Note: Descriptions are shown in the official language in which they were submitted.
This application has been divided out of our co-pending
Applieation NoO 278,41Q.
That application relates to certa;n novel benzo~c~quinolines and
more particularly to l~9-dlhydroxyoctahydrobenz~l~}q~inoline~ ydrox~hexahydr
benzo[e~quinoline9~8H)-ones and l-hydroxy-tetrahydrobenzo~c~quinolines and
derivatives thereof useful as CNS agents, especially as analges;es and tran-
quilizers, as hy~otensives in mammals, includlng man, as agents for the treat-
ment of glaueoma and as diureties~ The present applleation relates to inter-
mediatas therefor, and to proeesses for -the preparation of the aforementioned
eompounds.
Ineluded among sueh aetive eompounds are compounds having the
formula~
A
Z-W : O . XX
wherein A is seleeted from the group consisting of:
~ I;, ~ II',
R4 ¦6
and the pharmaceutically acceptable acid-addit;on salts of the eompounds
wherein A is I' or II', wherein -O-alkylene-O- is alkylenedioxy having from
t~o to four carbon atomsS and wherein R, R~, R', R1, R2, R3~ R4, R53 R6, R7,
_~_
. .
;
.
Z and W ar~ as defln~d below. Some of -the a~ove compounds may also be de-
picted as shown in Formulae I, II, III~ :~V, V, VI and VII below.
An acceptable alterna-tive nomenclature ~or the her~in deæ-
cribed compounds of Formulae I-IV is based upon replacement of the root
"Benzo~c]quinoline" ~ith "phenanthrid;ne". Thus, ~ -trans-5,6,6a~,7,8,9-
10,lOao~,-octahydro-l-acetoxy-9~-hydro~cy-6~-methyl~3(5-phenyl-2-pen~yloxy`)-
benzo~c]quinoline becomes d,l-trans-5,6,6a~,7,8,9,10,10aa-octahydro-1-ace-
toxy-9~-hydroxy-6~-methyl-3-(5-phenyl-2-p~ntyloxy)phenanthridine~
Despite the current availability of a number of analges;c agent~,
the search foY naw and improved agents continues, thus poin-ting to the lack
of an agent useful for the control of broad leveIs of pain and accompanied
by a minimum of side-effects. The most commonly used agent, aspirin, is o~
no pract;cal value for the control of severe pa;n and is known to exh;bit
various undesirable s;de-e~fects. Other, more potent analgesic agents such
a~ d-propoxyphsne, codeine, and morphiDe~ possess addlctive liability. Tha
need for improved and potent analges;c agents is 9 therefore, ev;dent
The analgesic properties of 9-no~-9~hydroxyhexahydrocannabinol
a
and of other cannaboid structures, such as ~ -tetrahydrocannabinol ~Q -T~C~
a
an~ its primary metabolite, ll-hydroxy-~ -THC, have been reported by ~ilson
and ~ay, Absts D ~ Am. ChemD Soc D ~ 168 Meet~, MEDI 11 (1974), J MedO
Chem. 1~, 475-476 (1974), and J. Msd ChemO, 18, 700-703 (1975)D
V S. Patents 3,507,885 and 3,636,058, issued April 21, 1970 and
January 18, 1972, respectively, descr;be various 1-hydroxy-3-alkyl-6H-diben~o-
~b,dlpyran6 having at the 9-poeition substituents such ae: OXQ, hydrocarbyl,
and hydroxy or chloro, hydrocarbylidene, and intermediates thereforO
U~S. Patent 3,6495650, ;esued March 14, 1972, d;scloses 2 series
o~ tetrahydro-6,6,9-tr;alkyl-6H-d;benzo[b,d]pyran dar;vativee hav mg at tha
l-posit;on an ~-d;alkylam;noalkoxy ~roup aative ae psy~hothe~apeutic agentsO
German Speci~ica~;on 2,U51,934, p~bllshed ~ay 7, 1975, describe6
1,9-d;hydroxyhexahydrodibenzotb,d~pyrans and certain l-acyl der~vatives
thereof having at ~he 3-po6it;on an alkyl or alkylene group, as hypota~sivs,
--3--
~,
, ,: - , . ..
. . ~, ,
- ' ' ' , - . ' .
psychotropic~ sedative and analgesic agent~. The precur60 hexahydro-9H-
diben~o[b~d]p~ra~-9-ones used in their preparation, and which are reported
to have the s~me utility as the corresponding 9-hydroxy compounds, are de-
scribed in German Specification 2,451,932, published May 7, }975.
U.S. 3,856,821, issued December 24, :L974, describes a series o~
3-alXoxy substituted dibenzo[b,d]pyr&ns haYing anti~rthritia, antiin~lam-
matory a~d central ner~ous system acti~ity.
Bergel et al. 7 J. Chem. Soc,, 286-287 ~1943) inrestigated the re-
placement o~ the pentyl group at the 3-position o~ 7,8,9~}0-tetrahydro-3-
pentyl-6,6,9-trimethyl-6H-dib~n~oEb,d]pyrQn-l-ol by alkoxy (buto.xy,pentyl-
oxy, hexyloxy and octyloxy) and found that it led to biological i~activity.
The hexyloxy derivative was reported to exhib~t ~eoble ha~hish activity at
}O to 20 mg./kg~ The remaining ethers Yhowed no activity in do6es up to
20 mg./kg.
I~ ~ mora recent 6tudy, Loev et al., J. Med. Chem., 16, 1200-1206
(1973) report Q compariso~ of 7,8,9,10-tekrahydro-3-substituted-6,6~9-tri-
methyl-6H-dibenzo[b,d]pyran-l-ol~ in which the 3-subst1-tuont is -OCX(CE3)
C5Hll~ -CH2CH(CX3)C5Hll; or -CH(cH3)c5Hll. The ether side ch~in containin~
compound was 50% less active in oentral nervous system activity than the
-- 20 corresponding compound in which the ~lkyl side chain is direct}y ~ttached to
the aromatic ring, rather than through an intervening oxygen atom; and 5
~; times a~ acti~e as the compound in which oxygen is replaced by methyleneO
Hoo~s et al , J. Or~. Chem., 33, 2995-2996 (1968) describe the
preparation of the 5-aza analog of ~6a(la)-tetrahydrocannabinol re~erred
to therein as 7,8,9,10-tetrahy~ro-l-hydroxy-5,6,639-tetramethyl-3-n~pe~tyl-
- phenanthridine, but report no utility ~or the compound. Beil9 in "Psycho-
mimetic Drugs", edited by E~ron, R~ven Press, New York, 1970, page 336,
~;; reports the compound was "completely inert in anim~1 pharmacologyO"
Eardman et al., Proc. West. Ph~r=~col. Soc., 14, 1~-20 (1971)
reports some pharmacological activity ~or 7,8,9,10-tetrahydro~l-hydroxy-
~4-
,: :
6,659-~rimethyl-3-n-pentyl phenanthridine, a 5-a~a ~6 ~l)Q_tetrahydrocan_
~abinol~
Mechou}am and Edery in "MariJuanal', edited by Mechoulam, Academic
Press, New York, 1973, page 127, observe tha~ ma~or structural changes in
the tetr~hydrocannabinol molecule seem to resul-t in steep reductions in
anal~e~ic scti~ity.
'
:` ~ :~ :
::
~ : . .
~,
:: : : : : ::
'
', : :
,
Ii -5~
`
, ,~
66~
Paton, in Annual Revicw of ~ EC~ 15, 192 (1975) presents
generalizatlons on structure-act;on relat;onshi~s among cannabinoidsO The
presence of the gem dimethyl group m tha pyran r;ng ;s crltical for cannabin
oi~ activ;ty and substitution of N for 0 in the pyran ring removes ~ctivity,
According to the prasent invent;on there is provided a process
for the productlon of ;ntermed1a~es for use in the productio~ of the ~ct~ve;: :
compounds ment;oned above.
Accordingly the present invention prov;des a process for prepara-
t;on of a compound hav;ng the formulao
~ - Z-U ............................ III
where;n Ro ;s oxo or alkylened;oxy of two to four carbon atoms; Rl ;s hydrogen~
or an acyl group selected from benzoyl, alkanoyl hav;ng from one to five
carbon atoms or -C0-(CH2)p-NR2R3 where;n p is 0 or an integer~from l to 4;
each of R2 and R3 when taken ;ndlv;dually ;s the same or d;fferent and ;~
hydrogen or alkyl hav;ng from one to four carbon atoms; R2 and R3 when taken
together with the:n;trogen to whlch they are attaahed form a 5- or 6-membered
heterocycl;c r;ng, sa;d r;ng be;ng p;perid;no, pyrrolo, pyrrolld~no, morphol;no
or N-alkylpiperaz;no hav;ng from one to four carbon atoms m the alkyl group;
R4 ;s hydrogen, alkyl having from l to 6 aarbon atoms or -(CH~)z-C6H5 wherein
Z is an ;nteger from l to 4, R5 ;s hydrogen, methyl or cthyl; R6 ;s hydrogen,
formyl, alkanoyl hav;ng from two~to;f;ve carbon atoms, alkyl having from ~
one to s;x carbon atoms; -(CH2) -C6H5 wherein x ;s an ;nteger from l to 4, or
-Co(CH23 l-C6H5; Z is a1kylene hav;ng from one to n;ne carhon atoms, or
-~alk~)m-X-~alk2)n- whereln each of ~aIkl3 and (alk2~ is the same o~ d~fferent
and ;s alkylene hav;ng from one to nine carbon atoms, with the provlso that
the summat;on of carbon atoms ;n (alkl) plus ~alk2) ;s not greater than
`
, .
nine, each of m and n is o or 1, and x is o, S, SO or S02 3 and N is hydro-
~~ :
gen, methyl, pyr.l.dyl ~ Wl wherein Wl is hydrogen, ~luoro or chloro;
which comprises reacting a compound of the formula:
)1~ ORl
R7 ~ . .VII
CHO
wherein Rl is hydrogen, benzyl, methyl or ethyl,
R4, R5, Z and W are as de~ined above; a~d : :
R7 is hydrogen or formyl~ with a base, and ~h.n:required to
produ¢e a compound where Ro is alkylenedioxy ketalizing the compound obw
tained and when required to produae a aompound wherein Rl is other than
hydrogen es~erifying the product wherein Rl is hydrogen.
:
~ '
, .
~ .
' :
:
~ 7-
,,~ ~ ' .
.
Co~pounds having the Formulae I, II and III above contain
asymmetric centers at the 6a- and/or 10a-positions. There may be additional
asymmetric centers in the 3-posltion substituent (-Z-W~, and S-, 6- and 9-
positions. Diastereomers with the 9~-configuration are generally favored
over the 9~-isomers because of greater ~quantitatively) biological acti~ity.
For the same reason, the trans(6a,10a)dlastereomers of compounds of Formula
I are generally favored ~ver the cis ~6a,10a)diastereomers. As regards
compounds of Formula II when one of R4 and R5 is other than hydrogen, the
cis-diastereomers are preferred because of their greater biological activityO
~mong the enantiomers of a given compound, one will generally be favored
over the other and ~he racemate because of its greater activity. The
enantiomer; favored is determined by the procedures desaribed herein. For
example, the l-enantiomer of 5,6,6a~,7,8,9,10,10a~-octahydro-i~acetoxy 9~
659
hydroxy-6~ methyl-3-~5-phenyl-2-pentyloxy)benzo [c] quinoline is favored
over the d-enantîomer and the racemate because oE its greater analges;c
activity~ For convenience, -tha above formulae depict the r~cemic compounds.
However, the above formulae are considered to be generic to and embracive
of the racemic modifications of the aompounds o this invention, the
diastereomeric mixtures, the pure enantiomers and diastereomers thereof
The utility of the raq~mic mixtures, the diasteromeric m;xtures as well as
of the pure enantiomers and diastereomers is detarmined by the biological
evaluations described below.
.
,;
'
_9_
, ; .
6~
Intermediates of tha formulae:
0 OY H0 0 QY
R5~ 1
R6 (V) S R6 ~VI
and ~
~-W
5 1 8
R7 (VII)
wherein R4~ R5, R6 and Z-W are a defined above;
R7 is selected from the group consisting of hydrogen and formyl,
and
Y is selected from the group consisting of hydragen and
hydroxy protecting groups, particularly methyl, ethyl or benzyl are of u~e
in the production of the intermediat=s of the present invention.
Asymme~ric centers may exist in intermediates ~, VI, and
VII at the 2-position and in the 7-position substituent (-Z-W) and of course~
at other positions e.g. in th& l-position substituent. The 2- and 7-posi-
tions in Formulae V-VII correspond to the 6- and the 3-positions, respec-
tively, of compounds having Pormulae I, II, III and IV.
Favored, because of the greater biological activity of the
compounds of Formula I and II obtainable therefrom relative to that of other
compounds describad herein, are compounds wherein Ro is as defined above,
~ Rl is hydrogen or alkanoyl,
; ~ 20 R5 is hydrogen, methyl or ethyl,
and each of R4 and R6 is hydrogen or alkyl,
Z and W have the values shown below:
-10-
_ Z _ m n _ W
alkylene having from 5 ~o 9 - - H or CH
carbon atoms
alkylene having from 2 to 5 - - C H , 4-FC HL~ 4-
carbon atoms C~C6HL~, 4-pyrîdyl
-(alkl)m-0-(alk2)n 1 1 ~ C H , 4-FC H 4-
-(aLkl)m~0~(alk2~n lo 1 { H or CH3
1 0 { H or CH3
Preferred compounds have the trans-confîguratioD.
Especially preferred are those preferred compounds wherein:
Rl is hydrogen or ac~tyl
R5 is hydrogen;
R4 is methyl or propyl;
R6 is hydrogan, methyl or ethyl;
when Z is alkylene- having from 2 to 5 carbon atoms N ls
phenyl or 4-pyridyl;
when Z is -(alk1)m-0-(a1k2)n- wherein m is 0 and n ls~
~alk2)n is alkylene having from four to nine carbon atoms, W is hydroge~
or phenyl, and
when Z is alkylene having from five to nine carbon atoms,
is hydrogen.
. :
--11--
,
: ~ :
The compound~ ~f this invention of formula V are prepared from
appropriately sub6tituted anilines, e.g., 3-hydroxy-5-(Z-W-substituted)-
anilines (VIII) or derivatives thereof in which the 3-hydroxy group is pro-
tected by a group (Yl) easily removable to regenerate the hydroxy group.
S~it~bIe protectiyegroups are tho~e which do not inter~ere with su~sequent
reactions of said 3-(protected hydroxy)-5-sub3tituted anilines and which
can be removed under conditions which do not cause undesired reactions at
other sites of said compound or of products produced therefrom. Represen~
~ ative protective groups (Y ) are methyl, ethyl, benzyl, substituted benzyl
,,. 1
wherein the substituent is, for exampleg alkyl having ~rom 1 to 4 oarbon
atoms, halo ~Cl, ~r, F, I), and alkoxy having from one to four carbon atoms.
The exact chemical structure of the protectlng eroup is not
crltical to this invention since its importance resides in its abil~ty to
perform in the manner described above.
': 4 ~
The selection and identifi~cation o~ appropriate protecting groups
can easily and readily be made by one skilled in the art. The suitability
and effectivenes~ of a group as a hydroxy protecting group are det~rmined
by employing such a group in the above-illustrated reaction se~uence. It
should, therefore, be a group which is easily removed to permit restoration
of the hydroxy group60 Methyl ia favored as ~ protecting alkyl group slnce
it i8 easliy removed by treatment with pyridine hydrochlorlde. The ben~yl ~ ;
gr~up, also a ~avored protecting group, is removed by catalytic hydrogen-
olysis or acid hydrolysis.
- When Z is -(alkl)m-X-~alk2)~-, Yl ie preferably ben~yl or a sub-
stituted be~zyl group since it can subsequbntly be removed without detriment
to the Z group.
~ ~ The protected aniline deriv~tive (VIII) is then converted to a
- compound of f~rmula IX by known technolo~ a6 deecribed herein~
An abbreviated reaction se~uence (Flow Sheet A~ for preparing re-
presentative compounds of formula V beginning with a 3-(protected hydroxy)-
-12-
:' :
5~(Z-W-substituted)aniline (VIII) wherein -Z-W iB OC~3 is given below:
Flow Sheet A
3 R4-Q-CH2COO R~ ~ 3 COOR
I l HOAc
3 NH2 CH30 H
(VIII) \ R4R5C CH COOR I X (IX)
¦ \ R4-COCH2COOR ~ 2
\~ NaCN:E~H4
/ OCH3 0 (2) OH 5 ~ 3 COOR
/ ~ ~ (3) PPA r ~
1 0 1 1 < - i V
/ CH O ~ ~ ~ R4 CH3 ~ 7 R4
/ 3 COOC2H5 H (R5 ~ H
(V-A) / (X)
\ HBr--` / H3r-
\ /HOAcj ~ HOAc
OH O OH O
" ~ 0/ ~ ~4
(V-B) (V-C)
R in the above flow sheet represents alkyl havin~ from one to
six carbon atoms. (R5, :~or the purpose of illustra~ion in the over~11 Flow
Sheet, is represented a~ hydrogen. However~ in the sequence VIII ~ X or
VIII ~ V-B, R5 CQn be hydrogen, methyl or ethyl.)
10The 5-su~stituent of formula VIII compounds OQn be ~roup -Z~W
desired in compounds of formulae II or I, or a group readily con~ertible to
said group. When the Z moiety of group -Z-W is -(aIkl)m-X--~alk2)n-wherein
X is O or S and each of m and n is 0, the 5-substituent, ~hen W is hydrogen,
, iB -XH (i.e.~ ~H -~or ~$H3 . - :or a ~otecte~' -XE ~
group o~ ~he ~ormula -X~Yl ~h~erein ~ Yl i~ as
-13-
- . . . . :, : .
defined above. When, of course, -Z-W iB -(~lkl)m-X~(alk2)n-W wherein m
is 1, n i5 0 and W is hydrogen, the 5-substituent becomes ~(alkl)m-X-H.
The -XH group is advantageously protected in the m~nner described above.
The appropriate 3-hyaroxy-5~substituted anilines discussed above
are reacted, pre~erably in the form of derivatives in which the 3 hydroxy
group (and 5-hydroxy group i~ one is present) i9 protected Q9 mentioned
abo~e in order to achieve satisfactory reactions, with an alk~ ketoester~
e~g., an alXyl acetoacetate, in the presence of acetic acid to provide the
correspondin~ ~[(3-protected hydroxy)-5-sub6tituted a~ilino)-~(R~)-acryl-
; 10 ate (IX). The reactio~ is generally conducted in a reaction-inert solvent
such as benzene or toluene at temperatures of from about 50C. to the reflux
temperature of the solvent under conditions ~hich result in removal of by-
product w~ter. Benzene and toluene are efficisnt ~olvents when the reaction
is conducted at the reflux temperature, since they permit ~zeotropic removal
o~ by-product water. Other means of water removal - or effective removal
water - such as molecular seives can be employed, as can ~ther solvents
which permit azeotropic removal of water~
Favored protecting groups for the 3-hydroxy-5-substituted anlline
reactants are methyl, ethyl and benzyl groups slnce the ethers are easily
prepared, afford satisfactory yields of compounds of formul~e IX and X and
are co~venientl~ removed.
The alkyl ~-ketoester, preferably one in which the alkyl group has
from one to 5iX carb~n atoms, is generally used in excess to insure maximum
conversion~ o~ th~ aniline reactant to the corresponding ~lkyl ~-anilino-
~-~R4)-acr~late tIx). Ten to twenty percent excess of ~lXyl ~-ketoester is
usually sufficient to achieve satisfactory conver~ions. Acetic acid is
used in catalytic amounts to facilitate reaction.
The alkyl ~-anilino~ R~-acrylate (IX) is then reduced to the
corrsspondine alkyl-3-[(3-protected hydroxy)-5-substituted anilino]-3-(R4)-
~; 30 propionate (X) by, for example, sodium borohydride-acetic acid an~ catalytic
' . :' . . --1~--
/:.1
hydrogenationD A preferred cataJ.yst is platinum dioxide since it conven-
iently perm~ts the reaction to be carried out at low pressures, i~eO, at
pressures under 50 p.9.i. Other catalysts such as noble metals, e.g.,
pl~tinum, pall~dium, rhodium, supported or un3upported, c~n be used along
with pressures of`hydrogen ranging from about atmospheric to superatmospheric,
e.g., 2000 p~soi~ In addition to such catalysts which are heterogeneous
catalysts, this step can be carried out using homogeneous catalysts such as
Wilkinson's catal~st,tris-(triphenylphosphine)chlororhodium(I).
; Of course, when the ~rotecting group or groupq are benzyl or sub-
stituted bynzyl, catalytic hydrogenation will re~ult in their removal. For
this re~son, methyl or ethyl groups are preferrea as protecting groups ~or
the 3- and/or 5-hydroxy eroups of formul~ VIII reactants.
Alternatively, compounds of formula X can be prepared directly
from compounds o~ formula VIII by reaction o~ formula VIII compounds with
an alkyl 3,3-R~R5-acrylate in acetic acid. The reaction is conveniently ;-
carried out by reacting equimolar quantities of the alkyl 3,3-R4R5-acrylate
and disubstituted aniline ~VIII) in from 0.1 to 2 equivalents o~ glacial
; acetic acid at temperatures ranging from 0C. to the reflux temperatureO
Alternatirely, compounds of ~ormula V-B may be prepared dlrectly
by condensation of equimolar ~uantities of VIII wlth the appropriate substi-
tuted acrylic acid (R4R5C=CH-COOH) in pyridine hydrochloride at 150-200Co
In ~ddition, when the R4,R5 groups are both alkyl, treatment o~
VIII and the alkyl R4,R5 acrylate in a reaction-inert solvent, e.g. tetra-
h~dro~uran, ~ith mercuric acetate followed by reduction with sodium boro-
hydride give6 X~
Dlrect conversion of compounds of formula VIII to compounds offormula X is also convenientl~ achieved by treating a 3,5-(diprotected
hydroxy)-aniline hydrochloride with an excess o~ an alkyl acetoacetate, e.g.
ethyl acetoacetate, in the presence o~ sodium cyQnoborohydride in a solvent
such as methanol.
-15-
;~
The alkyl 3-anilino-3-(R~ propionate (X) iB then cycllzed to the
corresponding 2-(R4) quinolin-4`one (fo~nula V~A or -B) by means o~ a suit-
able cycli7ing agent such as polypho6phoric acid (PPA), hydrogen bromide-
acetic acid, sulfuric acid, oleum (fuming sulfuric aci~)~ hydrogen flouride,
triflouroacetic acid, phosphoric acid-formic acid and others known to those
skilled in the art. In a modification of this conversion, the alkyl 3-anilino-
3-(R~ propionate (X) can be converted to the correqponding scid by, for
example, saponi~icRtion of the ester followe~ by acidification~ prior to
cyclization.
The ether protecting, or blocking, group~ on the 3-~and 5-)hydrox~
groups can be removed &t the time of cycli~ation through the use of hydro-
bromic acid in acetic acid as cycliæing agent and deblocking agent. Hydro-
bromic acid 48~ aqueous, i~ generally uæed since it Qffords satis~actory
cycliæation and debloc~ing. The reaction i~ conducted at elevated temper-
atures and desirably at the ref`lux temperature. However, when Z is -(alkl)m-
X-(alk2) ~ cyclization condition such as polyphosph~ric acid or trifluoro-
acetic acid must be used to avoid cleavage of the ether or thioether linkageO
Altern~tively, the protecting group (or groups) can be removed sub-
sequent to the cylcization reactionO Hydrobromic acid-acetic acid is also
a favored agent for deblocking at this stage of the overall 6ynthesls~ The
reaction is carried out as described ~bove.
Other reagents such as hydriodic acid, pyridine hydrochloride or
hydrobr~mide can be used to remove protecting ether groups such as methyl
and ethyl groups. When the protecting group6 are benzyl or substituted benzyl
groups, they can be removed by catalytic hydro~enolysis. Suitable cat~ly~ts
are palladium or platinum, especially when suppor~ed on carbon~ Alterna-
tively they can be re~oved by solovoly6i6 using trifluoroacetic acid~ Of
eourse, when group -Z-W contains sulfur, acid deben~ylation is used rather
than catalytic debenzylationO
A favored methoa for the trans~ormation o~ compounds o~ Formula X
-16-
~1 .
to compo~mds o~ Formula V which affords satis~actory yiel~s and permits use
of relatively mild conaitions comprises conversion of Formula X compounds to
~-carbalkoxy derivatives wherein the N-carbalkoxy group has from two to five
: carbon atoms by reaction with the appropriate alk~l or benzyl chloro~ormate~
; 5 The N-carbalkoxy or carbobenzyloxy derivative of Formula X is then cyclized
by means of a polyphosphoric acid to the corresponding N-carbalkoxy or carbo-
benzyloxy derivative of Formula V compounds ~'he N-substituted derlvatives
of Formula X compounds can, if desired, be hydrolyzed. to the corresponding
3-[(N-substituted)-3-(protected hydroxy)-5-substituted anilino}-3-(R~
propionic aci.d prior to cyclization. Polyphosphoric acid generally produces
maximum cyclization and.is a preferred oyclizing agent.
Compounds of Formula V in which the hydroxy ~roup or groups are
protected and in which the nitrogen atom is substituted with carbalkoxy are
treated with hydrobromic acid-acetic acid to give compounds of Formula V-Ao
When the hydroxy protecting group or groups are benzyl or ~ubsti-tuted benzyl9
regeneration of the hydroxy groups is aocomplished by catelytic hydroge~olys~sO
A carbalkoxy group if present on the nitrogen atom is unchanged by this re-
actionO It can, if desired, be subseguently removed by treatment with hydro-
bromic acid-acetic acid or any o~ a veriety of acids or basesD Removal of
20 the benzyl protecting group by treatment with trifluoroacetic acid also
removes any ~-carbalkoxy group present.
When the -Z-W substituent of Formula V compounds is -XH (X ~ O or S),
and it is desired to h~ve said -Z-W substituent represent, in compaunds of
.~ Formulae II or I, a group -X-(alk2~ -W wherein X is O, S, SO or 92' and W
is as previous}y defined, conversion of group -XH to group -X-(alk2)n-W is
convenientl~ and advantageousl~ undertaken at this ~oint in the overall
reaction se~uenceO Thus, the 7-XH group of For~ula V~B above representea,
for the~purposes of illustratlon, as -OH, i8 transformed by the William:on
;~ reaction with the appropriate bromide ~Br-(alk2 ~W], mesylate or tcsylate,
to group -0-(alk2)n-W (Formula V-C)~
-17-
.
; i `
6~
Similarly, when group -Z-W of Formula V is -(alkl)-X-H, its con~
version to -(alkl)-X-(alk2)n-W wherein n is O or 1 and W iB other than
hydrogen is conveniently undertQker~ at this stage of the reaction sequence
via the Willia~son reaction.
A v~riety o~ groups, such as thos~ included wlthin the de~inition
of R6, can be used in place of carbalkoxy or carbobenzyloxy in this f~vored
method to mask the nitrogen ag~inst protonation.
Group R6~ if not already pr~sent in compounds o~ Formulae V-A,
V-B or V-C, can be introduced prior to formation of the hydroxymethylene
derivative (Formula V1~by reaction with the appro~riate Cl~R6 or Br~R6
reactant according to known procedures. Of courae, when Rn acyl, e.g.g
acetyl group R6 is desired in products of Formulae I or II, such groups are
generally introduced at that point in the reaction sequence (Flow Sheet B)
following formation of Formula II compounds wherein R6 is hydrogen, e.g., by
acylatlon with the appropriate acyl halide according to known procedures.
Compounds of Formula V and, of course3 of Formulae V~A, V-B and
V-C, are converted by the following illustrRtive se~uence (Flow Sheet B) to
representative compounds of Formulae II and I (R5 - H in the illustration~O ~
:
~ ~ :
::
' : ~ : ~ '
, :'
-18-
~i
:
:~.~3'a;1~6~
Flow Shee-t 3
OH O OH O OH
~ 1 ~}IIX~L
(V) H R4 CHO (VI)
CH -CO-CH-CH2
O O Bas3e, CH30H
'~ L~ L.l'
~ R4 7 z w 4 CHO Z-W ~
~ (III) (VII:~ E ~ 1,3-bis~ormyl
.~ ~i/NH3 derivative (VII-A)~
',
> ~ W
H H
(II) [~ cis isomer] / tI)
The quinolines of Formula V are converted to hydroxymethylene deri-
. ~
atives of Formula VI by reaction with ethyl formate and sodium hydride.
m is reaction, a ~ormyl~tion reaction, produoes the ~is ~ormulated derivative
(VI) in excellent y1eld. Treatment of the ~ls-form~lated derivative with
meth~l -vinyl ketone gives a mixture of the corresponding mono-N-formylated
, 10 Michael adduct (VII) ~nd 1,3-bis-formylated Michael-Qdduct. The two pro-
; ducts are conveniently separated by colum~ chromatogra~hy on silica gelO
; : :
~he conversion of compounds o~ Formul~ VII to compounds o~ ~ormu-
.'. 19
'~ ~
- . :
. . : . - -
la III i3 achieved by an aldol condensation of the mono-~T-~ormyl compound
o~ Formula VII. The 1,3-bis-formylated Michael aaduct when sub~ected to
the aldol condensation produces a spiro-annelation product (III-A) as the
ma~or product. However, VII-A can be converted to VII by treatment with
an equivalent of
R CH0 Z-W R H Z-W
(VII-A) (III-A)
potassium carbonate in meth~nol~
In addition to the spiro-annelation product, small amounts of the
desired enone (Formula III) and (V) are also produced.
