rle(~ Lt:Leo."er 1)
The synthesis was carried out as in e~r~mple 102, using (+/-)-N-(6-(4-chloluphenyl)-
hex-1-yl)-4-(3-llliel.yl,llethylthio)-2-oxo~7Pti~in-1-yl~er~mi~le (4.12 g, 9.1 mmol).
Cryst~lli~tion of the crude product from ethyl acetate and recryst~lli~tion fromacet~ o gave a sample of diastereomer 1 (0.57 g), m.p. 158-9~C. IH NMR ~
(CDC13) 1.33 (4H, m), 1.55 (4H, m), 2.56 (2H, t), 2.94 (lH, dd), 3.23 (2H, m), 3.44
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(lH, dd), 3.73 (lH, d), 3.98 (lH, d), 4.11 (lH, d), 4.06 (lH, d), 4.51 (lH, dd), 6.61
(lH, m), 7.01-7.41 (7H, m). nc=O 1791 cm~l
Found: C, 56.45; H, 5.62; N, 6.02%
C~H27ClN203S2 requ~res: C, 56.58; H, 5.83; N, 6.00%
S Example 130 - (+/-)-N-t6-(4Chl~ JI,e,-,ylheAyl)]-4(3-ffiienyln-t U-y' ~'phinyl~
o~ f ~ n l-yk~ .ude (dia~ ,o~ 2)
The mother liquors from eY~mrlP 129 were recryst~llice~ cce~ssiv~ly from e~yl
acetate, ~et~ ;l. ;1P and ethyl acetate to obtain a sample CC.I~ ;n~ 80% of
ct~preomer 2 (1.42 g), m.p. 109-111~C. lH NMR ~ (CDC13) 1.34 (4H, m), 1.55
(4H, m), 2.56 (2H, t), 2.93 (lH, dd), 3.24 (3H, m), 3.89 (lH, d), 4.09 (lH, d), 4.18
(lH, d), 4.23 (lH, d), 4.59 (lH, dd), 7.02-7.42 (7H, m). nc~ 1793 cm~
Found: C, 56.55; H, 5.65; N, 6.03%
C22H27ClN203S2 l~uiles. C, 56.58; H, 5.83; N, 6.00%
F.Y~mple 131 ~ )-N-[~(4-Chloroph~,-yllleAyl)]-4(3-ll-ie,~ ne~-y~ nyl)-2
15 oYn~q7pff~lin~l-y~r~?t~ P
The synthesis was carried out as in example 107, using N-(~(4-chlorophenyl)hex-1-
yl)-4-(3-thienylmethylcl-lrhinyl)-2-oxo~7Pti-lin-l-yl~et~mi~P (0.81 g). Cyss~tli~ti~ n
from ethyl acetate/pet. ether gave the title compound (0.67 g), m.p. 114- 116~C. 'H
NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m), 2.57 (2H, t), 3.05 (lH, dd), 3.15 (lH,dd), 3.25 (2H, m), 3.84 (lH, d), 3.94 (lH, d), 4.38 (lH, d), 4.43 (lH, d), 4.83 ~lH,
dd), 5.96 (lH, m), 7.08-7.43 (7H, m). n~O 1794 cm~l
Found: C, 54.62; H, 5.44; N, 5.83%
C22Hz7ClN204S2 requires: C, 54.70; H, 5.63; N, 5.80%
Examplel32 - (~ -N-[6-(4Chlorophenylhexyl)3-4(thiazol-~ U.~I~l,io) 2
25 oY,)~7P1i~in l y~ et~ P
a) (+/-)-4(2-Thi~olyl..letl.ylll~io)~7Pff~ 2-one
The synthesis was carried out as in el~mplP 101a, using 2-(acety~thiomPthyl)thiazole
(23 mmol) and 4-acetw~y~ in-2-one (23 mmol). Tnt~ tion with ether gave the
title compound (1.48 g), m.p. 89-92~C. IEl NMR ~ (CDC13~ 2.76 (lH, m), 2.30 ~lH,m), 4.26 (2H, s), 4.85 (lH, m), 7.68 (lH, d), 7.73 (lH, d), 8.63 (lH, br s).
b) (+/-3-N-t6-(4-Chloropl-~ Il.exyl)]-4(thiazol-~yl...t~ 111.io)-2-
nY~7Ptirlin.l_y~ et~mi/lP
The synthesis was calIied out as in example 101b, using (+/-)~(2-thiazolylme~yl-thio)~P-ti~ln-2-one (6.9 mmol), N-(6-(~chlorophenyl)hex-1-yl)-2-bromc~~~ P
(6.9 mmol), tetrabutylammonium bromide (0.69 mmol), and powdered KOH (6.9
mmol) in dry THF (40 ml). P~epe~t~d chromatography (silica, 2-6% MeOH in
C~7Cl?; silica, t-BuOMe) gave the title co,~ d as an oil (0.04 g). IH NMR o
(CDC13) 1.33 (4H, m), 1.55 (4H, m), 2.56 (2H, t), 2.99 (lH, dd), 3.23 (2H, m), 3.44
(lH,dd),3.73(1H,d),3.90(1H,d),4.12(1H,d),4.21 (lH,d),5.02(1H,dd~,6.19
(lH, m), 7.07-7.26 (4H, m), 7.31 (lH, d), 7.69 (lH, d).
F.Y~mrle 133 - (+J-)-N-~6-(4-Chlorophenylhexyl)1-1 (thiazol-2-~h...,tl~y! ~,~lrhinyl)-
2~Y~7e~ in-l-y~ Pt~m;rlp (~ .,el 1)
The synthesis was caIIied out as in example 102, using (+/-)-N-(6-(4-chlorophenyl)-
hex-l-yl)~(2-thiazolylmethylthio)-2-oxo~7Ptitlin-l-yl~et~mi~ (1.03 g, 2.28 mmol).
45 Trituration of the crude product with ethyl acet~te gave a sample collts.;..; -g 96% of
- 54-
CA 02225627 1997-12-23
W O 97/02242 PCT~EP96/02765
diastereomer 1 (0.35 g), m.p. 15~157~C. IH NMR ~ (CDC13) 1.33 (4H, m), l.SS
(4H, m), 2.56 (2H, t), 3.02 (lH, dd), 3.23 (2H, m), 3.36 (lH, dd), 3.80 (lH, d), 4.14
(lH, d), 4.35 (lH, d), 4.42 (lH, d), 4.92 (lH, dd), 6.46 (lH, m), 7.09 (2H, m), 7.2'S
(2H, m), 7.43 (lH, d), 7.84 (lH, d). nOO 1760, 1791 cm~l
S Found: C, 53.91; H, S.SS; N, 8.94%
C2lH26ClN303S2 reqnires C, 53.89; H, 5.60; N, 8.98%
FY~mrl~ (+/~)~N~t6~(4~chloro~ exyl)~4(th;~7~ yl~ p~yl~-
in.l.yl ~r~ ~omer 2)
The mother liquors from PY~mplP 133 were con~e~-l-; tPd and diluted with pet. ether to
induce cryst~llic~tion of a sample c~ .g 94% of dias~lev~er 2 (0.49 g), m.p. 103-
104~C. IH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m), 2.57 (2H, t), 3.11 (lH, dd!),
3.25 (2H, m), 3.33 (lH, dd), 4.08 (lH, d), 4.29 (lH, d), 4.44 (lH, d), 4.50 (lH, d),
4.98 (lH, dd), 7.09 (2H, m), 7.24 (2H, m), 7.34 (lH, m), 7.42 (lH, d), 7.84 (lH, d).
nOO 1793 cm~l
lS Found: C, 54.12; H, 5.56; N, 8.87%
C2lH26ClN3O3S2 requires: C, 53.89; H, 5.60; N, 8.98%
FY~mp'e 135 - (+/-)-N-[6-(4-Chlo~ V~~ ll.exyl)] ~ (5 ~h~ ~ I,onyl-~
ru~ ell~ylll~io)-2-oY~7eff~lin-l-ylacetamide
a) Mefflyl 5-(ac~lyl~ u ~ yl)furan-5-~all~Aylalt:
20 A sollltion of pot~ccillm thio~ret~t~ (45.7 g, 0.4 mol) in dry DMF (100 ml) was added
to an ice-cooled sol~lti~n of methyl S-(chloromethyl)furan-2-c~l,~"ylate (6~ g, 0.35l
mol) in dry DMF (300 ml). Cooling was removed, and the u~ ulc; stirred for a fur~her
30 min, then poured into water and extracted with ether. Chromatography (silica, 0-
30% ether in pet. ether) of the organic extracts gave the title compound as an oil (42.7
2~ g). IH NMR ~ (CDC13) 2.36 (3H, s), 3.88 (3H, s), 4.16 (2H, s), 6.35 (lH, d), 7.08
(lH, d).
b) ~(~-(Metho~.all,onyl)2-ru, ~ -ethylthio)~7~ffAin-2-one
The synthesis was carried out as in example lOla, using methyl S-
(ace~ylll.iomPthyl)furan-S-carboxylate (47 mmol), 4-aceto~Ly~7PIi~lin-2-one (47 mmol),
30 and sodium mPtllQxitle (47 mmol) in place of sodium ethoxitl~ The crude product was
a~d with ether to give the title compound (8.7 g), m.p. 102-103~C. IH NMR o
(CDC13) 2.85 (lH, dd), 3.43 (lH, dd), 3.88-3.92 (SH, m), 4.92 (lH, dd), 6.33 (lH,
m), 6.78 (lH, br. singlet), 7.09-7.11 (lH, m).
c) (+/-)-N-t6-~4-Chlorophenylhexyl)]-1 (5-mpth~xy~~ onyl-2
35 lul~ ylll~io)-2-oYo~7~tiAin l y~ t~
The synthesis was carried out as in eY~mplP- 101b, using (+/-)-4-(S-
(methoAyc~bonyl)2-furylmethylthio)~7p3~ n-2-one (21 mmol), N-(6-phenylhex-1-~yl)-
2-bromo~cet~mi~le (21 mmol), tetrabutylammonium bromide (3 mmol), and powdered
KOH (211 mmol) in dry THF. Chromatography (silica, EtOAc/pet. ether) gave the
40 title compound as an oil (5.0 g). IH NMR o (CDC13) 1.29-1.35 (4H, m), 1.43-1.63
(4H, m), 2.55 (2H, t), 2.94 (lH, dd), 3.19-3.27 (2H, m), 3.24 (lH, dd), 3.78 (lH, ~d),
3.88-3.90 (3H, m), 3.95-3.97 (lH, m), 4.04-4.17 (2H, m), 5.01 (lH, dd), 6.25 (lH, br
triplet), 6.33-6.35 (lH, m), 7.06-7.10 (3H, m), 7.20-7.26 (3H, m).
CA 02225627 1997-12-23
W O 97/02242 PCT~EP96102765
Example 136- (+/-)-N-t6-(4Chloroph~l.;lh~A~ 1 (S-me~ ~l,onyl-2-
~U~ ..ell~ o~ ide (~ omer l)
The synthesis was carried out as in e~mrlp 102, using (+/-)-N-(6-phenylllc;A-l-yl)~
(S-meth~y.,a,l~,lyl-2-furylmethylthio)-2-oYrl~7p~ n-l-yl~r~t~m~ p (4.0 g, 8 mmol).