The enone o~ Formula III is converted by Birch reduction to the
compound of Formula II~ Both the cis- and trans-isomers are produced. This
reduction is conveniently carried out using lithiu~ as the metal~ Sodium
or potassium can also be used. ~he reaction i~ conducted at a temperature
of ~rom about -35C. to about -80C The Birch reduction is ~vored because
it o~fers stereoselectivity resulting in formation o~ the desired trans-
ketone of Formula II as the ma~or product. Catalytic reduction over a noble
metal is ~avored when the cis-diastereomers are desired as the maJor product.
; The hydroxy ketones of Formula II (compounds wherein Ro is oxo and
Rl is hydrog~n) and ~ ) appear
to be rather unstable. Upon standin~ they undergo oxidation as evidenced
by formation of purple to red colors. Form~tion of the colored by-products
occurs even when the hydroxy ketone is subJected to sodium borohydride re-
duction~ It has been found that ~ormation o~ the colored by-products can
be prevented by acylation, particularly acetylation, o~ the l-hydroxyl
--~0--
36~
group (ORl) with acetic anhydride in pyridine, and_b~ fo mation of acid
addition salt6~ e.g.l_~ydrochlorides. ~he acetyl derlvatlves are stable
upon standing and even when subJected to further reaction~
I'he aforesaid colored by-products are believ~d to have a ~uinonoid
structure arising ~rom oxidation of the l-hydroxy group (ORl) to oxo and
introduction of a second oxo group at the 2- or the 4-positlon. q'he by-
products are themselves active as C~S agents, especially as an ~gesics and
tran~uilizers, and as hypotensives, and ~re uaed in the same manner and at
the same dosage le~els as are com~ounds o~rForn~l~e~I~ana.II.
Reduction of the 9-oxo group of compounds of Formula II, and
preferably for reasons o~ stability ~entioned above3 of the acetylated de-
rivative of Formula II, vla metal hydride reduction af~ords compounds of
Formula I wherein the hydroxyl group at the l-position is present as its
acetylated derivativq. Sodium borohydride iB ~avored as reducing agent
; 15 in this step since it not only a~ords satis~actory yield~ o~ the desired
product, but retains the acetoxy group at the l-position, and reacts slowly
enough with hydroxylic solvents (methanol, ethanoI,~wàter) to permit their~ ~ ;
use as solvents. h temperature of from about 0G. to about 30C. is gener3l
ly used. Lower temperatures, even down to about -7GC., can be used to ~ ;~
:
~ ~ 20 increaqe selectivity o~ the reduction. Higher temperatûres cause reaction
~ : :
o~ the sodium borohydride with the hydroxylic solvent and deacety}ation. If
hi~her temperatures ~re desired, or required ~or a given reduction, i80-
propyl alcohol or the dimethyl ether o~ diethylene ~lycol are used as sol-
vente. A preferred reducih6 a6ent is potassium tr1-sec-butyl borohydride
sin~e it f~vors stereoss1eotive formation of the 9~ hydroxy group. The
reduction is conducted in dry tetrahydro~uran at a temperature below about
50C. usine aQuimolsr qua~tities o~;the 9-oxo compound and reducing agentc
Reducing agents~such as lithium borohydride or lithium aluminum
hyaride require anhydrous conditions and non-hydroxylic solvents, such as
1,2-dimsthoxyethanel tetrahydro~an, ether, dimethyl ether sf ethylene
-21-
. ~ . . . ,., , : .
glycol.
Alternately, and more desir~bly, compounds o~ Formula III, es~
pecially those w~ereln the 1-hydroxy group is protected as an ester or benzyl
ether, are converted to compounds of Formula I by catalytic hydrogenation.
A convenient procedure com~rises catalytic hydrogenation over palladium, e.g.
palladium-on-carbon, or other noble metal, supported or unsupportedO
The acetylated derivatives o~ Formula I thus produced are co~vert-
ed to the correspDnding hydroxy deriva~ives by ~lea~age of the acetyl group
by standard methods.
~, 10 The isomeric 9-a- and 9-~-hydroxy compounds having Formula I are
produced in the above-described reducing steps. Treatment of the Leto com-
pounds of Formulae II-IV with the appropri~te alkylene gl~col or alkylene
dithiol having two to four carbon atoms in the presence o~ a dehydrat~ng
agent such as p toluenesulfonic acid, or other acid, used in ketalization
(oxalic, adipic), a~fords the corresponding ketals or thloketals (Fahrenholtz
et al., J0 Am~ Chem. Soc., ô~, 5934 [1967J)~
Compounds of Formula I wherein R is hydroxymethyl are prepared
via the Wittig reaction of the corresponding 9-oxo compound of Formula II
wlth methylenetriphenylphosphorane or other approprlate methylide. The
reaction is conducted under relatively mild conditions to produce the corre-
sponding 9 methylene compound. Hydroboration-oxidation of the 9-methylene
compound then a~ords the hydroxymethyl derivative. Borane in tetrahydro-
furan ia ~avored ~or the hydroboration step since it is commerically arail-
abl0 and gives satisfaotory yields of the desired hydroxymethyl compound.
The reaction iB generally conducted in tetrahydro~uran or diethylene glycol
dimethyl ether (diglyme). ~he borane product is not isolated but is directly
oxidized with alkaline hydrogen peroxide to the hydroxymethyl compound.
Compounds of Formulae I and II, lncludlng those wherein each of R4
and R5 i8 alkyl, are also prepared by the sequence o~ Flow Sheet C below:
-22-
....
~ . .
Flow Sheet C
~ oAo
ket~liz~:tion_ ~
H III (R4 ~ R5 ~ H) N Z~W
H IIA
r~ ~ +
Z-W
Li lFt6X III B IV-A
A ~ / \
~'/0 R6III-CR51,i 1(R6 - H) IV-B
5 J~ OH ~ oAo
~-W ~
. ~ R5 N Z-W
I'l-A
X Z-W ,.
-23-
~:~ .
. _
~he first step o~ this sequence comprises conversion of' the pre-
viously described enones (Formula III, Flow Sheet B) to the correspo~ding
ketals by reaction with an appropriate al~ylene ~ly~ol (e.g., ethylene
glycol) in the presence of approximately equivalent amoUnts of' p~toluene-
5 sulfonic acid or other acid commonly used for ketal ~orm&tion as described
above in benzene with aæeotropic removal of waterD A mixture of two ketals
is obtained; II-A, the reduced form, and IV-A, the oxidized form0 Formation
of IV-A is farored by addition of aeents such ~s air, Pd/C, sulf~r or 2~3-
dichloro-5,6-dicyanobenzoquinone to the reaction mixture. ~he exclusion o~
10 oxidizing aeents ~rom the reaction mixture or the addltion of reducin~ aeents to the reaction mixture favors formation of II-A.
Deketali:zation of Formulae II-A and IV-A compounds by procedures
known to those skilled in the art affords compound~ o~ Formulae II and IV.
These latter compounds are.then converted to compounds of Formul~e I and IV
15 by the procedure~s of Flow Sheet Bo
~he reduced Formul& II-A compounds are o~idized (dehydrogen~ted)
. by a variety of oxidants, including i~dine, by standard techniques to pro-
~duce Formula IV-A compoundsO
The heteroaromatic system~of compound~ o~ FormNla:IV-~ r adily :
~ adds organometallic reagents to the~azometbine bondO 0rganol:ithium~reaeents,
eDgO meth~1 and ethyl lithium~ re&ct with IV-A to~produce adducts o~ Formula ~:~
III-Bo 0xidation~of the thus-formed adduct by various oxidizing agents, con-
::
; reniently air, arom&tizes the adduct to give~Formula IV-B substituted ~n
the 6-position~ Further reaction o~ the 6-substituted IV-B compounds with
25 organolithium rea6ents affQrds:the 6,6-disub:tituted produots o~ Formul.a ; -~
B~
he~addltion of t4e aecond group (R5) to the 6-position, partiou-
larly when R5 is larger than methyl, is facilitated by activation o~ the:
:l azomethine bond by quaterniz&tion. Aotivation is conveniently achiered by
30~ reaction of Formula III-B with~an alkyl halide ~e0gO methyl or ethyl iodide),
-.
: : -24-
'
.:
`:
or an aralkyl halide~ desirably an aralkyl bromide [C6H5(CH2)XB] such as
benzyl bromide to gîve Form~la III-C compounds substitutea in the 5-position.
The thus-actlvated compounds read-lly re~ct w1th an excess o~ -
organolithium or Gri~nardreagents (se~ Hoops, et al., JO ~. Chem., 33,
2995-6, 1968~ to provide trisubstituted Formul~ B compounds~ E~drolysis
o~ the ket~ls of Formulae II-B and III~C ~f~ords the corresponding enones
which are converted to Formulae II and I compounds by procedures described
above. 0~ course~ ~hen R6 ~ Formulae III or III-C compounds is benzyl,
lithium-Q~monia reduction of the enone also cle~ves the ben~yl group.
A further procedure for introduction o~ alkyl groups at the 6-
position with ultim~te production o~ compounds of Formulae I and II is that
Or Flow Sheet D:
'
~ : -
.
-25-
:,
'~ .
Flow Sheet D
.
r~ ~
O O O O
OH
Z-W l~.~Z-W
¦R61X Il-~ ¦R6~X
I~ /--\
0~ ~ I
R6 ~ R6 ~ IV~^E
x ~ R~MgX / 4~gX
~ ~ ~ ' ~/
0~"~0
114~Z_W
III ~ 5
6 I}-B
''
.
'
~26
'
,
$~q9
The 6-oxohexahydrobenzo~c]quinolines of Formulae IV~C and IV-E are
prepared from compounds of Formula IV-A and IV-D by reacting them w~th sodium
or potassium hydroxide at elavated temperatures, eOgO at about 200-300C.
Quaternization o~ the nitrogen of IV-A, by reacting IV-A with methyl or
ethyI iodide, benzyl bromide or other aralkyl halide~ permits the reaction
with sodium or potassium hydroxide to be carried out under milder conditions.
The intermediate adduct formed is easily oxidized with mild oxidizing agents,
including air, to the oxo compound of Formula IV-E but which, of cour~e,
as a result of the ~uaternization reaction, bears a substituent (methyl,
ethyl, aralkyl) on the nitroge~ atomO
An alternative procedure comprises treating IV-A with a perac;d,
eOgO m-chloroperbenzoic acid, peracetic, to ~orm the corresponding N ox~de
which iB then reacted with acetic anhydride in an N-oxide rearrangement to
give IV-C (~oekelheide Rearrangement). Other methods known to those skilled
in the art can be used for the conversion of N-oxide~ bo lactams.
Compounds of Formula IV C or IV-E are then treated with an excess
.
of appropriate Grignard reagent, e g. methyl or ethyl magnesium bromlde9 to
give the corre~ponding 6,6-dialkyl compound II~
., :
The 3-hydroxy-5-(Z-W-substituted)anilines 2re prepared from
corresponding S-(Z-W-substituted~resorcinols via the Bucherer Reaction which
comprises reacting the appropriate 5-(Z-W-substituted)resorcinol with agueous
ammonium sul~ite or bisul~ite. The reaction is conduQted in an autoclave
at elevated temperatures, e.g. from about 150 to about 230C. The aniline
product is isolated by acidifying the cooled re~ction mixture and extractlng
the acid mixture with, for example, ethyl ace-tate. r~he acid solution is
neutralized and extracted with a suitable solvent, eOg. chloroform, to re-
cover the aniline product. Alternatively, t~ an~line prodùct ~5 ~olated
~y extractlng:t~e cooled reaction`mixture ~it~ an appropriate olvent ~ollow-
column;~hroma-tography of the crude product.
The 5-(Z-W-substituted)resorclnols, if not know~, are prepared
-27-
` ~
~rom 3,5-dihydroxybenzoic acid. The procedure comprises estar~in~ 3,5-
dihydroxybenzoic acid in ~hich the hydroxy groups are protected (eOg., ~s
methyl, ethyl or benzyl ethers)j or alternatively~ amidating the 3,5-[di(pro-
tected hydroxy)~-benzoic acid.
The overall abbreviated se~uence i9 illustrated belou (Flow Sheet E)~
P'lo~ Sheet P Y1
~ YlO~CO-Y2
HO COOH
(XI) / ~XF )
OH ~ 1 1
NO ~ Z-W Y O ~ ~C-Z~-U
(XIV) (XIII)
~1, .
OH
S N ~ Z-W
2 `
(VIII-A)
10 ~ The starting material, 3,5-dihydroxybenzoic acid XI is converted
to~a compound of Formula XII wherein Y2 repres.nts an alkoxy group, desirably
methoxy or ethoæy ~or ease o~ preparatlon, or an ~nino group; and Yl is a
hydroxy protecting grou~, by methods descr;bed in the literatureO
The diprotected benzoic ac;d derivative XII i8 then converted to
:
a compound of Formula XIV bg known technology. ~In one procedure XII ;s
hydrolyæed to the corresponding acid (Y2 ~ OH), or lith;~n ~alt, and reacted
with the appropriate alkyl lithlum to produce an alkyl d;su~stituted phenyl
~ keto~e (Y2 - alkyl)O When methyl l;th;~n is used, the result;ng acetophenone
;~ derivative is treated with a Grignard Reagent (W-Z'-MgBr). The intermediate
-28-
:;~
adduct is hydrolyzed to the corresponding alcohol which is then hydro-
genolyzed to replace the hydroxy group with hydrogen. This procedure is
especially useful for those compounds wherein Z is alkylene.
The ether groups are deblocked by suitable means: treatment
with pyridine hydrochloride (Yl = methyl) or catalytic hydrogenolysi~ (Y
benzyl), or by treatment with an acid such as trifluoroacetio acid, hydro-
chloric, hydrobromic or sulfuric acids. Acid debenzylation is, o~ course,
used when the group -Z-W contains sulfur.
A further method for converting compounds of Formula XII to those
of Formula XIV comprises reaction of a ketone o~ Formula XII (Y2 = alkyl)
with the appropriate triphenyl phosphonium bromide derivative ~(C6H5)3~-Z-W]
Br in the presence of a base (e.g., sodium hydride). ~he reaction proceeds
via an alkene which iB subsequently catalytic&lly hydrogen~ted to the cor
responding alkane (Z-W) and deblocked to the dihydroxy compound XI~. Of
çourse, when -Z- ls (alk])m-X-(alk2) and Y1 iB benzyl, the catalytic hydro
genation also results in cleavage o~ the benzyl e~hers.
Alternatively, conversion o~ structure XII compounds to those o~
structure XIV can be achievea by the se~uence XII ~ XIII XIV. In this
seguence, the diprotected benzamide (XIII,Y2 = NH2) is converted to the
ketone (XIII,Z' = Z less one CH2 group) by reaction with the appropria~e
Grigna~d reagent (BrMg_Z'-W) ~ollowed by reaction with methyl- or ethyl-
magnesium halide to ~orm the corresponding carbinol. Dehydration o~ the
; carbino1, e.g., with p toluenesul~onic acid, affords the corresponding alkene
which is then catalytically hydrogenated ~Pd/C) to the alkane (XIV). The
~ether group~ are deblocked (converted to hydroxy~ as descrlbed above.
When Z is alkylene, Yl is desirably alkyl having from one to ~our
carbon ~toms or benzyl. The funotion o~ group Yl is to protect the hydroxy
groups during subsequent reactions. It is its ability to per~orm a specific
~uncti~n; i.e., protection of the hydroxy ~roups, rather than its structure
which is important. The selection and identification of appropriate protect-
-29-
.. ....
ing groups can easily and re~dily be made by one skilled in the art. The
suitability and effectiveness of a group as a hydroxy protecting ~roup are
determined by employing such a group in the above-illustrated reaction
sequence. It should, therefore, be a group which is easily remo~ed to ~er-
mit restoration of the hydroxy grouRs. Methyl :Ls ~aYored as a protectingalkyl group since it is easily removed by treatment with pyridine hydro-
chloride The benzyl group, if used a9 a protecting group, i9 removed by
catalytic hydrogenolysis or acid hydrolysis.
( kl)m X (alk2)n-, Yl is preferably benzyl or a sub_
stituted benzyl group since it can subsequently be remo~ed without detrimen~
to the Z grot1p.
Formula VIII-A oompounds can, alternatively, be prepared from ~-
amino-5~hydroxybenzoic acids via the procedure o~ Flo~t Sheet F below.
Compound6 o~ Formula VIII-A wherei~ -Z W is -alkylene-W or ~(alkl)-
X'-(alk2)n-W ~herein (alkl), (alk2), W and n are as de~ined a~ove and X~ ls
; O or Sl are obtained by the followine se~uence (Flott Sheet F):
~ , .
.
.
-3o-
~i
. ~ .
`: . ' ~,, ", ~
. .
Flow Sheet F
(Ac - acetyl )
OY Y
1 1 1
~ (C6H5 ) P=CHCOOC2H~ ~ 4CH
AcNH C ~ AcNH CH 2~COOC2H5
~R " ~Y
R ' = X, alk~
AcNH Cl CH2H
- / R"
C H N /Tosyl \ PBr3
D~ 5 ~1 r:Lde `k~
( 2 )n (C6H5 ) 3P
AckH [~CH 2`CH2 Ac5HJ~J I ~ ~3S 5 9
aci~ w I !
. ~ R " -C- ( CH2, ~
OH O , ~.
AcnH~ w H llc~lH~\CH CH-C-~CH2)V-~
R" R "
(VIII-A)
-~ ~
~: '
_31-
~. .
~ : . . , . :
L~
The flrst step in the above sequence (the Wittig reaction) pro-
vides opportunity, by choice of appropriate re~ctants, to produce compounds
having straight or branched alkylene groups. 5'he amino group i8 protected
by acetylation according to standard procedures. In the ~iven illustration,
the value OI' R~ as methyl or ethyl permits formation of a compound having
alkyl substitution on the carbon atom (~) adJacent to the ph~nyl group.
Substitution of a methyl or ethyl group ~t other ~ites, eOe.~ the ~-carbon
atoms of the alkylene group, is achieved by cho;ce of the appropriate carbo-
alkoxy alkylidene triphenylphosphorane, e~g. (C6H5)3P~CR~ COOC2H5. The
unsaturated ester thus produced is reduced t~ the corresponding saturated
alcohol by reaction with lithium ~luminum hydride. ~he presence o~ a small
amount of aluminum chloride sometimes accelerate6 this reaction. Alterna~
tively, when Y1 is other than benzyl (e.g. methyl), the ~lcohol is produced
by catalytic reduction of the unsaturated ester using palladium-carbon, ~ol-
lowed by treatment of the saturated ester thus produced with lithium al-
umi~um hydride. Conversion of the alcohol to the correspondlng
tosylate or mesylate ~ollo~ed ~ alk~lat~on o~ ~t~e to~ylate
or mesylate wi-th an alkali metal ~alt ~o~ ~*~e~
appropriate HX'-(alk2)n-W reactant, and finally removal of the protecting
groups (Yl) a~fords the desired compound VIII-A. When X' is sulfur, the
protecting group Yl is methylO
A variation of the above sequence comprises bromination of the ;~
alcohol rather than converting it to a tosylate or mesylate. Phosphorou~
; tribromide is ~ convenient brominating agentO The bromo derivative is then
reacted with the appropriate HX'-(alk2) -W in the presence o~ a 6uitable
base (Williams3n reaction).
The bromo compounds also ~erve as valuable intermediates for
increasing the ehain length of the alkylene moiety ln the above sa~uenoe to
give compounds wherein Z is -al~ylene-W. The proce~s comprises treatin~ the
bromo derivative with triphenyl phosphine to produce the corresponding tri-
-32
.
phenylphosphonium bromide~ Reaction of the triphenylphosphonium bromlde
with the appropriate ~ldehyde or ketone in the presence o~ a ~ase such as
sodium hydrlde or n-butyl lithium affords a~ uns~turated derivative which
is then catalytically hydrogenated to the corre~sponding saturated compoundO
In this variation~ the value of the protecting group (Yl) selected
depends upon the particular seguence ~ollowedO When the verbical se~uence
on the right ia used, benzyl is the preferred protecting group by reason o~
~ the catalytlc hydrogenation step. ~ethyl is the preferred protecting group
- when the left vertic~l sequence is followed, since it is conveniently re-
moved by treatment with acid as aescribed herein
Compounds of Formula II wherein -Z-W is -(alkl)m-X-~alk2)n-W and
X is -SO- or -S02- are obtained by oxidatlon of the correspondine compounds
in which X is -S-. Hydro~en peroxide is a convenient agent for oxidRtion
of the thio ethers to sulfoxidesO Oxidation of the thio ethers to cor-
;
responding sulfones is conveniently accompliahed by means o~ a peraoid such
as perbenzoic~ perphthalic or m-chloroperbenzoic acid. This~latter p:racid
~ ls especially usefu} aince the~by-product~m-chlorobenzoic aoid la easily
;~ removedO
Estcrs of compounds of Formulae II - IV wherein Rl is alkanoyl or~
-CO-(CH2)p~R~R3 are readily prepared by reacting Formulae II ~ IV compou~d~
; with the appropriate alkanoic acid or acid of~Formula HOOC-(CH2)pN~2R3 in
th: presence of a condensing agent such as dicyclohexylcarbodiimideO AIter-
natively, they are ~repared by reaction of a Formula II - IV compou~d with
the appropriate alka~oic acid chloride or ~nhydride, e.g " ac:tyl ohloride
or acetic anhydride, in the presence of a bas: such as pyridine.
Esters of F~rmula I oompounds;in which each o~ the R and Rl group
is esterified ar: pr par:d by :cylation acoordin~ to the above~described
procedures. Compounds in which only the 9-hydroxy group i~ acyla~ed are ob-
tained by mild hydrolysis of the corresponding 1,9-diacyl derivative3 advan-
tage being taken of the greater ease of hyar~l~sis of the phenolic acyl eroupO
-33-
::
Formula I compounds in which only the l-hydrox~ group is esterl~ied are
obtained by borohydride reductlon of the corresponding Formula II ketone
esterified at the l~positionO The thus-produced Formula I compounds bear_
ing l-acyl-9-hydroxy substitution or l-hydroxy-9-acyl ~ubst;tut~on can then
be acylated f'urther with a diff'erent acylating agent to produce a diesteri~ied
compound of' Formula I in which the estsr group at the 1- an~ the 9-positions
are diff`erent.
The presence of a basic group in the ester moleb~ (OR~ the
compounds of` this i~vention permits f`ormation of` acid-additlon s~lts in~olv-
ing said basic group. When the herein described basic esters are preparedvia condensation of' the appropri&te amino acid hydrochloride (or other acid
addition salt) with the appropriate oompound of Formulae I - IV in the
presence of' a condensing agent, the hydrochlorlde aalt o~ the basic ester
is produced. Caref'ul neutraliz&tion af'f'ords the f'ree base. The f'ree base
f'orm can then be converted to other acid add;tion salts by known procedure6.
Acid addition salts~can, o~ course, as those skilled in the art
will recognize, be formed with the nltrogen of` the benzo[c]qui~noline system.
Such salts are prepared by standard procedures. The basic ester derivatives
are, of course, able to form mono- or di-acid addition salts because of
~ .
thair dibasic functiOnalitD0
$~ analge~ic properties o~ the comp~unds of this invention are
debermined by tests using thermal nociceptive 6timull, ~uch as the mouae tail~
flick procedure, or chemical nociceptive stimuli, such as measuring the abil-
ity of a compound to suppress phenylbenæoquinone irritant-induced writhing
: : `
in mice. These tests and others are described below.
~G
a) Mouse ~ot Plate Analgesic Testin~
The method used is modified a~ter Woolfe and MaaDonald, J. Phar-
:
macol. ~ . Ther., 80, 300-307 (1944). A controlled heat stimulus is ap-
,
~ 30 plied to the feet of mice on a l/8" thick aluminum plate. A 253 watt re-
: :
~34~
,.,:
L /~_,¦
8~
flector infrared heat l~mp is placed under the bottom of the alumlnum plate.
A thermal regulator, connected to thermistors on the plate sur~ace, progratns
the heat lamp to maintain a constant temperature of 57C. E~ch mouse i3
dropped into a glass cylinder ~6 1/2" diameter) resting on the hot plate,
and timing is begun when the animal's feet touch the plate. At 0.5 and 2
hours after treatment with the -test compound the mouse is observed for the
first "flicking" movements of one or both hind ~eet, or until 10 seconds
elapse without such movements. Morphine has an MPE5~=4-5.6 mg~/kg. (sOc.).
bl Mouse Tail Flick Anal ~sic Testi~
rrail ~lick testing in mice is modified after D'Amour and Smith, J.
Pharmacol. ~. Ther., 72, 74-79 (1941), using controlled high intensity
heat applied to the tail. Each mouse is placed in a snug fitting metal cyl-
inder, w1th the tail protruding through one end. r$his cylinder is arranged
so that the tail lies flat over a concealed heat lamp. At the onset of test-
ing, an aluminum flag over the latnp is drawn back, allowing the light beam
to pass through the slit and ~ocus onto the ena of the tail. A timer is
simultaneously activated. The latency of a sudden ~}ick of the tail is as-
certained. Untreated mice usually react within 3-4 seconds after exposure
to the lamp. The end point for protection is 1~ seconds. Each mouse is
tested at 0.5 and 2 hours after treatmen-t with morphine and the~test compouna.
Morphine has an MPE50 of 3.2-5.6 mg./kg. (s-c.)-
Test U _ g Chemical Nociceptive Stimul~Suppression of Phen~lbenzoquinone Ir _tant-Induced Writhi~
Groups of 5 Carworth Farms CF-1 mice a~e pretreated subcutaneouæl~
or orally with saline, morphine, codeine or the test compound. Twenty min-
utes (if tre~ted subcutaneously) or fift~ minutes (if treated orall~) later,
each group is treated with intraperitoneal inJection of phen~lbenzoQuinone,
an lrritant known to produce abdominQl contractions. The mice are observed
for 5 minutes for the presence or absenc& of writhing starting 5 minutes
after the in~ection of the irritant. MPE50's of the drug pretreatments in
-35-
blocking writhing are ascertained.
Results of the above tests ~re recorded as percent maximum pos-
sible ef~ect (% MPE). The % MPE of each group i6 6tatistically aompared to
the % MPE of the standard and the predrug co~trol v~lues. q'he % MPE is cal-
culated as follows:
MPE _ test time - control time x 100
cutoff time - control time
In the tables below, the a~slgesic activlty i6 reported ~n terms
of MPE50, the dose at which half o~ the ma~imal pos~ analge~ic e~e~t
is obaer~ed in a given test
The compounds of the present ~nvention are aat~ve ana1gesics via
oral and parenteral administration and are conveniently ad~inistered in com-
position form. Such compositionq include a pharmaceutical carrier selected
on the basis of the chosen route of administration ana standsrd pharmaceuti-
cal practice. For example, they may be administered in th~ form of table-ts,
pills, powders or granulea containing such excipients as starch, milk sugQr,
certain types of clay, etc. They may be administered in capsules, in ad-
mixtures with the same or equivalent excipients. ~hey m~y also be adminis-
tered in the form of oral suspensions, ~olutions, emulsions, syrups and
elixirs which may contain flavoring and coloring agents For oral ~dminis-
tration of the therapeutic agents of this invention, tablets or capsules con-
tainine from about 0.01 to about 100 mg. are suit~ble for most applications.
The physician will determine the dosage which will be most suit-
able for an individual patient and it will vary with the age, weight and
re6ponse of the particular patient~and the route of administration. General-
ly~ however, the initial analgesic dasage in adults may range fro~ 0.01 to
500 mg per day in single or divided doaes. In many in6tances3 it is not
necessar~ to ~xceed lOp mg. daily. The farored oral d~sage range is fr~m
about 0.01 to about 300 mg./day; the preferred range is from about 0.10 to
about 50 mg./da~. The favored parenteral do6e is from about 0.01 to about
100 mg,/d~y; the prefarrea ra~ge from about 0.01 to about 20 mg./day.
-36-
~ . . i
By means o~ the abov~ procedures, the anal~esic activity af several
compounds of this invQntion and of cert~in prior ~rt compaunds are determined.