S Recryst~ tion of the crude product from ethyl acetate gave a sample of dia~ Gu,l,er
1 (0.8 g), m.p. 141-142~C. IH NMR o (CDC13) 1.20-1.35 (4H, m), 1.40-1.65 (4H,
m), 2.55 (2H, t), 3.05 (lH, dd), 3.19-3.33 (3H, m), 3.83 (lH, d), 3.90 (3H, s), 4.09-
4.16 (3H, m), 4.71 (lH, dd), 6.46 (lH, br. triplet), 6.55-6.56 (lH, m), 7.07-7.26 (SH,
m). nOO 1792 cm~l
Found: C, 56.65; H, 5.68; N, 5.55%
C24H29ClN206S requires: C, 56.63; H, 5.74; N, 5.50%
F-Y~P'C 137 - (+/-)-N-t6-(4Chl~,lo~llt,~ eYyl)]-4(5 ~~t~ c~l onyl-2-
rul~IIllell~ ..lp~inyl)-2-o~ t~ n-l-~ de(~'~ ' .D~ner2)
The mother liquors from example 136 were evaporated and recryst~ P,d from ethyl
acetate to give a sample of diastereomer 2 (l.S g), m.p. 113-114~C. IH NMR ~
(CDC13) 1.29-1.40 (4H, m), 1.50-1.64 (4H, m), 2.56 (2H, t), 3.00 (lH, dd), 3.23-3.40
(3H, m), 3.90 (3H, s), 4.03 (lH, d), 4.19-4.29 (3H, m), 4.72 (lH, dd), 6.53-6.55 (lH,
m), 7.00 (lH, br. triplet), 7.07-7.26 (5H, m). n~=O 1795 cm~l
Found: C, 56.73; H, 5.69; N, 5.57%
C24H29ClN206S requires: C, 56.63; H, 5.74; N, 5.50%
Example 138 - (+/-)-4( 2-ful ~ Il..etl.~ io)-l-(9-~he..~lllonyl)~ 2-one
A s-lspencion of sodium hydride (3.65 mmol) in dry THF (10 ml) was cooled in
ice/salt, and a ~olutiorl of (+/-)-4-( 2-fulyl~ -yl~lio)azetidin-2-one (0.61 g, 3.32
mmol) in THF (10 ml) was added dropwise below 5~C. The res llting sol~ltion was
further cooled to -10~C, and a sollltion of 9-phenylnonyl-1-triflate (1.17 g, 3.32 mmol)
in THF (10 ml) was added gradually over 1 min. After stirring for a further S min at
0~C, the reaction Illii~Ulc~ was poured into brine and Ç~tr~t~tP~ with ether.
Chromatography of the organic extracts (silica, 10-25% EtOAc in pet. ether) gave the
title compound as an oil (0.38 g). 'H NMR ~ (CDC13) 1.2-1.7 (14H, m), 2.60 (2H, t,
J=8 Hz), 2.9 (2H,m), 3.3 (2H, m), 4.78 (2H, s), 4.68 (lH, m), 6.20, 6.32 (each lH,
m), 7.15 - 7.3 (5H, m), 7.36 (lH, m).
Fr p!- 139 - (+/-) 1-( 2-ru,~ )-l-(9-phenylnonyl)q7~ n-2-one
The synthesis was carried out as in Py~mplP 102, using (+/-)-4-(2-furylmethylthio~l-
(9-phenylnonyl)q.7~ti-lin-2-one (0.37 g, 0.97 mmol). Chromatography (silica, 50-70%
EtOAc in pet. ether) gave ~Lhe title compound as an oil (0.28 g), cont~inin~ about 63%
of diastereomer 1, 37% of diastereomer 2. IH NMR ~ (CDCI3) 1.2-1.7 (14H, m),
2.55 (3H, m), 2.90, (lH~ dd, J=5, 15 Hz), 3.10 (lH, dd, J=5, 15 Hz), 3.15-3.5 (3H,
m), 3.954.15 (2H, m), 4.42 (lH, m), 6.42 (2H, m), 7.1-7.3 (SH, m), 7.43 (lH, m).n~=O 1776 cm~l
Found: C, 68.5; H, 7.8; N, 3.3%
C23H31NO3S requires: C, 68.8; H, 7.8; N, 3.5%
F~ 140 - (+I-) 4 ( 2-rurrlu~ yllllio~1-(9~4-flu-)lopl.~ l)nonyl)q7~ti~l;n-2-one
The synthesis was carried out as in example 138, using (+/-)-4-( 2-furylmethyl-
thio)azetidin-2-one (1.5 g, 8.2 mmol) and 9-(4-fluol~,phenyl)nonyl-1-triflate (2.9 g, 7.8
mmol). Chromatography (silica, 10-25% EtOAc in pet. ether) gave the title compound
- 56-
CA 02225627 1997-12-23
WO 97/02242 PCT/EP96/0276~
as an oil (0.56 g). 'H NMR ~ (CDC13) 1.2-1.7 (14H, m), 2.56 (2H, t, J=7.7Hz), 2.5l0
(2H, m), 3.29 (2H, m), 3.77 (2H, s), 4.68 (lH, m), 6.20 (lH, m), 6.31 (lH, m), 6.9'5
(2H,m),7.10(2H,m),7.36(1H,m).
Example 141 - (+/-) 1 ( 2-lu~ ~1)-1-(9-(1
5 flu~ ."' yl)nonyl)~7~t;A;n-2-one
The synthesis was carried out as in ex~mrlP- 102, using (+/-)~(2-rulyl~u~ ylll~io~l-
(9-(1 fluorophenyl)nonyl)~7p-tidin-2-one (0.52 g, 1.28 mmol). Chromatography (silica,
50-70% EtOAc in pet. ether) gave the title compound as an oil (0.42 g), co..~ g
about 65% of diastereomer 1, 35% of ~ t~Preompr 2. 'H NMR o (CDC13) 1.2-1.7
(14H, m), 2.55 (3H, m), 2.90, (lH, dd, J=5, 15 Hz), 3.10 (lH, dd, J=5, 15 Hz), 3.1';-
3.5 (2H, m) 3.95-4.15 (2H, m), 4 42 (lH, m), 6.42 (2H, m), 6.95, 7 10 (each 2H, m),
7.43 (lH, m). nOO 1776 cm~l
Found: C, 65.7; H, 7.2; N, 3.2%
C23H30FNO3S requires: C, 65.8; H, 7.2; N, 3.3%
FY~nPI~ 142 - (+/-)~( 2-fUrYIm~IIJY1!~ Q~YI)-1~(9-(4
fluorophenyl)nonyl)~ ~u.l;. 2-one
The synthesis was carried out as in PY~mplP 107, using (+/-~( 2-
furylmethyl~ r)hinyl)-1-(9-(4-nuo.ophenyl)nonyl)~7Pti~lin-2-one (88 mg).
Chromatography (silica, EtOAc/peL ether 2:1) gave the title compound as an oil (56
mg). lH NMR ~ (CDCI3) 1.2-1.7 (14H, m), 2.56 (2H, t, J=8 Hz), 2.99 (lH, dd, J--.2,
15 Hz), 3.15 (2H, m), 3.45 (lH, m), 4.37 (2H, s), 4.57 (lH, m), 6.45, 6.55 (each lH,
m),6.95,7.10(each2H,m),7.47(1H,m).
FY~mrle 143. N-[6-(4-Fluorophenyl)hex-1-yl] 3 (S-allyl~ lîur~.-2-
yll~io)-2-oY- ~7eh'Ain-l-~ e~u~
A solution of 4-(5-allyloxyc~onylfuran-2-methyl)thio~pti~lin-2-one (4 g, 0.015 mol)
and N-(4-fluorophenylhex-1-yl)bromo~ret~mi~lç (4.73 g, 0.015 mol) in dry
tetrahyd,oru,~n (150 ml) was cooled to -30~C and a solution of pot~inm t-butoxide
(1.85 g, 0.0165 mol) in dry tetrahydl.ru~ (80 ml) added dropwise over 15 min. The
t~mrçr~t--re was allowed to rise to 10~C over 2 hr, then the mixture diluted with water
and ç~tr~ted with ethyl acetate, filtPrin, off and discarding any in~olnbl~ solids. the
extracts were dried (MgS04), evaporated, and the product purified by flash
chromatography (silica, ethyl acetatelpetrol), to give the title colllp~,u..d ac a yellow oil
(2.54g, 33% yield). lH NMR ~ (CDC13) 1.32 (4H, m, N(CHz)2(CH~)2), 1.~2 (4H, m,
NCH2CH2 + FPhCH2CH2), 2.55 (2H, t, FPhCH2), 2.96 (lH. dd, H3a)7 3.24 (2H, m,
NCH,), 3.49 (lH, dd, H3b), 3.76-4.06 (4H, CH2CO + CH2S), 4.79 (2H. m, OCH2),
5.03 (lH, dd, ~4), 5.36 (2H, m, C_2CH), 5.99 (lH, m, CHCH2), 6.30 (lH, m, NH),
6.35, 7.12 (each lH, d, furan-_), 6.92-7.12 (4H, m, FPh-_)
Example 144. N-t6-(4-Fluorophenyl)hex-l-yl] 1 (5-allylo~ ln,l-~lru~--~
111~ ll~yl~ .hinyl)-2-o~ 7Ptirlin-l-yl~r~ P (D;ssl~l~omer 1)
Tre~tmçnt of N-[6-(~fluorophenyl)hex-1-yl]~-(5-allylo~y~;albollylr~-2-
methylthio)-2-o~co~7Pririin-1-yl~cet~millP with mCPBA in dichloromP-th~nP at low~--,pe,ature gave, after work-up and recryst~llic~tion as described for Example 102,
the title compound as white crystals, m.p. 122-5~C, 16% yield. lH NMR o (CDC13)
1.32 (4H, m, N(CH2)2(C_2)2), 1.54 (4H, m, NCH2CH2 + FPhCH2CH2), 2.56 (2H, t,
FPhC_2), 3.08 (lH, dd, H3a), 3.23 (2H, m, NC_2), 3.30 (lH, dd, H3b)~ 3.55~ 3.73
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CA 02225627 1997-12-23
W O 97/02242 PCT~EP96/02765
(each lH, d, SCH~), 3.84, 4.13 (e~h lH, d, CH~CO), 4.73 (lH, dd, H4), 4.80 (2H, m,
OCH7), 5.38 (2H, m, CH~CH), 5.97 (lH, m, CHCH2), 6.56, 7.18 (each lH, d, furan-
H), 6.91-7.14 (4H, m, E;Ph-H)
FY~mp'~ 145. N-[6-(4-~uorophenyl)hex-1-yl]~(5~allylox~ ylru~ 2-
S ~ yl)-2-u~ n 1-yla~ unide (l)iastereomer2)
Recryst~llic~tinn of the mother liquors from FY~mpl~ 144 gave the title co...l O...l~i
(diasteresicom~r 2:1 ca 83:17) as white crystals, m.p. 79-82~C, 29% . v 00 1793 cm~
1 Found: C, 59.82; H, 5.93; N, 5.40%. C26H31FN206S requires: C, 60.22; H, 6.03;
N, 5.40%
Fy~n~rle 1~6. N-[6-(1 Fluorophenyl)hex-l-yl] 1 (~ yruldn-2-
yl~ yl)-2~oq~ 1in-l~yl~ e (I)iastereomer 2)
A sQllltit)n of triphenylrhosrhin~ (0.81 g, 0.31 mmol), py~rrolidine (0.027 ml, 0.31
mmol) and N-[6-(4-fluorophenyl)hex-1-yl]~(5-allyl~Ay~l,onyllu~l-2-
methylc-llrhinyl)-2-oxo~7etiflin-l-yl~et~mirlP (diastereomer 2, 0.16 g, 0.31 mmol) in
15 dichloromPth~n~ ( 10 ml) wa~s treated with tetrakis triphenylphospl.;...~l,Rll~Aillm(0)
(10.7 mg, 0.0093 mmol) and the mixture stirred for 2 hr. The solvent was evaporated
and the residue purified by flash chromatography (silica, dichlorom~th~n.o /acetone
/acetic acid). The crude product was dissolved in dichloromPth~n~q (10 ml), washed
with brine, dried (MgS04), and evaporated to an oil which was treated with
20 dic-hlorom~th~np and ether to give the title compound as a solid (46mg, 31% yield),
m.p.l24-7~C. lH NMR ~ (CDCl3)1.31 (4H, m, N(CH2)z(C_2)2),) 1.53 (4H, m,
NCH2CH2 + FPhCH2CH2), 2.56 (2H, t, FPhCH2), 3.07 (lH, dd, H3.), 3.26 (2H, m,
NC_2), 3.40 (lH, dd, H3b), 4.21-4.34 (4H, m, SCH2 + CH2CO), 4.76 (lH, dd, ~4),
6.55, 7.10 (each lH, d, furan-_), 6.92-7.16 (4H, m, FPh-H), 7.60 (lH, NH)
Fy~mrle 147. N-(6-~4-Chlorophenyl}hexyl)-4(~allyloxy~ 1~o.. ~lr~l~.-2-
ylll~io-2-oY0~7~h~lin l y~ e~ e
Tre~tm.ont of 4-(5-allyloxyc~bonyl~ul~-2-methyl)thio~7ptirlin-2-one (2.4 g) and N-(4-
chlorophenylhex-1-yl)bromo~cet~mi-le* (2.99 g) in dry te~ahydrofuran (175 ml) with
a solution of potassium t-butoxide (1.03 g) in dry tetrahydrofuran (50 ml) at -40~C,
followed by work-up as described for Example 143 gave the title compound as a
yellow oil, 37% yield. IH NMR ~ (CDC13) 1.30-1.60 (8H, m, 4xC_2), 2.55 (2H, t,
J=7.6 Hz, CH~Ph), 2.92, 2.98 (lH, dd, J=2.2, 15.4 Hz, H~), 3.24 (2H, m, NHCH~),
3.46, 3.52 (lH, dd, J=5.2, 15.4 Hz, ~3), 3.94 (4H, m, NCH~, SCH7), 4.79 (2H, m,
CO2CH~), 5.02 (lH, m, ~4) 5.35 (2H, m, CH~=CH), 6.0 (lH, m, CH2=CH), 6.26 (lH,
m, N_ ), 6.34 (lH, d, J=3.4Hz, furan-H), 7.06-7.26 (SH, m, furan-H, Ph-H)
*obtained by treating of 6-(~chlorophenyl)hexylamine (2.0g) and Hunig's base (1.33g)
in dry dichlorom~th~nP (25 ml) with bromoacetylbromide (2.07g) in dichloroln~th~nP
(10 ml) at 0-5 ~C.
FY~n~rle 148. N-(6-{4-Chlorophenyl}hexyl~1 (~allyloAy~l~uJ~ylru~
40 ~ lhyl~ iyl-~o~o~ in-l-yl)~r~ (D;a~ ~ 1).
Colourless solid, m.p. 135-136~C, 15% yield. IH NMR o (CDCl3) 1.3023-1.60 (8H,
m, 4xCH7), 2.56 (2H, t, J=7.6 Hz, C_2Ph), 3.03, 3.09 (lH, dd, J=4.7, 15 Hz, ~3),3.24 (2H, m, NHCH7), 3.28, 3.34 (l~I, dd, J=5.4, 15 Hz, ~3), 3.81, 4.13 (each lH, d,
J=17.2 Hz, NCH~), 4.09 (2H, s, SOCH~), 4.70 (lH, m, ~4), 4.80 (2H, d, J=5.8 Hz,
CO2CH2), 5.37 (2H, m, CH2=CH), 6.0 (lH, m, CH2=CH), 6.44 (lH, m, NH), 6.56
- 58 -
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W O 97/OZ242 PCT~EP96/0276;5
(lH, d, J=3.5 Hz, furan-H), 7.07-7.26 (5H, m, furan-H, Ph-_). v c=o 1792 cm~l.
Found: C, 58.2; H, 5.8; N, 5.3%. C26H3ICIN2O6S l~U l~S. C, 58.4; H, 5.8; N, 5..!%
Example 149. N-(6-{4Chl~,.ul~h~ hexyI)-4(5 allyluA,~I,on~Irul~,.2.
U~yl ~ yl~ ;Ain.l yl)~ 'e (Diast~ 2).
S ~'olollrl-ps~ solid, m.p. 89-92~C, 13% yield. IH NMR ~ (CDC13) 1.30-1.60 (8H, m,
4xCH~), 2.56 (2H, t, J=7.6 Hz, CH7Ph), 2.99, 3.05 (lH, dd, J=2.4, 15.4 Hz, H3), 3.24
(2H, m, NHCH~), 3.32, 3.39 (lH, dd, J=5.4, 15.4 H_, H3), 4.03, 4.25 (each lH, d,J=17.2 Hz, NCH2), 4.20 (2H, m, SOCH2), 4.72 (lH, m, ~4), 4.79 (2H, d, J=5.8 Hz,
CO2C_2), 5.37 (2H, m, CH2=CH), 6.0 (lH, m, CH2=C_), 6.55 (lH, d, J=3.5 Hz,
furan-_), 7.02 (lH, m, NH), 7.07-7.26 (5H,m, furan-H, Ph-H). v 00 1795 cm~l.
Found: C, 58.2; H, 5.8; N, 5.3%. C26H3ICIN2O6S requires: C, 58.4; H, 5.8; N, 5..!%
FY~mrl~P 150. N-(6-{4chlo~ l}he~y~yl) 1 (S-~b~ylu~
Ulyl~..lrl~inyl-2-oYn~7etirlin.1.yl)~ ? (D~.~~ . 2).
Tre~tment of a solution of triphenylphosphine (53.3 mg), pyrrolidine (14.3 mg) and N-
[~(4-chlorophenyl)hex-l-yl]-4-(5-allylu~y~ ylfuran-2-methy~ r~ yv-2-
~IY~o~7Pt~ n-l-yl~ret~mi~e (diastereûmer 2, 105 mg) in dichlûrom~th~np (4 ml) with
with tetrakis triphenylphQsphinp~ m(o) (6.5 mg) and wûrk-up as ~Psrr~ fûr
FY~mpl~P 146 gave the title eolllpl)u-ld as a cream sûlid, m.p. 166-167~C, 49% yield.
'H NMR ~ (DMSO) 1.26 (4H, m, 2xCH~), 1.37 (2H, m. CH7), 1.52 (2H, m, CH~),
2 50 (2H, m, CH~Ph), 2.95. 2.99 (lH. dd, ~3), 3.05 (2H. m, NHCH~), 3.83, 4.07
(each lH, d, J=17.2 Hz, NC_2), 4.29, 4.42 (each lH, d, J=14 Hz, SOCH2), 4.86
(lH, m, ~4), 6.60 (lH, d, J=3.2 Hz, furan-H), 7.15-7.32 (SH,m, furan-H, Ph-H), 8.l38
(lH, m, NH). Found: C, 54.5; H, 5.3; N, 5.6%. C23H27CIN206S l~ Uil~i. C, 55.8,;
H, 5.5; N, 5.7%
FY~r~PIe 151. N-[6-(4 F1UOr~ henYI)heX-1-YI]-4-(5 ~Pth~ ~h~ 1rU~-2
m ethyl~io) 2 o~o~ . 1 yl~C~ P
TrP~tmpnt of 4-(5-metho~yc~l~ouyl~u~n-2-methyl)thi 7Pti~in-2-one (FYZ~m[)lP 135b)
and N-(4-fluorophenylhex-1-yl)bromo~et~mitlP in d~y tetralIyd~urulan with a sohltion
of pot~csinm t-butoxide in dry tetrahydrofuran at -30~C, followed by work-up as
~lescri~e~i for F~c~mrl~ 143 gave the title compound as a pale yellow oil, 55% yield.
lH NMR o (CDC13) 1.32 (4H, m, N(CH2)2(CH7)2), 1.54 (4H, m, NCH2CH7 +
FphcH2cH~)~ 2.56 (2H, t, FPhCH~), 2.95 (lH, dd, H3"), 3.24
(2H, m, NCH7), 3.48 (lH, dd, H3b), 3.88 (3H, s, OC~3), 3.75-4.05 (4H, m, SCH
CH~CO), 5.02 (lH, dd, ~4), 6.30 (lH, m, NH), 6.3~, 7.12 (each lH, d, furan-H),
6.90-7.13 (4H, m, FPh-H)
Tre~tmPnt of N-(6- {4-fluorophenyl }hexyI)~(~-methoAy~ onylrul~uI-2-metllyllllio-
2-0~0~7Pti~lin- l-yl)~cet~mitie with mCPBA under the conditions described for
FY~mpl~s 102 and 103 gave Examples 152 and 1~3 after recryst~llic~tion as ~iesrri~
for Fl~mF~lps 102 and 103.
F~ c 152. N-[6-(4-Fluorophenyl)hex-l-yl]-4-(~ ~thQ~ l,o.. ylr.. r~.-2-
~ell~y~ )hinyl)~2~oy~7~ti~l;n~l~yl~r~
White crystals, m.p. 137-8~C, 16% yield. lH NMR ~ (DMSO) 1.27 (4H, m,
N(CH2)2(CH2)2) 1.39 (2H, m, FPhCH2CH2), 1.53, (2H, m, NCH~CH7), 2.55 (2H, I,
FPhCH2), 3.04 (4H, m, NCH, + ~3a + .~3b)~ 3.68, 4.03 (each lH, d, SCH7), 4.13, 4.39
~9
CA 02225627 1997-12-23
W O 97/02242 PCT~EP96/02765
~each lH, d, CH2CO), 4.99 (lH, m, _ 4), 6.64, 7.30 (each lH, d, furan-H), 7.04-7.24
(4H, m, FPh-H)
EY~unple 1~3. N-[6-(4Fl~olv~ l)hex-l-yl]-4(~ ~rbonylfuran-2-
ll~ell~tl~ l) 2 ~n~ 1 r~ le (Diastereomer 2)
S White crystals, m.p. 100-2~C, 16% yield. v c~, 1795 cm~l. Found: C, 58.53; H, 5.90;
N, 5.68%. C24H29FN2O6S lc:~lui~l:s: C, 58.52; H, 5.93; N, 5.69%
E~nple201 N-~6-(Phenyl)hexyl)-(4(2-nuv~ )-2-,~ t'lin-l-
yl)acetamide
A sol-~tion of 4 (2-fluo~ henoxy)~7Ptitiin-2-one (O.Sg, 3 mmole), N-(6-
phenylhexyl)bromo~- e~ P (0.9g, 3 mmol) and 18-crown-6 (5 mg) in dry 1~- (20
ml) was cooled to -30~C and treated with pot~ lm t-butoxide (0.3g, 3 mmol). The
reS~ltin~ mixture was stirred for 90 min, warmed to 0~C, ~lnPn~hP(I with ~quPous citric
acid and ethyl acetate. The organic layer was ,~Pp~tP~, washed with brine, dried(Na2SO4) and evaporated. The residue was purified by flash chromatography to give
the title compound as a colourless oil (0.33g, 28%)
Found: C, 59.8; H, 5.9; N, 5.5%; C23 Hz7FN203 Ø97CH2Cl2 requires: C, 59.9; H,
6. 1; N, 5.8%
The following compounds were prepared by the method ~lPsrrihed for FY~ml~lp 201
using the required ~7Pti~linonP and bromo~cet~mi~P.