The followin6 abbreviations are used in the t~ble6:
PBQ = phenylbenzoquinone-induced writhine; TF = tail flic~
HP = hot ~late.
-37-
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36~9
Their antihypertensive utility is determined by thelr ability to
lower the blood pressure of conscious hypertensive rats ~nd do~s a statis-
tically significant degree when administered orally to said hosts at khe
above-mentioned dosages.
Their tranquilizer activity is demonstrated by oral administration
to rats at doses of ~rom a~out 0~01 to 50 mg./kg. with subsequent decreases
in spontaneous motor activity. ~he daily dosage range in m~m~als is from
abou~ Q.Olto about lOO mg.
The use of these compounds for the trea~ment Or glaucoma is b~
lieved td be due to their ability to reduce intraocular pressure. Their
effects on intraocular pressure are deter~ined b~ test~ on dogs, The test
drug is instilled into the eye of Q dog in the form of Q solution or ls ad-
ministered sy~temically at various pèriods of time after which the eye is
anesthetized by instillation of tetracaine hydrochloride, l/2%, 2 drops. A
few minutes aPter this local anesthe6iQ, intraocular pressure readings are
taken with a Schiotz mechanical tonometer and, after fluorescein dye is ad-
ministered, with a Holberg hand application tonometer. The test arug is
convenlently used in a solution such ~s the following: test drug (l mgO),
ethanol (0.05 ~l~ ween 80 (polyoxyalkylene derivative of sorbitan mono-
oleate, available from Atlas po~der Co., Wilmington, Delaware 19899) (50 mgO)
and saline (to make l ml.), or in a more concentr~ted solution wherein the
ingredients are present in proportions of lO mg., 0.10 ml., lOO mgO and l ml.,
respectively. For human use, concentrations of drug from 0.01 mg./kg. to
lO mg./kg. are useful.
; 25 Their activit~ as diuretic agents is determined b~ the procedure
of Lipschitz et al., J. Pharmacol., 79, 97 (1943) which utilizes rats as the
test animals. The dosage range for this use is the same as that noted above
with respect to the uqe of the herein described compounds as analgesic
agents.
This in~ention also provides pharmaceutical compositions, includ-
-~2-
;
;
ing unit do~age forms, valuable for the uae o~ the herein described com-
pounds as anal~esics and other ut$1ities disclosed herein. The dosage form
may be given in æingle or multiple doses, as previously noted, to achieve the
daily dosage effective for a particular utility.
The compounds tdrugs) described herein can be ~ormulated for ad-
ministratio~ in solid or li~uid for~ ~or oral or ~arenteral administration.
Capsules containing drugs of this invention; i.e., compounds of Formulae I
or II are prepared by mixing one part by weight of drug with nine parts of
excipient such as starch or milk sugar and then loading the mixture înto
telescoping 2elatin capsules such that each capsule contains 100 parts of
the mixture. Tablets containing compounds o~ Formulae I or II are prepared
by compounding suitable mi~tures of drug and standard ingredients used in
preparing tablets, such as starch, binders and lubricants, such that each
tablet contains from Q.01 to 100 mg. of drug per tablet.
Suspensions and solutions of these drugs, particularly those where-
in Rl (Formulae I and II) is hydroxy, are generally prepared Just prior to
use in order to avoid problems of stab;lity of the drug (e.g. oxidation) or
- of suspensions or solution (eOgO precipitation) of the drug up on storage.
Compositions ~uitable for such are generally dry solid compositions which
are reconstituted for inJectable administration.
A mixture of 3,5-dimethoxyaniline (95.7 g., 0 624 mole), ethyl
acetoacetate (87.2 ml., o.670 mole), benzene (535 ml.) and glacial acetic
acid (3.3 ~1.) is refluxed for 15 hours under an at~osphere of nitrogen and
water collected by means of a Dean-Stark trapO The reaction mixture is cool-
ed to room temperature, decolorized with activated charcoal, filtered, and
then concentrated under reduced pressure to give the product, ethyl 3-[3,4-
~ ,~
`~ dimethoxy)anilino]-2-butenoate, as an oil (16807 ~.)0
A mixture o~ ethyl 3-(3,5-dimethoxyanilino)-2-butenoate (5.0 g.,
-43-
, --
.
18.7 mmole) in glacial acetic acid (42 n~.) and pla~inum oxide (250 mg.) ~s
hydrogenated in a Parr shaker at 50 p.s.i. for 105 hours. The reaction mix-
ture is filtered through filter-aid, ben~ene (50 ml.) added and the solution
concentrated under reduced pressure to an oil. The oil is taken up in chlo~o-
form, the solutlon washed successively wi~h saturated sodium bicarbonate
solution (2 x 50 ml.) and saturated sodium chloride solution. It is then
dried (MgS04), filtered and concentrated under reduc0d pressure to gire the
product as an oil (5.1 g.).
Repetition of the above procedure but using 168.7 g. of ethyl 3-
(3,5-dimethoxyanilino)-2-butenoate, glacial acetic acid (320 ml.) and
platlnum oxide (2.15 g.) gives 160.8 g. of product.
EXAMPLE 2
Ethyl dl-3-(3,5-Dimethoxyanilino)but~rate
To ~ solution of 3,5-dimethoxyaniline hydrochloride (370 g., 1.45
mole), reagent grade methanol (4.5 1.) and @thyl acetoaaetate (286.3 B.,
; 2.64 mole) in a 12 liter round bottom, 3 neck flask f;tted with methanical
stirrer and reflux condensor i8 added sodium cyanoborohydride (54 g., 0.73
mole) in one portion. After the refluxing subsides (10 minutes) the mlxture
is heated ona steam bath for an additional 20 minutes. To the cooled reaction
mixture is added addition~l sodium cyanoborohydride (5.4 e., 0.07 mole) and
ethyl acetoacetate (28.6 gt~ 0.26 mole) and the mixture refluxed for 30 min-
utes. This latter process is repe~ted once more.
The reaction mixture is isolated in portions by pouring
ca. 500 ml. onto 1 liter of ice-water/500 ml. methylene chloride, separating
the layers and backwashing the aqueous phase with additional methylene
chloride tlOO ml.). (This process is repeated usine 500 ml. portions until
the entire reactisn mixture i8 worked up.)
The methylene chloride layers are combined and dried (MgSOI~), de-
colorized with charcoal, filtered and evaporated to yield a yellsw colored
oil.
-44-
~`~
The excass ethyl acetoacetate iB distilled (at 130~C. oll b~th
temperature and 1-5 mm. pressure) lea~ing the crude eth~1 3-(3,5-dimethoxy-
anilino)butyr~te (an amber colored vlscous oil): 37G g, (72% yield) which
is u3ed without ~urther puri~ication.
It has the ~ollowing spectral char~cteri~tics:
H NMR ~60 MHz) ~CDCl (ppr~): 5082~6.0 (m,3H,aromatic), 4-20(~,2H,
ester meth~lene), 3.80-4.00(m~2H,-NH and -N-CH-CH3), 3.78 (s, 6H~ -OCH3),
2.40-2.55 (m,2X,-CH2COOEt), 1.78 (d,3H,mebh~}) ana 1.~9 ~t,3H,methyl).
EXAMPLE_3
~
Followin~ the procedure of Example 2, condensation of 3,5-dimethoxg-
aniline hydroçhloride and ethyl butyrylacetate gives ethyl d,l-3-(3,5-dimethoxy-anilino)bexanoate. It is converted to the hydrochloride salt by addition
of hydrogen chloride to a methylene chloride solution thereo~, m.p. 127-
; 15 129.5C Recrystallization ~rom cyclohexane/benzene (5:1) gives the analytic-
al sample, m.p. 126-128.5C.
Analysis~ C~lc'd for C16H2504~ HCl C, 57.91; H, 7.gO, N, 4.22%
Found: C, 57.89, H, 7.7~, ~ 7 4.40%
m/e - 295 (m )
H NMR (60 MHz) ~CDCl (ppm): 10076-11.48 (b, vari~ble, 2H, ~H2~)3
6.77 (d, J-2Hz, 2H, meta H's), 6.49, 6045 (d o~ d, J~2Hz, lH, meta X), 4008
~q, 2E, OCH2), 3.77 (s, 6H, [OCH3]2), ca. 305-4.8 (m, lH, CH-N), 2.go (t, 2H,
CH2-C=O), ca. 1.4-2.2 (m, 4H, [C~2]2), 1.21 (t, 3H, O-C-CH3), o.84 ~b, 3H,
-C-CH3).
EXAMPLE 4
d11-Ethyl 3-~(3,5-Dimethox~ ethoxyc~rbonyl)anilino}but~rate
Method A - ~~
Ethyl chloroformate (7104 ml. 0.75 mole) i~ added c~op~ise over a
45 minute period to a mixture of eth~l 3-(3,5~~;methoxy~nilino)butyrate
-45-
I A
6~
(159~8 g., 0 598 mole), methylene chloride (100 ml.), and pyridine (100 ml~,
1024 moles) at 0CO under a nitrogen atmosphere. The mixture is stirred ~or
40 minutes following addition of the ethyl chloroformate and is then poured
into a mixture of chloroform (,50 ml.) a~d ice-wat~r (500 ml.). trhe chloro
form layer is separated, washed successively with 10% hydrochloric acid (3 x
500 mlO),saturated a~ueous sodi~m bicarbon~te (1 x 300 ml.) and saturated
aqueous sodiwa chloride (1 x 400 ml~) and then ~ried ~MgS04). It is then
decolorized with activated charcoal and concentrated under reduced pres6ure
to an oil (215 g.). The product is used as is.
Meth
Under a positive nitrogen atmosphere a mixture of ethyl 3 (3,5-
dimethoxyanilino)butyrate (376 gO~ 1.4 mole), methylene chloride (104 liters)
and anhyarous potassium carbonate (388.8 g., 2.81 mole) is stirred and cool-
ed in an ice bath to 0 ~ 5C. Ethyl chloroformate (153 g., 1.41 mole) 1
added in one portionO The mixture is ~llowed to warm to room temperature
over a period of one hour, eth~l chloroformate (153 gO~ 1.41 mole) i5 added
once more and the mixture i5 refluxed on a steam bath for one hourO Ib is
then allowed to cool to rsom temperature and the potassium carbonate removed
by filtrationO The red colored filtrate iB washed ~uccessively with water
(2 x 1000 ml.), brine (1 x 500 ml.), drie~ (MgS04), and then decolorized
a~d evaporated under reduced pressure to afford 439 gO of crude product which
is used without further purificat;on.
H NMR (60 MXz) ~cMcsl (ppm): 6.2-6042 (m, 3H, aromatic), 4.65
(sextet, lH, -N-CH-, CH3), 4010-4.15 (2 quartets, 4H, ester methylenes),
3070 (s, 6H, -OCH3), 2033 2060 (m, 2H, -CH2COOEt), 1.00-1040(m, 9H, 3 methyl).
EXAMPLE_5
, .
Method A -
Ethyl 3-[(395-dimethoxy-N-ethoxycarbonyl)anilino]butyrate (202 ~.,
0.595 mole)3 a~ueous sodium hydroxide (595 ml. o~ lN) and eth~nol ~595 mlO)
-46-
~3 ,
,
. . ' . . :., ' .' : ~ ,.
~ . : , . .
6~3?
are combined and stirred at room temperature o~ernight. ~he reactlon mix-
ture is concentrated to about 600 ml. ~olume under reduced pressure, the
con~entrate diluted with water to 1200 ml~ vol~e and extracted with ethyl
acetate (3 x 75O ml.). The a~ueous l~yer is then acidi~ied with 10% hydro-
chloric acid to pH 2 and extracted a~ain with e!thyl acetate (3 x 750 ml.).
~hese latter extracts are combined, washed with brine, dried (MgSOI~), filter-
ed and concentrated in acuo to yield the title product as an oil (163,5 g.,
8802%).
Uethod ~ -
A 5 liter 3 neck, round bottom ~lask equipped with mechanical
stirrer and reflux condensor is charged with a solution of ethyl 3-~(3,5
dimethoxy-~-ethoxycarbonyl)anilino]-butyrate (439 g., 1.41 moles) in ethanol
(2 liters). Sodium hydroxide (2 liters o~ lN) is added and the mixture re-
Pluxed on Q steam bath ~or 3 hours. The reaction mixture is poured onto
5 liters of ice-water and extracted in one liter portions with diethyl~ether
(5O0 ml./portion). The aqueous layer is cooled by adding C&. one liter o~
ice and then acidified with concentrated hydrochloric acid (1.75 ml., 2.1
moles)O It is extracted in portions o~ one liter wlth mekh~lene chloride
(250 ml./portion). ~he methylene chloride layers are combined and dried
over magnesium sulfate, decolorized with charcoal and evaporated to dryness
to yield a viscous yellow oil. Crystallization ~rom ether/cyclohexane
(1:2) af~ords 224 g. (55.3~) of crystalline product, m.p. 78 80C. ~his
material is used withoub further purifications in the ~ollowing step.
H NMR (60 MH~) ~CDCl ~ppm): 6.24-6.53 (m, 3H, aromatic), 4.65
(sextet, lH, -N(CooC2X59CH(CX3)CH2Cooc2H5)~ 4.10 ~u~rtet, 2H~ es~er meth~lene),
3.78 (s, 6H, -oCH33, 2.40-2.60 (m, 2H, -CH2COOH), 1.18 (t~, 1.28 ~d, 6H, methyl),
10.8 (bs, variable,;lH~ COOHj.
MS (mol.ion) m/e - 311.
An analyticHl sample, obtained by recrystallization ~rom ethyl
acetate/hexane (1:5), melted at 89-91C.
-47-
Analysis: Calc'd for C15H2106~: C, 57.86, H, 6.80; N, 4.50%
Found: C, 58008; H, 6.65, N, 4.46%
EXAMPLE 6
d~ and 1-3[3,5-Dimethoxy-4-~-ethoxycarbonyl)-
_ _
A mixture of ~L~-3-[(3,5-dimethoxy-~-ethoxycarbonyl~anilino]
butyric acid (136.6 ~ " 0.44 mole) and l-ephedri~e (72.5 g., 0.44 ~ole) is
dissolved in methylene chloride (500 ~1.). The meth~le~ chlorlde is then
removed in vacuo t4 yield the l-ephedrine s~lt o~ d,l-3-[(3,5-dimethoxy-N-
~ 10 ethoxycarbo~yl)-anilino~utyric acid as an oil, [a]D5 ~ -20.0 (c~l.O~ CHC13)
; Addition o~ ether (1500 ml.) cau6es crystallization of a ~hite solid which
; is separated by filtration and dried (102 g.), m.p. 114-116C. Recrystal-
lization from ethyl acetate/hexane (1:1) a~fords 71.1 g. (34%) of the 1-
ephedrine salt of 1~3-[(3,5-dîmethoxy-N-ethoxycarbonyl)anilino~butyric acid;
m.p. 126-127C.
Analysls: Calc'd for C25H367N2 C~ 63.00, H, 7.61~ N, 5-88%
Found: C, 62.87, H, 7.64, N, 5i88%
[ ]25 43 5 ( 1 0 CHCl )
The l-ephedrine~salt of the l-isomer is stirred in a mi~ture o~
ethyl acetate (1000 ml.) and 10% hydrochloric acid (400 ml.) for ten ~inute6.
The organic phase is separated, washed with 10% hydrochl~ric acid (2 x 400
ml.), drled and conce~trated under reduced pressure to an oil. Crystalliza-
;;~ tion of the oil from ethyl acetate/hexane (400 ml. o~ 1:1) affQrds 34.6 g.
" ~ .
o~ 1-3-[(3,5-dimethoxy-~-ethox~carbonyl)anilino]butyric acid, m p. 96-97C.
Analysis Calc'd for C15H2106N: C, 5? ~6; H~ 6.80~ ~, 4-50%
Found: C, 57.90, H, 6.66, N, 4.45
[~]D5= -25.4 (c=l.0, GHC13).
The mother liquor remaining ~rom recrystallization o~ the 1-
ephedrine salt of the 1 isomer is treated ~ith hydrochlori~ acid as described
above to giYe crude d~3-[(3,5-dimethoxy-~-ethoxycarbo~yl)anilino~butyric
-48-
' ~
. . . . . . ,: . . .
acid. ~reatment of th~ crude acid with d-ephedrine af~ords, a~ter crystal-
lization ~rom ether, the d-ephedrine salt of the d-lsomer, m.p. 124-125C.
Analysis: Calc~d for C25H3607N2: C, 63.oo, H, 7.61; N, 5.ô8~
Found: C, 62.82; H, 7.47; N, 5.97%
[~]D5~ ~44 (c=l.O, CHC13).
The d-ephedrine salt is converted to a-3-[(3,5-dimetlloxy-~-ethoxy-
carbonyl)anilino~butyric acid in the same manner as described above for con-
version of the l-ephedrine salt to the free acid. M.p. 96-97C. after re-
crystalli~ation from ethyl acetate/hexane (3:5).
Analysis: Calc'd for C15H2106N: ~C, 57.86, H, 6,80; N, 4.50%
Found: C, 57.95; H, 6.575 ~, 4.35
[~]D5 ~ ~25.3 tc=l.O, CHC13).
EXAMæLE 7
Methyl 3-~3,5-Dimethoxyanilino~propionate
A mixture of 3,5-dimethoxyaniline (114.9 g., 0.75 mole~, methyl
acrylate (69.73 g., 0.81 mole) and ~lacial ~cetic acid (2 ml.) is refluxed
for 20 hours. Reflux is discontinued and the reaction mixture~is conceD-
trated ana then distilled in vacuo, to yield 106.8 g. (73.9%) of the title
product, b.p. 174-179C. (007 mm.).
~ ) CDC13 (ppm): 5.62-5 95 (m, 3E, aromatlc), 4.1
ariabIe, bs, lX, -~H), 3.74 (s, 6H, -OCH3), 3.68 (s, 3H, COOCH3), 3.41
and 2.59 (two 2H triplets, -NCH2CH2C02).
; EXAMPLE 8
A mixture o~ 3-hydroxy-5-(5-phenyl-2-pentyl)-aniline (1.0 g.),
methyl acrylate t345 mg.), and acetic acid (0.1 ml.) is heated ab 106-110C.
overni~ht. The cooled residue is dissolved in 100 ml. ethyl acetate and
washed twice with 100 ml of saturated sodium bicarbonate solution. The
or~anic phase is then dried (MgS04) and evaporat~d to a crude residue ~hich
is chromatographed on 130 ~. of silica gel using benzene-ether (2:1) as the
~ -49-
:
' :
- ~ . .
. . ..
.
eluant. After elution o~ less polar impuritiea, 540 mg. (40%), ~ -methyl
3-{[3-hydroxy-5-(5-phenyl-2-pentyl)]anilino}propionate is collected. It
has the following spectral characteristics:
) CDC13 (PP~): 7.14 (6~ 5EI, aro~atic), 5.83_6 13
(m, 3H, aromatic), 3.66 (s, 3H, -COOCH3), 3~37 (t, 2H, -~CX2), 2.16-2.78
(m, 5H, -CH2COO and benzylic), 1.28-1.69 (m, 4E, -(CH2)2~ 11 (d, 3~,
CH3), 4.4-5.2 and 1.28-2.78 (variable, lH, NH, OH).
m/e - 341 (m )
EXAMPL~ 9
~ ~' ~
Ethyl chloroformate (~.0 g., 8.4 mmole) i5 aaded dropwise over a
10 minute period to a mixture of methyl 3-(3,5-dimethoxyanilino)propionate
(1.0 ml., 10.5 mmole), methylene chloride (5 ml.) and pyridine (5 ml.) at
0C~ under a nitrogen atmosphere. The mixture i8 stirred ~t 0C. ~or 20
minutes following addition of the ethyl chloroformate and then at room
temperature ~or an additional 20 minutes, and is then poured into a mixture
of methylene chloride (75 ml.) and ice-water t50 ml.)~ The methyle~e chlor-
ide l~yer is separated, washed successively with 10% hydrochlorlc acid (2 x
50 ml.), saturated aqueous sodium bicarbonate tl x 30 ml.) and saturated
aqueous sodium chloride (1 x 40 ml.) and dried (M~S04). It is then decolor-
ized with activated charcoal and concentrated under reduced pressure to an
oil (2.72 g.), The product i9 used as i~.
EXAMP~E 10
3-~t3,5-Dimethoxy-N-ethoxycarbonyl~anilino~-
Meth~l 3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino~propionate t2072
g., 8.36 mmoles), aqueous sodium hydroxide ~8.4 ml. o~ lN) an~ eth~nol (8 4
ml.) are combined and ~tirred overnight under nitrogen at room temperature.
The reaction mixture i~ then concentratea under reduced pressure to hal~-
volume, diluted with water t35 ml.) and then extract~d with ethyl acetate.
_5o_
~. ~
The aqueous phase is acidified to pH 2 with 10% hydrochloric acid and ex-
tracted wlth methylene chloride (3 x 50 ml.). The com~ined extracts are
washed with brine, dried (MgS0l~) and concentrated to give the product as an
oil (2.47 g.) which is used as iso
EXAMPLE 11
; l-Carbethoxy-517-dimethox~-4--_xo- ~ tetrahyd_o~uinoline
A mixture of 3-~(3,5-dimethoxy-~-ethoxycQrbonyl)anllin~]propionic
ac~d (1 ~0 g." 3.7 mmole) and polyphosphoric acid (4 g.) is heated at 65C.
for 45 minutes under an atmosphere a~ nitrogen and is then cooled to 0C.
It is then taken up in a mixture of met~ylene chloride-water ~200 ~1. o~
1:1). The organic layer is separated and the agueous phase extraated again
with methylene chloride (2 x 100 ml.). The combined extracts are was~led
with saturated sodium bicarbonate (3 x 100 ml.), brin~ (1 x 100 ml.) and
then dried (MgS04). Concentr~tion o~ the dried extract ~ives the product
as an oil which crystallizes ~rom benzene. Yield ~ 645 mg., m.p, 109 111Co
~nalysis: Calc'd ~o~ C14H1705M: C, 60.21; H, 6.14j N, 5.02%
- ~ound: C, 6001}j H, 6.14; ~, 4080%
.
5~7-Dihy ~ -oxo-1,2,3~4-tetrah~droquinolirle
; 20 A mixture of glacial acetic acid (60 ml.), 48~ ~drobromic acid
(60 ml,) and 1-carbethoxy-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydroguinoline
(4.0 g., 14,3 mmole) is refluxed overnight and is then concentrated in vacuo
to a dark oil. The oil is dissolved in water (50 ml.) and the a~ueous solu-
; tion neutralized to pH 6-7 with lN odium hydroxide. A saturated solution
of salt water (50 ml.) is added and the resulting mixture extracted with
ethyl acetate (3 x 150 ml,). The extractsare c~mbined, dried (MgS0~ and
; concentr~ted under reduced pressure to an oil. The oil is taken u~ in
benzene-eth~l acetate (1:1) and the solution char~ed to a s:ilica gel column.
The column i6 eluted with a vDlume of benzene eaual to the ~olume o~ the
column and then with benzene-ethyl acetate (250 ml. of ~:1) and benzene-
-51-
ethyl acetate (250 ml. o~ 1:1). Fraction6 (75 ml.) are colleoted. Fractions
4-9 are combined and eYaporated under reduced pressure. ~he oily residue
is crystall~z~d rrom ethanol-hexane (1:10). Yield Q 1.86 g., m.p. 166-
169C.
Furtber recrystallization raises the melting pcint to 171-172.5C.
m/e - 179 (m )
Analysis: Calc'd for CgH903N C, 60033; H, 5.06, ~, 7 82%
Found: C, 60.25, H, 4.94, N, 7.55%
EX~MFL~ 13
~ -1-Carbethoxy-5,7-dimethoxy-2-methyl-4-o~o-1,2,3~4-
tetrahvdro~uinoline
A solution of 3-t[3,5-dimethoxy-~-ethoxycarbonyl)anilino]butyric
acid (4.0 g., 12.8 mmole) in chloroform (2 ml.) i8 added dropwise with stir-
ring to polyphosphoric acid t5,0 g~) heated to 60C. on a stèam bath. ~he
reaction mixture is held at 60-65C. ~or two hours ana is then poured into
a mixture of ice (100 g.) and ethyl acetate (100 ml.)0 The agueous layer
is fur-ther extracted with ethyl acetate (2 x 100 ml.) and the combined
; organic extracts washed successively with saturated sodium bicarbonate so-
lution (3 ~ 100 ml~), brine tl x loo ml.), and then dried over anhydrous
magnesium sul~ate. Concentration of the dried extract under reduced pre~sure
give6 2.6 ~. o~ crude product.
Purification is accomplished by column chromatography o~ a benzene
solution of the crude product (2.5 e . ) on silica gel (95 g.). The colu~n
is eluted with a volume of ben~ene e~ual to one-hal~ the volume of the
; 25 column, followed by benzene/ethyl acetate (1:1). `Fractions (40 ml.) are
collected. Fracti~ns 9-18 are combined and evaporated in vacuo to give 1.55 g.
of product which is purified ~urther by recrystallization from petroleum
ether-1.33 g., m.p. 92.5-94C.
; Recrystallization of this product ~rom hot ethyl acetate/hexane
~ 30 (1:1) affords ap a~alytical sample; m.p. 94-95C.
-52-
Analysis: Calc'd ~or C15H1~05N: C, 61042; H, 6.53; N, 4.78%
Found: C, 61 54; H, 605S; N, 4:.94
m/e - 293 (m )
IR ( KBr) - 5~85, 5.95 ~ 0)
EXAMPLE 14
~ ,3,1~-t~5~ Dy
Method A -
A mixture of glacial acetic acid (240 ml.), 48% hydrobromic acia
(240 ml.) and 1-carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-
quinoline (16.0 g., 55 mmole) is refluxed overnight and iB then concentrated
in vacuo to a dark oil. The oil is dissolved in ~ater (200 ml.) ~nd the
aqueous solution neutralized to pH 6_7 with 1~ soaium hydroxide. A satur~ted
solution of s~lt water (200 ml.) is added and the re~ultin~ mixture e~tracted
with ethyl acetate (3 x 500 ml.~. ~he ex~racts are combined, dried (MgS04)
and concentrated under reduaed pressure to a dark oil (12.8 g.). ~exane-
; ethyl acetata (10:1) is added to the oil and the resulting crystals recovered
by filtration (3.8 gO)~ mOp~ 158-165C. Trituration of the crystala in
ethyl acetate gives 1.65 gO of produat; m.p. 165-168C.
Additional material separates from the mother liQuors on standing
(209 g.), m.p. 168-170C. Column chromatography o~ the ~iltrate on silica
gel using benzene-~ther (1:1) as solvent eives an addition~l 4.6 g. of prod-
uct, m.p. 167-169C.
Further puri~ication is achieved by recrystallizing the product
from ethyl acetate; m.p. 17~-174C
Anal~iso Calc'd for ClOH113N Ca 62-16; H~ 5-74~ N~ 7 25%
Found. C, 62000j H, 5.83; N, 7.14%
m/e - 193 (m )
; Method B -
A mixture of ~ 3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino¦butyric
acid (100 g., 0.32 mole) and 48% hydrobromic acid (500 ml.)/glacial acetic
-53-
.
acid (300 ml.) i8 heated in an oil bath at 110~C. ~or 2 hours. The oil-
bath temperature is then increased to 145C. and heating is continued ror
an additional 2 hours. Durin~ this last heating period an azeotropic mix-
ture distills (boiling poinb 42 ~ 110C., ~200-300 ml.) and the deep-red
homogeneous solution is allowed to cool to room temperature. The mixture
is poured onto ice-water (3 llters) and ether (2 liters)~ the layer6 are
separated and the a~ueous solution is washed with ether (2 x 1000 ml.).
The ether layer~ are combined and washed successively with water (2 x 1000
ml.), brine (1 x 500 ml.), saturated NaHCO3 solution (4 x 250 ml.) and
brine (1 x 5O0 ml.) and then dried (MgSO~). Decolorization with charcoal
and e~aporation o~ the ether affords a yellow foam which i~ crystQllized
~rom ca. 300 ml. methylene chloride ~o give 31.3 g. (50.4% of pure 5,7-
dihydroxy-2-methyl 4-oxo-1,2,3,4-tetr~hydroquinol;ne. Additional product
can be isolated ~rom the mother li~uor by silica gel chromatogrQphy.