FY~mpl~ 202 N-[6-(4-Chlorophenyl)hexyl]-~4-(2-fluorophenoxy2-oxo ~ ~f;~
yl) ~et~m;~l~
Colourless solid, m.p. 79-80~C, 31% yieldFound: C, 63.6; H, 6.0; N, 6.5%; C23
H26ClFN2O3 requires C, 63.8; H, 6.1; N, 6.5%
FY~mp~e 203 N-(6-(4Phenyl)heYyl)-(4-(2 metl.~ xy) 2
yl)~et~r~ide
White solid, m.p. 53-4~C, 55% yield
Found: C, 72.6; H, 7.5; N, 7.2% C24 H30N2O3Ø04CH2Ck requires C, 72.5: H, 7.5; N,
7.1%
FY~mp~? 204 N-(6-(4-Phenyl)heYyl)-(4-(2-bellzyloYyrh~n~Yy-2-ox~ ~;~1;~~ 1-
yl) ~
White solid, m.p. 87-8~C, 38%yield
Found: C, 74.0; H, 7.1; N, 5.8% C30H34N203 requires C, 74.1; H, 7.1; N, 5.8%
FY~mpl? 20~; N-(6-(4-Phenyl)heYyl)-(4-(2-m~ ylllliorh~~~oYy)-2-~
yl) ~ce~ le
White solid, m.p. 79-80~C, 32% yield
Found: C, 67.0; H, 7.0; N, 6.8% C24H30N203S requires C, 67.6; H, 7.1; N, 6.6%
F~ 206 N-(6-(4-phenyl)he~y-yl)-(4-(4chloroI)h~nnxy)-2-~y~7~ n-l-yl)
Colo~rlP~s oil, 32.0% yield
Found: C, 64.5; H, 6.4; N, 6.5%; C23H2,ClN203 0.21CH2Ck .requires: C, 64.4; H,
6.4; N, 6.5%
F.Y~m-, ' ? 207 (N-(6-(4-Phenyl)hexyl)-4-(~ -rh ~- ~Yy)-2-o~ n~
yl)~ t- -1P
Pale yellow solid, m.p. 43-45~C, 30% yield
Found: C,70.3; H, 7.5; N, 7.1 %; C24H30N204 requires C, 70.2; H, 7.4; N, 6.8%
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F ,'~208 N-(-(4 PhenYI)heYYI~ (4,~ 2
yl)~~et~ide
Colourless oiL 15.5% yield
Found: C, 67.0; H, 6.9; N, 6.6%; C24H30N203S requires: C, 67.0; H, 7.0; N, 6.5%
FYqn~rl~ 209 N-(6-(4Chlo~ nyl)hexyl)-(4(4allyl~ ~bonyl-
~lell~y~ n-y-y)-2-oy~7ptiA~ -yl)aA~t~
'H NMR ~ (CDC13) 1.37 (m, 4H), 1.53 (m, 4H), 2.55 (t, 2H,7.6Hz), 3.21
~ (dd,lH,J=16.1Hz), 3.24 (m, 2H), 3.39 (dd, lH, J=1.6Hz), 3.59 (s,2H), 3.99, 3.94,3.99
(each lH, d, J=17.1Hz), 5.59 ~m, 2H), 5.25 (m, lH), 5.72 (m, lH), 5.86 (m, lH), 6.'34
(bm, lH), 6.81-7.26 (m, 8H)
FY~~nP'e210 N-(6-(4 PhenYI)heYYI~(4 PhenOYY-2~ -1-YI)aCeb~n~de
Pale yellow solid. m.p. 45-48~C, 41% yield,
Found: C, 72.3; H, 7.3; N, 7.7 %; C~3 H28N203 requires: C, 72.6; H, 7.4; N, 7.4 %
F-Y~mP'C 211 N-(6-(4-Phenyl)hexy}~(~ben~yloYy-2~Y~7~ in- l-yl)acetamide
Pale yellow oil, 46% yield,
Found: C, 71.5; H, 7.9; N, 6.7 %; C24 H30N203 O.5GEI802 requires: C, 71.4; H, 7.7; N,
6.4 %
~Y~mp'~ 212 N-(6-(4-Phenyl)hexyl)-(4-(4JI~ell~ hi~ Yy~
()Yn~7-t~ n-l-yl)~ p
Tre~tmPnt of N-(6-(4-phenyl)hexyl)-(4-(4-methylthiophenoxy)-2-o~o~7Ptillin
yl)~~rPt~mitlr with meta-chloiupe~ ;oic acid (m-CPBA) (l.lequivalent) in
dichloroml-th~nP at -70~C gave the title compound as a colourless oil in 92% yield
after chromatography.
Found: C, 61.6; H, 6.5; N, 6.0%; C24H30N204SØ4CH2Cl2 requires: C, 61.5; H, 6.5;
N, 5.9o%F~n~ e 213 N-[6-(4phenyl)hexyl]-[4(4lm~ y~ h~
OXO ~7~t~ n-l-yl) ~CC~t,~ P
Tre~tmPnt of N-(6-(4-phenyl)hexyl)-(4-(4-methylthiophenoxy)-2-oxo~7pti~lin
yl)~ret~mi-lP with meta-chloloper~ zoic acid (m-CPBA) (4 equivalents) in
dichlornmPth~nP at 20~C gave the title compound as a colourless solid, m.p. 101-2~C',
in 85% yield after chromatography.
Found: C, 62.3; H, 6.5; N, 6.1%; C24H30N205S requires: C, 62.8; H, 6.6; N, 6.1%
FY~mrle 214 N-(~(4-Phenyl)hexyl)-(4(2-~ -y~ henoxy)-2-
~y~ 7~iAin-l-y~
Trç~tmPnt of N-(6-(4-phenyl)hexyl)-(4-(2-methylthiophenoxy)-2-oxo~7p-titlin
yl)acet~mi-le with meta-chlorûp~ nzoic acid (m-CPBA) (1.2 equivalent) in
dichlorometh~nP at -30~C gave the title compound as a colourless oil in 75% yield
after chromatography.
Found: C, 62.9; H, 6.5; N, 6.1%; C24H30N204SØ25CH2Ck requires: C, 62.8; H, 6.6;
N, 6.0%
FY~mp'e 215 N~ 4-Phenyl)hexyl)-(4-(2 methylcl-lp~o-~y~ Yy)-2-
~ ,P~ _y~ t~ Ae
Tre~tmPnt of N-~6-(4-phenyl)hexyl)-(4-(2-met-h-ylthiophenoxy)-2-~xo~7pti~lin
yl)~cet~miflP with meta-chlolup~;llJen~oic acid (m-CPBA) (3 equivalents) in
dichloromPth~ne at 20~C gave the title compound as a colourless solid, m.p. 127- 128~C, in 82% yield after chromatography.
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l;ound: C, 62.6; H, 6.5; N, 6.1%; C24H30N20sS requires: C, 62.8; H, 6.6; N, 6.1%F l~lt?216 N-(6-(4Phenyl)heAyl)-(4(2~ A,~ Yy)~ idin-l-
yl)a~,~ide
T~e~tmP,nt of N-(6-(4-phenyl)he~cyl)-(1 (2-benzyl~y~hello~cy)-2-o~ in
S yl)~e~ lP with hydrogen/10% ~ Aillm on charcoal in T~ at room ~r ...
for 1 h gave the title compound as a colollrlP~ oil in 71% yield after chrQmS-to~,.~
Found: C, 64.4; H, 6.6; N, 6.4%; C23H2sN204Ø5CH2Cl2 reqllirPs C, 64.3; H, 6.7; N,
6.4%
FY~mp'e 217 N-t~(4~hlorophenyl)heAyl]-t4(4ca-boA~ henoxy~ oxo-
10 ~7~ti-1in l-yl]- $~r~_"~
Tr~P~tmPnt of N-(6-(4-chlol~,phellyl)hexyl)-(4-(4-allylu)~yc~ul-yllut~ yll.l.P-~o~y~2-
oxo~7pti~iin-l-yl)~cet~mitle with tetrakis(~iphellylph~srhino)r~ Aillm~
triphenylphosrhinP and pyrrolidine in dichlor~)mpth~np- at room l~ ,.I . . . e ovel---gl t
and subsequent work-up followed by flash chromatography gave the title co.--pc u..d as a
lS gum (38%)
lH NMR ~ (CDC13) 1.13 (4H, bm), 1.53 (4H, m), 2.55 (2H, t, J=7.5Hz), 3.07 (lH, d,
J=lSHz), 3.23 (2H, m), 3.39 (lH, dd, J=15,3Hz), 3.59 (2H, s), 3.91 and 4.05 (lH each,
d, J=17Hz), 5.71 (m, lH), 6.36 (lH, bs), 6.83 (2H, d, J=8Hz), 7.07 (2H, d, J=8Hz),
7.24 (4H, m)
FY~mrle 218 N-(~(4-Phenyl)hexyl~(~methyl-4-~ ,xy 2 ~ '' 1-yl)
~r~ rlc-
3-methyl~pheno~y,.7PIi-iin-2-one was prepared ~om 3-methyl-~ac~o~y~ n-2-
one as described in Prep 1 above and subsequently treated with N-(6-
phenylhexyl)bromo~cet~mi-le as for F.lr~mple 201 to give the title co,llpouild as a pale
yellow oil, 52.3% yield.
Found: C, 71.8; H, 7.4; N, 7.1%; C24H30N203Ø1 CH2Cl2 requires C, 71.8; H, 7.6; N,
6.9%
F.~ c 219 4-Benzyloxy-1-(~phenyl-2-ox~butyl) ~7~tiAin-~one
To a solution of 4-benzyloxy~7P-ti-lin-2-one (2g, l l.Ommol), 1-bromo-2-oxo~
phenylbutane (2.9g, 12.0mmol), tetrabutyl ammonium bromide (TBAB) (0.4g,
1.2mmol) was added pott~c~ m hydroxide (0.68g,12.0mmol). The mixture was stiIredfor 2 hr. It was quenrhPd with water and extracted with ethyl acetate. The organic
extract was dried and evaporated and the residue purified using flash chromatography
to give the title compound a pale yellow oil (1.7g, 47% yield).
Found: C, 73.7; H, 6.6; N, 4.4%; C20H2,NO3 O.15H20 requires C, 73.7; H, 6.6; N,
4.3%
F~---l-k 220 4-Phenoxy-1-(4-phenyl-2-oxo-butyl) ~7et~lir 2-one
4-phenoxy~7Pticlin-2-one (lg ,6.2mmol), 1-bromo-2-oxo-4-phenylbutane (l.SSg,
6.7mmol), TBAB (0.2g, 0.7mmol) and potassium hydroxide (0.4g,6.7mmol) were
reacted as described above to give the title compound (0.65g, 31% yield) as a pale
yellow solid, m.p. 59-60~C, after flash chromatography and recryst~lli~tio~ frometherln-hexane.