H NMR (60 MHz) ~ (100 mg. sampletO.3 ml. CDC13/0.2 ml. CD3COCD3)
(p~m): 12.40 (s,lH,C5-OH), 5~72 (d,2H,meta H), 5.38-5.63(bs,1H,C7-OH), 3.50-
4.00(m,lH,C2H), 2.38-2.60(m,2H,C3-H2), 1.12(d,3H,methyl).
m/e - 193 (m )
Analysi6: Calc'd for CloH1103N: C, 62016; H, 5.74; ~, 7.25%
Found: C, 62.01; H, 5085, N, 7.02%
Similarly, methyl d,1-3-{[3-hydroxy-5-(5-phenyl-2-pentyl)]anilino)-
propionate is converted to d,l-5-hydroxy-7-(5-phenyl-2-pentyl)-4-oxo-1,2,3,4-
tetrahydroquinoline which is purified by column chromatography using silica
gel and benzene/ether (5:1) as eluant.
m/e - 309 (m )
) CDC13 (ppm) 12 22 (s~ lH, 50H) 7 14 (s 5H
C6H5), 6.o4 (d, J=2.5Hz, lH meta H), 5.87 (d, ~=2.5Hz, lH meta H), 4.19-4.6O
(b, lH, NH), 3.48 (t, 2H, CH2N), 2.18-2.89 (m, 5H, ArCH, ArCH2, CH2-C=O),
1.38-1.86 (m, 4H, -[CH2]2 ), 1.13 (d, 3H, CH3).
and ethyl d?1-3-(3,5-dimethoxyanilino)hexanoate hydrochloride is
-54-
. ~a
.~
~`: .
converted to ~ -5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroguinoline;
m.pO 117-119C. (~rom methylene chloride).
m/e ~ 221 (m ), 135 (base peak, m - prop~l).
and 1-3-~(3,5-aimethoxy-(N-ethoxy carbony1)anilino]butyric acld
is converted to d-5,7-dihydroxy-2-methyl-4-oxa-1,2,3,4-tetrahydroquinolin~,
m.p. 167-168C.
[~25= -~167.8(c=l.0, CH30H)-
m/e - 193 (m )
Analysis: Calc'd for C10~103N: C, 62.16, H, 5.74; N, 7.25%
Found: C, 61.87, H, 5.62; N, 6.~6%
and d-3~3,5-dimethoxy-~-ethoxycarbonYl)anilino]butyric acid is
con~erted to 1-5,7 dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoli~e;
m.p. 166-169C.
~D5~ -168.5 (c~l.0, CH30H).
m/e - 193 (m )
Analysis Calc'd for CloH1103N C, 62.16~ H~ 5-74~ N~ 7-25%
~ .
Found: C, h.82; H, 5.83, N, 7.22
EXAMPLE 15
d 1-5 7-Dihvdroxv-2-methvl-4-oxo-1 2 3 4-tetrahYdroquinoline
A mixture of 3,5-dimethoxyaniline (230 g., 1o5 moles), methyl cro- ;
tonate (150 g., 1.5 moles) and glacial acetic acid (90 g., 1.5 moles) is
heated at re~lux for 6 hours. AdditionQl glacial ac~tic Qcid (90 g , 1~5
mOle9) i8 added and the mixture re~luxed overnight. Hydrobromic acid (1000
ml. o~ 48% so1ution~ and glacial acetic acid (850 ml.) are added to the
reaction mixture which is heated at ~eflux for 4.5 hours. The titlq product
:
is isolatea Qnd purified according to the procedur0 of Example I2. Yield =
36 g., m~pq 166-170C.
EX~MPLE 16
A mixtur0 of 3,5~dimethox~aniline (4.6 g., 0.03 mole), cr~tonic
-55-
;~
`
~,
acid (2.54 gO~ 0O03 mole) and p~ridine hydrochloride (3.~ g., 1.26 moles)
is heated at 185-200C. ~or 45 minutes. ~he cooled reaction mixture is
suspendea in water (500 ml.) (pH ~3) and the pH adjusted to 7 and the ~e~
sultant mixture stirred ~or 10 minutes. The organic layer i8 S~parat
S dried (MgS04) and concentrated to 302 g. of yellow oil.
A mixture of glacial acetic acid (11.0 ml.), 48% hydrobromic acid
(110 ml.) ana the yellow oil is refl~ed for one hour ana i8 then concen-~-
trated in vacuo to a dark oil. The oil is di~solved in ~ater and the aqueou6
solution neutralized to pH 6-7 wi~h lN sodium hydroxide. A saturated solu-
tion of aalt water i8 added and the resulting mixture extracted with ethyl
acetateO The extracts are combined, dried (MgS04) and concentrated under
reduced pressure to a dark oil (2.8 g.). Column chromatography of the
crude residue on ~ilica gel using benzene-ether (4:1) a~ eluant gives an
additional 510 mg. of product, m.p. 168-170C.
Further purification i8 achieved by recrystalliæing the product
~rom ethyl acetate; m.p. 173-174C.
Analysis: Calc'd for CloH1103N: C, 62016; H, 5.74; N, 7.25~
Found: C, 62.00, H, 5.83; N, 7.1~%
m/e - 193 (m )'5 178 (m - methyl, base peak).
In a similar manner, 3,3-dimethyl acrylic acid and 3,5-dimethoxy
aniline gives a~ter puxi~ication by ~ilica gel chromato~raphy (ben~enel`ether
1:1 as eluant) 5,7-dihydroxy-2,2-aimethyl-4-oxo-1,2,3,4-tetrahydro~uinoline
~8 a yellow oil.
. ~ .
Parent peak (m )
Calc d ~or CllH1303N: 207O0895
Founa: 207O0895
Base peak (m - 15)
Calc d ~or C1oH10O3N: 192O0661
~; 30Found: 192.0655
-56-
.
' ~
Similarly, styryl acetic acid and 3,5 dimethox~aniline are con-
densed to yield ~ ~5~7-d~hydro~y-2 benzyl-4-oxo~1,2,3,4-tetrah~droquinoline
as an oil after puri~ication using benzene/ether ~3~ s eluant.
m/e = 269 (m ) and 178 (m -benzyl,base ~eak)
NMR (CDC13) ~ (ppm): 8.76 (s, lH, 5-OH),` 7.18-7.6 (m, 5H, C6 ~),
5.84 (d, J=3Hz, lH) and 5.62 (d, J=3H~, lH) fo:r the meta coupled aromatics9
and 2.14-4.82 (4m, 7HO, ~or the remaining protons (7-OH, CH-N, CH2-C=O,
~2 6 5 ~)
d,l-5-Hydrox~-2-~eth~1-7-(2-he~tylox~)-4-oxo-1,2,3 ? 4_tetrahydro uinoline
Potassium hydroxide pellets (235 mg., 52 mmole) i6 added to a 801u-
; tion of d,l-5,7-dihydroxy-2-methYl-4~oxo-1,2,3,4~tetrahydrOqUinoline (1.0 g.
52 mmole) in N,N-dimethyl~ormamide (10 ml.). The mixture is slowly heated
to 100C. and to the resulting solution d,l-2-bromoheptane (1.08 g., 60
mmole) is added all at once with good stirring. After 10 minutes additional
potassium hydroxide (160 mg.) is added followed b~ additional d,1-2-bromo-
heptane (500 mg~). The addition of potassium hydroxide ~nd d?l-2-bromo-
heptane was repeated two more times using 80 mg. potassium hydroxide ana
250 mg. ~ -2-bromoheptane each time. The reaction mixture is stirred an
additional 10 minutes and is then cooled. Chloroform (50 ml.) and aqueous
sodium hydroxide (25 ml. ~f lN) are added, the mixture stirred ~or 10 ~in-
utes and th~ layers separated. The chloroform extraction is repeated, the
extracts combined, dried (MgSO~) and concentrated under ~educed pressure
to a dark oil ~he oil is chromatographed on silioa gel (120. e. ) using benzene
ether as solvent. Fractions of 30 ml. each are collected. The 12th~18th fract~
ions are combined ~nd c~ncentrated under reduced pressure to a ligh~ yellow oil
-~ (850 mg.) which crystallizes upon s~anding. The desired product is sep~rat2d
; by filtration and recrystallized from hot hexane, m.p. 76-77C.
~he above procedure is repeated on a 20-fold scale but using
benzene-ethyl acetate (9:1) as chromatographic solven~. Fracti~ns of 750 ml.
.,
6~
each are collectcd. Combination of the 2nd-6th ~ractions ~ords 32 g. o~
oil which partially crystallizes from hexane upon standing and cooling to
give 18.2 g. o~ produc~. An additional 3.2 g. is obtained by conce~rating
the mother liguor and allowin~ it to crystalli~.e by standing i.n the cold.
Total yield - 21.4 gO
Analysis: Calo'd for C17H2503N: C, 70.07; H, 8.65; ~, 4,81%
Found: C, 69.82; H, ô.67; N, 4.93%
m/e - 291 (m~)
IR (KBr): 6.01 ~ (=0)
In like manner, 5,7-dihydroxy-~-oxo-1,2,3,4 tetrahydro~uinoline
con~erted to d,l-5-hydroxy-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetr~lydroquinoline, ~-
an oil.
H NMR (60 M Z) ~CDC13 (ppm): 13.3 (s, lH, ~henolic), 5.5 and 5.7
(d, 2H, J = 2H~, aromatic), 4.6 (bs, lX, -NH), 4.1-4.6 (m, lH, -0-CH-), 3.3
(t, 2H, J = 7Hz, -CH2-), 2.6`(t, 2~, J = 7Hz, -CH2-), 2.0-0.7 (~, rem~ining
i~¦ protons).
EXAMPLE 18
d~l-5-Hydroxy-2-methyl-7-(5-~henyl-2-pentyloxy)-4-oxo-
_ 1,2,3l4-tetrahydroquinoline
A mixture of 5-phenyl-2-(R,S)-pentanol (1604 ~., 100 mmole), tri-
,
ethylamine (28 ml " 200 mmole) and ary tetrahydrofuran (80 ml.) under a
nitrogen ~tmosphere is cooled in an ice/water bath. Methane6ul~onyl
chloride (8,5 ml., 110 mM) in dry betrahydrofuran~(20 ml.) is added dropwise
at such a rate that the temperature holds essentiaily constant. The mix-
ture is allowed to warm to room temperature and is then ~iltered to remo~e
..
trieth~lamine hydrochloride. rrhe filter ca~e is washed with dry tetrahydro-
furan and the combined wash and filtrate evaporated under reduced pressure
., _
to give the produc~ as an oil. rrhe oil is aissolved in chloro~orm (110 ml.)
and the solution washed with water (2 x 100 ml.) ~nd then with saturated
brine (1 x 20 ml.). Evaporation o~ the aol~ent affords 21.7 g. (89.7%)
-58-
.,
. '~ ~ ,
.
L8~
yield of the mesyl&te of ~ -5-phenyl~2-pentanol ~hich iB used in the next
step without further puri~ication.
A mixture of ~1_-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydro- -
quinoline (1.0 g., 5.2 mmole), potassium carbonate (14.35 g-5 0.104 mole),
N,N-dimethylformamide (60 ml.) and ~ 5-phenyl-2~pent~nol mesylate (13.68g.,
57 mmole), undor a nitrogen atmosphere, is he~ed to 80-82Co in an oil
bath for 1.75 hours. The mixture is cooled to room temperature and then
poured into ice/water (300 ml.). Th~ aqueous solution is extracted with
ethyl acetate (2 x 50 ml.) and the combined extracts washed successlvely
with water (3 x 50 ml.) and saturated brine ~1 x 50 ml.). The extr~ct is
then dried ~MgSOI~), de¢olorized with charcoal and e~aporated to give the
product.
m/e - 339 (m )
The above procedure i5 repeated but using 114.8 g. (0.594 mole) o~
d,l-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquino-
line, 612 ml. o~ N,N-dimethylformamide, 174.8 g. (1.265 mol~s) of potassium
carbonate and 165.5 gO (o.638 mole) o~ d,l-5-phenyl-2 pentanol mesylateO The
; reaction mixture is cooled and poured onto ice Y~ter (4 liters) and the
aqueQus solution extracted with ethyl acetate (2 x 4 liters). The combined
extract is washed with water (4 x 2 liters), brine (1 x 2 liters) and dried
(MgSO~). Evaporation affords 196 gO o~ the title produat. It is used with-
out further purification.
H ~MR (60 MHz) ~CDC13 (ppm): 12c73 (s, lH, OH), 7.22 (s, 5H, aro-
matic), 5.80 (d, J=3 H3, lH, meta H), 5.58 (d, J-3 H3, lH, meta H), 1.25 (d,
6H~ CH3-CH-~ and CH3-CH-0-), 1.41-4.81 (m, llH, remaining protons).
EXAMPLE 1~
d ? l-5-Hydroxy-7-(5-phenyl-2-pentyloxy)-4-oxo-},2,3 ~-
Repetition of the procedure of Example 18 but using 537-d~hydroxy-4-
oxo-1,2,3,4-tetrahydroquinoline ln place o~ the 5,7-dihydro~-2-methyl_4-
-59-
~''
86~
cxQ-1,2,3,4-tetrQhydroguinoline a~fords ~-5-hydroxy-7-(5-phenyl-2~pentyl-
oxy)-4-oxo-1,2,3,4-tetrahydroquinoline as an o:Ll in 74% yield.
m/e - 325 (m )
Analysis: Calc'd for C20H23No3 C, 73.70; E, 7-12; ~ 4 31%
Found: C, 73.69; H, 7.15; N, 4.o8%
; H NMR (60 M~z) ~CDCl (ppm): 12.6 (bs, lH, phenolic), 7 3 (s,
5H, aromatic), 5.8 (d, lH, aromatic, J = 2Hz), 5.6 (d, lH, aromatic J - 2Hz),
4.7-4.1 (m, 2H, NH and O-CH), 3~5 (t, 2H, CH2, J - 7Hz), 3.1-2.1 (m, 4H, 2-
CH2-) 2.1-1.5 (m, 4H, 2-C~2), 103 (d, 3H, -CH-CH3, J = 6Hz).
Similarly ~ -5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetr~hydroquino-
line (27 g., 0.14 mole) is al~ylated with 4-phenylbutyl methanesulfonate
(35.2 g., 0.154 mole) to;yi~ld 41.1 g. (90%) of the desired d,l-5-hydroxy-
2-methyl-7-(4-phenylbutyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, m.p. 88-goc.
Recrystallization from ethyl acetate-hexane (1:2) give6 the analytlcal samplQ,
m.p. 90-91C.
Calc'd for C20H233N C~ 73082~ H~ 7.~2~ ~
Found: C, 73.60, ~, 7.09; N, 4.26%
m/e - 325 (m )
H NMR (60 M~z) ~TcMcl (ppm): 12.58 (s, lH, -OH), 7.21 (s, 5H,
C6H5), 5.74 (d, J = 2.5 Hz, 1~, meta H), 5.5 (d, J = 2.5Hz, lH, meta H),
4.36 ~bs, lX, NH), 3.33_1~.08 (m, 3X, -O-CH2, -CH--N), 2.29-2.83 (m, 4H, -CH2-
C=O, C6H5-CH2), 1-51-1-92 (m, 4H, -~CH2~2~), 1-23 (d, 3H, CH3-).
In like manner, alkylation o~ d-5,7-dihydroxy-4-oxo-1~2,3,4-tetra~
hydro~uinoline with d-2-octylmethanesul~onate gives d~5-hydroxy-2-methyl-7-
(2-(R)-octyloxy)-4-oxo 1,2,3,4-tetrahydroquinoline, m.p. 64-68C.
[~]D5 ~ ~110.2 (c=l.O 7 CHC13).
and alkylation of ~ -5,7-dihydroxy-2-propyl-4-~xo-1,2,3,4-tetra~
hydroquinoline with ~ -5-phenyl-2-pentanol mesylate giv~s d~l-5-hy~roxy-7-
(5-phenyl-2-pentyloxy)-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline; ~/e - 367
(m )~
-60-
..
. ~
,
.
8~1
EXAMPLE 20
Formgl-5-hydroxy-3~hydroxymethylene-2-methyl-f-(5-
A solution of ~-5-hydroxy-2-~ethyl-7-t5-phenyl-2-pentyloxy)-4-
oxo-1,2,3,4-tetrahydroquinoline (195g.,ca. oO58 mole) in ethyl ~ormate
(1140) g., 14.6 moles) is added dropwise to sodium hydride ~72 g., 3.0 moles,
obtained by washing 144 g. of 50% sodium hydride with hexane, 3 x 500 mlO),
with good stirrin~. After about 1.5 hours when 2/3 of the ethyl ~ormate
solution is added, the addition is discontinued to allow the vigorous ~oam-
ing to subside. Diethyl ether (600 ml.) is added and the mixture stirred
for 15 minutes before adding the remainaer of the ethyl ~ormate solution.
When addition ia complete diethyl ether (600 ml.) is adaed, the reaction
mixture stirred ~or an additiona]. 10 minutes a~d then poured onto ice
water (2 liters). It is acidified to pH 1 with 10~ HCl and the phase sepa-
rated and extracted with ethy} acetate (2 x 2 liters). ~he combined organ-
ic solutions are washed successively with water (2 x 2 liters), brine (1 x
one liter) and dried (UgS04). Concentration gives 231 g of red-brown oil
which is used without ~urther puri~icationO
) R~ = 0.1-.5 (stretched) on thin layer chromatography, silica gel
; 20 plates, benzene/ether (1:1).
Similarly, d?l-5-hydroxy-7-(5-phenyl-2-pentyloxy)-2-propyl-4-oxo-
1,2,3,4-tetrahydro~uinoline is converted to d,l-1-~ormyl-5-hgdroxy-3-hydroxy-
methylene-7-(5-phenyl-2-pentyloxg)-2-propyl-4-oxo-1,2?3,4-tetrahydrog,uino
line. It is used in subseguent examples as is.
E ?l
-l-Formyl-5-hydroxy-3-hydroxymethglene-2-methyl-T-(2-
he~tvloxv)-4-oxo-1 2 3 4-tetrahvdroauinoline
~o sodium hydride (18.2 g~, o.38 mol) obtsined by washing 50
sodium hydride ln mineral oil dispersion with pentane is added dropwise, over
- 30 a hal~-hour period, a solution o~ -5-hydroxy-2-methgl-7-(2-heptyloxy)-4-
-61-
, .... ~
'
oxo-1,2,3,4-tetrahydroquinoline (11.1 gO~ 0.038 mole) ln ethyl formate (110
g~/ 1 48 moles). E~othermic reaetlon occurs wlth ~igorous evolution o~ hydro-
gen and ~ormation of a ~ellow precipitate. The reaction mixture is cooled,
ether (750 mlO) added and the resultin~ mixture then heated at reflux and
stlrred for 3 hoursO It is then cooled to 0C. and neutralized by aadition
; of lN hydrochloric acid (400 ml.). The ether layer i9 separated and theaqueous phase extracted with ether (2 x 150 ml.). The ether extracts are
combined, washed succe~sively with saturated sodium bicarbonate solution
(2 x 100 ml~) and brine (1 x 150 ml.) and then dried (MgS04). Concentration
o~ the dried extract affords an orange foam (10.8 g.). An additional 2.3 g.
is obtained by acidifying the sodium bicarbonate wash solutions wlth con- -
centrated hydrochloric acid followed by extraction of the acid solution with
ether (2 x 100 ml.). Concentration of the combined ethereal extracts after
drying gives 2~3 g~ of product (Total - 1301 g.). The product is used as
iso
~ Z) ~CDC13 (PP~) 12027 (bs, lX, ArOH), 8.8_11 9 (m,
lH, variable, =COH), 8073 (s, lH, N-CHO), 7.41 (s, lH, =CH), 6.32 (s, 2H,
aromatic), 5.52 (q, lH, -CH-N), 4.18-4.f7 (m, lH, -O-CH), 006-2.08 (m, 17H,
~` CH3-C-C5Hll and CH3 C_~)o
In like manner, d,l-5-hydroxy-2-methyl-7-(5-phenyI-2-pentyloxy)-4-
oxo-1,2,3,4-tetrahydroquinoline is converted to d,l-1-formyl-5-hyaroxy-3-
hydroxymethylene-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydro-
, quinolineO
:
) CDC13 (60 MHz) ~C~Cl (ppm) 12-22 (bs~ lH3
ArOX), 808-1106 (variable, lH, =COH), 8.64 (s, lH, -CHO), 7.21 (bs~ shoulder
,
at 7D30~ 6H, Qrom~tic and =CX), 6.23 and 6.17 (two lH doublets, J = 2H~, meta),
5.42 (b~, lX, N-CH), 4.18-4 ~70 ~m, lH, -OCH), 204-3.0 (m, 2-H, Ar-CH2), 1.53-
2.0 (m, 4H, -(CX2)2-), 1029 (overlapping doublets, 6H, CH3-C-N and CX3-C-O).
d~_-5-hydroxy-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahyd~oqu;noline is
~ .
converted to d,l-1-formyl-5-hydroxy-3-hydroxymethylene-7-(2 heptyloxy)-4-
-62-
' ~
, ` .' ~ , ' . ~ ~ '
oxo-1,2,3,4-tetrahydroquinoline, an oilO
CDC13 (PP~): 12-1 ~bs, lX, phenolic), 8.8 (s
lH, -N-C~O), 8.1 (9, lH), 7.3 (s, lH), 6.1 (s, 2X, aromatic), 4.5 (bs, 2H,
-CH2-), 4.2-4.8 (m, -0-CH2-), 200-0.7 (remaining protons).
d~l-5-hydroxy-7-(5-pentyl~2-penty}oxy)-4 oxo-1,2,3,4-tetrahydro-
quinoline is converted to d~,l-l-formyl-5-hydroxy-3-hydroxymethylene-7~(5-
phenyl-2-pentyloxy)-4-ox~-1,2,3,4-tetrahydroquinoline.
H ~MR (60 MXz) ~CDCl (ppm): 12-4 (bs, lH, phenolic), 8.5 (s,
lH, CHO), 7.2 (m, 6H, aromatic ~nd =CH-), 6.2 (m, 2H, &romatic), 4.5 (s, 2H,
~CH2-), 4.4 (m, lH, -CH-CH3), 2.6 (bt, 2H, -CH2-), 1.7 (m, SH, remalning
protons), 1.3 (d, 3X, -CE-CH3, J - 6Hz).
and ~ -5-hydroxy-2-methyl-7-(4-phenylbutyloxy)-4-oxo-1,2,3,4-
tetrahydro~uinoline is converted to ~ -1-formyl-5-hydroxy-3-hydroxymethylene-
: .
2-methyl-7-(4-phenylbutyloxy)-4-oxo-1,2,3,4-tetr~hydro~uinoline, m.p. 132-
; 5 135C. (from hexane). Rearystalli~ation from hot methanol provides the
analytical sample, m.p. 131-132C.
` Calc'd ~or C H O N: C, 69.27; H, 6008; N, 3.67%
Found: C, 69025, H, 5.88, N, 3.88%
m/e - 381 ~m )
H NMR (60 MHz) ~CDC1 tpPm) 12.4-13.6 (m, H, c~ooH)~ 12.26 (~,
lH, 5-OH), 8.62 (s, lH, -C(=O)-X), ca. 7 18-7.48 (m, lH, = ~ H), 7.27 (s, 5H,
C6H5)~ 6.26 (bs, 2H, meta HtB), 5.46 (q, lH, CH-~), 3.82-4.23 (m, 3H, -CH2-0),
2.49-2080 (m, 3H, ArCX2), 1.67-2002 (m~ 4H, -[CX2]2-), 1.27 (d, 3H, CH3).
EX~MPLE 22
~ -1-Formyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pent~loxy)-4-oxo
3-(3-oxobutvl)-1 2 3 4-tetrah~droquinoline
To a soluti~n ~ formyl-3~hydroxymethylen~-5~hydroxy-2-
methyl-7-(5-phenyl-2~pentyloxy)-4-~oxo-1,2,3,4-tetrah~droguinoline (229 g.,
ca~ 0058 mole) in methanol (880 ml.) under a nitrogen Qtmosphere i~ added
triethylamine (27.2 ml.) with stirring. Methyl vinyl k~tone (97.0 ml.) is
-63-
~.~
then added ~nd the mixture stirred overnight at room temperature.
The reaction is complete at this point and comprises a mixture
of the title compound and ~ 3-diformyl-5-hydroxy-2-methyl-7-(5-phenyl-
2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline. The ~ollow-
ing steps are reguired to convert the diformyl compound to the desired titla
compound,
The reaction mixture is diluted w;th ether (6 llters) and then
washed successively with 10% aqueous sodium carbonate (4 x 1700 ml ), bri~e
(1 x 2 liters) and then dried (MgS04)0 Concentration of the aolution af`~ords
238 g. of a red-brown oilO The oil is dis601ved in methanol (1920 mlO) and
the solution cooled to 0CO Potassium carbonate (21.2 g,) 1s added, the
mixture stirrea for 3 hours at 0CO and then treated with acetic acid (1807
e. ). ~he methanol is removed under reduced pre6sure ~nd the result~nt oil
stirred with water (2 liters) and ethyl acetate (2 liters) ~or 10 minutesO
~he aqueous phase is separated, extrQcted with ethyl acetate (1 x 2 liters?
and the combined ethyl acetate solutions washad with water (2 x 2 liters),
.~ :
brine (1 x 2 liters~ and dried (MgSOLI)o Concentration under reduced pras-
sure and chromatography of the concentrate on silica gel (lo~ kgo ) gi~es
159 g. of the title productO
mle - 437 (m )
H NMR (60 MHz) ~CDCl (ppm): 1207 (s, lH, OH), 8078 (bs, lE,
-CEO), 7022 (s, 5H, aromatic), 6.22 (bs, 2H, meta X~s), 2.12, 2007 (s, 3H~
~- -CH3-CO-)~ 1031 (d, 3H, -CH3-C-O-)~ ana 1.57-5.23 (m, 13H, remainlng protons).
Similar treatment Of 35 e~ ~oOog mole) of~dl-l-form~1-5-hydroxy-
3-hydroxymethylene-2-methyl-7-(4-phenylbutyloxy)-4-oxo-1,2,334-tetrahydro-
~uinoline gi~es 22.7 g. (60%) of` dl-1-formyl-5-hydroxy-2-mathyl-7-(4-phenyl-
. .
- butyloxy)-4-oxo-3-(3-oxDbutyl)-1,2,3,4-tetrahydroguinolinQ~_m~p. 101-103Co
The analytical sample is obtained by recrystallization ~rom methanol, m~pO
~`~ I04-105C.
,~.
Calc'd fior C25H2905~: C, 70~90; H, 6.90; N, 3~31%
-64-
.' ."
,~ ,
. . ~ . ~ :
Found: C, 70.77; H, 6.81; N, 3.46%
H NMR (60 ~Hz) ~CDCl (ppm): 12.88 (s, lH, -OH), 9.o8 (bs, lH,
-CH0), 7.29 (s, 5H, C6H5), 6.25 (bs, 2H, meta H's), 4.88-5 43 (m, lH, -CHN),
3.86-4.21 (m, 2~ CH2-0-), ca. 2.49-3.02 [m, '7H, ~rCH2, -(CH2)2-C(~0)-,
S -CH-C(=0)], 2.18 [s, 3H, CH3-C(=0)], 1.68-2.03 [m, 4H, -(CH2)2-~, 1.13 ~d,
3H, CH3)-
m/e - 423 (m )j ~
- and d?l-l-formyl-5-hyaroxy-3-hydroxymethylene-7-(5-phenyl-2-pentyl-
oxy)-2-propyl-4-oxo 1,2,3,4-tetrahydroquinoline affords ~21-l-formyl-5-hydroxy-
7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4~tetrahydroqulnoline
which is used as is.
EXAMPLE 23
Formyl-5-hydroxy-2-methyl-7-(2-heptyloxy(-4-oxo-3-(3~oxobutyl~-1,2,3,4~-
tetrahydroquinoline and d71-1,3-Diformyl-5-hydroxy-2-methyl-7-(2-heptyloxy-4-
_ oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline
To a solution of d~l-5-hydro~y-3-hydroxymethylene_2_methyl_7_(2_
heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline (1301 g., 37~7 mmol.)g in methanol
.,
(56 ml.) and methyl rinyl ketone (5052 mg " 68 mmolO) is added triethylamine
(1 3 ml., 903 mmol.). The mixture is stirred ~or lô hours under a nitrogen
~, atmosphere at room temperature and is then dilutea with ether (550 ml,).
The solution i8 washed with 10% a~ueous sodium bicarbonate solution ~4 x
60 ml.), followed by brine (1 x 100 ml.) and dried (MgSOI~) Removal of the
ether by evaporation gives a dark oil (16 g.) The oil is dissolved in a
minimum volume of benzene and the solution charged to a column of silica gel
(5 B~)- The column is bheneluted with a volume of benzene equal to the
volume of the column The eluting solvent is then changed tv 15% ether-
benzene and 100 ml. fractions collected when the first color band be~ins to
elute off the column. Fractions 5-13 are combined and concentra~ed under
reduced pressurq to give ~ 1,3-diformyl-5-hydroxy-2-methyl~7-(2-heptyloxy)-
~-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline as a yellow oil (8.7 g ).