Found: C, 73.0; H, 6.2; N, 4.6% ClgH,gNO3 0.2H2O requires C, 72.9; H, 6.2; N, 4.5%
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F r~ 'e 301 N-l6-(naphth-l-yl)-s-hexgn-l-y~ l-yl
A miAture of 4-bel~yl~-io-2-o~n~7Pti~in-l-yl acetic acid (3.4g), 6-(naphth-lyl~5-
heAyn-l-ylamine (3.0g), l-hyd~ yl~ 7~'~ hydrate (1.82g) and
5 dicycloh~Aylca~l,o liimi-ie (2.77g) were stirred tC~eth~-r in dry di ~ lylr(~ P
(lOOml) overnight. The solvent was e~apo~led and the residue was taken up in ethyl
acetate, filtered, and eytr~t~tpcl with water. The aqueous sol-lti~n was e~ --~d with
ethyl acetate and the cQmhinPd organic sohltion~ were washed with brine, dned and
t:v~ P~l Flash chrr)m~tQ~r~rhy (silica gel, ethyl acetate-heAane) afforded the title
compound (4.65g) as an oil, 75% yield
1H NMR o (CDCl3) 1.66-1.82 (4H, m), 2.5~-2.63 (4H, m), 2.91 (lH, dd), 3.29-3.40
(3H, m), 3.55, 3.72 (lH each, d), 3.78 (2H, s), 4.78 (lH, dd), 6.21 (lH, br. sin~l~t)
7.22-7.85 (llH, m), 8.28-8.32 (lH, m)
FY~mple 302 N-t6-(Naphth-l-yl)-5-heyyn-l-yl~-4-L~ 1-2-~
15 l-yl ~ le (~ ler~oiso --er 1)
A solution of m-CPBA (1.2g) in dichloromlo-th~nP was added dropwise to a sollltic~n of
N-t6-(naphth-l-yl)-S-hexyn-l-yl]~benzylthio-2-oxo~7~t~ n-l-yl ~et~mide (2.6g) indichloromethane (lOOml) cooled to -60C. The l~liA~UlC~ was stirred at this ~..~,.
for 1 hour, poured into a mixed solntion of sodium hydrogen carbonate and sodium20 s--lphitP. and the layers separated The ~qneouc solllti- n was ~ d with
dichlorc-m~th~n~ and the combinpd organic solutionc washed with bnne. The solution
was dried and evaporated to give an oil which gave the title compound as white
crystals from ethyl aces~ase, m.p. 138-139~C, 22% yield
Found: C, 70.7; H, 6.0; N, 6.0%; C28H28N203S +0.3H20 requir~c C, 70.4; H, 6.0;
N, 5.9%
FY~mple 303 N-[6-(Naphth-l-yl)-5-hexyn-1-yl~-4-b~l~y~ 1-2-.,~ ;rUn-
l-yl ~~~ ~ (~li~le.~ r 2)
The mother liquors were evaporated and LliLulaLed with ether to give the title
compound (~ cser~omer 2) as white crystals, m.p. 95-97~C, 56% yield
30 Found: C, 70.8; H, 6.0; N, 6.0%; C28H28N203S requ res:C, 71.2; H, 6.0; N, 5.9%
The following compounds (FY~mrles 304-8) were prepared from (4-'oenzyltnio-2-
n~o~7pti~1in-l-yl)acetic acid and the required amine by the method described forExample 301.
Example 304 N-t6-(3-chlorophenyl)hexyn-5-yl]-(4bel~ o-2
35 yl)~ P
Colourless oil, 67.8% yieldlH NMR ~ (CDC13) 1.34-1.67 (4H, m, 2xC_2)~ 2.44 (2H,
t, J=6.51Hz, ArCCCH2), 2.94 (lH, dd, 2.43Hz, 15.34Hz, H3a), 3.31 (2H, m,
NHCH2), 3.37 (lH, dd, J=5.22Hz, 15.43Hz, _3b)~ 3.63 & 3.78 (lH each, J=16.49Hz,
- NC 2)~ 3.87 (2H, s, SC_2Ph), 4.80 (lH, dd, J=2.46Hz, S.llHz, H4), 6.36 (lH, m,
40 NHC=O), 7.15-7.46 (9H, m, 9xArH)
FY~mple 305 N-t6-(2-Chlorophenyl)hexyn-5-yl] 1 b~ llllio-2~ox~7~1iAin-lyl
e
Colourless oil, 76.2% yieldlH NMR ~ (CDC13) 1.47-1.81 (4H, m, 2xCH2), 2.51 (2H,
t, J=6.48Hz, ArCCC_2)~ 2.94 (lH, dd, 2.43Hz, 15.38Hz, H3a), 3.22 (2H, m,
45 NHC_2)~ 3.35 (lH, dd, J=5.13Hz,l 5.38Hz, H3b), 3.54 & 3.76 (lHeach, J=16.79Hz,
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NCH2), 3.81 (2H, s, SCH2Ph), 4.80 (lH, dd, J=2.45Hz, 5.13Hz, 4), 6.10 (lH, m,
N_C--O), 7.17-7.44 (9H, m, 9xArH)
F-Y~nP'e 306 N-(6-Phenyl-3-hexynyl)-(41~ 1U-io-'~ n~ idin-l yl)acetamide
('olonrl~ss solid, m.p. 96-97~C, 78% yield
lH NMR ~ (CDC13) 2.34 (2H, m, CCC_2)~ 2.46 (2H, m, CCCH2), 2.80 (2H, t,
J=7.4Hz, PhCH2), 2.91, 2.95 (lH, dd, J=2.4, 15.3Hz, 3), 3.34 (3H, m, NHCH2,_3),
3.44, 3.73 (each lH, d, J=16.8Hz, NCH2), 3.80 (2H, s, SCH2), 4.83 (lH, m, H,~), 6.0
(lH, m, N_), 7.20-7.33 (lOH, m, 2Ph-H); v ~=0 1771 cm~l
Found: C, 70.9; H, 6.5; N, 7.0%; C24H26N202S ,e~lu~s: C, 70.9; H, 6.5; N, 6.9%
Fy~ ple 3o7 Z-N-(6-phenyl-~hexenyl)-(4bel~yl ' '~-2-~ idin-1-
yl)~r~ ~ide
Colourless oil, 65% yield
lH NMR o (CDC13) 2.18 (2H, m, C-CCH2), 2.35 (2H, m, C=CC_2)~ 2.66 (2H, t,
J=7.6Hz, PhC_2)~ 2.89, 2.93 (lH, dd, J=2.4, 15.3Hz,_3), 3.20 (2H, m, NHCH2),
lS 3.31, 3.37 (lH, dd, J=5.2, 15.3Hz, H3), 3.47, 3.65 (each lH, d, J=15.1Hz, NCH2),
3.75 (2H, s, SCH2), 4.80 (lH, m, ~4), 5.35 (lH, m, CH=), 5.51 (lH, m, CH=), 5.93(lH, m, NH), 7.16-7.41 (lOH, m, 2Ph-H)
F~ e 308 E-N-(6-phenyl-3-hexenyl)-(4bel~,~ uo-2-o~
Yl)~f ' ' ~~
Colourless solid, m.p. 9~97~C, 78% yield
lH NMR ~ (CDC13) 2.18 (2H, m, C=CCH2), 2.33 (2H, m, C=CCH2), 2.68 (2H, t,
J=7.7Hz, PhCH2), 2.90, 2.96 (lH, dd, J=2.4, 15.3Hz, H3), 3.24 (2H, m, NHCH2),
3.33, 3.39 (lH, dd, J=5.2, 15.3Hz, H3), 3.48, 3.71 (each lH, d, J=16.8Hz, NC_ 2)~
3.81 (2H,s,SCH2),4.81 (lH,m,H1),5.34(1H,m,C_=),5.53 (lH,m,CH=),5.87
(lH, m, NH), 7.15-7.36 (lOH, m, 2Ph-_); v c=o 1771 cm~l
Found: C, 70.5; H, 6.9; N, 7.0%; C24H28N2O2S requires:C, 70.6; H, 6.9; N, 6.9%
F~ 309 N~(~~Phe~OA~ y~ ~ylll~io.2 nYn~7r1iAin l yl~ ide
Yellow oil, 74% yield
lH NMR ~ (CDC13) 1.4-1.9 (6H, m, 3 x C_2)~ 2.93 (lH, dd, J=2, 15 Hz, H3), 3.3
(2H, m, NHC_2). 3.36 (lH, dd, J=5, 15 Hz, H3), 3.55, 3.72 (each lH, d, J=17 Hz,
NC_2). 3.81 (2H, s, SCH2), 3.95 (2H, t, J=6 Hz, CH20), 4.81 (lH, m,_4), 6.13
(lH, br s, NH), 6.9 (3H, m, Ph-H), 7.3 (7H, m, Ph-
F-~p'e 310 N-(2-(2-PhenoAyethoAy)ethyl)~l~ lU-.o-2-o~ r 1-
..~ide
35 Yellow oil, 84% yield
lH NMR ~ (CDC13) 2.89 (lH, dd, J=2, 15 Hz, H3), 3.31 (lH, dd, J=5, 15 Hz, H3),
3.50 (3H, m, NHC_2 + NCH2), 3.63 (2H, m, CH20), 3.80 (5H, m, CH20 + SC_2 +
NCH2), 4.10 (2H, m, CH20Ph), 4.82 (lH, m, H,l), 6.38 (lH, br s, NH), 6.9 (3H, m,Ph-H), 7.3 (7H, m, Ph-H)
Fy~mp~e 311 N-(2-(3-Pht~ loxy)ethyl)~be-~lll-i~2-~
yl~r~t~m;~l~
Yellow oil, 77% yield
lH NMR ~ (CDC13) 1.90 (2H, m, CH2), 2.68 (2H, t, J=8 Hz, C_2Ph), 2.93 (lH, dd,
J=2, 15 Hz, H3), 3.36 (lH, dd, J=5, 15 Hz, H3), 3.45 (7H, m, NHC_2 + C_2~ +
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W O 97/02242 PCT~EP96/02765
NCH2), 3.80 (3H, m, SCH2 + NCH2), 4.85 (lH, m, ~4), 6.25 (lH, br s, NH), 7.3
(lOH, m, Ph-_)
The following snlfo~ e~ (FY~mrl~s 312 - 327) were prepared in the same way as
(l~scnhe~l for Fy~mrl~s 2 and 3.
Example 312 N-[6-(3-Chlorophenyl)hexyn-S-yl~ 1 be~ I-2-oxo-
q7PtiA;n.l_yl ace~amide
Whi{e solid, m.p. 133-134~C, 15.5% yieldFound: C, 62.8; H, 5.4; N, 6.13%;
C24H2sClN203S requires: C, 63.1; H, S.S; N, 6.1%
Example 313 N-[6-(3-Chlo.~ e"~l)hexyn-~-yl] 1 ~ b-,l~hinyl-2 ox~
~7~tiA;r~ l-yl ~
White solid, m.p. 68-70~C, 18.0% yieldFound: C, 62.8; H, 5.5; N, 6.2%;
C24H2sClN203S requires: C, 63.1; H, 5.5; N, 6.1%
FY~mple 314 N-[6-(2-Chlorophenyl)hexyn-5-yl~-4-~e ~ 2-oxo-
~7~tillin.l.yl ~ret~",~
lS White solid, m.p. 132-134~C, 48.1% yieldFound: C, 62.8; H, 5.5; N, 6.1%;
C24H25ClN203S requires: C, 63.1; H, 5.5; N, 6.1 %
F ~ 31~ N-t6-(2-chlorophenyl)hexyn-~-yl~e~ p~:nyl-2
~7~tiA;n-l-yl ~
White solid, m.p. 91-92~C, 48.1% yieldFound: C, 62.9; H, 5.6; N, 6.2%;
C24H25ClN203S requires:C, 63.1; H, 5.5; N, 6.1 %
Example316 N-(6-Phenyl-3-hexynyl)-(4 bt~ lsulphinyl-2-o~
yl)~ret~nide(~lia~ ;eo~.~. 1)
Colourless solid, m.p. 186~C, 14% yield
lH NMR ~ (CDC13) 2.34 (2H, m, CCCH2), 2.46 (2H, m, CCCH2), 2.80 (2H, t,
J=7.4Hz, PhC_2)~ 2.91, 2.95 (lH, dd, J=4.4, 14.8Hz, 3), 3.31 (2H, m, NHCH2),
3.41, 3.44 (lH, dd, J=2.0, 14.8Hz, _3), 3.78-4.01 (4H, m, NCH2, SOCH2), 4.59 (IH,
m, H4), 6.38 (lH, m, NH), 7.20-7.40 (lOH, m, 2Ph-H); v c=o 1791 cm~l
Found: C, 68.0; H, 6.1; N, 6.6%; C24H26N203S requires: C, 68.2; H, 6.2; N, 6.6C~o
FY~mple 317 N-(6-Phenyl-3-hexynyl)~(4~b~ yl~ k~ lir 1-
yl)~et~rnill~ (diastereoisomer2)
Colourless solid, m.p. 127-128~C, 48% yield
lH NMR ~ (CDC13) 2.34 (2H, m, CCCH2), 2.46 (2H, m, CCCH2), 2.72-2.81 (3H, m,
PhCH2, H3), 3.09, 3.13 (lH, dd, J=5.6, 15.2Hz, _3), 3.34 (2H, m, NHC_2)~ 3-93~
4.19 (4H, m, NC_2~ SOC_2)~ 4.65 (lH, m, H4), 6.74 (lH, m, N_), 7.20-7.40 (lOH,
m, 2Ph-H)
Example 318 Z-N-(6-Phenyl-3-hexenyl)-(4-~e~ o~ lin-1-
yl)~ *~ (diastereQieom~
Colourless soild, m.p. 145-146~C, 19% yield
lH NMR ~ (CDC13) 2.21 (2H, m, C=CCH2), 2.35 (2H, m, C=CCH2), 2.66 (2H, t,
J=7.6Hz, PhC_2)~ 2.91, 2.95 (lH, dd, J=4.8, 14.8Hz,_3), 3.19 (2H, m, NHC_2)~
3.42, 3.45 (lH, dd, J=2.0, 14.8Hz,_3), 3.73, 4.02 (each lH, d, J=17.6Hz, NCH2),
3.87, 4.01 (each lH, d, J= 13.2Hz, SOC_2)~ 4.53 (lH, m, H1), 6.47 (lH, m, N_),
7.16-7.41 (lOH, m, 2Ph-_); v ~=o 1791 cm~l
Found: C, 67.6; H, 6.6; N, 6.7%; C24H28N203S requires: C, 67.9; H. 6.7; N, 6.6%
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E~nple319 Z-N-(6-phenyl-3 '~ 1)-(4-1~ l 2-~ idin-1-
yl)A~ de(~ t .~ - 2)
Colourless solid, m.p. 104 105~C, 14% yield
lH NMR ~ (CDC13) 2.21 (2H, m, C=CCH2), 2.37 (2H, m, C=CCH2), 2.67 (2H, t,
S J=7.6Hz, PhCH2), 2.79, 2.83 (lH, dd, J=2.4, 15.6Hz, H3), 3.12, 3.16 (lH, dd, J=5.6,
15.6Hz, H3), 3.22 (2H, m, NHC_2)~ 3.90, 4.18 (each lH, d, J=16.8Hz, NCH2), 3.97,4.16 (each lH, d, J= 12.8Hz, SOC_2), 4.61 (lH, m, H"), 5.35 (lH, m, C_=), 5.51
(lH, m, CH=), 6.95 (lH, m, N_), 7.16-7.41 (lOH, m, 2Ph-_); v ~=0 1793 cm~l
Found: C, 67.4; H, 6.6; N, 6.7%; C24H28N203S ~ es. C, 67.9; H, 6.7; N, 6.6%
F~ c 320 E-N-(6-Phenyl-3-lltAt:JIyl)-(4 b~y~ idin-1-
yl)~~~ de (Ji:~l~.~. ~.-~-- 1)
Colourless soild, m.p.l82-183~C, 18% yield
lH NMR ~ (CDCl3) 2.19 (2H, m, C=CCH2), 2.31 (2H, m, C=CC_2)~ 2.67 (2H, t,
J=7.7Hz, PhCH2), 2.91, 2.96 (lH, dd, J=4.7, 14.8Hz,_3), 3.24 (2H, m, NHCH2),
3.41, 3.47 (lH, dd, J=2.2, 14.8Hz, H3), 3.73, 4.02 (each lH, d, J=17.3Hz, NCH2),3.88, 4.01 (each lH, d, J= 13.1Hz, SOCH2), 4.55 (lH. m, H1), 6.44 (lH. m, N~),
7.16-7.40 (lOH, m, 2Ph-H); v 00 1790cm~l
Found: C, 67.5; H, 6.6; N, 6.6%; C24H28N203S requires: C, 67.9; H, 6.7; N, 6.6%
Example 321 E-N-(6-phenyl-3-l~A~ l)-(4
yl)~e~ ide (~lia~ ~ieom~r2)
rlp~ solid, m.p.l l l-112~C, 13% yield
lH NMR o (CDC13) 2.21 (2H, m, C=CC_2)~ 2.34 (2H, m, C=CC_2)~ 2.67 (2H, t,
J=7.6Hz, PhCH2), 2.78, 2.84 (lH, dd, J=2.5, 15.3Hz, H3), 3.11, 3.17 (lH, dd, J=5.3,
15.3Hz, H3), 3.28 (2H, m, NHC_2)~ 3-90, 4.18 (each lH, d, J=17.1Hz, NC_2)~ 3-97
4.16 (each IH, d, J= 12.9Hz, SOCH2), 4.62 (lH, m, H1), 5.38 (lH, m, =C_), 5.53
(lH, m, =C_), 6.86 (lH, m, N ), 7.16-7.42 (lOH, m, 2Ph-_); v ~=0 1793cm~l
Found: C, 67.8; H, 6.6; N, 6.6%; C24H28N203S requires: C, 67.9; H, 6.7; N, 6.6%
FY~nnrle322 N (S ph~noxypentyl~(4_be.~l~u~finyl2
yl)acetamide
White solid, 18% yield, m.p. 132-135 C
lH nmr ~ (CDC13) 1.17-1.54 (6H, m, CH2CH2CH2), 2.94 (lH,dd, J=15.0, 4.75Hz,
H3b), 3.25 (2H, m, NH-C_2)~ 2.44 (lH, dd, J=15.0, 2.25Hz7 _3a)~ 3.68-4.16 (6H, m,
C_2-OPh, N-CH2, SOC_2Ph), 4.52 (lH, m, H4), 6.74 (lH, m, NH), 6.86-6.95, 7.22-
7.35, 7.37-7.40 (3H, 4H, 3H, m, O-Ph-_, SOCH2Ph-H).
FY~mp~e 323 N-(~-ph~no~y~llLyl)-(4-~ ulr~ o~ ;n-l-
yl)~e~ ~de
Whitesolid,21%yield,m.p. 116-118 C
lH nmr ~ (CDC13) 1.46-1.86 (6H, m, C_2C_2CH2), 2.87 (lH, dd, J=15.5, 2.0Hz,
--3a)~ 3.17 (lH, dd, J=15.5, S.OHz, H3b), 3.26-3.39 (2H, m, NH-C_2)~ 3.85-4.29
(6H, m, N-C_2~ C_2-OPh, SOC_2Ph), 4.60 (lH, m, _4), 6.86-6.94,7.22-7.43 (3H,
8H, m, CH2Ph-H, O-Ph- , N_).
Found: C, 64.2; H, 6.4; N, 6.5%; C23H2gN204S requires: C, 64.5; H, 6.6; N, 6.5%
FY~mrle 324 N-(2-(2-Phenoxyethoxy)ethyl)-(4-bt:l~y~ .hinyl 2 o...~,-~1;.l;,- 1-yl)~e~ ~iso~
Colourless solid, m.p. 133-5~C, 40% yield
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lH NMR ~ (CDC13) 2.89 (lH, dd, J=S, lS H~, H3), 3.39 (lH, dd, J=2, lS Hz, H3)
3.45 (2H, m, ~NCH2), 3.64 (2H, m,OCH2), 3.80 (2H, m, OCH2), 3.90 (4H, m, NCH2
+ SOC_2)~ 4.12 (2H, m, CH20Ph), 4.60 (lH, m, H4), 6.65 (lH, br s, NH), 6.95 (3H,m, Ph-H), 7.3 (7H, m, Ph-H); v ~=0 1789 cm~l
S Found: C, 61.1; H, 6.0; N, 6.6%; C22H26N20sS requires: C, 61.4; H, 6.1; N, 6.5%
F -- 'C 325 N~ ..uA~ u~)ethyl)~ hinyl-2-~ idin.l.
yl)acetamide (Diasl~ e~ 2)
Colourless solid, m.p. 109-12~C, 47% yield
lH NMR o (CDC13) 2.67 (lH, dd, J=2, 15 Hz,_3), 3.06 (lH, dd. J=S. lS Hz, _3)
3.5 (2H, m, NCH2), 3.65 (2H, m,OCH2), 3.82 (2H, m, OC_2)~ 4.0 (6H, m, NCH2 t
SOCH2 + CH20Ph), 4.65 (lH, m, H,l), 7.06 (lH, br s, N~, 6.9 (3H, m, Ph-H), 7.3
(7H, m, Ph-H); v ,~0 1790 cm~l
Found: C, 61.0; H, 6.0; N, 6.5%; C22H26N20sS requires: C, 61.4; H, 6.1; N, 6.5~Yo
FY~n~P'~ 326 N-2-(3-Phel.yl~ loYy)ethyl~ h~yl~ulphinyl-2
yl)acetamide (Dia~.k~ omPr 1)
(~olonrl~ solid, m.p. 124-5~C, 27% yield
lH NMR ~ (CDC13) 1.90 (2H, m, CH2), 2.68 (2H, t, J=8 Hz, CH2Ar), 2.91 (lH, d,~,
J=S, lS Hz, H3), 3.4 (7H, m, NCH2 + H3 + 2 x OCH2), 3.85 - 4.0 (4H, m, SOCH2 +
NCH2), 4.62 (lH, m, H4), 6.61 (lH, br s, NH), 7.15 - 7.45 (lOH, m, 2 x Ph-H); v ~=O
1789 cm~l
Found: C, 64.2; H, 6.5; N, 6.6%; C23H2gN204S requires: C, 64.5; H, 6.6; N, 6.5~7FY~mr'e327 N-2-(3-Pht~ v~yloxy)ethyl-(4-l~e~l~y~ lrhinyl-2~ e~ ]I-
yl)~et~niAP (Di~l~:.~isoll.er2)
Colourless solid, m.p. 82-4~C, 24% yield
lH NMR ~ (CDC13) 1.85 ~2H, m, CH2), 2 7 (3H, m, C_2Ar + H3), 3.09 (lH, dd,
J=S, lS Hz, H3), 3.45 (6H, m, NC_2 + 2 x OCH2), 3.9 - 4.2 (4H, m, SOCH2 +
NCH2), 4.67 (lH, m, ~4), 6.97 (lH, br s, N_), 7.15 - 7.4 (10H, m, 2 x Ph-_); v c~o
1790 cm~l
Found: C, 64.3; H, 6.5; N, 6.6%; C23H2gN204S requires: C, 64.5; H, 6.6; N, 6.5~7FY~mrl-P 328 N-[6-(2-chlorophenyl)he~y~yn~5-yl]~b~ ,
~7Pti~ yl ~'el*~ P
Treatment of N-[6-(2-chlorophenyl)hexyn-S-yl]~ben_yl~nlrhinyl-2-oxo-~7Pti-lin-l-yl
~cet~mi~le (diastereoisomer 1) with mCPBA (1 equivalent) in dichlorom.o~h~n~ at room
telllper~tL~l~ gave the title compound as a white solid, m.p. 114- 117~C, 86.7% yield;
Found:C, 60.4; H, 5.4; N, 5.8%; C24H2sClN204S requires:C, 60.9; H, 5.3; N, 5.8'~O
The following sulfones (FY~mI-1eS 329-331) were prepared in an analogous way, orwere isolated from the mixture formed when the corresponding sulfides were treated
with mCPBA.