The column is eluted further with 15% ether-benzene. Fractlons
-65-
:
366~
19-37 are combincd and concentrated under reduced pressure to give ~
~ormyl-5-hydroY.y-2-methyl-7-(2-heptyloxy)-3-(3-oxobutyl~ 1~2,3,4-tetrahydro
~uinoline as an oil ~4.6 g.). Additional mono~ormyl product iB obtainea in
the ~ollowin~ manner: ~
1 gO of diformyl product is stirred with 200 mgO potassium car-
bonate in meth~nol (25 ml.) ~or two hours at 0C. The solvent is then
evaporated in vacuo and the residue suspended in ether and ~iltered. The
~iltrate is concentrated and the residue partitioned between ether and
water. The organic l~yer is separsted, the aqueous phase acidl~ied with
10% hydrochloric acid and extracted with etherO The combined ether extracts
are washed successively with saturated sodium bicarbonate and brine, and
then dried (MgS04), ~iltered and concentr~ted to yeild additional monofor~l
product.
The mono~ormyl derivative has the ~ollowing NMR spectrum:
( 2) ~CDC13 (ppmj: 12.73 (S, lH, ArOH), 8 87 (S, lH,
N-CHO), 6.12 (S, 2H, Aromatic), 4.78-5050 (M, lH, N~CH), 4.11~4.72 (M, lH,
-O-CH), 2.21 (S, 3H, CH3-C(=0)-)~ 0.63-3.12 (M, 22H, remaining hydrogens).
Similarly, the following compounds are prepsred from appropriate
reactants:
; 2Q ~ l-rormyl-5-hydroxy-7-(2-heptyloxy)-4-o~o-3-(3-oxobutyl)-1~2,3,4-
tetrahydroquinoline, an oilO
H ~MR (60 MH2) ~c~cS1 (ppm): 12.8 (S, lH, phenolic)~ 8.7 (S,
lH, N-CHO), 6 1 (S, 2H, aromatic), 4.1-406 (m, lH, -O-CH), 401 (d, 2H, J-5H2,
-CH2-), 2 3-3.0 (m, 3~, CH2 and CH-C~=O)), 202 (S, 3H, -C(~O)-CH3), 2.3-0.7
remainin~ protons).
~: .
ormyl-5-hydroxy-2-methyl-7~(5-ghenyl-2-pentyloxy)-4-oxo-3-
(3-oxobutyl)-1,2,3,4-tetrahydro~uinolina.
~) CDC13 (PP~): 12.6~ (S~ lH, OH), 8.82 (b s
lH, -C(O)H), 7.20 ~b, s, 5H, C6H5), 6.18 (b, s, 2H, aromatic), 4.78-5.34
-66-
' ' .
.~
. .
.
` ` ~ -- ~ \
(m, lH, -N-CH), 4018-4~68 (m, lH, -O-CH), 2.17 ~S, 3H, -C(O)CH3), 130 (d,
3H, -0-C-CH3), 1~12 (d, 3H, -N-C-CH3), 104-3.1 (m, llH, remaining H's).
~L_-l-formyl-5-hydroxy-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3 oxo-
butyl)-1,2,3,4-tetrahydro~uinollne.
m/e 423 ~m )
Also produced as by-product in each o~ these preparations is the
corresponding 1,3-di~ormyl derivative.
EXB~PLE 24
~-5,6,6a,7-Tetrahydro-1 hydroxy-6~-methyl-3-(5-phenyl 2-
pentyloxy?benz_[c]quinolin-9(8H)-one _ _
A solution o~ d~ ormyl-5-hydroxy-2-methyl-7-(5 phenyl~2-pentyl-
oxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydro~uinoline (174 g., 00398 mole)
in methanolic 2N KOH (5.9 liters) and methanol (5.9 liters) is stirred and
heated at reflux overnight under a nitrogen atmosphere. To the cooled solu-
tion is added acetic acid (708 gO) dropwise with stirring over a 15 minute
period. The resulting solution 1s concentrated by rotary evaporation (in
vacuo7 water aspirator) to a semisolid which is filtered and washed ~irst
with water to remove potassium acetate and then with ethyl acetate until all
the black tar is removedO Yield = 68 gO (44%) yellow solids, mOpO 188~
190C. Recrystallization from hot ethyl acet~te a~ords the pure productg
m~pO 194~-lg5C.
m/e - 391 (m )
Analysis: Calc'd for C25H2903N: C, 76009, H, 7047~ N, 3058%
Found: C, 760~3; H, 7~48; N, 3.58%
X ~MR (60 MHz) ~ S (100 mgO dissolved in 003 ml. CD30D and 003 ~;
mlO CD3S(O)CD3) (ppm): 7021 (s, 5H~ aromatic), 5080 (s, 2H~ meta H's), 1.20
(d, 6H, CH3-CHO and CH3-CH~
From the mother liguors, a small amount o~ the correspondine axial
methyl derivative is obtained upon evaporation. It is purified by column
chromatography on silica gel using benzene/ether (1:1) as eluantO Evapora-
-67-
.: -
, ~ '
ation of the ~lu~te and recryst~lliz~tion of the re~idue from ether/hexane
(1:1) a~fords analytically pure material, mOp. 225-228C.
Its Rf value upon thin layer chromatography on silica gel using
2.5% methanol in ether as eluant and visualizàtlon ~ith fa~ blue is 0,34.
The 6~-methyl derivQtive exhibits Rf = Oo41
m/e - 391 (m )
lH ~MR (60 MHz) ~TMS ~(100 mg di~sol~ed in 0.3 ml. CD30D and 0.3
ml. CD3S(O)CD3) (ppm): 7.19 (s, 5H, aromatic), 5.75 (s, 2H, meta H's) 1.21
(d, 3H, CH3-CH0-), and O.g5 (d, 3H, CX3~CH~
Similar tr~atment of 22 g. of ~ ormyl-5-hydroxy-2-methyl-7-
(4-phenylbutyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinolineq gi~es
17.1 g. (87%) o~ 5,6,6a,7-tetrahydro 1-hydroxy-6~-methyl-3-(4-phènyl-
butylox~)~benzo[c]quinolin-9(8H)-one, m.p. 222-224C. The analytical
~ample i~ obtained by recry~tal}ization from methanol, m.p. 224 225C.
Calc'd for C24H2703N: C, 76-36; H, 7-21; ~, 3-71%
Found: C, 76.03, H, 7.08, N, 3.68%
H NMR (60 MHz) [1:1 mixture of (CD3)2SO and DC30D~: 1 24 (d, 3H,
-~ 6~-CH3)
m/e - 377 (m )
~ . ,
Evaporation of the mother liguor g~ves 208g(m.p. 185-195C.) o~
product shown by NMR to be a mixture o~ the 6~-methyl derivative (ca. 40~)
and ~-5,6,6a,7-tetrahydro-1-hydroxy-6a-methyl-3-(4-phe~yl butyloxy)-benzo[c]-
~uinoline-9(8H)-one~
lH NMR (60 MHz) [1:1 mixture of (CD3~2SO and CD30D): 1.24 (d, 1.2H,
~-CH3] and 0.95 (d, 1.8H, 6~-CH3)
EXAMPLE 25
_-5,6,6a,7-Tetrahydro-I-hydroxy 6~-methyl-3-
(2 heptylox~?benzo[~]guinolin-9(8H)-one _
A solution of d,l-l-formyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-
oxo-3-(3-oxobutyl)-1,2,3,4-tetrahy~oquinoline (4.5 g., 11.5 mmol.) in
-68-
methanol (150 ml.) is tr~&ted with 2N methQnollc pot~saiu~ hydroxde solu-
tion (150 ml.~. ~he mixture is stirred for one hour at room temperature
and then heated at re~lux under a nitrogen atmosphere for 20 hours. The
dark red mixture is allowed to cool to room temperature, ~eutralized with
Qcetic acid and concentrated under pressure to about 100 ml. The concen-
tr~te is diluted with wQter (400 ml.) and the brown-red solid sep~rated by
filtration5 washed with water and dried (~6 g~. It is tritu~ated ~lrst in
ether and then in methanol, ~iltered Qnd driçd (1.96 g.); m.p. 223-229C.
~ecrystsllization ~rom hot methanol af~ords crystals melting ~t 235-237C.
Analysis: C~lc'd for C21H2903N: C, 73.43; H, 8 51, N~ 4.o8%
Found: C, 73.22, H, 8.30, N, 4.11%
; Addition~l material is recovered by evaporQtion of al~ mother
liquors and by chloroform extraction o~ the agueous solution from which the
brown-red crude product is obtained and subseguent e~aporati.on o~ the extr~ct
The combined residues are purified ~y silica gel chromatography using ether
~s eluant.
In like manner, the following compounds are prepared from ~ppro-
priate reactants:
d,l-5,6,6a,7-tetrQhydro-l-hydrQxy-3-(5-phenyl-2-pentyloxy)benzo[c~-
~uinolin-9(8H~-one; m.p. 170-173Co ~recrystallized ~rom chloro~orm).
m/e - 377 (m )
An~lysis: C~lc'd for C24H2703~: C, 76~36; H, 7.21; ~, 3.71%
Found: C, 76038j H, 7.21; N, 3.ô5%
d,l-5,6,6~,7-tetrahydro-}-hydroxy-3~(2~heptyloxy)benzo[c]quinolin-
9(8H)-one; m.p. 208-20gc~
m/e - 329 (m )
An~lysis: Calc'd for C20H2703N: C~ 72.92; H, 8.26; ~5 4.25%
Found: C, 72.92; H, 8.31; ~5 4.42%
~-55656a57-tetr~hydro-l-hydroxy-3-(S-phenyl-2-pentyloxy)-6,~-
propylbenzo~c]quinolin-9(8X)-one; m.p. 164-166C.
-69
~:,
Analysis: Calc'd for C27H3303N: C, 77.29; H; 7.937 N, 3.34%
Found: C, 76097,-H, 7.987 N, 3.41%
1-5,6,6a,7-tetrahydro-1-hydroxy-3-(5--phenyl~.2-pentyloxy)-6~-methyl-
benzo[c]quinolin-9(8H)-one; m.p. 176-178C.
[a]25 = -416.0(c-0.33, CH30H)
mle - 391 (m )
Ana1ysis: Calc'd ~or C25H2903~: C, 76.69; H, 7.477 ~, 3 58%
Found: C', 76~32; H, 7.367 N, 3.33%
d-576,6a,7-tetr~hydro-l-hydroxy-3-(5-phenyl-~-penty1oxy)-6~-~ethyl-
benzo[c]quinolin-9(8H)-one, m.p. 172-174C.
[a]D5 = ~12.9 (c-l.0, CH30H)
m/e - 391 (m ~
~: Analysig: Calc'd for C25~2903N: C, 76069; H, 7.47; ~, 3.58%
FounEd ~ LE62~4: H, 7,39; ~, 3.51%
d,l-5,6,6a,7,10,10a-~Ie~C~yaP5=z:hydroxy-6~-methyl-3
1 15 ~2-hetvloxv)benzo~clauin~lin-9( ax ) -one
;; , . ~ v .~,
A suspen5ion of d,l-59676a,7-tetrahydro-l-hydroxy-6~-methyl-3-(2-
heptyloxy)benzo[cJquinolin-9(8H)-one (1.0 g., 2.91 mmole) in tetrahydrofursn
(20 ml,) is added dropwise via an addition fun~el to a rapidly stirred solu-
t;on of lithium (0.1 g.) in liquid ammonia (75 ml., distilled through potas-
sium hydrQxide pellets). ~he addit;on funnel is rinsed with t~trahydrofuran
(10 ml.). The mixture is stirred for 10 minutes and the~ solid ammonium
chloride i9 addçd to discharge the blue color, The excess ammonia is allowed
to e~aporat0 and the residue taken up in water (100 ml.~ and ethyl acetabe
(50 ml.). The ~ethyl acetate layer is separated and the aqueous
phase extracted with ethyl acetate (2 x 50 ml.). The comb med extracts are
washed with brine, dried (M6so4) and concentrated u~der reduced pressure to
a brown se~i-solid product (1 35 g.)~ Tritura~ion of the semi-solid in
pentanejether (1:1) gives a light brown solid (o.884 g.); m~p. 130-138C.
.::
- The above procedure is repeated but using 1.84 g. (5,36 mmole) of
the benzoLclquinolin-g-one reactant, 0.184 g. of lithium, 140 ml. of liquld
ammonia and 45 ml. of tetrahydro~uran. The residue (2.1 e. ) remaining after
-7-
.~
~:
, ; ,,,
' ~ .,
, ~
evaporation of the ~mmonia is dissolved in benzPne and charæed to a chromato-
graphy column (3.8 x 61 cm) containing sillca gel (250 g.)O The column is
eluted with ~ volume of degassed benzene equal to the volume of the column
and then with 1700 ml. o~ degassed benæene-ether (y:l). Continued elution
(1100 ml.) gives a brillia~t red eluate which is concentrated to a light
purple solid (580 mg.) under reduced pressure and triturated in benzene-ether
1) to gîve 370 mg. o~ solid, 154-156C. It is stored under nitrogen
and in the dark. The isolated solids are mixtures of the cis- ~nd trans-
forms o~ the title product.
m/e - 345 (m )
) CDC13 (PP~): 6.85 and 7.49 (lH, broad variable
OH), 5.67, 5.71, 5.85, 5.93 (d, J = 2Hæ, 2~I total, aromatic h~vdrogens for
; cis/trans miXture), 0.90 (t, 3~ terminal CH3), 1.12-4.43 (m, remaini~g
EXAMPLE ?7
Isomeric 5,6,6a,7,10,10a-Hexahydro-l-aceto~Y~6~-methyl-3-(2-
heutvloxv)benzo[c]quinolin-9(8X)-ones
Pyridine (2.2 mlO) is added to a suspension of 5,6,6a,7,10,10a-
hexahydro-l-hydroxy-6~-meth,,vl-3-~2-heptylox"Y~benzo[c]guinolin-9(8H)-one(222
mg , o.642 mmole) in acetic anhydride (202 ml5) under a nitrogen atmosphereO
The mixture is stirred for 1.5 hours at room temperature and is then poured
onto iae (50 ml.). ~he gum~which separates is extracted with ether (3 x 50
ml.) and the combined extr~cts washed ~irst w;th water (4 x 5Q ml.) and then
with brine (1 x 60 ml.), The extract is dried (MgS04) and evaporated under
reduced pressure to a red oil (250 mg~).
The oil is dissolved in a minimum of hot ether ~nd charged to a
silica gel (45 g.) column, packed and eluted with pentane-ether (3~ The
; column is eluted with pentane-ether (3:1, 200 mlO~. Elution is continued
~ and ~ractions (10 ml.) collected. Fractions 22-32 are combined and concen-
i trated to a foam (113.5 mg.) which is crystallized ~rom petroleum ether as
white crystals, m.p. 112-114C.
6~ :
Fractions 33-50 are co~bined and concentrated to a foam (89.7 mg.)
which is re~cryst~llized from petroleum ether as white crystal~; m.p.
78-82C.
The pro~ucts arc the isomeric mono-acetylated compounds.
EXAUPLE 28
-5,6,6a,7,10,10a-Hexahydro-1-acetoxy~6~-methyl-3-(2-
The procedure o~ Example 26 is repqated but us~ double the ~uanti-
ties o~ reactants. The product (2.22 g.) is then directly acetylated accord-
ing to the procedure of Example 34 to give 2.35 ~. of acetylated product.
~his product i8 triturated in pentane-ether (3:1) to a t~n~solid t9Q5~mg.)
~hich when recrystall1zed from ethanol~gives 1~o4 mg. of 11ght tan crystQls;
m.p. 112-113.5C.
The mother liguors from which eaoh of the above solids is separated
are comblned and concentrated. The re~idue i5 dissolved in a minimum o~
benzene-ether-methy1ene chloride ~ 1) and char~ed to a s111ca gel ~275 g.)
colum~ (packed and eluted with petroleum ether ether ~3:1]). The column ~a
eluted first with 2 liters of petroleum ether-ether (3:1) followed by 1.5
liters o~ petroleum ether-ether (2:1) and 2 liters of petroleum~ether-ether
(I:1). Fractions 2-11 (50 ml. each) of eluate from the 1:1 solvent system
are collected and conoentrated under reduced pressure to a foam (496 mg.).
Crystallization from petroleum ether a~ords ~hite crystQls~ m.p. 100-113C.
:
(410 mg.~. Recryst~llization from ethanol-water (1:1) gives ~ -trans-5,6
6a~,7,10,10a~-hexahydro~l-acetox~-6~-methyl-3~(2-hepty10x~benzo[c~quinolln-
9(8H~-one melting at 111-112C.
m/e - 387 (m ~
. . .
Analy8i5: Calc'd ~or C23H3304~: C, 71-29; H, 8.58~ ~ 3-
Found: C, 70~95i H, 8 64; ~, 3.58~
Fract1ons 12-18 and 19-27 (50 ml. each) are collected and conce~-
trated to afford 273 mg. and 208 mg.~ respectively, of acetylated product.
CrystQllization of the residue from ~ractions 19-27 ~rom petroleum ether
~ -72-
,:- :
:
G~
gives white cryst~ls (119 me ); m.p~ 84-88C. Recry~talli~ation from ethyl
acetate-h2xane (1:10) gIves ~ cis-5,6 6a~,7,:LO,lOa~-hexahydro_l_acetoxy_
3-(2-h~ptyloxy)-6~-methyl-benæo[c]quinolin-9(8H)-one, m.p 84-86C.
AIlalysi9: Calc'd for C23H3304N: C, 71.29; X, 8.58; N, 3.61%
~ound: C, 71.05; H, 8.48; N, 3.56%
Similarly, the following compounds are prepared from appropriate
reactants:
~ trans-5,6,6a~,7,10,10a~-hexahydro-l-acetoxy-6~-methyl-3-(5-
phenyl-2-pentyloxy)benzo[c~quinolin~9(8H)-one, m.p. 80-82C.
m/e - 435 (m )
AnalysiB: Calc'd for C27H3304N: C, 74.45; H, 7.64; N, 3.22%
Found: C, 74 43; H9 ~.73; N, 3.28%
d,l cls-5~6~6a~7~lo~loa~-hexahydro-l-acetoxy-6~-methyl-3-(5-phen
2-pentyloxy)benzo~c]~uinolin-9(8H)-one, m.p 172-176C. a8 the hydrochloride
salt from acetone-ether (1:1).
An&ly8i9: CQ1C'd for C27H330 ~ HCl: C, 6a.71;~H, 7.26; ~, 2.97%
F~u~d: C, 68086; H, 7 16; M, 2~97%
~ -trans-5,6,6~,7,10~10a~-hexahydro-1-acetoxy-3-(5-phenyl-2-
pentyloxy)-6~-propylben~o[c]~uinolin-9(8H)-@ne; m.p. 79-ôOC~
m/e - 463 (m )
~2_,-ci~-5,6,6a,B,7,10,10a~-hexahyaro-l-acetoxy-3-(5-phenyl-2-pentyl-
oxy)-6~-propylber~zo~c]gui~olin-y(8H)-one; m.p. 144-146a., a9 the HC1 salt.
m/e - 463 (m )
d-cis-5,6,6Q~,7,10,10s,B-hex~hydro-l-acetoxy-3-(5-phenyl~^2-pentyl
oxy)-6~-methylbenzo[c~gui~olin-g(8H)-onei mOp. 90-94C. (dec.) ss the hydro-
c~loride sQlt.
[~]D5 ~ +22.8 ~c=0.31, CH30H)
; m/e - 435 (m )
Analy9is: Calc'd ~or C27H3304N HCl: C, 68.71~ H~ 7-26; N, 2-97%
Found: C, 690~4; H, 7.30; N, 3.01%
-73-
~a
L86~
d-tr~ns-5,6,6a~,3,7,10,10~B-hexahydro-l-aceto~y_3_~5-phenyl~2-pentyloxy~ ~,
6~-methylbenzo[c]guinolin-9(8H)-one; mcp. 90-95Co (dec.) a~ the hydrochloride
salt.
" [~]25 a +78.46 (c=0013, CH30H)o
m/e - 435 tm )
~nQl~Bis: Calc~d Por C27H3304N HCl: C, 68.71, H, 7-26; N, 2-97%
Found: C, 70,20i H, 7.23; N, 3.07%
l-cis-5,6,6a~,7,10,10&~-hex&hydro-1-acetoxy-3-(5-phenyl-2-pentyl-
oxy)-6~-methylbenzo[c]quinolin-9(8H)~on~, m.p. 90-92C. as the hydrochloride.
[~D5 = -20.5 ~c=0.19, CH30H)
m/e - 435 (m )
Analysis: Ca~c'd for C27H3304~ HCl: C, 68.71; H, 7.26; N, 2-97
~` Found: C, 68.92; H, 7.23; N, 3.09%trans-5,6,6a~97,10,10a~-hexahydro-l-acetoxy-3-(5-phenyl-2-pentyl-
:
oxy)-6~-methylbenzo[c]quinolin-9(8H)-one; m.p. 92-96~C. &s the hydrochloride.
.~ [~]25 = _79,o (caO.lO~ GH30H)
~; m/e - 435 (m )
Analysis: Calc'd for C27H3304N-HCl: C, 68.71; H, 7026; N, 2097%
Found: C, 68.67, H, 7O23~ N, 3.02%
a~
d,l-5,6,6a,7,10,10a-Hexahydro-}-acetoxy-6~-mebhyl-3-(5-phenyl-
~; 2-pentylo_y)benzo[c]~ulnolin-9(8H)-one, brans- ~ isomers
Ammoni~ (1150 ml,) is conden6ed directl~ into a flame-aried 3 liter/
3 neck fl~sk ~under ~ nitrogen atmosphere) equipped with mecha~icRl stirrer,
a 500 ml. dropping ~unnel and eolid C02/aeetone cooling (~~75Co). I,ithium
,~ ~
wire (2.2 g., cu~ into l/41' pieces) is added and a characteristic blue color
forms immediately. To the 6tirred blue~solution at -78C~is added ~-5,6,
~ 6a,7-tetrahydro-1-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy~henzo[c~quinolln-
,! 9(8H)-one (21.5 g., 0.055 mole) dissolved in tetrahydro~uran (250 ml.) drop-
wise over a 10 minute period. After an addition~l 5 minutes q~ ~tirring at
78C., the reaction mixture is quenched by the addition of dr~ ammonium
_71~_
. ~
chloride (20 g.). The cooling is then discontinued and the reaction mlxture
warmed slowly on a steam bath to evaporate the ~Imonia. When almost dry,
ethyl acetate (2 liters) and water (1 }iter) are added a~d the mixture
stirred for 10 minutes. The layers are then sepQrated ~nd the aqueous phase
is extracted once more with ethyl acetat~ (500 ml.). The combined organic
extracts are washed once with water (1 liter), dried (MgS04) and concentrated
to a brown semi-solid (~28 e. ) . Thls residue i8 immediatelg dissol~ed in
methylene chloride (200 ml.), 4-dimethylaminopyridine (7.5 g., 0.061 mole)
and triethylamine (6.1 g., 0.061 mole) added and the stirred solutio~ cool-
ed to 0C. (ice/water cooling) under a nitrogen atmosphere. Acetic anhydride
(6.1 g.~ 0.061 mole) is then added dropwise over 5 minutes with good stirring.
After an additional 30 minutes of stirring at 0C., the reaction mixture ia
diluted with ethyl ~cetate (2 liters) ana water (1 liber) and stirred for
10 minutes. The aqueous is extracted once more with water and the combined
organics washed successively with water (4 x 1 liter), saturated sodium
bicarbonate (1 x 1 liter), brine (1 x 1 liter), dried (MgSOl~ and concen-
trated to a light brown oil (~27 g.)O The residue i9 chro~atographed on
1,8 kg. of silica gel using benzene 15/ethyl acetate as the eluting solvent.
One liter fractions are collected.
After elution of less polar impurities, fractions 16-20 are com-
bined and evaporated to a residue which is crystallized from ether/petroleum
ether to yield 5.6 g. (23.4%) of the trans-isomer of the title product.
~ Fractions 21-27 are combined to give 7.6 g. (31.8%) of a mixture of the
-~ trans- and cis- i~omers, and fractions 28-32 are combined to give 2.5 g.
~ 25 (10~4%) of the cis- isomer of the title product.
-~ The trans-isomer exhibits the ~ollowing characterists:
m/e - 435 (m+)
) ~CDC13 (ppm) 7-24 (s, 5H, aromatic), 5.97 t6
2H, meta H's), 2.28 (s, 3H, CH3-COO), 1.23 (d, 3H, CH3-CH-0-), 1.20 ~d, 3H,
-75-
.
36~
CH3-CH-N), 1.3-4.5 (m, 17H, remaining pratons).
~P0 - ol 83C.
Analy9i8: Calc'd ~or C2fH3304N: C, 74.45; H, 7.64~ N, 3.22%
Found: C, 74.15; H, 7068; N, 3.18%
The cis-isomer has the ~ollowing characteristics:
m/e - 435 (m )
M.P. of HCl salt - 172-176C. (dec.) (from acetone~ether).
Analysis: C~lc~d for C27H334N ~Cl C~ 68-71; H~ 7-265 N~ 2-97%
Found: C, 68.86; H, 7.16; N, 2.97%
EXaMPLE 30
-5,6,6a,7,10,10a-Hexahydro-l-acetoxy-6~-methyl-3-(4-phenyl-
butyloxy)~enzo[c~quinolin-9(8~)-one,
trans- and cis-isomers
Following the procedure o~ Example 28 ~ 5,6,6a,7-tetrahydro-l-
; hydroxy-6~-methyl-3-(4-phenylbutyloxy)benzo[c]guinolin-9(8H)-one i9 first
reduced with lithium ~nd ammonia and then acyIated to yibld the desired
hexahydro isomers. Separation by column chromatography on silioa gel using
; ether as eluant provides first ~ trans-5,6,6a~,7,10,10a~-hexahydro-1-
acetoxy-6~-methyl-3-(4-phenylbuty}oxy)ben~o~c]quinolin-g(8~)-one~ m.pO 155-
156C. after recrystallization ~rom ethyl acetate/pentant (1:5)o
Analysis: Calc'd for C26H3104N: C, 74008; H5 7041; Ns 3-32%
Found: C, 74.00, H, 7.47; ~ 3.22%
m/e - 421 (m )
Further purification o~ later ~.raot~ons by additional column
chrom~tography on sillca ~el using cyclohexane-ether (1:1) as eluant yields
the isomeric ~a_-cis-5~6,6a~,7,10,10a~-hexahydro-1-acetoxy-6~-methyl-3-(4-
phenylbutyloxy)benzo[c]guinolin-9~8H) one~ m.p. 95-96C. a~ter recrystal-
lizat~on ~rom ethyl acetate/hexane (1:5).
m/e - 421 (m )
Analysis: Calcld ~or C26H3104M: C, 74.o8; H, 7.41, ~, 3.32%
Found: C, 73.95; H, 7.51; ~ 3.31%
_76-
o
EXA~IPLE 31
dL_-5,6, ~ ,7,10,10a-hexah~dro-i-acQtoxy-3-~2-heptylo~
benzo[~lauinolin-9(8H)-one
A solution o~ -5~6,6a,7-tetrah~dro-l-h~Jdroxy-3-~2-heptyloxy)-
benzo-[c]quinolin-9(8H)-one (9,3 g,) in tetrahydrQfurQn (1~0 ml,) is ad~ed
dropwise to a rapidly stirred solution of lithium (0.1 gO~ in liquid ammonia
~750 ml.), An additional 0,1 g, of lithium is added portionwise during the
addition to insure a blue color, The mixture is stirred for 10 minutes and
then the blue color discharged by addition o~ excess ammonium chlo~ide. ~he
excess ammonia is allowed to ev~porate and the residue i3 taken up in a
mixture of water and ethyl acetateO The organic layer is separabed and the
aqueous phase extracted twice more with athyl acetate, The combined extracts
are washed with water, brine dried (MgS04) and evaporated to give 8,45 g, of
crude product as a brown solid.
The crude product (8.o g,) i9 suspended in methylene chloride ~48
mlO) at 0C, and treated with R,N-dimethyl-4-~minopyridine ~3,24 g.) and
triethylamine (3,72 ml,)O Acetic anhydride (2052 mlO) is then added to the
mixture which is then stirred for 30 minutes at 0C, It is dil~ted with
methylene chloride t300 mlO) and the methylene chloride layer separ~ted,
20 washed with water (3 x 150 mlO), saturated sodium bicarbonate (1 x 100 mlO),
brine (1 x 100 mlO), and dried (MgS04), Evaporation of the methylene
; chloride gives 13,7 g, of dark oil which i9 chromato~raphed on a silica gel
(450 g,) column, The column i8 eluted sequentiall~ wlth ether-hexane (l~
ether-hexane (2:1) and ether. Fracbions of 18 ml, each are collected,
25 Fractions 176-224 are combined and concentrated to an oil which is crys-
talli~ed from hexane to give 3,24 g, (32~) yield of the trans-isomer of the
title compound as light yellow crystals; m,p, 65,5-68C,
m/e - 373 (m )
IR (KBr): 5,82 (ketone C=0)~ 5,75 (ester C=0), 295 (NH) ~,
Frac~ions 246-290 are combined and concentrated to giYe 0,55 g,
(5%) of crude cis-isomer of the title compound as ~n oil, It is purified
-77-
'
36~
further by column chromatography as deacribed above to give the pure cis
isomer as an oil,
n/e - 373 (m )
IR (CHC13): 5.82 (ketone C~0), 5.67 (ester C=0), 2.92 (~H) ~.
Analysis: Calc'd ~or C22H3104~J: C, 70O75; H, 8.37; U, 3.75 %
Found: C, 70.90; H~ 8054~ N~ 3,79 %
Fractions 225-245 are combined and e~aporated to giV9 2069 g.
~` (26%) of a mixture of cis - and trans-isomers ~hich are separated by the
procedure described above.
The following compounds are similarl~ prepared from ~ -5,6,6a,7-
~; tetrahydro-l-hydroxy-3-(5-phenyl-2-pentyloxy)benzo[c]quinolin-9~8H)-one:
~ -trans-5,6,6a~,7,10,10~-hexahydro-1-acetoxy-3-(5-~henyl-2-
pentyloxy)benzo~c~quinolin-9~8H)-one, an oil.
m/e - 421 (m )
Analysis: Calc'd for C26H310~N: C, 74~089 ~, 7.41; N, 3.32 %
Found: C, 74,16; H, 7-59, ~? 3-20 %
d,l-cis-5,6,6à~,7,10,10a~-hexahydro-1-aoetoxy-3-~5-phe~yl-2 pentyl-
o~y)benzo~c]quinolin-9~8H)-one, an oil.
; m/e - 421 (m )
Analysi8: Calc'd for C26H3104N: C9 74.o8; H, 7.41, N, 3.32 %
Found: C, 74.04; X9 7.4~; ~, 3.54 %
and dl-5,6,6a,7-tetrQhydro-l-hydroxy-6~-methyl-3-~5-phenYl-2-
pentyloYy)benzo~c]qui~olin-9~8H)-one i~ convert~d bo:
; dl-trans-5,6,6a~7,10,10a~-hexahydro-1-acetoxy-6~-methyl-3-(5-
phenyl-2-pentyloxy)benzo~c~quinolin-9(8H)-one,
and: dl-cis-5,6,6a~,7910,10a~-hexahydro-l-acetoxy-6~-methyl-3-~5-
phenyl-2-pentyloxy)ben~o~c]quinolin-9(8~)-one.
The isomeric product~ are transformed to their hydrochloride qalts
;
~ as described in the general proced~re of salt ~ormation. Characterizing data
.;
:~30 on the salts is provided below:
. ~ .
.~ ,.
~ICl Salt /t R (a)
Isomer ~ ~m ) f C H N
trans 107-110 l~35 o 74 68;92 7.172.86
cis 94-1~2 1~35 0 72 68.7~ 6.933.12
5 (a) thin layer chromato~r~phy in ben~ne/ether ~
(~) Calc'd for C27H3304~'HCl C, 68 71; H~ 7-26;
~ ~.
d,l-~rans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetoxy-9-hydroxy-
6B-meth~rl-3-(2-hevt~lox~)benzo~cJquinoline
To a stirred su~pension of 150 mg. (0.39 mmolej d,l-trans-5~6,6a~,
7,10,13a~-hexahydro-1-acetoxy-6~-methyl-3-(2-heptyloxy)-beDzo[c]quinolin-
9(8H)-ona in ethanol (10 ml.) at 0C'~ i9 added 40 mg. of sodium borohydride.
After 0,5 hr., the reaction mixture i3 ooured inbo a mixture of ice cold 5%
acetic acid (50 ml.) and ether (75 ml.). Afber separation of the ether
layer9 the agueous phase is extracked further with ether (2 x 50 ml.). The
combined ether extracts are wa hed successively with water (2 x SO ml.)~
saturated sodium bicar~onate (1 x 50 mlO), brine ~1 x 75 ml.), dried (Mg~4)
filtered and concentrated under reduced pressure to yield 156 m~. of a white
foam containing a mixture of the axial (minor ~mount) ~nd equatorial (maJor
20 amounb) alcohols Or ~ -trans-5,6,~a~,7,8,9,10,10a~-octahydro-1-acetoxy-g-
hydroxg-6~-methyl-3-(2-heptyloxy)benzo[c]quinoline.
m/e - 389 ~m )
IR (CHC13) 5.72~ (ester carbonyl).
~MR (60 M~z, ~CD~l ) - showea a c~aracteristic ~ingle-t at 2,28 ppm
5 Por the acetate methyl.
r~he ma~or and minor i~omers are ~epa~ated in the following manner:
180 mg. of the alcohols of ~ -trans-5,6,6a~,7,8,9,10,10a~-octab~dro-1-
acetoxy-9-hydroxy-6~-methyl-3-~2-he~tyloxy~-benzo~c]guinoline are charged to
a col~n containing 15 grams oP ~ilica ~el ~nd eluted with a 301vent mixtura
0 o~ 3 parts benzene to 1 part ether. 15 ml. Fractions are collected.
-~9-
Fractions 6-8 are combined and concentrated under r~duced pre~sure to yield
13 mg of ~L_-trans-5,6,6a~,7,8,9,1O,10a~-octa~ydro-1-acctoxy-9~-hydroxy-6~-
met}~ 3-(2-heptyloxy)-benzoEc]g,uinoline.
Fractions 11-16 are combined and coneentrated to yield ô3 m~. of
dl-trans-5~6~6a~7~8~9~lo~loa~-octahydro-l-Qcetoxy-9~-hyaroxy-6~-methyl-3
~2-heptyloxy)benzo~cJquinoline.
Other compounds prepared from appropriate reactants by the above
procedure include the following:
dl-trans-5,6,6a~,7,8,9,1O,~0a~,octahydro-1-acetoxy-~-hydroxy-6~-
methyl-3-(5-phenyl-2-pentyloxy)benzo~cJquinoline.
m/e - 437 (m )
IR (CHC13) - 5.70 ~ (ester carbonyl)
Conversion to the hydrochloriae yielded a solid (m.p. 188-19~C.).
Recrystallization f`rom acetone/methanol/~ther (25:1:100) af`ford~ an
15 analytical sQmple of the 9~-aleohol, m.p. 193-194C.
AnQlysis: Calc'd for C27H35O4N.HC~: C, 68.42; ~, 7.66, N, 2096%
Found: C, 68 48; H, 7.7O; N, 2.89%
Conversion to the methane~ulfonate (with methanesu}fonic aeid in
dichloromethane) gives a solid which is recrystallized from ethyl acetate to
20 gield white erystals, m.p. 110-114C.
IR (CHC13): 2.95, 3.70, 3.95, 5.60, 6 o6, 6.~ and 6.27 ~
Analysis Cale'd for C27H35O4N~CHl03$: C, 63.02; H, 7.37; N, 2~63 %
Found: C, 62.90; H, 7.31; N, 2074 %
~; -cis-5,6,6a,B,7,8~9,10,10a,B-Qctahydro-l-acetoxy-g-hydroxy-6~-
:
methyl-3-(5 phenyl-2-pentyloxy)be~zo~cJquinoline
m/e - 437 (m )
IR (CHC13) - 5.71 ~ (ester carbonyl)
- ~-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetoxy-9~-hydro~y-6~-
meth~l-3-~5-phenyl-2-pentyloxy)benzo[e]quinoline, m.p. 120~-125C (dec.) as
the hYdroehloride salt.
-80-
.
[a]D5 a -98.57 (c-0.351, CH30H)
m/e - 437 (m )
Analy~is Calc'd f~or C27H3504N.HC1: C, 68.42; H, 7.66; N~ 2-96
Found: C, 68.24; H5 7.68; ~, 3.00~0
5d-trans-5~6~6a~7~8~9~lo~loaQl~oct~hydro l-~cetoxy~9B-hydrox~r-6~-
methyl-3-(5-phenyl-2-pentyloxy)benzoEc]quinolilne; m.p. 120-125C. ~dec.)
as the hydrochloride salt.
['~D = ~99 33 (c=0.30, CH30H)
m/e - 437 (m
Analysis: Calc'd ~or C27H3504N.~ICl: C, 68.42; H, 7.66, N, 2.967Found: C, 68.41; ~I, 7.54; N, 2.95%
In like ma2~ner, the compounds tabulated below are prepared ~rom
~ppr ~pri~ts re:ct~nts .
-
~ - ~
6~
O ~ ~ ~
~;1 o o o
o ~ ~ ~ o
o ~ 0
0 ~ o~ 0
U~
o ~ U~
; C~
~D O ~ ~ ~
'`' ~ ~U ~
~; C~l ~ ~ ~ ~.
~ \D U~
o ~ ~3 0
0
.
o ,,
.~: ~ ~ ~ ~o o ~
~i Z
o;t o~ o o~
U~
~o ~ ~ x
~ ~ ~ C J N ~ N ~ O
U r ~
g~
~f, y ~ ~ N ~ ~ N ~D
4: ^ O ~U~ CO \D
I CO ~r-~ 11 N r
o r~ 1 C~ co~l O
* I
r~ r~ r~ rlrl O
~ ~ Q bD
~ V
V X X X ~ ~ ~ P ~ o
~J N N N ~ ~ N N
r~ ~ r~ ~ r~l ~ r~ X r l ~--i r~ r~ ~ r~
1 ~ r~ ~ rl ~> r~ ~ r~ r I ~ r~ ~d
. a) ~ a) ~ ~ o X ~) x ~
.. ~ $ ~$
~ -82-
' ~
., ,-. ~ , ,
:~ , .
36C)
E(_
dl-trans-5,6,6a~,7,8,9,10,10a~~ocbahydro 1-acetoxy-9~-
hydroxy-6~-
Sodium borohydride ~7 57 g~3 0 20 mole) is added to
methanol ~200 mlO) under a nitrogen atmosphere and cooled in anacetone/dry ice bath to about -75C. qhe mi~ture i8 stirred ~or about
- 20 minutes to dissolve most~ 1~ not all, the sodium borohydride. A
solution of dl-trans-5,696a~,7,10,10a~-hexahydro-l-acetOxy-6~-me~hyl-
- 3-(5-phenyl-2-pentyloxy)benzo~cJquinolin-9~8H)--one (ô.71 g., 0 02
10 mole) in tetrahydrofuran t88 ml ) i9 cooled to about -50Co an4 then
added dropwise over a 5-10 minute period to the sodium borohydride
solution The reaction mix~ure is stirred at about -70C. ~or 30
minutes and is then poured onto a maxture o~ water ~1000 ml.) con-
taining ammonium chloride ~45 g., o,80 mole), crushed ice ~250 ml.)
and ethyl acetate t250 mlO) The layers are separated and the a~ueou9
extracted with ethyl acetate (3 x 200 mlO). The combined extracts
are washed with water ~1 x 100 mlO) and dried (MgS0~ he dried
extract is cooled to about 5C A solution of ethyl acetate ~15 mlO)/
HCl7 1 5N (00025 mole) i~ then added dropwise over a 15 minute perlodO
Upon stirring the mixture at 0-5C , the hydrochloride salt of bhe
title product precipitates The mixture as sbirred for Q half-hour~
filtered and the salt dried at 25C /0.055 mm, to give 6,378 g
(67.3%) o~ product, m p 195-198C. (dec.).
Alternatively, bhe title compound is prepared by the
~ollowing procedure.
-trans-5,6,6a~,7,8,9~10,10~-octahydro-1-acetoxy-9~-
A heterogeneous mixture o~ ~L~-5,6,6a,7-tebr~hydro-1-
acetoxy-6~-methyl-3-(5-phenyl-2-pentyloxy)ben~o[c]quinolin-9(8H)-one
30 (3O0 gO~ 7 mmole) and palladium-on-carbon (5%, 300 g.) in methanol
(30 ml.) i hydrogenated at room temperature i~ a Parr &pparatus
-83_
under 50 p.soi. hydrogen for three hour~. rLhe catalyst is then fil-
tered and the ~ethanol filtrate evaporated under reduced pre~sure to
give the title product.
The product is taken up in ethyl aaetate (300 mlO) and
the resulting solution cooled to 0C. An excess of a ~aturRted 901u-
tio~ of hydrogen chloride in ethyl acet~te is then added to precipitate
~; the hydrochloride salt o~ the title product as ~ white o}idO It i
filtered, washed with ethyl acetate, and driedO
The d~l-5,6,6a,7-tetrahydro-1-aceto~y-6~-methyl-3-~5-
phenyl-2-pentyloxy)be~zo[c]r~uinolin-9~8H)-one i~ prepared as follow~.
'I'o a stlrred solution of d11-5,6,6a~7-tetrahydro-1-hYdrOXY-
6~-methyl-3-(5-phenyl~2-pent~}oxy)benæo[c~quinolin-9~8H)-onr3 (4,5 gO,
0.0115 mole) in pyridine (45 nllO) at room temperatUre i9 added acetic
anhydride (45 m}0)O 'Ihe resulting ~olution i~ stirred for 3,5 hours
and is then poured onto iqe~water(250 mlO) and the mixture extracted
with diisopropyl ether (2 x 250 ml.). The combined extracts are -
~ashed with ~ater (3 x 200 mlO)~ dried (MgS04) ana evaporated und~r~
reduced pressure to a ye~low-bro~- oil which solidifies on scratching
the walls of the ~lask containing ito Trituration of the solid wit~
n-hepta~e gives 200 g, of the 1-~cetoxy derivative (40% yield)O It
i9 purified by recrystallization from hot chloroform-~-hexQne (1 4
to give the pure ester;m.p~ 136-140C.
m/e - 433 (m )
H NMR (60 MHz) ~ CD 1 (ppm): 7,21 (b~, 5H, aromabic),
6062 ~d, J=1,5 Hz, lH, C~C H)~ 5097 (d, J=3 Hz, lH, meta H~, 5,ô6 (d,
J=3Hz, lH, meta E), 2027 ~s, 3H, CH3-C(=0)], },21 ~d, J=7Hz, 6H, CX3-
.' ~ C-~7 CH3-C-0), 1049-4051 ~m, 14H, remaining protons)~ -
"
~: . .. . . . .
~.
; -84-
.
: .
~Lf~ L8~ "
EX~MPLE 34
dl-cis-5,6,6a~,7,8,9,10~10a~-octahydro-1-aaetoxy-9~-
hydrox~6~-methyl-3-~5-phenyl-2-pent~loxy)benæo ~ _
To a solution o~ dl-cis-5,656a~,7~10,10a~-hexahydro-l-
acetoxy-6~-methyl-3~(5 phenyl-2-pentyloxy)benzo[c]guinolin-9~8H)-one
(1.0 g" 2.296 mmole) in dry tetrahydrofuran (lt)0 ml ) at -78C. i9
added, with stirring, potassium trl-3ec-but~l borohydride ~406 ml. of
0.5M, 2.296 mmole) dropwise over a period o~ five minut~3. me re-
action mixture is stirred an additional 30 minutes ~t -78C. and is
then poured, with stirring,~into Q solution of 5% acetic acid (250 ml.)
and e~her (500 ml.) pre-cooled to 0C0 The layers are separ~ted and
the ~gueous layer e~.tracted with additional ether ~250 ml ). The
combined ether extracts are wQshed successively with water ~2 x 250
ml.), satùrated sodlum bicarbonate solution ~1 x 250 mlO) and brine
15 (1 x 250 ml.), dried (MgS04) and concentrated ln vacuo to gi~e c
yello~ oil (104 g )0 The cruds oil is chromato~raphed on siliQa gel
(100 g.) using benzene/ether ~3 1) as eluantO After elution o~ less
polar impurities, the title compound i9 i~olated a3 a clear oil
(700 mgO). me oil is dissolved in ether (35 ml ) and tr~ated with
ether saturated with HCl gas to give the bydrochloride ~alt o~ the
title compound t448 mg~), m~pO 115-124C~ a~ter recrystallization
from ether/chloro~orm
~S (mol.ion) - 437.
IR (KBr): 5.58 ~ ~ester >C-3).
Analy~i8: Calc'd ~or C27X354N HCl: C, 68041~ H~ 7066;
~ .
FoundO C, 68052 3 H, 7.91;
N, 2,~3% `
e ~ollowing compounds are prepared in like manner from
appropriate reactants:
` .
85-
.: ~
:
R
~ ~ ~ 3
R
R
-Z-W R4 R5 6 8 (C.)
-- _ __ _
5-phsnyl-2-pentyloxy CH3 H H !~H 16a-170 437
: H CH3 H ~ H oil
H CH3 H ~ I oil 437
*HCl s~lt. Analysis:
Calc'd for C27H350~N,HC1: C, 68,41; ~, 7.66; ~, 2.96 %
Found: C, 68.48; H, 7.57, N, 2~93 %
dl-trans-596~6*~B~7~8~9~lo~loc~ octahydro-l~g-diacetoxy-6~B
1 2 gO O~tbe unchromatographed reduction product of dl-
; trans-5,6,6a~,7,10,10a~hexahydro-1-acetox~-6~-methyl-3-(2-heptyloxy)
benzoEc]-quinolin-9(8H)-one from Example 40 is stirred with excess
acetic anhydride and pyridine overnight at room temperature. ~he
mixture is poured into ice water, the agueous mixture extracbed with
et~e~ (3 x 100 ml.` ~nd the combined extract~ washed with water,
brine, then dried (MgS04) and evaporated, ~he residue i8 sub~ected
to column chromatography (40 g silica gel, benzene/ether ~9:1~ as
eluting solvent) to give 680 mgO of the desired dl-trans-5~6~6a~7~8
9,1Q~a~-octahydro-1,9-diacetoxy-6~-methyl-3 (2-hepbyloxy)be-n~o[c]
, ~
quinoline~ which cryætallizes on addition o~ hexane a~ ethyl
acetate? m.p. 86-87C.
_86-
m/e - 431 (m )
IR (K:13r) ~ 5073 u (ester carbonyls)0
H NMR ~60 MHz) ~CDCl (ppm): 5.88 (bs, H2, X4 - 2H), 2.28
and 2.05 [2 three-p3 oton 9in~;1et5, CH3-C(=~0)-], and ca. o.8-~.o
5 (multiplets, remaining protons).
Analysis: C~lc'd fo~ C25H3705~: C3,269%57;
Found: C, 69.51; H, ô.54; ~,
3014 %
Similar t~reatment OI 60 mg, dl-trana-5,6,6aB,7,8,g,1~,IOa~-
octahydro-l-aceto3cy-9B-hydroxy-6B-methyl-3-(4-phenylbutyloxy)benzo~o~
10 quinoline in pyridine ~1 ml.) and acetlc anhydride ~1 ml.) ~or 1
hour at room temperature yields the desired dl-trans-5,6,6~B,7,8,9,
lO,lOaa-oçtahydro-1,913-diacet~xy-6~-methyl-3-~4-phenylbutyloxy)benzo
[c]quinoline, mOp, 146-147~C. after recryætallization from ebh~1
acetate/hexane (l l ) o
m/e - 465 (m )
Analysis: Calc'd for C 8~ N C, 72023; ~I, 7058; N,
- Found: C, 72017; H, 7~61; N,
3~08 %
EXAMPLE 36
.~,al-tran~-5,6,6a~,7,8,9,10,10acL-octahydro-1~9-dihydroxy-6,B-
A solution of 130 mg. ~_-trans-5,6,6a~,7,8,9,10,10a~-
octahydro-l-acetoxy-9-hydrox~r-6B-methyl-3-~2-hep~yloxy)-be~zo~c]
quinoline and 46 mg. potassium carbonate in 35 mlO m~thanol iæ stirred
at room temperature. After 30 minutes, the reactiotl mixture i9
Z5 neutrRlized with acetic acid and concentratea under reduced pres-
sure, lrhe residue i8 dissol~red in ether (100 ml ), w~æhed successi~ely
with water ~2 ~ 35 mlO), saturated sodium bi;~arbonate ~1 x 35 ml.~),
brine ~1 x 40 ml.), driod ~MgS04) and concentrated under reduced
-87-
pressure to give 96 mg. ~ -trans-5,6,6a~,7,8,9,10,10Q~octahYdro-1,9-
dihydroxy-6~-methyl-3-(2-heptyloxy)-benzo~c]quinolln~ a~ an amorphou~ ~olid,
m.p. 80-100C. (dec.).
m/e - 347 (m )
The NMR (CDC13, 60 MH~) Rhow~ no absorption ~or the acetate
methyl and the IR (CHC13) had no ab30rption for an ester oarbonyl.
In like manner, the following compound ic prepared from the
corresponding l-acetoxy deri~ati~e of Ex~ple 32,
d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1,9-dihydroxy-6~-
methyl-3-(5-phenyl-2-pentyloxy)benzo[c]~,uin41ine.
mte - 395 (m )
Conversion to the hydrochloride gives a powder, m.p. 151-156C.
~3
IR (KBr): 3.00, 4.00 (EN~), 6.10 and 6.25 ~.
Similarly, d:,l-tranc-5,6,6a~,7,10,10a~~hexahydro-1-acetoxy-5-
methyl-6~-methyl-3-(2-heptyloxy)benzo~c~quinolln-9~8H)-one i 8 hydrol~zed
to the corresponding l-hydrox~ compound; m pO 157-160C.
m/e - 359 (m )
Analysis: calc~a for C22H3303~: C, 73.50; H, 9.25, ~, 3.90 %
Found: C, 73.16, H, 9.14; N, 3.85 %
- 20 EXAMPLE 37
-tranc-5,6,6a~,7~10,10a~-hexahydro-1-acetoxy-3-~2-heptyloxy)-
5-ben~oyl-6~-methylben$o~c~ ~uinolin-9~8~)-one
; To a stirred solution of the product of Example 28 d,l-trans-5,6, ~a~j,7,10,10a~-hexahydro-1-acetoxy-6~-methyl-3-(2-heptyloxY)-benZo[c3
quinolin-9(8H)-one (812 mg.) in 2.5 ml. ~yridine ia added 421 mg. ~enæoyl
chloride in 5 ml. chloro~orm. After two hours, the reaction mixture is
~,
poured onto ice and extracted twice with ether. The combined ether extract~
; are washed with water, ~odium bicarbonate, dri~Q (MgS04) ~na~filtered to
yield, a~ter concentration and cr~stallization from ether/petroleum ether,
~ -tran~-5,6,6a~,7,10,10a~-hexahydro-1-acatoxy-3-(2-hept~loxy)-5-benzoyl-
~8~-
:` :
&~3
6~-methylbenzo[c3quinolin-~(8H)-one, m.p. 108~-:L10C.
m/e - 491 (m )
~ epetition of this procedure but using an eguivalent amount of
acetyl chloride in place of ben~o~l chloride an~ the ~ppropriate benzo~a~
quinoline af~ords the followi~g compound:
~ L_-trans-5,6,6a~,7,10,10aa-hexahydro-l-acetoxy-3-~2-heptyloxy)-5-
acetyl-6~-methylbenæo~c]quinolin-9(8H)-one.
m/e - 433 tm )
1~ d,l-trans-5,6,6a,B,7flO,lOao~-hexs.hydro-l-~cetoxy-5-methyl-6,B-
To a stirred solution of 387 mg. ~L_-trans-5,6,6a~,7,10,10a~-
~exahydro ~l-acetoxy-6~-methyl-3-e2-heptylox~)-ben~Lc]quinolin-9~8H)-one
ln 3 ml. acetonitrile cooled to 15C. is added 0.5 ml. 37% aqueous form-
aldehyde ~ollowed by 100 mg. aodium cyanoborohydride. Acetic acid is addedto maintain a neutral pH until the reactlon is complete a~ e~idenced by no
remaining starting material by thin layer chromatography The~product i~
isolat~d in the following manner
Ice water and ether is added to the reaction mixture, the ether
layer separ~ted and the ~queous extracted once more with ether. The com-
bined ether layers are combinqd, dried and evaporated to yield the desired
d~l-trans-5,6,6a~,7,10,10aa-hexahydro-1-acetoxy-5-methyl-6~-methyl-3-~2-
heptyloxy?-benzo[c]quinolin-9~aH)-one as an oil.
H NMR (60 UHz, CDC13) show~ a charQcteristlc absorption at 2.85
ppm for ~-CH3.
In like manner, the following compounds are prepared from ~ppro~
priate reactants:
.~
d~l-trans-5,6,6a~,7,10,10aa-hexahydro~-1-acetoxy-5-methyl-3-(2-
heptyloxy)ben~o[c]quinolin-9(8H)-one, an oil.
~ trans-5,6,6a~,7,8,9,10,10aa-octahydro-1,9-diQcetoxy-5-methyl-
-89-
'
. ~ : , , . ~ . .
~-methyl-3-(2-heptyloxy)benzo[c~q~inoline, an oilO
mle - 445 (m )
In addition, the following compound3 are simil~rly prepared:
¦ ¦~ 0-C-CEt3
~`
R4 ~ ~ Z-W
16
m/e
z_~ 4 ~ 6 R8 M.P
.-- - - - _
~H3
-0-~H-(CH2)3C6H5 CH3 H CH ~H 9l~_97C. 449
ICH3
-0-CH-~CH2)3C6H5 CH3 El CH3 J~H oil2 4L~9
--(CH2)4c6H5 CH3 H CH3 ,~IlH 102-103C.3 435
~: lAs the HCl s~t.
Analysis:
Calc'd ~or C28H3504N.HCl: C, 69019; H, 7~47; N, 2~88 %
Found: C9 68 72; H, 701.8; N, 2074 %
: 2Analysis:
Calc'd for C28H3504N: C, 74.80; H, 7085; N, 3012 %
15 ~ Found: C, 74066; H, 8005; N, 2066 %
m.p. 69-75 C. as the HCl saltO
3Analysis:
CaIc'd for C27H3304~: C, 74045; H~ 7 64; N, 3022 %
Found: C, 7308gi H~ 7 51; N, 3004 %
EX~MP~E 39
-trans-5~6,6a~,7~8,9,10,10a~-octahydro-1,9-dihydroxy-5-
To a solution o~ 100 mgO llthium aluminum hydride 1~ 5 ml.
dry tetrahydro~uran (ccoled in an ice/ water bath) i3 added dropwise
--go--
`
. ~
a solution of 90 mg. ~ -t~ans-5,6,6a~,f,8,9,10,10a~-octQhydro-l,9~dihydroxy-
5-acetyl-6~-methyl-3-(2-heptyloxy)ben~o~c]quinoline in 3 ~1, tetrahydrofura~0
After the addition is complete, the reaction mixture i~ heated at reflux for
one hour and is then allowed to cool to room temper~ture. Eguivalent
amounts of water, followed by 3N pota~slurn hydroxide are added, the re9ulant
precipitate filtered and the filtr~te concentrated in ~acuo to yield the
de3ired N-ethyl derivative as an oil.
m/e - 375 ~m )
EXAMPLE 40
d~l-trans-5,6,6a~,7,8,9,10,.10a~-octahydro-1-acetoxy-9-hyQro~y-
For~aldehyde (1.1 ~1. of 37% aqueous) iQ added to a solution of
~ -trans-5,6,6a~,7,10,10a~-hexahydro-1-aceto$y-3~(5-phenyl-2-pentyloxy~
benzo~c~quinolin-9(~ one in acetonitrile (15 ml.) at ro~m temperature,
followed by sodium cyanoborohydride (0,262 g.). The reaction mixture iB
stirre~ for one hour during which time the pH is maintained at neutral pH
by ~ddition of acetic acid as needed. Additional sodium cyanobrohydride
(0.262 g.) and methanol (15 ml.) are added to the reaction mixture,~which
i5 thqn acidified to pH 3, stirred for two hours, and concentrated under
reduced pressure to an oil. The oil is diluted with water (59 mlO) the pE
then ad~usted to 9-10 by means of agueous sodium hydroxlde~ and the alkaline
mixture ex~racted with ether (3 x 200 ml.). The combined ether extracts are
washed with brine, dried (~a2S04) and concentrated under reduced pres~ure to
a clear oil. The oil is then dissol~ed in 5Q~ ether hexsne and charged to
a silica gel column The column is eluted fir~t with 50% ether-hexane
followed by 60%, 70% and 75% ether-hex~ne~ The eluate 1~ monitored b~ thin
layer chromatography (ether-10, hexane-l)0 The first product collected i
s~L-trans-5,696a,7,10,10a-hexahydro-l-acetoxy-5-methyl-3-(5-phenyl-2-
pentyloxy)benz~[c]quinolin-9(8H)-one (O.125g )
m/e - 435 (m )
' ' , '
~nAlygl8: Calc d ~or C27H33~4N , 7 5; ~ 7 ; , 3 %
Found: C, 71ioO6; H, 7.77; N, 3.31 %
The second product i9 the 9~-hydroxy diastereomer o~ the title
compound (25 mg.).
m/e ~ 437 (m )
An~lysis: Calc'd ~or C2~H~504N: C, 74.11; H, 8.o6; N, 3.20 %
Found: C, 73.96; H3 8.34; N, 3,00 %
; The third product is the 9~-hydroxy diastereomer o~ ~he title com-
pound (0 7 g.)