F~~ ,IC 329 N t6_(3 ChlOrOPhenYI)heXYn-5-YI]-4b~ 1.OnYI-2-OXo-
~7~ti~1;n_l_yl ~et~miA~
White solid, m.p. 122-124~C, 5.6% yield
Found: C, 60.7; H, 5.3; N, 6.0%; C24H2sClN203S requires: C, 60.9; H, 5.3; N,
5.9%
FY~nnr1e 330 N-(6-PhenYI-3-heXYnYI)-(4-beI~ nYI-2-~A~ ;r 1-
Yl)~t~,n;~
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Colourless solid, m.p. 135-136~C, 88% yield
lH NMR o (CDCl3) 2.33 (2H, m, CCCH2), 2.47 (2H, m, CCCH2), 2.81 (2H, t,
J=7.4Hz, PhCH2), 2.94, 3.00 (lH, dd, J=2.4, 15.3Hz,_3), 3.07. 3.13 (lH, dd, J=5.1,
15.3Hz, _3), 3.30 (2H, m, NHCH2), 3.6g, 3.97 (each lH, d, J=18.9Hz, NCH2), 4.30,S 4.37 (each lH, d, J=14.2Hz, S02C_2)~ 4.89 (lH, m, H1), 5.77 (lH, m, N_), 7.20-
7.40 (lOH, m, 2Ph-H); v c=o 1792 cm~l
Found: C, 65.4; H, 6.0; N, 6.4%; C24H26N204S requires: C, 65.7; H, 6.0; N, 6.4%
Example331 E-N-(6-phenyl-3 "-YPnyl)-(~ be,.-~yl Irhonyl-2-; e'~
y~ t~ de
Colourless solid, m.p. 115-116~C, 39% yield
lH NMR ~ (CDC13) 2.17 (2H, m, C=CCH2), 2.35 (2H, m, CCCH2), 2.69 (2H, t,
J=7.6Hz, PhC_2)~ 2.94, 3.00 (lH, dd, J=2.4, 15.4Hz,_3), 3.07, 3.13 (lH, dd, J=S.l,
15.4Hz, H3), 3.24 (2H, m, NHC_2)~ 3.74. 3.95 (each lH, d, J=16.9Hz, NC 2)~ 4-30-4.37 (each lH, d, J=14.2Hz, S02C_2)~ 4.87 (lH. m, H4), 5.33 (lH, m, =CH), 5.53
(lH, m, -C_), 5.70 ( lH, m, NH), 7.16-7.44 (lOH. m. 2Ph-H); v ~=0 1794 cm~l
Found: C, 65.1; H, 6.3; N, 6.4%; C24H28N204S requires: C, 65.4 H, 6.4; N, 6.4%
Example332 1-(2-(6-Phenylhexyloxy)ethyl-4-Le,~lll io-2~ idine
A 60% ~licpPrciQn of sodium hydride in mineral oil (0.30 g, 7.5mmoles) was ~ Pd
in dry THF (lS ml) at -10~C under nitrogen and a solution of 4-('~ll~yl~uo)-2-
~7Pt~ nonP (1.35g) in THF (10 ml) was added over 10 mins k~epin~ temp <0~C. The
was stirred at 0~C for 15 mins, cooled to -10~C and 2-(6-phenylhexyloxy)ethyl
triflate(3.54g,) in THF(10 ml) was added over 3 mins keeping temp <0~C. The
mixture was stirred at RT for 30mins then poured into brine (50 ml), separated and the
aqueous extrAetP~l with ether. The combined organics were dried over MgS04 and
evaporated to a red oil. This was purified by ch~ atography on silica gel (40-60petroleum ether/ethyl acetate) to give 1-(2-(6-phenylhexyloxy)ethyl~bel~yllllio-2
oXo~7Ptirlin~ as a colourless oil (1.71g, 62%)
lH NMR o (CDC13) 1.3-1.7 (8H, m, 4 x C_2)~ 2.59 (2H, t, J=8 Hz, CH2Ph), 2.88
(lH, dd, J=2, lS Hz, _3), 3.0 (lH, m, NCH2), 3.27 (lH, dd, J=5, 15 Hz, _3), 3.4
(5H, m, NCH2 + C_20CH2), 3.81 (2H, s. SCH2), 4.75 (lH, m, _4), 7.15-7.35 (lOH,
m, Ph-H ).
The following F.x~mpl.-s (333-336) were prepared from 4-bell~yllllio-~7Pti-iin-2-one
and the corresponding triflate in an analogous manner to FY~mrl~ 332.
FY~mrl~P 333 1-(~(6-(4-Chlorophenyl)hexyloxy)ethyl)~bt~ lU.io-2-
~,Y~ ;,,P
Colo~lrl~s oil, 62% yield
lH NMR o (CDC13) 1.2- 1.7 (8H, m, 4 x C_2). 2.55 (2H, t, J=8 Hz, CH2Ph), 2.88
(lH, dd, J=2, 15 Hz, H3), 3.0 (lH, m, NCH2), 3.28 (lH, dd, J=5, 15 Hz, H3), 3.4
(5H, m, NCH2 + C_20CH2), 3.81 (2H, s, SCH2), 4.75 (lH, m, H4), 7.07 (2H, m,
ClPh-H), 7.35 (7H, m, Ph-H + ClPh-H)
F~y~rnple 334. 1-(2-(6-(4-~luo,o,~he~ l)hexyloxy)ethyl) 1 a~ lll.io-~
O~f~~l7el ;AinP
Colourless oil, 22% yield
lH NMR o (CDC13) 1.2-1.7 (8H, m, 4 x C_2)~ 2.55 (2H, t, J=8 Hz, C_2Ph). 2.88
(lH, dd, J=2, 15 Hz, H3), 3.05 (lH, m, NC_2)~ 3.27 (lH, dd, J=5, 15 Hz,_3), 3.4
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(SH~ m~ NCH2 + CH20CH2), 3-81 (2H, s, SC_ 2)~ 4.75 (IH, m, H4), 6.95, 7.10 (ea~:h
2H, m, Fph-H), 7.25 (SH, m, Ph-_)
Example 33~ N-3-(Ph~-uA~ 31)-4b~ 1lluo~ e
Yellow oil, 82% yield
lH NMR ~i (CDCl3) 2.0 (2H, m, CH2), 2.89 (lH, dd, J=2, 15 Hz, _3), 3.08, 3.41
(each lH, m, NCH2), 3.26 (lH, dd, J=5, lS Hz, H3), 3.78 (2H, s, SCH2), 3.95 (2H,m, CH20Ph), 4.63 (lH, m, _ 4), 6.9 (3H, m, Ph-H), 7.3 (7H, m, Ph-H)
F~ C 336 1-(2-Benzyl~ lu~io-azetidin-2-one
Colourless oil, 74% yield
lH NMR o (CDC13) 2.7 (lH, dd, J=2, 15 Hz, H3), 3.0 (lH, m, NC_ 2)~ 3.26 (lH, dd,J=5, lS Hz, H3), 3.5 (3H, m, NCH2 + CH2C_ 2~)~ 3.76 (2H, m, SC_2Ph), 4.50 (2H,
m, OCH2Ph), 4.7 (lH, m, H4), 7.2-7.4 (lOH, m, 2xPh-_).
The following sulfoxides (FY~mr1~ 337-345) were prep~d by treating the
corresponding sulfides with mCPBA, as described in FY:ImI)1PS 302 & 303.
Example 337 1-(2-(6-Phenylhexyloxy)ethyl-4be~ line
(80% Dia~ o-~-~. 2)
Colourless solid, m.p. 47-9~C. 37% yield
lH NMR ~; (CDC13) 1.2-1.7 (8H, m, 4 x CH2), 2.6 (3H, m C_2Ph + H3), 2.98 (lH,
dd, J=5, lS Hz, H3), 3.3-3.8 (6H, m, NCH2 + CH20CH2), 4.05 (2H, d, J=13 Hz,
SCH2), 4.52 (lH, m, _ 4), 7.14-7.4 (lOH, m, Ph-_ ); v ~=0 1776 cm~l
Found: C, 69.7; H, 7.4; N, 3.5%; C24H31N03S requires: C, 69.7; H, 7.6; N, 3.4%
FY~nrl~P 338 1-(2-(6-(4-chlorophenyl)he~y-ylo~y~y)ethyl)~4-~ h.~nyl-2
1inP (Dia~,~.~J.
Colourless oil, 27% yield
lH NMR ~ (CDC13) 1.2-1.65 (8H, m, 4 x CH2), 2.58 (2H, t, J=8Hz, C_2Ph), 2.87
~lH, dd, J=S, lS Hz, H3), 3.25 - 3.7 (7H, m, NCH2 + CH20CH2 + H3), 3.84,3.98
(2H, 2 x d, J=13Hz, SOC_2)~ 4.51 (lH, m, H4), 7.09 (2H, m, ClPh-_), 7.3 (7H, m,
Ph-_ + ClPh-_); v c=o 1777 cm~l
Found: C, 64.1; H, 6.6; N, 3.1%; C24H30CIN03S requires:C, 64.3; H, 6.8; N, 3.1~~7
Example 339 1-(2-(6-(4-Chlorophenyl)hexyloxy)ethyl) 4be,~ 1-2-
n~ 7f ~ inP (Diastere~)ico~l~r2)
Colourless solid. m.p. 86-8~C, 37% yield
lH NMR ~ (CDC13) 1.2-1.7 (8H, m, 4 x C_2)~ 2.55 (3H, m, CH2Ph + _ 3), 2.99 (lH,
dd, J=S, lS Hz, H3), 3.3 - 3.8 (6H, m~ NC_2 + CH20CH2), 4.01,4.09 (2H, 2 x d,
J=13Hz, SOCH2), 4.52 (lH, m, H4), 7.09 (2H, m, ClPh-H), 7.3 (7H, m, Ph-H + ClPh-H); v 00 1777 cm~l
Found: C, 64.2; H, 6.6; N, 3.3%; C24H30ClN03S requires: C, 64.3; H, 6.7; N, 3.1~3~o
Example 340 1-(2-(6-(4FluulolJhenyl)hexyloxy)ethyl)-4h~l~L~ ph;nyl-2-
~J.~ ine (Diastere--icom~r 1)
Colourless oil, 12% yield
lH NMR ~i (CDC13) 1.25-1.65 (8H, m, 4 x C_2)~ 2.58 (2H, t, C_2Ph), 2.87 (lH, dd,J=5, lS Hz, H3), 3.25 - 3.7 (7H, m, NC_ 2 + CH20C_2 +_3), 3.84,3.98 (2H, 2 x d,
J=13Hz, SOC_2)~ 4.52 (lH, m, H~l), 6.95, 7.10 (each 2H, m, FPh-_), 7.3 (5H, m, Ph-
H); v ~=0 1777 cm~l
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~:xample 341 1-(2~ (4Fluu .~nyl)hex~lo~y)ethyl)~ ,hinyl 2
A, ~;-7;~r (Di~~ 2)
Colourless solid, m.p. 77-8~C. 37% yield
lH NMR ~ (CDCl3) 1.25- 1.65 (8H, m, 4 ~c C 2)~ 2.55 (3H, m, CH2Ph + H3), 2.98
S (lH, dd, J=S, lS Hz, H3), 3.4 - 3.75 (6H, m, NC 2 + CH2OC_2)~ 4.02,4.09 (2H, 2 x
d, J=13Hz, SOCH2), 4.52 (lH, m, _4), 6.95, 7.10 (each 2H, m, FPh-_), 7.3 (SH, m,Ph- ); v c=o 1777 cm~l
Found: C, 66.5; H, 6.9; N, 3.2%; C24H30FNO3S ,eyu~es: C, 66.8; H, 7.0; N, 3.3%
FY~mp~ 342 4-B~l~y~ hinyl-l-(3-phL.~oAy~ one
(Di~S~ n~ ~Pr 1)
Colourless solid, m.p. 93-97~C
lH nmr ~ (CDC13) 2.05-2.17 (2H, m, CH2C_2CH2), 2.78(1H, dd, J=14.75, 4.75Hz,
H3b), 3.34-3.57 (3H, m,_3a~ N-CH2), 3.82, 3.92 (2H, dd, J=13.00, 13.00Hz,
SOC_2Ph), 3.95-4.06 (2H, m, C_2-OPh), 4.37 (lHt m,_4), 6.83-6.98 (SH, m, OPh-
lS _), 7.19-7.37 (5H, m, CH2Ph-H).
Found: C, 66.5; H, 6.2; N, 4.1%; ClgH21NO3S requires: C, 66.3; H, 6.2; N, 4.4%
F~ 343 4Benzylclllrllinyl-l-(3-rh - y~-ù~ e~ ~one
(D - ~isol..e. 2)
- Colourless solid, m.p. 62-65~C
lH nmr ~ (CDC13) 2.12-2.19 (2H, m, CH2C_2CH2), 2.47 (lH, dd, J=15.0, 2.25Hz,
H3a)~ 2.91 (lH, dd, J=15.0, 5.0Hz, 3b)~ 3.51-3.67 (2H, m, N-C_2)~ 3.95-4.07 (4H,m, C 2~~ SOCH2Ph), 4.42 (lH, m,_4), 6.83-6.97 (5H, m, OPh-H), 7.22-7.39 (5H,
m, SOCH2Ph-_).
Found: C, 66,5; H, 6.2; N, 4.1%; ClgH21NO3S requires: C, 66.4; H, 6.3; N, 4.4%
FY~mp~ 344 1-(2-Benzylc~xy~ yl)-4-b~ h;nyl-~7~ -2 one(57%
Diastereoiso...~
Colourless oil, 49% yield
lH NMR ~ (CDCl3~ 2.78 (lH, dd, J=S, lS Hz, _3), 3.35 (lH, d, J=13 Hz, _3), 3.
3.8 (4H, m, NC_2C_2)~ 3.95, 4.07 (each lH, d, J=lS Hz, SOCH2), 4.5 (3H, m,
OCH2Ph +_4), 7.2-7.4 (lOH, m, Ph-_); v c=o 1777 cm~l
F~Y~mrle 345 1-(2-Benzylo~yt:ll.yl)-4-b~.~y~ 7~ti ~ n-2~ne (80%
D~~ . 2)
~olol~rlPcc oil, 26% yield
lH NMR ~ (CDCl3) 2.49 (lH, d, J=lS Hz, _3), 2.93 (lH, dd, J=S, lS Hz, _3), 3.4-
3.8 (4H, m, NC_2CH2), 3.95, 4.07 (each lH, d; J=13 Hz, SOC_2)~ 4.4-4.6 (3H, m,
OCH2Ph + H4), 7.2-7.4 (lOH, m, Ph-_); v ~=0 1777 cm~l
Found: C, 66.4; H, 6.2; N, 4.3%; ClgH21NO3S requires: C. 66.5; H, 6.2; N, 4.1%
F.Y~mrl~ 346 4-Methylthio-l-(3-phenoxyl~lu~u~ 7~t~ n-~ûne
A solution of 4-methy]thio~7~ti~in-2-one (0.7g, S.g7mmol) in dry THF (lOml) was
added dropwise over 10 min~ltes to a s~lcpen.cio l of NaH (0.24g, 6.07mmol) in dry
THF (Sml) at -20~C under a N2 at nosphere. A solution of 3-iodo-1-phenox~ p~e
(1.56g, 5.97mmol) in dry THF (lOml) was added dropwise over 10 ..~i..u~s at-55~C.
This ~ u,~ was stirred for 18 hours overnight then poured onto ice/water (50g),
filtered and partially evaporated. The residue was dtreated with ethyl acetate and the
45 organic layer was washed with brine (x2), dried (MgSO4) and evaporated under
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W O 97/02242 PCTAEP96/02765
reduced pl~Lue tO a yellow oil. The oil was purified by fiach chrom~togr~phy on
silica gel to give 4-methylthio-l-(3-phenu~y~ yl)~7Pt~ n-2-one a cclonrlPcs solid
(0.64g, 42%), m.p. 41-2~C.
lH NMR ~ (CDC13) 2.04 (3H, s, SC 3), 2.10 (2H, m, CH2), 2.95 (lH, dd, J=2, 15
Hz, H3), 3.25 (2H, m, H3 +NC_2)~ 3.56 (lH, m, NCH2), 4.02 (2H, m, CH2OPh),
4.66 (lH, m, H4), 6.9 (3H, m, Ph-H), 7.3 (2H, m, Ph-
F - A ? 347 4Mell.~ "vA~ )~7~ ;n 2-one
Tre~tmPnt of 4-methylthio-1-(3-phenoxy~l~yl)~7P,ti~lin-2-one (0.59g,2.34mmol) ~qth
mCPBA as in FY~mplP 302 gave 4-Methylclllphinyl-l-(3-phenuAy~ yl)~7~ptitiin-2
one as a waxy white solid (0.39g, 62%).
lH nmr ~ (CDC13) 2.12-2.23 (4H, m, 2xCH2CH2CH2), 2.43(3H, s, SOCH3), 2.5l5
(3H, s, SOCH3), 2.78 (lH, dd, J=15.00, 2.50Hz,_3a)~ 3-07 (lH, dd, J=14.5, 4.75Hz,
H3b), 3.24 (lH, dd, J=15.00, 5.25Hz,_3b)~ 3.47-3.71 (5H, m, 2xN-CH2, H3a)~ 4.()5-
4.20 (4H, m, 2xCH2O), 4.40 (lH, m, _4), 4.50 (lH, m, H4), 6.8-7.0, 7.2-7.33 (6H,4H, m, 2xAr-_).
Found: C, 58.4; H, 6.4; N, 5.2%; C13H17NO3S requires: C, 58.1; H, 6.5; N, 5.3~7
F.Y~mplr 348 1-(2-(6-(~Fluv.vlJhenyl)heAyloAy)ethyl)-4-(4
ethvAy.srl~v.,yll>e~ o)-2-vx~
A sollltion of 4 (4-(etho,~yc~L,onyl)benzyllhio)~7Pti~1in-2-one (1.85g, 0.00697 moles),
2-(6-(1 Fluorophenyl)hexyloxy)ethyl triflate (2.62g, 0.00704 moles),
terabutylammonium bromide (0.22g, 0.00068 moles) in dry tetrahyd.~,ru,dll (40ml),
cooled to iooc, was treated with powdered po!~ .Ci~ hydroxide (0.47g, 0.00838
moles). The cooling bath was removed and the reaction was stirred at room
for 2 hours, partitioned be~weell brine (70rnl) and ethyl acetate (75ml).
The organic layer was dried (MgSO4) and t;va~ al~d to an oil (3.7g). Purified byflash column chromatography on silica gel eluted with 2:1 P.E. 40-60~C:ethyl acetate
to give 1-(2-(6-F-luorophenyl)hexyloxy)ethyl) 1 (4-ethoxy~ lJollylbel~ylll~io)-2-
oXo~7Pti~linP as a colourless oil (1.15g, 34%).
1H nmr ~ (CDC13) 1.42 (1 lH, m, CH2x4, CH3), 2.55 (2H, t, J=7.6Hz, CH2Ph), 2.84,2.90 (lH, dd, J=l.9, 15.2Hz, H3), 3.03 (lH, m, 1 of NCH2), 3.26, 3.32 (lH, dd, J= 5,
15.2Hz, H3), 3.40 (5H, m, CH20CH2,1 of NC_2)~ 3.85 (2H, s, C_2S), 4.36 (2H, q,
CH2O), 4.75 (lH, m, _4), 6.91-7.11 (4H, m, p-F-Ar-_), 7.39, 8.01 (4H, 2xd,
J=8.3Hz, Ar-H)
F~ c 349 1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4(4
~ x~ u~lbe~,yl~ulphinyl)-2-v~
Tr~tmPnt of 1-(2-(6-fluorophenyl)hexyloxy)ethyl)~(4-etho~y-;~L,onylbenzyl-
sulphinyl)-2-oxo~7Pti~linP (1.05g) with mCPBA (0.67g) following the method of
FY~mplP 302 gave, after chromatography and re-cryst~lli.c~tior-c, the title colllpou--d as
a g6:4 ratio of diastereoicomers 2: 1 as a colourless solid, m.p. 75-75~C, 25% yield
lH nmr ~ (CDC13) 1.42 (1 lH, m, CH2x4, C_3), 2.56 (2H, t, J=7.7Hz, CH2Ph), 2.63,2.69 (lH, dd, J=2.2, l5.1Hz, H3), 3.05, 3.10 (lH, dd, J= 5, 15.1Hz,_3), 3.37-3.73 (
6H, m, CH2OCH2, NCH2), 4.08 (2H, s, C_2SO), 4.36 (2H, q, CH2O), 4.54 (lH~
m, _4), 6.91-7.11 (4H, m, p-F-Ar-H), 7.38, 8.05 (4H, 2xd, J=8.3Hz, Ar-H)
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F~y~mple35o 1-(2~(6~(4El~ el,~l)hexyloxy)ethyl~4L~4
1)
The recryst~llic~tio~c of FY~mplP 349 also gave the title colll?oul,d as a 68:32 r~t;
of diastereoi.comP-rs as a colollrl~ss solid, m.p. 53-55~C, 12.5%yield
lH nmr (diastereoicrmpr 1)~ (CDC13) 1.42 (1 lH, m, C_2x4, C_3), 2.56 (2H, t,
J=7.7Hz, C_2Ph), 2.85, 2.90 (lH, dd, J=4.6, 14.6Hz, H3), 3.30-3.7 (7H, m, H3,
C_2OCH2, NCH2), 3.93 (2H, m, C_2SO), 4.36 (2H, q, CH2O), 4.53 (lH, m, H4),
6.91-7.11 (4H, m, p-F-Ar-H), 7.33, 8.05 (4H, 2xd, J=8.2Hz, Ar-_)
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R:ol~,;r~l Data
1. Screen for Lp-PLA2ir~ihi~
Enzyme activity was ~Iç~ d by m~cllring the rate of turnover of the
artificial substr~tç (A) at 37 ~C in SOmM HEPES (N-2-hy~ yt:~yll il~.,.i;..~-N'-2
lphonir acid) buffer co.~ g 1~0mM NaCl, pH 7.4.
~ ~ _O(CH2)9CH3
N~2~--~o_ O
--O ~o(cH2)2NMQ3
(A)
Assays were ~l~",~ed in 96 well titre plates.
Lp-PLA2 was partially purified by density gra~liPnt centrifugation of human
plasma. Active fractions were pooled and used as the source of Lp-PLA2. The
enzyme was pre-inc~lb~tP-d at 37 ~C with vehicle or test compound for 10 min in a total
volume of 180 ~11. The reaction was then initi~tçd by the a(l~ition of 20 ~Ll lOx
s~bstrat~ (A) to give a final snbstr~tP conrçntrati~n of 20 ~IM. The reaction was
followed at 40~ nm for 20 mimlt~s using a plate reader with -~lltom~tir mixing. The
rate of reaction was measured as the rate of change of abso,l,ance.
20 RPe~
The compounds according to the present invention are found to have IC~;o values in
the range 0.7-100.000 nM.
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