~/e - 437 (m )
;~ An~ly8is: Calc'd ~Gr C27H3504N: C, 74.11; H9 8.o6, N, 3.20 ~
Found: C, 73.56; H, 7,86; N, 3.21 %
Similarly, ~ trans-5,676a~,7,10,1aa~-hexahydro-l-acetoxy-3-(2-
heptyloxy)benzoEc]quinolin-g(8X)one i~ troated with sodium cyanoborohydride
to give:
d,l-trans-5,6,6a~,7,10,10aa-hexahydro-1-acetoxy-5-methyl-3-~2-
heptyloxy)ben~o[c]qulnolin-9(8H)-one 69 an oilO
m/e - 387 (m~)
IR (CXC13): 5.80 ~ketone C=0), 5.65 (ester CaO), ~.
Analysis: Calc'd ~or C23H330l~N: C, 71-29; H, 8.58; N, 3.61 %
Found: C, 70~78, H, 8.71; N, 3.27 %
~ -trans-5,6,6a~,7,ô,9,10?10~o~-oct3hydro-l-s.cetoxy-9,B-hydroxy-5-
methyl-3-(2-heptyloxy)benzo[c]quinoline9 an oil.
m/e - 389 (m )
IR (CHC13): 2.80 (0-H)9 5,70 ~ester C~0), ~.
Analysis Calc'~ for C23X35~4N C, 70.g2; X, 9.06~ N~ 3 60 %
Found: C, 70.56; X, 8.95; N, 3.56 %
and d,l-trans-5,6,6a~,7910,10aa-hexahyaro-l-acetoxy-6~-meth~1-3-~5-phenyl-
2-pentyloxy~benzoEc]quinolin-9~8H)-one is converted to:
~ trans-5,696a~97,10,1Qa~-hexQhydro 1-acetoxy-5-methyl-6~-
~ -92-
methyl-3-(5-phenyl-2-pentyloxy)be~zo[a]quinolin-9(8H)~one;
~L_-trans-5,6,6a~97,8,9,10,10a~-octahydro~ cetoxy-9~-hydroxy-5-
methyl-6~-methyl-3-(5-phenyl-2~pentyloxy)benzo Ec ] ~uinoline, which is isolatedaq the hydrochloride salt; m.p. 163~-165C,.
S m/e - 451 (m )
EXAMPhE 41
dl-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetox~-5-asobubyryl-
A solution of isobutyryl chloride (114 mg., 1.07 mmole) in chlor-
form (20 ml,) i8 slo~ly addPd with ~qtirrin~ to a solution of dl-trans-5,6,
6a~,7,1G,lOa~-hçxahydro-l-acetoxy-3-(5-phen~1-2-pentyloxy~ben~olc]quinolin-
9~8H)-one (450 mg., 1.07 mmole) in dry pyridine ~1.5 ml.) at 0CO and under
a nitrogen atmoqphere. The reaction mixture ia ~tirred far fire hours and
i9 then poured into ice/water ~50 ml.). The chloroform lQ~er i~ ~eparated
; 15 and the aqueous layer extracted with chloro~orm ~2 x 20 ml.). The chloro-
form extracta are combined and washed with 10% hydrochloric acid
(2 x 10 mlO), followed by brine ~l~x 10 mlO), and then dried ~MgS04)o Con-
centration of the chloroform solu~ion in vacuo ~iYe a ~ellow oil which
solidifies upon standing. Tritur~tion of the solid with hexane af~ords a
white cry~talline solid, which i8 recovered by filtration and dried
(400 mg.), m.p. 128~129C.
Concentration of the hexane ~iltrate gives 121 mg. of oil.
EXAMPLE 42
dl-trans-5,6,6a~,7,8,9,10,10~-octahydro-1-acetoxy-9~-b~droxy- -
Sodium borohydride (38 mg., l O mmole) is slowly added to a
~olution of dl-trans-5,6,6a~,7,10~,10a~-hexahydro-1-aoetoxy-5-iiobutyryl-3-
(5-phenyl-2~pentyloxy)benzo[c~quinolin-9(8H) one ~260 me., ~,529 mmole)
in a~301ute ethanol (20 ml.) 5-lO~C, under a nitrogen atmo3phere. ~he
; I :
reaction mixture is stirred for one hour and i8 then acidified ~ith 10%
hy~rochloric acid. ~he ethanol i~ removed by C~ncentrQtiOn under reduced
-93-
.. . . .
.: ' ,. .
.: ~
-
8~i~
pressure. Water (10 ml~) i8 added to the remainlng solution which i~ then
extracted with ethyl acetate ~2 x 50 ml.). The extracts are combined~
washed t~ith brine and then dried (MgS04). Concentration in vaouo affords
the title compound as an amorphou~ solid (213 mg.) which is used withou~
further purification.
EXAMPLE 43
dl-trans-5,6,6a~,7,8,9,10,1,0Qcl-oc~Qhydro-199~-aiacetoxg-5-iso-
: but~r~l-3-(5-phenyl-2-pent~loxy~benzoEc~qulnoline
Unde-r a nitrogen atmosphere, a solution o~ trQns-5,6,6a~,7,a,
9510,10a~-octahydro-l-acetoxy-9~-hydroxy 5 isobutyryl-3-(5-phenyl 2-
pentyloxy)benzo~c]quinoline (213 mg., 0.432 mmole) in tetrahyarofuran ~5 ml.)
is added to a slurry of lithium aluminum hydride (100 mg., 2.6 mmole~ in
tetrahydrofuran (5 ml.) at room temperature. The mixture iB stirred over-
night and then water (0.1 ml.), 15~ sodlum hydroxide solution (0.1 ml.) and
water (0.3 ml.~ are added. It i~ then ~iltered under nibrogen and the
filter cake washed with tetrahydrofuran (2 x 5 ml.). The combined filtrate
- and wash solution are concentrated to a reddish oil ~0 174 g.).
- The oil is dissolved under nitrogen in pyridine (1 ml.) and the
solu~ion cooled to 0C. ~oetic an~ydride (1 ml.) is added, with stirring,
to the pyridine solution and the reaction mixture stirred for 30 minutes at
0C It is then poured into water (25 mlO) and extracted with ethyl acetate
(3 x 25 ml.). The extracts are combined, washed with brine, dried ~MgSOL~)
and concentrated to a brown oil (184 mgO). The oil is ~lushed with nitrogen
and chromatographed on silica gel (40 g.) u~ing benzene/ether (9:1) as
eluant. Fractions of 10 mlO each are collected. Fractions 2-10 are combined
and concentrated to an oil (109 mg.).
m/e - 521 (m )
~nalysis: Calc~d ~or C32H4305N: C, 73.67; H, 8.31; ~ 2068 %
Found: C, 74.33; H, 8.89; ~, 2023 %
) CDC13 (PP~): 7-22 (s, 5H, aromatic) 6 05
~94-
:
~lQ~
(d, l~I, aromatic), 5.90 (d~ 1~, aromatic), 4,90 ~bs, l~I), 4.30 (bs, lH),
3.10 (d, 2H, N-CH2), 2090 (d, 2~ CH2), 2.70 (bs, 2-l), 2.40 and 2,15
(s, 6H, 2-CH3-COO-), 1.85 (bs, 2H, H7 and ~l8), 1.5 (m), 1.05 (d, 6H ~ ),
1~O-3DO (variable, remaining protons). 3
EXAMPLE 44
trans-5,6,6a~,7,10,10a~-Hexahydro-l-hydroxy 5-acetyl-6~-
Triphenylmethyl phosphonium bromide ~742mg., 2.12 mmole) is added
to a solution of sodium hydride (OD95 g " 2.0 mmole) in dimethyl sulfoxide
(50 ml.) at 50C. The reaction mixture is then heated at 7GC. for three
hours a~ter which d~-trans-5,6,6a~7~10~10a~hexahydro-1-acetoxy~5-acetyl-
6~-methyl-3-(2-heptyloxy)benzotc]quinolin-g(8H)-one (o.858 g.j 200 mmole) in
dimethyl sul~oxide (50 ml.) is added. The reaction mixture i9 heated at
70C. overnight, and then cooled and poured into a mixture of ice and water
containing sodium bicarbonate (12,5 gD)~ The agueous mlxture i5 extracted
with benzene, dried (Na2S04) and e~aporated under reauced pre~sure to give
the crude proauctD It is puri~ied by column chromatography over silica gel
in hexaneben~en2 (1~
~ ~'
~1_-trans-5,6,6a~,7,8,9,10,10a~-octahydro-l-hydroxy-5-ethyl-9-
hydroxymethyl-6~-meth~l-3-~2-he~tylox~)benzo~cJ~uinoline
To a solution of ~L_-trans-5,6,6a~S7,10,10a~-hexahydro-1-hydroxy-
5-acetyl-6~-methyl-9-methylene-3-(2-heptyloxy)benzo[c]quinoline (oD855 g"
2 mmole) in tetrahydro~uran (30 ml,) at 0~5C " is added dropwise a lM
solution of dibDrane in tetrahydrofuran (borane-tetrah~dro~uran complex)
(6 mlD~, A~ter the addition the reaction mixture i9 held at room tem-
perature ~or 30 minutes and then treated with w~ter to dec4mp~se exces~
hydride.
The reaction mixture is then warmed to 50~Co on a water bath and
3N sodium hydroxide (3 ml.) added followed by dropwise addi~ion of 30%
,.~
-95-
hydrogen peroxide (3 ml.)O After addition~ the mixture i8 held at room
temperature for one hour, potassium carbonate ~1 5 g ) added and the tetra-
hydrofuran layer separated. m e ag~eou~ phase is extracted with tetra-
hydrofuran (3 x 10 ml ), the extracts combined, dried (MgS04) and con-
centrated to give the pro~uct Purification i3 achieved by col~mn chro-
matography on silica gel using ether-hexane~
EXAUPLE 46
7,10-dihydro-1-hydrox~-3-~2~heptyloxy)benzo[c~quinolin-9-
(8H)-one ethylene ketal and ~ -5,6,6a,7,10,10a-~exahydro-~
~
A suspension of ~ -trans-5,6,6a~,7-tetrahydro-l~hydroxy-3-~2-
heptyloxy)benzo[c]quinolin-9(8X)-one (0,50 g~ 52 mmoles), eth~lene glycol
(0.43 ml., 7.70 mmoles) and p-toluenesulfonic acid monohydrate (0028 gO~
1.46 mmoles) in benzene ~25 ml.) iB heated at reflux for 45 minutes. The
by-product water is azeotropically removed. The dark suspension thus pro-
duced is taken up in a mi~ture of ether and s&turabed sodium bicarbo~ate
solution. The organic l~er is separated, washed with saturatea a~ueous
sodium bicarbonate solution~ dried (MgS04), ~nd concentra~ed to an oil whîch
is then chromatographed on silica gel (50 g,) using ether as eluant. Frac-
tions of 10 ml. each are collected.
Fractionsl2-18 are combined and evaporated t~ give 203 mg of the
ethylene ketal of the hexahydro derivative~
m/e - 375 (m )
IR (CHC13): 2098 ~ ~uperposition o~ ~-H and O~H stretch)
) C~C13 ~ppm): 5 7 (s, 2H, aromatic), 4.0 (5 4H
ketal ethylene) and ab~orption for remaining protons.
Fractions 42-65 are combined and concentrated to afford 146 mgO
of a yellow solid. Trituration of the solid in ether-pentane(l:l) give 85
mg of 7,10-dihydro 1-hydroxy-3~-(2-hep~yloxy)benzo[c]quinolin-9(8H)-one
30 ethylene ketal, m.pO 171-173C
',
~ -96-
m/e - 371 (m ), IR (l~r): 2~98U ~0-H).
) CDC13 (ppm): 8,6 ~s, lH, C-6 aromatic), 6.6 and
7.0 (bd, 2H, aromatic ), 4 1 ~bs, 4H, ethylene ketal), 3.9 ~bg, 2H, C-10
methylene), 3.1 (t, 2H, C-7 ethylene), 2 0 (bt~ 2H, C-8 methylene) and other
absorptions for remaining protons.
Analysis: Calc'd for C22H2904N: C, 71-13; ~ 7 ~7i N~ 3-77 %
Found: C, 71.19, H, 7 67; N, 3 61 5
In like manner, ~_-5,6,6a,7,10,10a-hexQhydro-l-h~droxy-3-~2-
heptylox~ 6-methylbenzo[cJquinolin-9(8H)-one ethylene ket~ con~Tert~ed
to ~-7,10-dihydro-1-hydroxy-3-~2-heptYloxy)-6-methylbenzoEc]guinolin-9
(8H)-one ethylene kets.l.
m/e - 385 (m )
H IlklE~ (60 MHz) ~CDCl (ppm): 6.8 and 6.4 (two lH doublets,
aromatic), 5.7 (bs, lH, phenolic), 4.0 (bs, 4H, ethylene ket~l), 3.9 ~bs,
2H, C-10 -CH2-), 3.1 (bt, 2H, C-8 -CH2-), 205 ~s~ 3H, 6-CH3), 2.0 (bt, 2H,
C-7 -CH2-), and other absorptions for remaining protons.
d,l-5,6,6aB,7,10,10aol-Hexahydro-l-hydroxy-6B-methyl-3-
. (2-heet~lsulfinyl~be3~3 ~ guinolin-~ ~ H)-on _
Equimolar amounts of m-chloroperben~oic acid an~ 5,6,6a~,7,10,
lOacl-hexahydro-l-hydroxy-6~ methyl-3-(2-heptylthio)benzolc]guinolin-9~ôH)-
one are added to a mixture oE chloroEorm and acetic acid ~2:1) and the
reaction mixture stirred îor one hour at room temperatureO ~he organic
phase is then separated, washed with water, dried (MgS04) and evaporated to
dryness to give the title product~
AMPL13 4O
trans-5,6,6a,7,10,10a-Hexah~rdro-l-hydrox~r-6~-met~1-3-
'~ ~o~
The procedure o~ Example 47 is repeated but u~ing two eguivalents
o~ m-chloroperbenzoic acid or oxidizing agent per mole of thio ethPr
-97--
"
i,
1 t ,,
' ' ' ';
reactant to give the title compound.
d,l-5,6,6a,7 Tetrahydro-1-(4-morpholinobutyr~loxy)-6~-methyl-3-
(2-heptyloxy)benzo~c~uinolin 9~ô~
To a solution o~ ~ -5,6,6a,7-tetrahydro-1-hydroxy 4 ~-methyl-3-
(2-heptyloxy)benzo[c]quinolin~9~8H)-one (0~51 g., 1,5 mmole) in dry methyl-
ene chloride (25 mlO) is added 4-morpholinobutyric acid h~drochloride
(0.315 g., 1.5 mmole) and the mixture stirred at room temporQture under a
nitrogen atmosphere. A O.lM solution of dicyclohexylcarbodiimide in methyl-
lQ ene chloride (12.5 ml., 1.5 mmole) is added dropwise and the mixture stirred
for 24 hours. It is then filtered and evaporated to give -the title product
which is purified by column chromatography on silica gel.
EXAMPLE 50
d,l-trans-5,6,6a~,7,8,9,10,10a~-Octahydro-1-(4-N-piperidyl-
butyryloxy)-9-hydroxy-6~-methyl-3-(5-phenyl-2-pentyIoxy)benzo-
[c]~uinoline hydrochloride ~_~
To a 25C. solution of d,l-trans-5,6,6a~,r7,8,9,10,10a~-octahydro-
1,9-dihydroxy-6~-methyl-3-(5-phenyl 2-pentyloxy)benzo[c]guinoline (loO go
2053 mmoles) in methylene chloride (20 mlO) is added 4-~-piperi~ylbutyric
acid hydrochloride (0.524 g., 2.53 mmoles) and dicyclohex~lcarbodiimide
(0.573 g., 2.78 mmoles). The reaction mixture ia stirred at 25C~ for 6
hours and then cooled for 12 hours and filtered. Evaporation of the fil-
trate and trituration o~ the residue with ether gives 1.3 g. of solid of
the monohydrochloride salt.
IR ( Br): 2.95, 3 70, 5065 (e-ter C~O)? 6 13 ~n~ 6-27 ~
Preparative laye~ chrom~tography 0~ a portion o~ this solid on ~.5
mm. thick silica gel and elution with 10% methanol-methylene dichloride
affords the free base, ~L_-trans-576,6a~,7,8,9,10,10a~-octahydro-l-(4-~-
; piperidylbutyryloxy?-9-hydroxy-6~-methyl-3-(5-phenyl~2-penty-loxy)benZo~C]
quinoline.
) CDC13 (ppm)~ ,12 (d, J~7 Hz9 C-3 side-chain
-98-
36~
methyl), 1.25 (d, J=6 Hz, C~6 methyl), 5.84 ~8, two ArH) and 7 16 ~, 5~I).
Treatment of this free ba~e with exc~s~ hydrog~n chloride in
ether yield the dihydrochloride 3alt a~ a hygroscopic ~owder~
AMPLE ~
~ 5,6,6a,7-Tetrah~dro-1-(4-N-piperidylbutyryloxy)-6~-methyl-
methyl-3-~5-phenyl-2-pentyloxy)ben~o~c]quinolin-9-(8H)-one
~_.
To a 25C solution of ~L_-5,6,6a,7-tetr~hydro-1-hydroxy-6~-
methyl-3-~5-phenyl-2-pentyloxy)benzo~c]guinoline-9~8H)-one ~550 mg., 1.41
mmole) in methylene chloride ~26 ~1.) i8 added 4-~-piperidylbu~ric acid
hydrochloride (291 ~g., 1.41 mmole) and dicyclohexylcarbodlimide (319 mg.,
1.55 mmole). This reaction mixture i9 stirred for 18 hQurs ~nd i3 then
cooled to 0C. and ~iltered. Ev~poration of the filtrQte and tritur~tion
o~ the residue with ether give~ 800 mg. ~ 1 -5,6,6a,7-tetrahydro-1-(4-N-
piperidylbutyryloxy)-6~-methyl-3-~5-phenyl-2-pentylox~)benzo~c]~uinoline-9
(8~)-one hydrochloride as a hygroscopic yello~ powder.
IR (CHC13): 2.92, 4.14 (HN=), 5.69 (ester), 60~o, 6.20 an~ 6.40
In like manner, d71-trans-5,6,6a~,7,8,9,10,10a~-octahydro~ N-
morpholinobutyryloxy)-9-nydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo~c]-
quinoline hydrochloride is prepared from 4-~-morpholinob~tyric ~cid and a~
trans-5,6,6a~,7,8,9,1G,lOa~-octahydro-l,9-dihydroxy-6~-methyl-3-(5-phenyl-
2~pentyloxy)benzo[cJquinoline:
IR (KBr): 3.00, 3.75, 5.67 (esber C~O), 6.15 ana 6.30 ~.
EXAMP~E 52
d~l-7~lo-Dihydro-l-hydroxy-3-(2-heptyloxy)-6-methylbenzo~cJ-
A solution of d~_-7,10-dihydro-1-hydroxy-3-(2 heptyloxy)benzo~c]-
quinolin-9-(8~)-one ethylene ketal (371mg.l 1.0 mmole~ in ether ~50 ml.) i8
slowly added to an ice-cold solution of methyl-lithium ~44 mg~, 2.0 mmole)
in ether (25 ml.) The 5-lithio-6-methyl derivative thus obtained i9 dig-
sol~ed in dry ether and treated with dry o~gen to give, a~ter filtration
.~
~ _99_
:
and evaporation of the solvent, the title compoundq
E~AMPLE 53
Exc~ss hydrogen chloride i~ pa3sed into a solution of the appro-
priate benzoEc~quinoline of Formulas I or II and the resulting preoipitate
separated and recrystallized from an ap~ropriate solven~, eogD methanol~
ether (1:10).
In this manner the following salt is prepared:
~L~tran3-5,6,6a~,7,8,9,10,10a~~octahydro-l-acetoxy-9~-hydroxy-6~-
methyl-3-(5-phenyl-2-pentyloxy)ben~o~c]quinoline, m.p. 191-193C.
m/e - 437 ~m )
Analysi9: Calc'd for C27H3604NCl: C, 68 48; H, 7.70; ~, 2.89 %
Found: C, 68.42; H, 7.66; N, 2.96 %
PPEPA3ATION A
To phosphorous pentabromide, prepared by addition of bromine
;; (9.0 g,) in methylene chloride ~10 ml ) to pho3phorou~ tribromide (15.0 g.)
in methylene chloride (15 ml.) at 0C , is added 5-phenyl-2-pentanol ~812 g.)
in methylene chloride at 0C. The mixture is stirred for 2.5 hours at 0C.
and i~ then allowed to warm to room temperature Water (50 ml.) i- added,
the mixture stirred for one hour and the methylene ohloride layer separated,
The extraction is repeated and the combined extracts washed with water,
~aturated sodium bicarbonate solution, brine and then dried o~èr magnesium
,~ ~
; fate. Concentration of the dried extracts gives 12 4 g. of title pro-
: 25 duct as a light yellow oil.
NMR; ~CDCl 1.6 (D,3,methyl,J = 7Hz), 1 6-2.0 (M,4,ethylene),
2.3-3.0 (bd,T,2,benzylic-methylene), 3.7-4.2 (M~l~methine)~ 609-7.4(M,5,
aromatic ) .
`''-
, 100-
36~
Ph PAIATION ~
A solution o~ 1-bromopropylben~ene (51 7 g.) in ether ~234 mlO)
is added dropwise over a 2-hour period to a re~luxing mixture of magnesium
~7.32 g.) in ether (78 ml.). The reacbion mixture is re~luxed for 30
minutes longer and then a solution of 3,5-dimethoxy-acetophenone (50 g5) in
ether (78 ml.) is added drop~ise and he~ted to re~lux for 1.5 hours. The
reaction is quenched by addition of saturated ammonium chloride (234 ml.),
the ether layer is separated a~d the agueous phase extracted with ether
(3 x 200 ml.), The combined ether extracbs are dried over magnesium sulfate
and concentrated under vacuum to yield 81 g. of an oilO Forty grams o~ the
oil i8 hydrogenated in a mixture containing ethanol (300 mlO), concentrated
hydrochloric acid (2 ml.) and 5% palladium-on-carbon (5 g.)5 The catalyst
iB ~iltered o~ and the ethanol removed under vac~um. The residue is di3-
tilled under vacuum yieldin~ 28 g. of 2-(3,5-dimethoxyphen~1)-5-phenyl~
pentane (b.p. ~,125 mm., 154-159C.)
~MR: ~CDCl 1.25 ~d,3,~-CH3), 1.3-251 ~M,4,etnylene~, 2.2-2.9 (M,
3,ben~ylic-methylene,methinyl), 3.45 (Sg6,metho~yl)9 652-6.7 (M,3,aromatic),
7.2 (S,5,aromatic).
PREPA2ATION C
2-(~ 5-Dihydroxyphenyl~-5-phenylpentane
A mixture of 2-~3,5 dimethoxyphenyl)-5-phenylpentane (22 g5) and
pyridine hydrochloride ~94 g5) under nitrogen is hested to 19QC5 for 2
hours with vigorous stirring. The reaction mixture i9 cooled, dissolved in
6N hydrochloric acid (200 ml.) and diluted with water to 600 ml. The
aqueous solution is extracted with ethyl acetate (4 x 100 ml5) the ethyl
acetate extracts dried over sodium sulfate and concentrated under vaouum to
yield 24 g. of crude product. The produet i~ puri~ied by silica gel chro-
matography to yield 19.2 gO of 2-(3,5-dihydroxyphenyl)-5-phenylpentane
-101 -
'
as an oil.
NMR: ~lc~cl 1.1 (d,3,o~-methyl), 1.35-1065 (M,4,ethylene), 2.2-2.8
(M,3,benzylic-methylene, methinyl), 6.1-6.5 (M,3,aromatic), 6.65 (bd.S, 2,
hydroxyl), 7-7.4 (M,5,aromatic).
Following the procedures o~ Preparatlolls B and C, th~ compounds
listed below are prepared by sub~tituting the appropriate l-bromoalkylbenzene
for l-bromopropylbenzene:
2-(3,5-dihydroxyphenyl)-6-phenylhexane--
~MR: CDCl 1.1 ~D,3,~-methyl, J-7 cps), 1.0-1.9 [M,6,~CH2~CH2)3-
10CX~CH3)-Ar], 2;2-2:8 ~M,3,benzylic methylene,methinyl), 6 . o ~bd.S, 2-phenolic
OH), 6.2-6.4 ~M,3,aromatic), 7.1-7.4 (M,5,aromatic)~
1-(3,5-dihydroxyphenyl)-2-phenylethane-
m.p.: 76-77C.
2-~3,5-dihydroxyphenyl-4-phenylbu~ane ~an oil)-
NMR: ~CDC1 1.1, 1025 (d,2,methyl), 1,45-200 (M,2,methylene~,
2,15-2.7 ~M,3,benzyIic-methylene,methinyl), 603 (S,3,aromatic), 6.85 (S,2,
hydroxyl D20 overlay), 7.1 (S55,aromatic).
; PREPARATION D
A solution of n-butyl lithium ~29 ml. of 2.2 M) is added dropwise
~o 3,5-dimethoxybenzyl triphenylphosphonium bromide (31.5 g.) in tetra-
hydrofuran ~20Q ml.) with stirring and the resulting deep red solution is
stirred for one-half hour. Benzyl acetone (9,4 g,) i9 added drop~ise and
, ''
the reaction mixtw?e stirred for 1.2 hours, It i8 then adjusted to pH 7 by
25 addition of acetic acid and concentrated under reauced pres~ure ~he
residu~ is extracted with methylene chloriae and the eXtr0ct etraporated
to give crude 1-(3,5-dimethoxypheny})-2-methyl-4-phenyl-1-bu~ene as an oil,
It i~ purified by chromatography on silica gel (400 g.) aEld elution with
benzene. Yield: 10 g. as an oil.
-1 02 -
: ~ . , -
36~ ~
~DC13 1.95 ~S,3), 2.~-3.1 (M,4), 3.8 (S 6) 6 15 6 6 (M
7.1-7.5 ~(M,6).
The 1-(3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene ~9.4 g )
thus prepared is dissolved in ethanol (250 ml.) and catalytic~lly hydro-
5 genated at 45 p.s.i. in the presence of pslladium-on-charcoal (l g. of 10%)
and concentrated hydrochloric acid (1 ml.)O Yield: 9.4 g. of 1-(3,5-
dime~hoxyphenyl)-2-methyl-4-phenylbutane as an oil.
CDC13 9 ~d,3), 1.35-1,95 (M,3), 2.2-2,9 ~M~4), 3.75 ~S 6)
- 6.35 ~S,3~, 7.25 ~(S,5). `
It is demethylated acoording to the procedur- of Preparation C
to give 1-~3,5-dihydroxyphenyl)-2-methyl-4-phenylbutane.
; The 3,5-dimethoxybenzyl triphenylphosphonium bromide iB prepared
by refluxing a mixture of 3,5-dimethoxybenzyl bromide ~12 g.) and triphenyl-
phosphine (14.2 g.) in acetonitrile (200 ml.) for one hour. The reaction
15 ~nixture is then cooled and the crystalline product recovered by flltration,
washed with ether and dried ~20 ~.); mOpO 269O_2700
P PARATION E
?-Methyl-2~3 ~-dih~drox~phenyl)-5-~hengl~entane
~o a olution of the Grign~rd rea8ent prepared from 2-phenylbromo-
20 ethane (5.5 g.), magnesium (o.8 g.) and dry ether (60 ml,) is added a
solution of 2~methyl-2-(3,5-dimethoxyphenyl)propionitrile (2.75 g.) in drY
ether (20 ml.). me ether i6 di~tllled off and replaced by dry ben~ene
(50 ml.) and the mixture refluxed for 48 hours. It :~8 then decomposed by
careful treatmen' with dilute sulfuric acid .nd heated on a steam bath for
one hour. me mixture is then extracted with ether, the extract dried
i~MgS04) and concentrated to arl oil. I)istillation of the oil in vacuo affords
2-methyl-2-(3,5-dimethoxyphenyl)-5-p~enyl-3-pent0none) b.p. 168aC /0.2 mm.
Yield: 2.32 g., 60%)
The thus-produced pentanone (58 g.) is dissolvea in ethanol ~400
-1û3-
. :
;, , .
, . ~
ml.) and treated with sodium borohydride (10 g ) at room t~mpera~ure.
The reaction mixture is stlrred for 12 hours and is then cooled and neu-
tralized with 6N hydrochloric acid. The ethanol i5 removed under reduced
pressure and the residue extracted with 0ther, rnhe extract is dried (MgS04)
and concentrated to give 2-methyl-2-~3,5-dimethoxyphenyl)-5-phenyl-3-
pentanol as an oil (52 g., 88% yield)~
~he pentanol ~16 g.) is taken u~ iD ether (100 ~ and reacted
with powdered potassium (2.5 g.) in ether (200 ml.). Carbon di~ulfide
(equimolar to the potassium) is added and the mixture ~tirred for a half-
hour. Methyl iodide (9.0 g,) i9 then added and the reaction mixture
stirred for 6 hours. ~he resulting suspension is filtered and the filtrate
concentrated under reduced pressure. qhe residue is taken up in ethanol
~150 ml.), Raney nickel add (25 g.) and the mixture reflux~d for 18 houra.
Evaporation of the alcohol and di~tillation of the residu~ gives 2-methyl
2-(3,5-dimethoxyphenyl)-5-phenyl-3-pentene.
The pentene derivative is catalytically hydro~enated according to
the procedure of Preparation D and the resulting 2-methyl-2-(3,5-dimethoxy-
phenyl)-5-phenyl-3-pentane demethylated via the procedure of Preparation C
to give the product
PREPARATION F
Qver a period of 1.5 hours, methyl lithium t531 ml. of Q 2 molar
solution, 1.06 M) is added under a nitrogen atmosphere to a rapidly stirring
solution of 3,5~dibenPylo~ybenzoic acid (}75 g., 0.532 M) in ether (250 ml )-
tetrahydrofuran (1400 ml.) maintained at 15-20C. After stir~ing an addi-
tional 0.75 hour at 10-15C , water (600 ml.) is slowly added keeping the
~eaction temperature below 20C The a~ueous layer is ~eparated and extrac-
ted wlth ether (3 x 250 ml ). The organic phases are comblned, w~shea with
s~turated sodiu~ chloride solution (4 x 300 ml.), dried over sodium sulfate,
and concentrated under vacuum to give an oil which slowly crystallized f~om
':
a
- ~
isopropyl ether. The crude produot i3 recrystallized from ether-hexane
to yield 104.7 g. (59%) of produ~t; m.p. 59-61C.
PREPARATI0~l a
Ethyl 3-~3,5-dibenz~o~sc~h~ crotonat ~
A mixture of 3,5-dibenzyloxy&cetophenone (43.2 g., 0.13 mole) and
carbethoxymethylenetriphenylpho~phorane (90 5 ~r" 0.26 mole) is heated under
a nitrogen atmosphere at 170C. for 4 hours, The clear melt i~ cooled to
room ~emperature, triturated with ether ~nd the precipitate of tr~phenyl
phosphine oxide removed by filtration. The filtrate iB concentrated under
vacuum to an oil residue w~ich i.9 chromatographed orer silica gel (1500 g.)
and elutéd with benzene:hexane solutions of increa.ing benzene concentration
; beginningwith 40:60 and ending with 100% benzene. Concentration of ~ppro~
priate ~ractions oeives an oily residue which i9 crystallized from hexa~e
Yield: 40.Z g. (77%) m.p. 73-75C.
Analysis: Calc'd for C26~2604: C, 77,58, H, 6,51 %
Found: ~, 77 72; H, 6.60 %
In like manner, ethyl 3-(3,5 aimethoxyphenyl)crotonate i~ pre-
pared ~rom 3,5-dimethoxyacetophenone (51.7 g.) and carbethoxymeth~lene
triphenylphosphorane (200 g.) Yield = 61 o g , 86%, b,p 146-162C.
at 0 3 mm.
PREPARATI0~ H
, :
3-(32~Dibenz~lo~$~nyl)-1-l but~nol
A 301ution of ethyl 3-(3,5-dibenzyloxyphenyl~crotonate (24.1 g.,
`60 mM) in ether (250 ml ) i9 added to a mixture o~ lithium aluminum hydride
- 25 (3.42 e~, 93 mM) and ether (250 ml.). Aluminum chloride (0 18 g., 1.35 mM)
iB added and the mixture refluxed ~or 12 hours and ~hen cooled. Water ~3.4
ml.), sodium hydroxide (3.4 ml. of 6N) and water (10 ml.) are then added
successively to the reaction mixture. The inorganlc salts which precipitate
are ~iltered off and the filtrate iB` then concentrated in vacuo to give the
desired alcohol as an oil - 2.4 g. (98%)
-105-
.' ~
.~
~Q~
Rf = 0.25 [silica gel:benzene(l8):ethyl acetate~1)].
m/e - 362 (m )
Analysis: Calc'd for C24H2603: C, 79.53; H, 7.23 %
; Found: C, 79.37; ~3 7.11 %
In like manner, ethyl 3-(3,5-dimethoxyphenyl)crotonate (60.4 g.)
is reduced to 3-(3,5-dimethoxyphenyl)butanol ~48.o g., 90~).
P2EPARATION I
Tosyl chloride (11.1 g., 58.1 mM) i9 added to ~ solution of 3-
~3,5-dibenzyloxyphenyl)-1-butanol (20.7 g., 57 mM) in pyridine ~90 ml.) at
-45C. m e reaction mixture i3 hela at -35C. for 18 hour~ and~i~ then
diluted with cold 2~ hydrochloric acid (1500 ml.) and extracted with ether
(5 x 250 ml.). The combined extract~ are wa3hed with ~aturated sodium
chloride solution (4 x 25p ml.) and then dried (NQ2SO4). Concentration of
}5 the dried extract affords the product as an oi}O It i9 crystollized b~v
I treatment with ether-hexane. Yield: 2~o63 g~ (84%).
.,
;~ Analysls CQ1C'd ~r C31~325S C9 72006~' H, 6.24 %
Found: C5 72 05; H, 6.29 %
P~EPARATION J
~ ~ne
A solution of phenol (4~56 g~ 48.6 mM) in dlmethylformamide (40
ml,) i3 ~aded under a nitrogen a~mosphere to a suspension of ~odium hydride
(2~32 g~ 48.6 mM of 50% previou~ly washed with ~entQne~ in dimethyl~ormamide
(70 ml.) at 60Ç. The reaction mixture i~ stirred for one hour at 60-70C.,
after which a solution of 3-(3,5-dibenzyloxyphenyl)butyl to9ylQte (23~93 g.,
46.3 mM)~in dimethylformamide (80 mlO) is~ added. The reactlon mixture is
stirred at 80C. for a h~lf-hour and is then cooled to room temperature,
diluted with cold water ~2500 ml.) and extrQcted with eth~r (4 x 400 ml.).
The combined extracts are wa~hed successivelg with cold 2N hydrochloric QQid
(2 x 300 ml.) and saturated sodium chloride solution (3 x 300 ml.) and then
-lo6-
;
dried (Na2S04). Removal o~ the sol~ent under reduc~d pre~sur~ affords the
product as an oil~ ~'he oily residue is di3~01ved in ben~ene and flltered
throu6h silica gel (100 gO)~ Concentration of the filtrate under reduced
pressure gives the product as an oil. Yield: 14 86 g. (73%~.
Rf = 007 (silica gel, benzene)~
m/e - 438 (m~)
~nalysis: Calc'd for C30H3003: C, 82.16; H~ 6~89 %
Found: C, ~2007; ~, 6084 %
PREPARATIOE K
3-~3~5-Dih~r~yphenyl ~ henox~y~
A solution of 3-(3,5-diben~yloxyphenyl)-1-phenoxybutane (14.7 g.
133.5 mM) in a mi~ture of ethyl acetate (110 ml.), ethanol (110 ml.) and
concentrated hydrochloric acid (0.7 ml.) is hydrogenated for 2 hour3 under
60 p.~.i. hydrogen in the presence of 10% palladium-on-c~rbon (1.5 g.).
Removal of the catalyst by filtration and concentration of the filtrate gives
an oil. The oil is purified by chromatography on silica gel (100 g.) and
.
eluting with benzene-ethyl acetate consi~ting of 0-10% ethyl =cet~te me
middle fractions are combined and concentrated to give the title product:
7.8 g. (80%), as an oil.
~ 20 Rf = 0.25 ~silica gel, benzene(4), methanol(l~]O
; m/e - 258 (m~)
Analysis: Calc'd for Cl~H1803: C, 74.39; H, ~-02 %
Found: C, 74.13; H~ l. %
PREPARA~IOE L
~
A solution of phosphorous tribromide (507 ml., o.o6 mole) in ether
(30 ml.) is added to a solution of 3-(3,5-dimethoxyphenyl)-1-butanol
(30.0 g., 0.1l~3 mole) in ether (20 mlO) at -5C. to -104C. a~d the reaction
mixture stirrPd at -5C. to -10C. for 2.5 hours. It is then warmed to
- 30 room te~perature and stirred for an additional 30 minutes. The mixture is
;~ -107-
'
~oured over ice (200 e~) and the resulting mixture extr~ated with ether
(3 x 50 ml.). The combined extracts are washed with 5~ sodium hydroxide
solution (3 x 50 ~lo)~ saturated ~odium chloride solution (1 x 50 mlO) and
dried (~a2S04). Removal of the ether and vacuum distillation of the re~idue
~f~ords the title product, 25 g. (55% yield); b,p, 125-132C, at 0,4 mm,
PREPARA~ION M
4-(3,5-Dihydro~y~n~ pen,tane
A mixture of 3-~395-dimethoxyphenyl)butyl triphenylphosphonium
bromide (19.0 gO~ 3504 mmoles) in dimethylsul~o~ide ~50 mlO) i3 added to 4-
1~ pyridinecarboxaldehyde (3075 g" 3504 mmoles) in ketrahydrofuran (40 mlO)O,~ The resulting mixture is then added dropwise to a slurry of 50~ sodium
,~ hydride (1.87 g., 39 mmole~) in tetrahydro~uran ~20 mlc) under a nitrogen
atmosphere at 0-5C. Following completio~ of addition, the mixture is
stirred for one hour at 0-5C, and then concentrated under reduced pres-
sure. The concentrate i8 diluted with water (200 ml.) and then acidi~ied
; with 6N HCl. The aqueous acid solution is e~tracted with benzene
(4 x 50 ml.). It is then made basic and extracted with ethyl acetate
(3 x 5Q ml.). Evaporation of the combined extracts after drying ~MgS04)
i: ~
,`~ affords 4-(3,5-dimethoxyphenyl)-1-(4-pyridyl)-1-pentene (7,1 g" 70%)
as an oil.
Catalytic hydrogenation of the thus-produced pentene derivative
- according to the procedure given in Preparation D gives 4-~395-dimetho~y-
phenyl)-1-(4-pyridyl)pentane in quantitative yield; mOp, 131-133Co
The pentane derivative thus obtained is demethylated by heating
" 25 a mixture of the compound ('~,15 g., 25 mmoles) and pyridine hydrochloride
(35 g.) under a nitrogen atmo3phere at 210C, ~or 8 hours, The hot mixture
is poured into water (40 ml.) and the resulting ~olution made basic with 6N
sodiwm hydroxide~ Wat~er and pyridine are removed by distillation in vacuo.
Ethanol (50 ml.) is added to the residue and the inorga~ic salt3 which pre-
cipitate are ~iltered of~, The filtrate is concentrated in vacuo and the
-~08-
'
residue chromatograp~ed on silica gel (150 gO) using as eluting aeents 5%
ethanol/benzene (4 liters), 10% ethanQl/ben~ene (1 liter)9 13~ ethanol/
ben3ene (1 liter) and 16% ethanol/benzene (5 liters)0 The product i9
isola~ed as a glassy solid by concentration o~ appropriate fractions o~ -
5 the eluate. Yield - 5.0 g ~78%)o
The 3-(3,5-dimethoxyphenyl)butylbriphen~lphosphonium bromide i~
prepared by refluxing a mixtur~ of l-bromo-3-(3,5-dimethoxyphenyl)butane
(2105 g., 78~5 mmoles) and triphenyl phosphine (20.5 g,, 78~5 mmoles)
in xylene (60 ml.) ~or lô hours. The reaction mixture is then cooled to
room temperature and filtered. ~he ~ilter cake is~washed w1th ebher and
dried in a vacuum desicator to give 36s4 g. (86%) yield of product, mOp.
19Q-200C.
:;
., .
. ,,
` ~
.
'
:
~'
.
`~; -109-
- . ..
PREPM ATION N
3- L:S~ bL=L~==~13~n~ Oxide
To a solution of dimethylsul~oxonium methyliae (69.4 mM) ln
dimethyl sulfoxide (65 ml.) at room temperature is added solid 3,5-dimethoxy-
acetoph~none (10 g., 5505 mM). ~he reaction mixture is stirred ~or one
hour at 25~C., ~or one-half hour at 5C and is then cooled. me mixture
is diluted with water (50 mlO) and added to a mixture o~ ice ~ater ~200 mlO)
ether (250 mlO)--low bolling petroleum ether (25 ml.). ~q~he organic ëxtraot
i9 washed twice with water (250 ml.), dried (MgS04) and evaporated to an oil.
10 ~ractional distillation oP the oil yields 8,o g, (7s%) 0~ 3,5-dimethoxy-~
o,methylstyrene oxide, b.p. 93-97C., 0.2 mm.
IR (CC14): 2780, 1595, 1196, 1151, 1058 cm 1
W (95% ethanol): ~max = 279 nm (E = 2068).
mle - 194 (m~)
PMR (CDC13) (60 MHz): ~ 1.70 (S,CH3-), 2.76 (~d,J ~ 6 Hz, ~ ~ ,
2.95 (d,J = 6Hz, ~ H), 3.81 (BgCH30-), 6.41 (t,J = 2Hz, ArH) and 6 58
(d,J = 2Hz, ArH). ~
Analy6is: Calc~d ~or CllH1403~ C, 68.02, H, 7~27%
Found: C, 67.96, H, 7.28%
F~YE~BATIOD O
?-( 3~5-Dimethoxyphenyl)-2-hydrox~propyl-2-p~ylethyl Ether
A mixbure o~ dry 2-phenylethanol (30 ml., 251 mM) and sodium
metal (690 mg., 30 mM) i9 heated at 110C ~or 30 minutes. ~he resulting
; lM solution o~ ~odium 2-phenylethoxide is cooled to 60C., 3?5-dimet~oxy-
25 ~-methylstyrene oxide (2 g., 1003 mM) added and the reaction heated 15
hours at 60C. me reaction mixture i8 cooled and added to a mixture of
ether and water The etber extract is dried over magne6ium sulfate Qnd
evaported. Exce~s ~-phenyle~hanol is remo~red by vacuum distillAtion
: , :
(b.p. 65C., 0.1 mm.) leaving a 3.5 gO re~idue. qhe re~idue is puri~ied
30 via column chromatography on Merck ~ilica gel 60 (300 g.) and eluted in 15
-llQ-
:
i
ml~ rractions with 60% ~ther-pentane. Fractions 52-88 yielded 2:.~ e ~
(89%) o~ 2-(3,5-dimethoxyphenyl)-2-hydro~y-propyl 2-phenylethyl e'ther.
IR (CC14): 3534, 1595, 1202, 1153 cm D
W (95% ethanol~: ~max = 278 (~ = 1830), 278 (~ = 1860).
m/e - 316 (m~)
PMR (CDC13, 60 MXz): c~ 1C46 (S,CH3~), 2.86 (S,OH), 2.86
(t,J = 7Hz,-C~2-Ph), ~.53 (S, -CH20)~ 3.71 (t,J = 7Hæ,_CX20), 3.80 (S,OCH3),
6.38 (t,J = 2Hz,ArX), 6.61 (d,J = 2H~, ArH) and 7 23 (S,PHH).
An~lysis: Calc d for ClgH2404: C, 72.12, H, 7.65%
Found: C, 71.92, H, 7.63%
PREPARATIO~ P
, :
To a 0'C - solution of 2-(3,5-dlmethoxyphenyl)-2-hydro~vpropyl 2-
phenylethyl ether (550 mg~ 74 mM) in pyridine (2 ml.) i8 added d,ropwi~e
15 ;phosphorou8 oxychloride (477 ml., 5.22 mM). Ihe reaction is allowed to
warm to 20C. over a 1.5 hour period~ It is the~ stirred for 1.5 hours at
20C. and ~hen added to ether (150 ml.) and 15% sodium carbo~ate (100 mlO). ~-
The OrgQnic phase i8 separated an~ washed with 15% sodiu~ c~rbonate
; (3 x 5~ ml.), dried over magnesium sulfate ~nd evaporated to an oilO Ihe
20 ail is di6solved in absolute ethanol (15 ml.), 10~ pall~dium~on-car~on (lOQ
mg.) added and the mixture stirred under one atmospher~ o~ hyclrogen gas
When hydrogen uptake ceases (26.5 ~l., 20 min.), the rea~tion is filtered
through diQtomaceous earthland the f'iltrate evaporated to an oil. me oil
; is purifie~ via preparative layer chromatography on siliaa gel plates, eluted
25 twice with 6:1 penta~e:ether to yield 211 mg. (~0%) o~ 2 (3,5-dimetho~yphenyl)
propyl 2-phenyletbyl ether.~
IR (CC14): 1600, 1205, 1155, 1109 am 1
'm/e -- 300 (m )
( 6 ~ `
30 c~ 1.22 ~d,J = 7Hæ, CN3-), 2.82 (t,J - 7Hz, CH2Ph~, 2.8 (X-C-Mej, 3.6
~ . '
(-CH2-0-CH2-), 3.75 (S,OCH3), 6.35 (~,ArH) and 7.18 (S,PhH).
=
~lethyl Ether
A mixture of 2-(3,5-dimethox~phenyl)propyl 2-phenylethyl ether
~195 mg., o.65 mM), pyridine (0.4 ml., 4.96 ~) and dry pyridine hydro-
chloride ~4 g , 34.6 mM) is heated at 190C. for 6 hours. Ihe reaction
mixture is cooled and added to a mixture of water (100 ml.~ and ether
~150 ml.). lhe ether extract is washed once with water (50 ml.) and, along
with a second ether extract (50 ml.) o~ the aqueous phase, is dried over
magnesium sul~ate and evapo~ated to an oii. Ihe oil is purified via
preparati~e layer chromatography on silica gel plates, eluted six times
with 30% ether-pentane to yield 65.8 mg. ~37%) o~ 2-(3,5-dihydroxyphenyl)
propyl 2-phenylethyl ether.
IR (CHC13): 3559, 3279, 1605, 1147, 1105 cm 1
m/e - 272 (m+)
PMR (CDC13, 60 MHz) ~ 1018 (d,J = 7Hz, CH3-), 2.80 (t,J = 7Hz,
-CX2Ph), 2.80 (H-C-Me), 3 4-3.8 (-CH2 QCH2-)9 6.o8 (t,J = 2Hz, ArH), 6.21
(d,J = 2Hz, ArH) and 7.16 (S,PhH).
PPEPARA~IOE R
Under a nitrogen atmosphere a mixture of 3,5-diben~yloxy-
acetophenone (50.0 e~, 0.~5 M) in tetrahydrofuran (175 ml.) ana 3-
phenoxypropyltriphenylphosphonium bromide (7.18 gO~ 0.15 M) in dimethyl-
sul~oxide (450 ml.) is added dropwise over 1.75 hours to-a suspension o~
50% sodium hydride (7.89 g., 0.165 M) (previously washed with pentane)
in tetrahydrofuran (75 ml.) maintained at 0 to 5C A~ter stirring for
4 hours at 0 to 5C. the reaction is allowed to warm to room temperature
and is then carefully stirred into ice water (2000 ~ acldi~ied with
concentrated hydrochloric acid, and extracted with ethyl acetate (5 x 400
ml.), ~he combined organic phases are washe~ with saturated soaium chloride
- -112-
,, ,~;,,j
'
i3611
solution (3 x 300 ml.), dried over sodium ~ulfate and concentrated
under vacuum to yield an oil which is triturated with ether to precipitate
trlphenylphosphine oxide. Filtration, followed by concentration o~ the
filtrate~ gives ~n oil residue which is chromatographed o~er silica gel
(1300 g.~ eluting with benzene-hexane consistin~ of 30% to 100% benzene.
From the middle fractions 51 e (75%) of 4-(3,5-dibenzyloxyphenyl) 1-
phenoxypent-3 ene i8 isolated ~3 an oil; Rf = o.8 (silica gel, 2-benzene:
l-hexane); m/e - 450 (m ).
Analysis: Calc d ~or C31H3003: C, 82 63; H, 6-.71%
Found: C5 82.90; H, 6.69%
:
A aolution of ~-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene
(51 g., 0.113 M) in a mixture of absolute ethanol (160 ml,), ethyl a~etate
(160 ml.) and concentrated hydrochloric acid (0.2 ml,) is hydrogenated for
12 hours under 55 lbs. hydrogen in the preaence oP 10% Pd/C. Removal
of bhe catalyst by ~iltration and concentration of the filtrate under
vacuum yields 30.8 g5 (100%~ of product as a ~lscous oil.
d for Cl7H203 C, 74597; X, 7 ~o%
Found: C, 74554; H, 7545%
; PPEPARATIO~ 3
~
Olivetol (1 8 g., O.OlM), ammonium chloride (2.65 g., 0005M),
sodium bisulfite (5.2 g.~ O.OSM) and ammonium hydroxide (12.5 ml.) are
combined and heated in a steel bomb at 230C. for a~hal~-hour. lhe bomb
~ i9 then cooled, the contents dissolred in ethyl acetate (350 ~15)5`~ 25 Hydrochloric àcid (300~ml of 10%) is added, the mixture sti~red and then
,, :
the organic layer separatedO The extraction is repeated two more times5
Ihe aqueous acid aolution i8 neutralized with 6N sodium hydrox de and then
. _
~` extr=cted with chloroform (3 x 300 mI.). The com~ined ch1oroform extracts
are dried and concen~rated. me residue is taken up in ethyl acetate,
decolorized with charcoal and concentrated. ~he addition of hexane
-113-
~ .
~`.1
~ . .,
. ~ .
to the residue causes it to crystallize: 270 me ; m.p. 88 to 91C.
When recrystalliz~d from hot ethyl acetate-hexane (1-1) it melts at
95 to 96Cc
Analysis: Calc'd for Cl1H17O~: C, 73.70: H, 9.56; N, 7.8]%
Found: C, 73.64: H, 9.62, N~ 7.91%
PREPARATlON T
A solution of 2.4 g. (9.5 mmole) ~ -3-hydroxy-5 (5-phenyl-2-
pentyl)aniline in 24 ml. pyridine and 24 ml~ acetic anhydride is stirred
at room temperature for 45 minutes. m e reaction mixture i9 poured onto
200 ml. each df water and ethyl acetate. After stirring for lO minutes,
the organic layer is separated and washed successively with water (4 x 100
ml,), brine (1 x 100 ml.), dried (MgSO4), ~iltered and concentrated to
yield 3.5 g. of crude 1 -N-acetyl-3-acetoxy-5-(5-phenyl-2-pentyl)aniline.
A solution of ~_-N-acetyl-3 acetoxy-5-(5-phenyl-2-pentyl)an;l~ne and 1 g
potassium carbonate in lOO mlO methanol i5 stirred at room temperature for
one hour, filtered, concentrated and dissolved ;n eth~1 acetate. m e
organic solution is washed with wsiter, dried (MgS04) and concentrated to an
~ oil which is crystallized from hexane to yield 1.5 g. ~ -N-acet~1-3-hydroxy-
- 20 5-(5-phenyl-2-pentyl)-aniline, m.p. 128 to 130C.
m/e - 297 (m+) ;~
H NMR (60 MHz) ~CDCl (ppm): 8 64 (bs, lH, -NH), 7.12, 6~58
and 6.45 (bs, lH variable, ArOH), 2 19-2.78 (m, 3H, Ar-CH and Ar-CH2), 2.05
(s, 3H~ CX3-C(=0)-), 1.3-1.78 (m, 4H, (CH2)2), 1.12 (d, 3H, -C-CH3).
PPEPA~ATI0~ U
To a stirred solution of 1.2 g~ ~ ~N-aaetyl-3~hydroxy-5-(5-
phenyl-2~pentyl)aniline (4.03 mmole) in 50 ml. tetrahydrofuran is added
193 mg. of 5O% 90dium hydride (4.03 mmole). After 3O minutes o~ stirring,
1.38 g. (8.o6 mmole) of ~-bromotoluene iB added and stirring continued for
-114-
16 hours. The reaction mixture is then filtered, 1 ml. o~ acetic acid
added to the filtrate which i3 then concentrated and chromatographed (silica
gel, benzene/ether [2:1] as eluent) to yield 1.43 g. ~ acetyl-3-
benzyloxy-5-(5-phenyl-2-pentyl)aniline a~ an oil.
m/e - 387 (m )
EI NMR (60 MHz) ~CDCl (ppm): 7.88 (bsg lH, N-H), 7.385 7.20,
6 84, 6.59 (bs, 5H3 6H, lH, lH, aromatic), 5.0 (s, 2H, ~0-CH2Ar), 2.21-
2.98 (m, 3H, Ar-CH and Ar-CH2), 2.07 (s, 3H, CH3-C(=0)-~), 1.30-1.69
(m, 4H, -(CH2)2), 1~15 (d, 3H, CH3-C~Ar).
A solution of 1.4 ~. ~L_-N-acetyl-3-benzyloxy-5-(5-pheny1-2-
pentyl)aniline, 14 ml. 20% potQsslum hydroxide, 14 ml. methanol and 10 ml.
2-propanol is heated at re~lux on a steam bath ~or 4 days, A~ter cooling,
water and ethyl acetate are added and the mixture stirred for 10 minutes.
qhe organic phase is separated and the aqueous phase extracted agai~ with
~ 15 ethyl ~cetate. qhe organic solutions are combined, dried (MgS04), con*~
; centrated in vacuo and chromatographed (35 g. silica gel, benzenelether
[3:1] as eluent) to yield ~ -3-benzyloxy-5-(5-phenyl-2-pent~l)aniline as
an oil.
m/e - 345 (m )
) CDC13 (ppm): 7.32 (bs, 5H, aromatic), 7 13
(bs, 5H, aromatic), 6.01-6,33 (m, 3X, aromatic), 4.95 (s, 2H, ArCH20),
3,48 (bs, 2H variable, NH2), 2.17-2.88 (m, 3H, Ar-CH and Ar-CH2), 1~32-1076
(m, 4H, (CH2)2~, 1 14 (d, 3H~ -C-CH3)
pp~P~O~ V
d ~-5-Phenyl- _Pentanol Me~yl~te
To a stirred solution of 5-phenyl-2-pentanol (482 g~., 2.94 moles)
in tetrahydrofuran (2250 mlO) at 0C. is added methanesulfonyl chloride
(300 ml.) at such a rate that the intern~l temperature does not rise abo~e
10~ (tot 1 addition time 4.5 hour~). A~ter addit~n is complete, the
reaction mixture is allowed to warm to room temperature and :tirring is
-115-
;'
l86~3i
continued for an ~ddition~l hour. me reaction mixture i9 ~iltered and
tbe supernate concçntrated to a light yellow oil (2800 g.) which is dis-
solved in chloro~orm (2.1) and washed with water (4 x 1 1,), brine
(1 x 1 1.), charcoal kreated (50 g.) dried (MgS04), filtered through
diatomaceous earth and concentra~ed to a light orange oil (687 g., 95%
~ield). This material is suitabl~ for use without further Purification.
) CDC13 (ppm): 7.23 (s, 5H, arom~tic) 4 53
5.13 (m, lH, -CH-0-), 2.93 (s, 3H, 0-S02-CH3), 2.42-2.93 (mS 2H, -CH2C6H5),
1.50-1,92 (m, 4H, -(CH2)2), 1~23 (s, ~H, 0-CH-CH3).
Similarly, the following mesylates are prepared from appropriate
alcohols:
4-phenylbu~anol mesylate, a yellow oil.
m/e - 228 (m~)
( Z) ~CDC13 (ppm): 7.22 (bs, 5H, aromatic), 4.o8-
1$ 4,~4 (m, 2H, -CH2_0-)j 3.93 (9, 3H, S02CH3), 2.40-2.82 (m, 2H, -CH2C6~5),
1.51~ 3 (m, 4Hs _tCH2)2_~
1-2-octanol mesylate, a colorless oil.
[a]D5 = -9.695 ~C - 2~6, CHC13)
H ~MR (60 MH~) ~CDCl (ppm): 4.79 (~g, lH, -CH-0-), 2.97 (s, 3H,
S~CH3), 1.40 (a, 3H, CH3-CH), oO87 (t, ~I, CH3-CH2), l.b-2.0 (m, 10 H, -(CH2)5-)
d-2-octanol mesylate.
~]D5 = ~9.238 (C = 2.8, CHC13)
H NMR, identical to the l-form.
.~
-- .
-116-
:
