Note: Descriptions are shown in the official language in which they were submitted.
~lZ;3936
Background of the Invention
Field of the Invention
This invention relates to certain azacycloalkanes a~d derivatives
thereof, including unsaturated analogsl having from 4 to 7 carbon atoms in
the azacycloalkyl ring and at the 3-position a 4-~Z-W-substituted)phenyl
group wherein Z is alkylene having from one to thirteen carbon atoms or
(alkl)m-O-~alk2)n- wherein each of m and n is O or 1 and each of ~alkl) and
~alk2) is alkylene having from one to thirteen carbon atoms with the proviso
-~ the summation of carbon atoms in ~alkl) plus ~alk2) is not greater than
thirteen and W is hydrogen, pyridyl, phenyl, fluorophenyl or chlorophenyl;
and a process for their preparation. The products are useful for preparing
CNS agents, especially analgesics, tranquilizers, sedatives and antianxiety
agents in mammals~ including man, and/or anticonvulsants, diuretics and anti-
diarrheal agents in mammals, including man.
Description of the Prior Art
Despite the current availability of a number of analgesic agents,
the search for new and improved agents continues, thus pointing to the lack
of an agent useful for the control of broad levels of pain and accompanied by
a minimum of side-effects. The most commonly used agent, aspirin, is of no
practical value for the control of severe pain and is known to exhibit various
undesirable side-effects. Other analgesic agents such as d-propoxyphene,
codeine, and morphine, possess addictive liability. The need for improved
and potent analgesic agents is, therefore, evident.
More recently, great interest in cannabinol-type compounds as anal-
gesic agents have been exhibited. ~R. Mechoulam, Ed., "Marijuana. Chemistry,
Pharmacology, Metabolism and Clinical Effects", Academic Press, New York,
N.Y., 1973; Mechoulam, et. al., Che ical Reviews, 76, 75-112 [1976]).
German Specification 2,621,535, published November 25, 1976, de-
scribes 3-~3,4-dihydroxyphenyl)piperidines having dopaminergic and hypotensive
activity. Also described in this specification are intermediates to said
~lZ8936
compounds, including N-benzyl-, O-benzyl- or mcthoxy-derivatives, ~2 and G3_
derivatives and 3-(3,4-dibenzyloxyphenyl)-3-hydroxy-N-benzylpiperidine. N-
alkyl, alkenyl and aralkyl derivatives of said compounds having the same
utility are described in German Specification 2,621,536, published November
25, 1976.
It has now been found that certain azacycloalkanes and derivatives
thereof, including unsaturated analogs, having at the 3-position a 2-hydroxy-
4-(substituted)phenyl group ~formulae I-II below) are effective as CNS agents,
especially as analgesics, tranquilizers, sedatives and antianxiety agents in
mammals, including humans, and/or anticonvulsants, diuretics and antidiarrheal
agents in mammals, including man. The compounds have the formulae:
R6 R6
N ~ ORl N OR
I R3 ~ \ O,
R2 Z-W R2 Z-W
I and II
(in which stereochemistry is not represented);
Wherein Rl is selected from the group consisting of hydrogen,
alkanoyl having from one to five carbon atoms, benzyl, -P~O)(OH)~ and the
sodium and potassium salts thereof, -CO(CH2)2-COOH and the sodium and potas-
sium salts thereof, and -CO-(CH2)p-NR4R5 wherein p is an integer from 1 to 4,
each of R4 and R5 when taken individually is selected from the group consist-
ing of hydrogen and alkyl having from one to four carbon atoms, R4 and R5
when taken together with the nitrogen to which they are attached form a 5-
or 6-membered heterocyclic ring selected from the group consisting of
piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having
1~28936
from one to four carbon atoms in the alkyl group;
R2 is selected from the group consisting of hydroxy and R2'
wherein R2' is selected from the group consisting of hydrogen, alkyl having
from one to six carbon atoms, phenyl and phenylalkyl having from one to four
carbon atoms in the alkyl group;
R3 is selected from the group consisting of hydrogen and hydroxy,
with the proviso that only one of R2 and R3 is hydroxy;
R6 is selected from the group consiting of hydrogen and R6'
wherein R6' is a nitrogen-protecting group selected from the group consisting
of alkyl having from one to six carbon atoms, cycloalkylmethyl having from
three to six carbon atoms in the cycloalkyl groupJ phenylalkyl having from one
to four carbon atoms in the alkyl group, 2-furfuryl, 2-tetrahydrofurfuryl, 2-
thienylmethyl and 2-tetrahydrothienylmethyl;
x is 0 or an intèger from 1 to 3;
- Z is selected from the group consisting of ~a) alkylene having from
one to thirteen carbon atoms; ~b) -(alkl)m-O-~alk2)n- wherein each of ~alkl)
and ~alk2) is alkylene having from one to thirteen carbon atoms, with the pro-
viso that the summation of carbon atoms in ~alkl) plus ~alk2) is not greater
than thirteen; each of m and n is 0 or 1; and
W is selected from the group consisting of hydrogen, pyridyl,
- ~ Wl wherein Wl is selected from the group consisting of hydrogen,
fluoro and chloro.
Also included are the pharmaceutically acceptable acid addition
salts of those compounds of formulae I and II which contain a basic group.
In compounds having two or more basic groups present, such as those wherein
the W variable is pyridyl and/or ORl represents a basic ester moiety, poly-
acid addition salts are, of course, possible. Representative of such pharma-
ceutically acceptable acid addition salts are the mineral acid salts such as
the hydrochloride, hydrobromide, sulfate, phosphate, nitrate; organic acid
salts such as the citrate, acetate, sulfosalicylate, tartrate, glycolate,
-- 4 --
112~936
malateJ malonate, maleateJ pamoate, salicylateJ stearateJ phthalate, suc-
cinateJ gluconateJ 2-hydroxy-3-naphthoateJ lactate, mandelate and methane
sulfonate.
Compounds of formulae I and II contain asym~etric centers at the
3- and the 4-positions in the azacycloalkyl moiety and may, of course, con-
tain additional asymmetric centers in the 4-position substituent (-Z-W) of
the benzenoid ring and in the R6 substituent. For convenience, the above
formulae depict the racemic compounds. However, the above formulae are con-
sidered to be generic to and embracive of the racemic modifications of the
compounds of this invention, the diastereomeric mixtures, the pure enantiomers
and diastereomers thereof. The utility of the racemic mixture, the di-
astereomeric mixture as well as of the pure enantiomers and diastereomers is
determined by the biological evaluation procedures described below.
Favored because of their greater bilogical activity relative to
that of other compounds described herein are compounds of formulae I and II
wherein Rl is hydrogen or alkanoyl; R2 is hydrogen or alkyl; and Z and W have
the values shown below.
Z n _ W
alkylene having from 5 to 10 carbon atoms - - H
alkylene having from 2 to 6 carbon atoms - - ~ W1J pyridyl
(alkl)m~~(alk2)n 0 1 ~ Wl, pyridyl
(alkl)m~~~alk2)n 1 0 _<~ Wl, pyridyl
Preferred compounds of formulae I and II are those favored compounds
wherein:
each of Rl and R2 is hydrogen;
x = l;
R6 is allyl and propargyl;
Z is -C(CH3)2(CH2)6 and W is hydrogen
or Z is -OCH(CH3)(CH2)3 and W is phenyl.
l~Z8936
The present invention provides intermediates useful in the prepara-
tion of compounds of formulae I and II. The intermediates have formula:
~ N ~ ORl
(~
R2 ' Z-W
wherein Rl, R2', x, R6, Z and W are as previously defined.
According to the invention, the compounds of the above formula
are prepared by reducing a compound of formula II
"
R6
Z-'N
wherein Rl, R2', x, R6, Z and W are as previously defined; and, where required
(a) when R6 is hydrogen, alkylating said compounds of formula I to produce a
compound wherein R6 is other than hydrogen; ~b) esterifying the compound of
formula I wherein Rl is hydrogen.
112~3~36
The compounds having formula I wherein R3 is hydroxy are prepared
from the appropriate 2-bromo 5-tZ-W substituted)phenol by a series of Teac-
tions which comprises as first step protection of the phenolic hydroxy group.
Suitable protecting groups are those which do not interfere with subsequent
reactions and which can be removed under conditions which do not cause un-
desired reactions at other sites of said compounds or of products produced
therefrom. Representative of such protective groups are methyl, ethyl, benzyl
or substituted benzyl wherein the substituent is, for example, alkyl having
from one to four carbon atoms, halo ~Cl, Br, F, I) and alkoxy having from one
to four carbon atoms.
The exact chemical structure of the protecting group is not critical
to this invention since its importance resides in its ability to perform in
the manner described above. The selection and identification of appropriate
protecting groups can easily and readily be made by one skilled in the art.
The suitability and effectiveness of a group as a hydroxy protecting group are
determined by employing such a group in the herein-illustrated reaction se-
quences. It should, therefore, be a group which is easily removed to re-
generate the hydroxy groups. Methyl is a favored protecting group since it
is easily removed by treatment with pyridine hydrochloride. The benzyl group
is a preferred protecting group since it can be removed by catalytic hydrogen-
olysis or acid hydrolysis.
The protected 2-bromo-5-(Z-W substituted)phenol is then subjected
to the Grignard reaction in a reaction-inert solvent with the appropriate aza-
cycloalkan-3-one (upper portion of Scheme A). Suitable reaction-inert solvents
; are cyclic and acyclic ethers such as, for example, tetrahydrofuran, dioxane
and dimethyl ether of ethylene glycol.
1128936
he Grl:nsrd reagent i9 formed ln known =inner, as, for example, by
¦ refluxing a mixture of one molar proportion of the bromo reactant and two
¦ molar proportions of magnesium in a reactlon-inert solvent, e.g., tetrahydro-
l furan. The resulting mixture is then cooled to about 0 C. to -20 C. The
¦ appropriate azacycloalkan-3-one is then added at a temperature of from about
0 C. to -20~ C.
The product of the Grignard reaction (formula I, Rl = benzyl, R3 =
OH) is then treated with an appropriate reagent to remove the protecting group.¦
If desired, the benzyl group on the phenolic hydroxy group and, if present,
that on the nitrogen of the azacycloalkyl moiety, are conveniently removed by
catalytic hydrogenation over palladium-on-carbon. Alternatively, the phenolic
benzyl group can be removed by acid hydrolysis using, for example, trifluoro-
acetic acid, if retention of the N-benzyl group is desired. A further alterna-¦
tive when retention of the N-benzyl group is desired comprises using an alkyl
ether of the phenolic hydroxy group, preferably a methyl or ethyl ether as
reactant in the Grignard reaction. Subsequent treatment of the Grignard reac-
tion product with, for example, pyridine hydrochloride, removes the alkyl
protecting group and retains the N-benzyl group.
Compounds of formula I wherein R3 is hydroxy are dehydrated by
treatment with a strong acid, such as hydrochloric, hydrobromic, sulfuric,
hydrofluoric or ~-toluenesulfonic acid to produce formula II compounds. Other
dehydrating agents such as thionyl chloride, pyridine, phospnorous oxychloride,
and tosyl or mesyl chloride -SO2 plus an acid acceptor can, of course, be used.
Catalytic hydrogenation of said compounds gives formula I compounds. Of
course, if either of Rl or R6 of the formula II compound is benzyl, it is
removed by this catalytic hydrogenation step.
il i
l ~12~6
l Since the compounds of this invention can have a group R6' (R6 ~ R6')
; I on the nitrogen of the azacycloalkyl moiety (formulae I-IV), it will frequently
not be desirable or necessary to remove the nitrogen protecting group R6'
¦ except, of course, when R6 is to be hydrogen, alkenyl or alkynyl. The pre-
¦ ferred nitrogen protecting group when removal of said group is neeessary is
¦ benzyl since it i9 readily removed by catalytic hydrogenation over palladium-
¦ on-carbon. Debenzylation is desirably carried out on the product of the
¦ Grignard reaction to provide the corresponding 3-hydroxy-3-[4-(Z-W)-2-hydroxy-
¦ phenyl]azacycloalkane which is subsequently dehydrated to a formula II compound
¦ wherein R6 = Rl = H. Catalytie hydrogenation (Pd/C) then gives a compound of
¦ formula I. Alkylation or aralkylation of the formula I or II compound with
¦ R6Cl or R6Br then provides the desired substi~ution on the azacycloalkyl group.
¦ The reaetion is eondueted in a solvent, e.g. alkanols such as ethanol, n-butano
l l-hexanol, at a temperature of from about 50 C. to the reflux temperature of
¦ the solvent. An acid acceptor, inorganie or organic, is used to bind the by-
produe~ aeid formed. Suitable bases are alkali metal carbonates and hydroxides
l pyridine, triethylami~e, N-methylmorpholine.
¦ A favored proeedure for introducing substituents on the nltrogen of
I the azaeyeloalkyl ring is reductive alkylation (or aralkylation) using the
¦ appropriate aldehyde in the presenee of a reducing agent. When the azaeyclo-
alkyl eompound is of formula I, the redueing agent ean be molecular hydrogen
and a catalyst, e.g. Pd/C, aetive metals and acids or metal hydrides. ~nen the
azacycloalkyl eompound is of formula II, i.e. an azaeycloalkenyl, a metal
hydride is used to avoid reducing the azacycloalkenyl group. Also, ~hen tne
substituent is an alkenyl or alkynyl group, a metal hydride is used as reducing
agent. Preferred as metal reducing agent is sodium cyanoborohydride. The
reaction is eonducted in a reaction-inert solvent such as acetonitrile, tetra- ~
hydrofuran, alcohols having from one to four carbon atoms, ethylene or pro?ylene
glycol, dioxane, benzene and toluene; and at a temperature of from about 10 C. !
to about 50 C. The reaetion is earried out at about a neutral pH by addit-on
~f an aeld su as acetle acld,
1 1128936
Scheme A
~ ~r
11 TPd/C /6Br ~2
d20 ~ ~
tPd/C, H2 tPd/C, H2
. I @R6 ~ = benzyl I @R6 ' $ benzyl
~6' ~ O ~
. 2) H2O2, OH
6 6
112~936
'I
Appropriate az~cycloalkan-3-ones are those having the formula
wherein R6' is a nitrogen protecting group. The function of such a group is
to prevent undesired reactions from occurring at the nitrogen atom and which,
when the desired reaction is completed, can, if desired or necessary, be
removed under conditions which do not cause undesired reactions at other sites
of the compounds or products produced therefrom. Representative of such
groups are phenylalkyl having from one to four carbon atoms in the alkyl group,
alkyl having from one to six carbon atoms, cycloalkylmethyl having from three
to six carbon atoms in the alkyl group, furfuryl, tetrahydrofurfuryl, 2-thienyl _
methyl and 2-tetrahydrothienylmethyl.
The general non-availability of compounds of formula V gives rise to
a situation where protection of said formula V reactant as its benzyl deriva-
tive frequently affords the most convenient route to compounds of formulae I-II
wherein R6 is other than hydrogen. Debenzylation of the formulae I-II compound~
wherein R6 is benzyl and subsequent alkylation of the pH group thereof with
R6Cl or R6Br according to known procedures affords the desired product wherein
R6 is other than hydrogen or benzyl.
Further, since benzyl is a favored protecting group for the phenolic
hydroxy group, protection of both the phenolic hydroxy and the nitrogen o~ the
azacycioalkan-3-one reactants by benzylation simplifies, by virtue of a sisgle
reaction, regeneration of the phenolic hydroxy and NH groups in formulae I-II
compounds wherein R6 is hydrogen.
' 1128936
~ In the lower portion of Scheme A, the 1,2,5,6-tetrahydropyridine is
¦ sub~eceed to hydroboration and then oxidation to produce a 4-piperidinol which,
¦ upon oxidation by means of chromium trioxide in acetone solution in the
¦ presence of acetic acid and sulfuric acid at a temperature of from about -10C.
5 ¦ to about 20 C , affords a 4-piperidone of formula III.
Preparation of 4-R2'-substituted compounds of formulae I or II can be
accomplished in any of several ways. One method (Scheme B) comprises reacting
a compound of formula III with an appropriate Grignard reactant R2'MgBr in a
suitable reaction-inert solvent under conditions such as are described above to
produce a 4-R2~-4-piperidinol which is dehydrated using an agent such as thiony 1
: chloride-pyridine to a 4-R2~-substituted-1,2,5,6-tetrahydropyridine. Catalytic
hydrogenation then gives a saturated compound of formula I.
Scheme B
,
d2, PdlC
liZf 3936
A fur her meChod comprise~ react1ng a fotmu1a I11 compound with an
¦ appropriate triphenyl-R2"-phosphorane in dimethylsulfoxide (Scheme C).
Appropriate triphenyl-R2"-phosphoranes are those wherein R2" has all values
l listed above ~ith respect to formula IV. The 4-alkylidene or aralkylidene
¦ compound thus produced (formula IV) is then catalytically hydrogenated (Pd/C).
Simultaneous debenzylation also occurs.
Scheme C
, IR6 '
~ @R6 i bmtry1
16 ~ IR6~ ~
R2 Z-W
.
Acid treatment of IV causes isomerization to a compound of formula II
- 13 -
llZB936
A still further method, and one which is favored since lt achieves
introduction of the R2~ substituent at an early stage, i9 that of Scheme D. Inl
thls scheme, a protected (R6') substituted 4-plperidone is reacted with an
: appropriate Grignard reactant to give the corresponding 4-R2'-4-piperidinol
which is dehydrated according to the procedure of Scheme B. Hydroboration
: and subsequent oxidation of the protected 4-R2'-1,2,5,6-tetrahydropyridine
produces a 4-R2~-3-piperidinol which is then oxidized with chromium trioxide
according to the procedure described above in Scheme A to give a protected 4-
R2~-3-piperidone of formula V. Subjection of this co,mpound to the reactions
outlined in Scheme A then produces compounds of formulae II and I.
. Scheme D serves adequately for preparation of R2~~substituted prod-
ucts except those wherein R2~ is benzyl. The benzyl group is conveniently
introduced via the procedure of Scheme C.
Scheme D
6' ~'
1) Hz~ _
( ~0 ~ (~\011
V
1128~36
The procedure described by 8eckett et al., J. Med. Pharm. Chem., 1,
37-58 (1959) affords a general procedure for preparation of 1-(R6'-substituted~
4-piperidone reactants of Scheme D. The procedure comprises reacting an
appropriate amine R6'-NH2 with excess ethyl acrylate in a suitable solvent such
as ethanol to produce che corresponding N-di-(2-carbethoxyethyl)-R6'-substitu-
ted amine. The di-ester is then cyclized via the Dieckmann reaction using
metallic sodium as base in a reaction inert solvent such as xylene to produce
the corresponding l-R6'-substituted-3-carbethoxy-4-piperidone. Decarboxylation
of this product is accomplished by refluxing with aqueous hydrochloric acid to
produce the desired 1-R6l-substituted-4-piperidone. The 4-piperidone thus
obtained is converted to a 3-piperidone via the method of Scheme D.
Prill et al., J. Am. Chem. Soc., 55, 1233-41 (1933), describe a
general procedure for preparation of azacycloalkanones by which the keto group
can, by ~udicious choice of reactants, be introduced at the 3- or the 4-posi-
tion. The procedure comprises reacting the appropriate N-substituted amino
acid ethyl ester with the appropriate ethyl ~-bromoalkanoate to form a diester
. which is then cyclized by means of sodium ethoxide to give a l-(substituted)-
azacycloalkan-3(or 4)-one.
~12B936
The 2-bromo-5-(Z-W substituted) phenol reactants are prepared by
bromination of the appropriate 3-(Z-W sub~tituted) phenol according to standard
procedures as, for example, by treatment with bromine in carbon tetrachloride
at a temperature of from about 20-30 C. The necessary 3-(Z-W substituted)
phenols, if not known compounds, are prepared by procedures illu~trated nerein.
A convenient method for preparing such reactants wherein the Z moiety is
alkylene or (alkl)-0-(alk2~n- comprises the Wittig reaction on an appropriate
aldehyde such as 2-(3-hydroxyphenyl)-2-methyl propionaldehyde, the hydroxy
group of which is protected by benzyl ether formation. The said aldehyde is
then treated with the appropriate alkyltriphenylphosphonium bromide, the alkyl
group of which extends the propionaldehyde group to the desired length. In a
typical procedure, the aldehyde reactant is added to a slurry of dimsyl sodium
and alkyl triphenylphosphonium bromide in dimethyl sulfoxide at a temperature
below 30 C., e.g. from about 10 to 30 C. When reaction is complete, the
alkene substituted protected phenol is recovered by known methods. Hydrogena-
tion of ~he alkene over palladium-on-carbon then affords the desired 3-(Z-W
substituted)phenol. Judicious choice of the starting (3-hydroxyphenyl)-
substituted aldehyde and alkyl triphenylphosphonium bromide reactants affords
the required 3-(Z-W-substituted)phenol reactants.
A further procedure for making 3-(Z-W substituted) phenols wherein Z
is alkylene or (alkl)-0-(alk2)n- comprises the Wittig reaction on an appropri-
ate phenolic aldehyde or ketone, e.g., 3-hydroxybenzaldehyde or a (3-hydroxy-
phenyl)alkyl ketone, in which the phenolic hydroxy group is protected as by
conversion to the benzyl, methyl or ethyl ether. By choice of appropriate
reactants, compounds having straight or branched alkylene groups (Z) can be
produced. When a ketone, e.g., 3-hydroxyacetophenone is used as reactant,
compounds wherein Z has a methyl group on the carbon atom adjacent to the
phenyl group are obtained.
, l
~lZ8936
j Suùst tutlon of ~ ~ethyl or ethyl grDup at other sites, e.g., the ~-
¦carbon atom of the alkylene group, i5 achieved by choice of the appropriate
¦carboalkoxy alkylidene triphenylphosphorane, e.g., (C6H5)3P-C(R')-COOC2H5.
¦The unsaturated ester thus produced is reduced to the corresponding alcohol by
¦reaction with lithium aluminum hydride, generally in the presence of a small
¦amount of aluminum chloride. Alternatively, when the phenolic protecting group ¦
¦is other than ben~yl (e.g. methyl), the alcohol is produced by catalytic reduc-
¦tion of the unsaturated ester using palladium-carbon, followed by treatment
l of the saturated ester thus produced with lithium aluminum hydride. Conversion
10 ¦ of the alcohol thus produced to the corresponding tosylate or mesylate followed
by alkylation of the tosylate or mesylate with an alkali metal salt of the
¦appropriate H0-(alk2)-W reactant, and finally removal of the protecting group
affords the desired resorcinol 3-(Z-W substituted) phenol.
I A variation of the above sequence comprlses bromination of the
15 ¦ alcohol rather than converting it to a tosylate or mesylate. Phosphorous tri-
¦ bromide is a convenient brominating agent. The bromo derivative is then reactecwith the appropriate H0-(alk2)-W in the presence of a suitable base (Williamson
reaction).
l The bromo compounds also serve as valuable intPrmediates for increas-
20 ¦ ing the chain length of the alkylene moiety in the above sequence to give com-
pounds wherein Z is -alkylene-W. The process comprises treating the bromo
derivative with triphenyl phosphine to produce the corresponding triphenyl-
phosphonium bromide. Reaction of the triphenylphosphonium bromide with the
appropriate aldehyde or ketone in the presence of a base such as sodium
hydride or n-butyl lithium affords an unsaturated derivative which is then
catalytically hydrogenated to the corresponding saturated compound.
~lZ8936
~n alternative method for introducing sn alkyl or aralkyl ~roup into
the aromatic nucleus, and specifically such a group wherein the carbon atom
adjacent the aromatic nucleus is a tertiary carbon atom, compri~es acid
catalyzed electrophilic substitution of guaiacol with a tertiary alcohol in th
presence of an acid, e.g. methane sulfonic acid. The general procedure con-
sists in reacting a mixture of methanesulfonic acid and equi lar amounts of
guaiacol and tertiary alcohol at temperatures of from about 30 C. to about ~0
C. until reaction is substantially complete. The product is isolated by
pouring the reaction mixture onto ice followed by extraction with a suitable
solvent such as methylene chloride. The 2-methoxy-4-alkyl phenol is then con-
verted to the desired 3-alkyl phenol by re val of the phenolic hydroxy group.
The process comprises converting the hydroxy group to a dialkyl phosphate group
by reaction with a dlalkyl chlorophosphonate, e.g. diethyl chlorophosphonate,
or with diethyl phosphonate and triethylamine. Treatment of the dial~yl phos-
phate with lithium/ammonia followed by demethylation of the resulting alkylated
methyl ether with boron tribromide or pyridine hydrochloride or other known
demethylating agents affords the desired 3-alkylphenol.
Esters of compounds of formulae I and II wherein Rl is alkanoyl or
- -C0-(CH2)pNR4R5 are readily prepared by reacting formulae I and II compounds
wherein Rl is hydrogen with the appropriate alkanoic acid or acid of formula
HOOC-(CH2)p-NR4R5 in the presence of a condensing agent such as dicyclohexyl-
carbodiimide. Alternatively, they are prepared by reaction of a formula I or
II compound with the appropriate alkanoic acid chloride or anhydride, e.g.3
acetyl chloride or acetic anhydride,in the presence of a base such as pyridine.
Phosphate esters are prepared by treating the appropriate l-R6-~3-(4-
Z-W)-2-hydroxyphenyl]azacycloalkane with potassium hydride followed boy dibenzyl _
phosphorochloridate. Catalytic hydrogenation of the dibenzylphosphate ester
affords the desired phosphate ester. Cautious neutralization with sodium or
potassium hydroxide provides the corresponding sodium or potassium salts.
~lZ8936
The analgesic propertles of the compounds of tllis invention are
' determined by tests using nociceptive stimuli.
¦¦ Tests Using Thermal Nociceptive Stimuli
li a) Mouse llot_Plate Anal~esic Testin~ ¦
5 ¦¦ The method used is modified after Woolfe and MacDonald, J. Pharmacol.
. Tner , 80, 300-307 (1944). A controlled heat stimulus is applied to the i
¦ feet of mice on a 1/8-inch thick aluminum plate. A 250 watt refle&tor infrared
heat lamp is placed under the bottom of the aluminum plate. A thermal regula-
l tor, connected to thermistors on the plate surface, programs the heat lamp to
- 10 ! maintain a constant temperature of 57 C. Each mouse is dropped into a glass
: cylinder (6 1/2-inch diameter) resting on the hct plate, and timing is begun f
jl when the animal's feet touch the plate. The mouse is observed at 0.5 and 2
i! hours after treatment with the test compound for the first "flicking" movements
¦¦ of one or both hind feet, or until 10 seconds elapse without such movements.
15 1 Morphine has an MPE50 - 4-5.6 mg./kg. (s.c.).
¦ b) Mouse Tail Flick Analgesic T sting
! Tail flick testing in mice is modified after D'Amour and Smith, J.
¦¦ Pharmacol. Exp. Tner., 72, 74-79 (1941) using controlled high intensity heatil applied to the tail. Each mouse is placed in a snug-fitting metal cylinder,20 ¦¦ with the tail protruding through one end. This cylinder is arranged so that
¦! the tail lies flat over a concealed heat lamp. At the onset of testing an
aluminum flag over the lamp is drawn back, allowing the light beam to pass
¦ through the slit and focus onto the end of the tail. A timer is simultaneously
l activated. The latency of a sudden flick of the tail is ascertained. Un-
25 1 treated mice usually react within 3-4 seconds after exposure to the lamp. Thei
¦¦ end point for protection is 10 seconds. Each mouse is tested at 0.5 and 2
¦¦ hours after treatment with morphine and the test compound. ~lorphine has an
1~ MPE50 of 3.2-5.6 mg./kg. (s.c.).
11 - 19-
~128936
:
Il c) Tail In~lersion Procedure
¦I The metllod is a modification of the receptable procedure developed by
Benbasset, et al., ~rch. int. Pharmacodyn., I22, 434 (1959). Male albino mice
(19-21 g.) of the Charles River CD-l strain are weighed and mar~ed for identi-
5 ¦¦ fication. Five animals are normally used in each drug treatment group with
¦¦ each animal serving as its own control. For general screening purposes, new
¦¦ test agents are first administered at a dose of 56 mg.lkg. intraperitoneally
¦l or subcutaneously, delivered in a volume of 10 ml./kg. Preceding drug treat- ;
Il ment and at 0.5 and 2 hours post drug, each animal is placed in the cylinder.
I Each cylinder is provided with holes to allow for adequate ventilation and is
closed by a round nylon plug through which the animal's tail protrudes. The
cylinder is held in an upright position and the tail is completely immersed
Il in the constant temperature waterbath (56 C.). The endpoint for each trial i3
¦, an energetic jerk or twitch of the tail coupled with a motor response. In
15 ¦ some cases, the endpoint may be less vigorous post drug. To prevent undue tis-
sue damage, the trlal is terminated and the tail removed from the waterbath
¦ within 10 seconds. The response latency is recorded in seconds to the nearest
¦! 0.5 second. A vehicle control and a standard of known potency are tested
il concurrently with screening candidates. If the activity of a test a2ent has
j not returned to baseline values at the 2-hour testing point, response laten-
- 1l cies are determined at 4 and 6 hours. A final measurement is made at 24
j; hours if activity is still observed at the end of the test day.
Ii .
- 20 -
1128~36
il i
Test Usin~ Cllemic~l Nociceptlve Stimuli
Suppression of PhenYlbenzoquinone Irritant-Induced Writhillg
¦ Croups of 5 Carwortll Farms CF-l mice are pretreated su~cutaneously
¦ or orally witll saline, morphine, codeine or the test compound. Twenty minutes
5 I¦ (if treated subcutaneously) or fifty minutes (if treated orally) later, each
¦I group is treated with intraperitoneal injection of phenylbenzoquinone, an
¦l irritant known to produce abdominal contractions. The mice are observed for
¦l 5 minutes for the presence or absence of writhing starting 5 minutes after
¦ the in~ect$on of the irritant. MPE50'R of the drug pretreatments in blocking ;
- 10 writhing are ascertained.
, ' , . . ~,
¦¦ Tests Using Pressure Nociceptive Stimuli
Il Effect on the Haffner Tail Pinch Procedure
¦i A modification of the procedure of Haffner, Experimentelle Prufung
Il Schmerzstillender. ~Iittel Deutch Med. Wschr,, 55, 731-732 (1929) is used to
15 !I ascertain the effects of the test compound on aggressive attacking responses
elicited by a stimulus pinching the tail. Male albino rats (50-60 g.) of the
Charles River (Sprague-Dawley) CD strain are used. Prior to drug treatment,
I and again at 0.5, 1, 2 and 3 hours after treatment, a Johns Hopkins 2.5-inch
¦ "bulldog" clamp is clamped onto the root of the ratls tail. The endpoint at
20¦¦ each trial is clear attacking and bitin~ behavior directed toward the offend- ,
ing stimulus, with the latency for attack recorded in seconds. The clam? is
¦, removed in 30 seconds if attacking has not yet occurred, and the latency of
¦¦ response is recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.
!
- 21 -
1
: !
~ . . . . . . . ... . .
~28~36
'
l~ Tests Usin~ Llectrical Nocice~tive Stimuli
l The "Flincll-Juml)" Tes_ I
A modification of the flinch-jump procedure of Tenen, Psychopharma-
colo~ia, 12, 278-285 (1968) is used for determining pain thresholds. Male
5 ¦¦ albino rats (175-200 g.) of the Charles River (Sprague-Dawley) CD strain are
~¦ used. Prior to receiving the drug, the feet of each rat are dipped into a
20% glycerol/saline solution. The animals are then placed in a chamber and
presented with a series of l-second shocks to the feet which are delivered in
increasing intensity at 30-second intervals. ~lese intensities are 0.26, 0.39,
10 ¦ 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 m~. Each
I animal~s behavior is rated for the presence of (a) flinch, tb) squeak and
¦¦ (c) jump or rapid forward movement at shock onset. Single upward series of
¦I shock intensities are presented to each rat just prior to, and at 0.5, 2, 4
¦¦ and 24 hours subsequent to drug treatment.
15 ¦I Results of the above tests are recorded as percent maximum possible
effect (%MPE). The %MPE of each group is statistically compared to the %MPE
of the standard and the predrug control values. The %~E is calculated as
follows:
.1
%MPE test time - control time 100
cutoff time - control time
I - 22 -
' ~1
. .
~j 1128936
The nalge~lc activlty o~ cert~ln compound~ o~ thls lnventlon as
determined by the phenylbenzoquinone irritant-induced writhing (PBQ) test
described above is presented below. Table I presents data for compounds kavin
the formula 16
S and Table II, for compounds having the formula
.
R~6
Analgesic Activity ED (mg./kg.) or % Protection
(mb.¦kg.) Subcutaneous51y
TABLE I: ~
R6 Rl R3 PBQ
: 10 benzyl benzyl OH 59(56)
H H H 49(56)
~: H H H >56
CH2C-CH H H 53(10)
CH2C--C~ H H 3.78
TABLE II:
R6 Rl PBQ
benzyl benzyl >56
: benzyl H 34.9(56)
H H 32(56)*
CH3 -H 23(56)
CH3 H 53(56)
CH2C--CH H 1.65
CH2C-CH H 0.75*
.
llZ8936
The compounds of the present invention are active analgeslcs via oral
and parenteral administration and are conveniently adminlstered in composltion
form. Such compositions include a pharmaceutical carrier selected on the basis
of tha chosen route of administration and standard pharmaceutical practice.
For example, they can be administered in the form of tablets, pills, powders
or granules containing such excipients as starch, milk sugar, certain types of
clay, etc. They can be administered in capsules, in admixtures with the same
or equivalent excipients. They can also be administered in the form of oral
suspensions, solutions, emulsions, syrups and elixirs which may contain flavor-
ing and coloring agents. For oral administration of the therapeutic agents of
this invention, tablets or capsules containing from about 0.20 to about 100
mg. are suitable for most applications.
The physicia~ will determine the dosage which will be most suitable
- for an individual patient and it will vary with the age, weight and response
of the particular patient and the route of administration. Generally, however,
the initial analgesic dosage in adults may range from about 1.0 to about 750
mg. per day in single or divided doses. In many instances, it is not necessary
to exceed 100 mg. daily. The favored oral dosage range is from about 1.0 to
about 300 mg./day; the preferred range is from about 1.0 to about 50 mg./day.
The favored parenteral dose is from about 0.1 to about 100 mg./day; the
preferred range from about 0.1 to about 20 mg./day.
This inventioD also provides pharmaceutical compositions, including
unit dosage forms, valuable for the use of the herein described compounds as
analgesics and other utilities disclosed herein. The dosage form can be
given in single or multiple doses, as previously noted, to achieve the daily
dosage effective for a particular utility.
,,,
112B936
The compounds (drugs) described herein can be formulated for adminis-
tration in solid or liquid form for oral or parenteral administration.
Capsules containing drugs of this invention are prepared by mixing one part by
weight of drug with nine parts of excipient such as starch or milk sugar and
S then loading the mixture into telescoping gelatin capsules such that each
capsule contains 100 parts of the mixture. Tablets containing said compounds
are prepared by compounding suitable mixtures of drug and standard ingrPdients
used in preparing tablets, such as starch, binders and lubricants, such that
each tablet contains from 0.10 to 100 mg. of drug per tablet.
Suspensions and solutions of these drugs are frequently prepared
just prior to use in order to avoid problems of stability of the drug (e.g.
oxidation) or of suspensions or solution (e.g. precipitation) of the drug upon
storage. Compositions suitable for such are generally dry solid compositions
which are reconstituted for injectable administration.
' !
28936
Their activity as diuretic agents is determined by the procedure of
Lipschitz et al., J. Pharmacol., 197, 97 (1943) which utilizes rats as the
test animals. ~le dosage range for this use is the same as that noted above
with respect to the use of the herein described compounds as analgesic agents.
S ¦ Antidiarrheal utility is determined by a modification of the pro-
cedure of Neimegeers et al., Modern Pharmacol~&y-Toxicolo~y, Willem van Bever
and Harbans Lal, Eds., 7, 68-73 (1976). Charles River CD-l rats (170-200 g~s)
are housed in group cages 18 hours before testing. The animals are fasted
overnight with water available ad libitum prior to administration of castor
~0 oil. The test drug is administered subcutaneously or orally at a constant
volume of 5 ml./kg. of body weight in a 5% ethanol, 57: F.mulphor EL-620 (a
polyoxyethylated vegetable oil emulsifying agent available from Antara
Chemicals, New York, N.Y.), and 90% saline vehicle followed one hour later
l with a challenge of castor oil (one ml., orally). The animals are placed in
15 ¦ small individual cages (20.5 x 16 x 21 cm.) having suspended wire floors. A
disposable cardboard sheet is placed beneath the wire floors and examined one
hour after castor oil challenge for the presence or absence of diarrhea. A
vehicle/castor oil treatment group serves as control for each day's testing.
l Results are recorded as the number of animals protected at one hour post
challenge. In general, the dosage levels for use of these compounds as anti-
diarrheal agents parallels those with respect to their use as analgesic agents
The tranquilizer activity of the compounds of this invention is de-
termined by orally administering them to rats at doses of from about 0.01 to
about 50 mg./kg. of body weight and observing the subsequent decreases in
spontaneous motor activity. The daily dosage range in ma~mals is from about
~ Olto~out100=û- ~
~ -25a-
112~936
~ Anticonvulsant activlty is determined by ~ubcutaneously administerlng
¦ the test compound to male Swiss mice (Charles River) weighing 14-23 g. in a
¦ vehicle of the type used for antldiarrheal utility. The mice are used in
l groups of five. The day beEore use, the mice are fasted overnight but watered
5 ¦ ad lib. Treatments are given at volumes of 10 ml. per kg. via a 25 gauge
hypodermic needle. Subjects are treated with the test compound and, one hour
after challenge, electroconvulsive shock, 50 mA. at 60 Hz. administered trans-
corneally. Controls are-simultaneously run in which the mice are given only
I the vehicle as control treatment. The elec`troconvulsive shock ~reatment
10 ¦ produces tonic extensor convulsions in all control mice with a latency of
1.5-3 seconds. Protection is recorded when a mouse exhibits no tonic extensor
convulsions for 10 seconds after administration of electroconvulsive shock.
Antianxiety activity is determined in a manner similar to that for
l evaluating anticonvulsant activity except that the challenge convulsant is
15 ¦ pentylenetetrazole, 120 mg./kg. administered intraperitoneally. This treatment
¦ produces clonic convulsions in less than one minute in over 95% of control mice
treated. Protection is recorded when the latency to convulse is delayed at
¦ least 2-fold by A drug pretreatment.
¦ Sedative/depressant activityis determined by treating groups of six
20 ¦ mice subcutaneously with various doses of test agents. At 30 and 60 minutes
post treatment, the mice are placed on a rotorod for one minute and evaluated
for their performance on the rotorod. Inability of the mice to ride the roto-
rod i8 taken as evidence of sedative/depressant ac~ivity.
. ' ,.
-25b-
11;Z8936
EXAMPLE 1
l-Benzyl~ 2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
_ 3-hydroxypiperidine
-
A solution of 20.0 g. (51.4 mmols) of 1-bromo-2-ben~yloxy-4-(1,1-
dimethylheptyl)benzene in 75 ml. o~ tetra~ydrofuran is slowly added to 2.5 g.
tlO3 mmol9) of 70-80 mesh magnesium metal. The resultiag mixture is refluxed
for 20 minutes and is then cooled to -10 C. A solution of 9.71 g. (51.4
mmols) of N-benzyl-3-piperidone in 25 ml. of tetrahydrofuran is then added at
such a rate that the reaction temperature is maintained below 0 C. The reac-
tion mixture is stirred for 30 minutes following completion of addition and isthen added to 500 ml. of saturated ammonium chloride and 500 ml. of ether. I
The ether extract is washed with two 250 ml. portions of sodium chloride, driedi
over magnesium sulfate and evaporated to an oil. The oil is purified via
l column chromatography on 700 g. of silica gel eluted with 50% ether-cyclohexane
15 ¦ to yield 17.1 g. (67%) of the title compound as an oil:
PMR: ~cDScl 0.85 (m, terminal sidechain methyl), 1.25 (s, gem
dimethyl), 3.05 (m, C-2 piperidine methylene), 3.10 (s, OH), 3.63 (bs, N-
benzyl methylene), 5.02 (s, benzyl ether methylene), 6.81 (bs, overlaps ~6.85,
Ar~), 6.85 (dd, J=8 and 2Hz, ArH), 7.60 (d, J=8Hæ, ArH), 7.25 (s, PhH) and
7.32 ts, PhH).
IR: (CHC13~ 3448, 1618 and 1572 cm
MS: m/e 499 (M ), 481, 408 and 390.
In like manner, the following compounds are prepared from appropriat~.
l-bromo-2-benzyloxy-4-~Z-W~benzenes and azacycloalkan-3-ones:
[~Z-II
- 26 -
,~ . i
llZ~3936
x Z , W
0, 1, 2 C~l(CH3)CH(CH3)(CH2)5 H
0, 1 (CH2)5 H
0, 1 CH(CH3)(CH2)2 C6H5
0,1,2,3 CH(CH3)(CH2)3 C6H5
1, 2 CH(CH3)(CH2)4 4-FC6H4
0, 1, 3 O(CH2)4 C6H5
1, 2 ( 3)(C 2)3 C6H5
1, 2 . oca (CH3)(cH2)3 4-ClC6H4
O, 1 (CH2)10 C6H5
0, 1, 3 (CH2)13 H
1, 3 O(CH2)6 H
1 O(CH2)10 3-pyridyl
. 0, 1, 2 CH(CH3)tCH2)3 4-pyridyl
1 (CH2)50(CH2)8 H
1, 3 CH(CH3)(C~2)20 C6H5
0, 2, 3 C(CH3)2(CH2)6 H
O, 1 O(CH2)4 C6H5
0, 3 CH(CZH5)(CH2)4 4-FC6H4
0, 2 ( 3)2( 2)10 4-FC6H4
0, 1 O(CH2)5 3-pyridyl
1, 2 (CH2)10 4-ClC6H4
0, 1, 2 CH(CH3)CH2-0-CH2 H
1 CH(CH3)CH20CH2 C6H5
. 0, 2 CH2cH(cH3)o(cH2)2 4-FC6H4
For convenience, various values of x Por given values of Z and W are
collectively tabula~ed.
1128936
EXAMPLE 2
3-~4-(1,1-DimethYlheptYl)-2-hYdroxyvhenyll-3-piperidin
A mixture of 8.5 (17.03 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1- l
dimethylheptyl~phenyl]-3-hydroxypiperidine, 2.0 g. of 10% palladium-on-carbon ¦
and 60 ml. of ethanol is stirred under one atmosphere of hydrogen for 2 hours.¦
The reaction mixture is filtered through diatomaceous earth with ethyl acetate
and evaporated. The residue is recrystallized from ethyl acetate to yield
3.8 g. (70%) of the title compound. A second crop of the title compound 0.396
g. (7%) is obtained from the mother liquor.
M.P.: 147 C.
P~ ~cTDcl 0.85 (m, terminal sidechain methyl~, 1.24 (s, gem
dimethyl), 3.08 (bs, C-2 piperidine methylene), 6.3 (bs, exchangeable H), 6.8
(m, ArH) and 7.20 (d, J=8Hz, ArH).
IR: (KBr) 3413, 3236 and 1613 cm
MS: m/e 319 (M ), 301, 286, 234 and 216.
Analysis: Calc~d for C20H33N02: C, 75-19; H, 10-41; N, 4-38 %
Found: C, 75.35; H, 10.13; N, 4.39 %
In like manner, the compounds listed in Example 1 are debenzylated
to give compounds having the formula below wherein x and Z-~ are as defined
in ~xa~ple 1
~ - ~8 -
.
llZ8936
l l
EXAMPLE 3
3-[4-~ -Dimethylheptyl)-2-hydro~yphen~ 2~5~6-tetrahydropyrid-ine
A mixture of 23.6 g. (74.2 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-
hydroxyphenyl]-3-piperidinol and 400 ml. of 2N hydrochloric acid is heated at
reflux for 2 hours. The reaction is cooled, evaporated and dissolved in
excess saturated sodium bicarbonate and 400 ml. of dichloromethane. The di-
chloromethane extract is combined with a second 400 ml. dichloromethane
extract of the aqueous phase, dried over magnesium sulfate and evaporated to
an oil. Crystallization from ether-pentane gave 13.0 g. (58%) of the title
compound .
M.P.: 122-123 C.
PMR ~CTMCl 0.84 (m, terminal methyl), 1.10 (s, gem dimethyl), 2.50
(m, C-5 methylene), 3.32 (bt, J=6Hz, C-6 methylene), 4.00 (bs, C-2 methylene),
5.90 (m, vinyl proton), 6.9 (m, ArH) and 8.42 (bs, OH, ~H).
IR: (KBr) 3448, 3289, 1613 and 1575 cm
MS: m/e 301 (M ), 286, 272, 258 and 216.
~ eutralization of this compound in ether with ethanolic hydrogen
chloride gives the HCl salt, M.P. 156 C. (from ether-ethanol.
Similarly, the compounds of Example 2 are dehydrated to corresponding
compounds having the formula:
H
~Z-U
llZ8936
¦ EXAMPLE 4
l-Benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-
I 1 2 5 6-TetrahvdroDvridine and the Free Phenol
l A mixture of 7.0 g. (14.0 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-
5 ¦ dimethylheptyl)phenyl]-3-hydroxypiperidine and 200 ml. of 2N hydrochloric acid
is heated at reflux for 6 hours. The reaction miY~ture is evaporated under
reduced pressure to a thick residue which is dissolved in 500 ml. of saturated ¦sodium bicarbonate-300 ml. of ether-100 ml. of dichloromethane. The organic
phase is separated, dried over magnesium sulfate and evaporated to an oil.
The oil is purified via column chromatography on 400 g. of silica gel eluted
with 50% ethar-cyclohexane to yield, in order of elution, 5.1 g. (76%) of
the title compound as an oil and 1.32 g. t24%) of 1-benzyl-3-[4-(l,l-dimethyl-
heptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine as an oll.
Title Compound:
PMR: ~TcDScl 0.87 (m, terminal sidechain me~hyl), 1.28 (s, gem
dimethyl), 2.48 (m, C-5 methylene of pyridine), 2.88 (m, C-6 methylene of
pyridine), 3.61 (bs, N-benzyl methylene), 3.82 (bs, C-2 methylene of pyridine),
5.10 (s, benzyl ether methylene)? 5.93 (m~ vinyl H), 6.8-7.3 (m, ArH) and
7.3-7.6 ~m, PhH).
IR: (CHC13) 1653, 1610 and 1565 cm 1,
MS: m/e 481 (M ), 396, 390 and 91.
Phe lic Compound:
PMR: ~cDScl 0.82 (m, terminal sidechain methyl), 1.22 (s, gem
dimethyl), 2,40 (m, C-5 methylene of pyridine), 2.88 (t, J=6Hz, C-6 methylene j
of pyridine), 3.42 (bs, N~-benzyl methylene), 3.82 (s, C-2 methylene of pyridin~),
5.87 (m, vinyl H), 6.6-7.1 (m, ArH) and 7.1-7.4 (m, PhH).
IR: (CHC13) 3509, 3175, 1667, 1623 and 1608 cm
MS: m/e 391 (M ), 376, 306, 300, 272, 187, 120 and 91.
_ 30 -
:.
llZ13936
Si~ilarly, the following compound~ are prepared from appropriate 1-
bromo-2-benzyloxy-4-(Z-W)benzenes and the approprlate azacyeloalkan-3-ons
according to th~ procedure of Example 1 and t~-e above procedure. ~he free
phenol is also produced. (0 - phenyl)
f0
~ O
x Z W
. 0, 1, 3 C(CH3)2(CH2)2 H
1, 2 c(cH3)2(cH2)10 H
1, 2 C(CH3)2(CH2)4 C6H5
1 C(CH3)2(CH2)10 C6H5
0, 1, 2 C(CH3)2(C~2)4 4-pyridyl
0, 1 C(CH3)2(CH3)3 2-pyridyl
1, 3 CH(CH3)(CH2)2 C6H5
l, 3 CH(C2Hs)(cH2)2 4-ClC6H4
O, 1 CH(C2H5) (CH2)4 4-FC6H4
2 (CH2)5 H
1, 2 ( 3)( 2)3 4-ClC6H4
, (CH2)l3 H
1 (CH2)4 C6H5
0, 1 (CH2)8 H
2 (CH2)3 2-pyridyl
1, 3 (CH2)4 4-pyridyl
2 CH(CH3)CH(CH3)CH2 3-pyridyl
2 CH(CH3)CH(CH3)CH2 4-pyridyl
0~ l CH(C2H5)(CH2)2 4-pyridyl
0, 2 (CH2)10 4-pyridyl
0, 1, 2, 3 OCH(CH3)(CH2)3 C6H5
1, 3 O C6H5
O, 1 0 4-FC6H4
1, 2 o 4-ClC6H4
1 O(CH2)4 4-FC6H4
2 O(CH2)8 C6H5
2 O(C~z~lO - 31 - 4-ClC634
. I
~128936
~ ,
X* Z W
O, 2 ocH(cH3)tcll2)8 C6~l5
1 OCH(CH3)CH2 4-FC6H4
1 OC(CH3)2(CH2)3 C6H5
2 OCH2CH(CH3)CH2 C6H5
~ 3 OCH(CH3)(CH2)10 H
2 ~CH2)30 3-pyridyl
1 OC(CH3)2(CH2)7 H
1 O(CH2)13 H
1, 2 (CH2)13 C6H5
OCH(C 3)( 2)6 4-FC6H4
( 3)2( 2)10 4-FC6H4
2 (CH2)30CH(CH3) 2-pyridyl
. 1 OCH(~2H5) (CH2)3 4-ClC6H4
O OC(CH3)2(CH2)6 H
2 0(CH2)2C(CH3)2(cH2)2
O O(CH2)6 C6H5
3 O(CH2)12 H
O, 1, 3 OCH(CH3)(CH2)3 4-pyridyl
1 O(CH2)2 4-pyridyl
1, 2 OC (C 3)( 2)3 2-pyridyl
O O(CH2)5 3-pyridyl
1, 2 0 4-pyridyl
O OCH(C2H5)(CH2)2 4-pyridyl
O, 1 O(C 2)10 2-pyridyl
1 (CH2)30(CH2)3 H
. 1 CH(cH3)(cH2)2o(cH2)4 4-pyridyl
1, 2 (CH2)20(CH2)8 H
: O, 1 ~CH2)60CH(CH3) H
O CH(C2H5)(CH2)20CH(CH3) 2-pyridyl
~ (CH~)2(c 2)10 H
' 3 (CH2)10(CH2)2 H
1, 3 C(CH3)2(CH2)20(cH2)4 H
O (CH2) 40CH2 C6H5
1 CH(CH3)(CH2)20 C6H5
1, 2 (CH2)130 H
1 (CH2)6 H
O (CH2) 60CH2 4-ClC6H4
(CH2)6 4-FC6H4
~ultiple values listed under column "x" indicate
preparation of compounds having the given values
of Z and W.
- 32 -
~1~8936
EXAMPL~
3-[4-(1,1-Dim thylheptyl)-2-hydroxypheny~ iperidine
l A mixture of 7.4 g. (24.5 mmoles) of 3-f4-(1,1-dimethylheptyl)-2-
¦ hydroxyphenyl]-1,2,5,6-tetrahydropyridine and 2.0 g. of 10~ palladium-on-carbon
¦ in 150 ml. of ethanol and 75 ml. of ethyl acetate is stirred under one atmos-
¦ phere of hydrogen for 2.5 hours. The reaction is filtered through diatomaceous¦
¦ earth and evaporated. Crystallization of the residue from ether-pentane gave
¦ 4.6 8. (62%) of the title compound.
I M.P.: 138-140 C
¦ P~ ~CDCl 0.80 (m, terminal methyl), 1.21 (s, gem dimethyl), 6.85
(m, ArH) and 8.7 (bs, NH, OH).
MS: m/e 303 (M ), 288, 260, 218 and 175.
IR: (KBr)- 3333 (broad), 1623 and 1592 cm 1.
l Neutralization of the compound in ether with ethanolic-hydrogen
¦ chloride gives the HCl salt as a hygroscopic glass after vacuum drying.
The remaining 1,2,5,6-tetrahydropyridines of Example 3 are similarly
reduced to the corresponding compounds having the formula:
~ 33 ~
112B936
I
EXAMPLE 6
3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]piperidine
A mixture of 4.2 g. (8.73 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-
dimethylhPptyl)phenyl]-1,2,5,6-tetrahydropyridine, 4.0 g. of 10% palladium-on-
carbon and 50 ml. of ethanol is stirred under one atmosphere of hydrogen for
2 hours. The reaction mixture is filtered through diatomaceous earth with
ethyl acetate, evaporated and the residue again dissolved in ethyl acetate and
flltered. The filtrate is evaporated and the residue crystallized in ether to
yield 1.1 g. (42%) of the title compound.
The product is identical to that of Example 5.
In like manner, hydrogenatlon of the compounds listed in Example 3
affords the corresponding compounds hav~ng the formula below wherein -Z-W and
x re a~ defin i~ Z-ampl
''
llZ~3936
~I EXA~PLE 7
l l'
enzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl~-4-piperidinol
To a mixture of 39.9 g. (80 ~mols.) of 1-benzyl-3-[2-benzyloxy-4-
(l,l-dimethylheptyl)phenyl]-lJ2,5,6-tetrahydropyridine and 4.8 g. (115 mmols.) I
of sodium borohydride in 50 ml. of tetrahydrofuran is added 21.6 ml. (180 mmolst)
of borontrifluoride etherate complex in 40 ml. of tetrahydrofuran during a 2
hour period at 0-5C~ Stirring is continued 2 hours longer at 25C The
reaction mixture is cooled in ice and quenched with 6.5 ml. of water and then
20 ml. of 2N sodium hydroxide and 20 ml. of 30% hydrogen peroxide are added
dropwise. After several minutes stirring the reaction is cooled and 20 ml.
of concentrated hydrochloric acid is added dropwise. The reaction mixture is
partially evaporated and then made basic with 6~ sodium hydroxide. The concen-
trated mixture is extracted with 250 ml. of ether, the ether extract washed
with 100 ml. of saturated sodium chloride, dried over~magnesium sulfate and
evaporated. The residue is purified via column chromatography on 400 g. of
silica gel eluted with 50~ ether-cyclohexane to yield the title compound.
Repetition of the above procedure but using the appropriate 1,2,5,6- ¦
tetrahydropyridine reactants (Example 4) affords 4-piperidinols having the
formula below erein -Z~ ed i= Example 4:
~128936
,
¦ EXAMPLE 8
l-Benzyl-3-~2-benzyloxy-4-(l~l-dimethylheptyl)phenyl]-4-piperidone
To a cooled solution of 24.8 g. (50 mmols.) of 1-benzyl-3-[2-benzy-
l loxy-4-(l,l-dimethylheptyl)phenyl-4-piperidinol, 100 ml. of acetone, 6.0 g.
(60 mmols.) of chromium trioxide, 15 ml. of water and 20 ml. of acetic acid
is added dropwise 20 ml. of concentrated sulfuric acid at such a rate as to
maintain the temperature at 5C. The reaction mixture is stirred 5 hours longeF
(t<18C.) and then neutralized with concentrated ammonium hydroxide. The
reaction mixture is extracted with 500 ml. of ether, the ether extract washed
once with saturated sodium chloride, dried over magnesium sulfate and evaporateb.
Purification is accomplished via rapid column chromatography on 100 g. of
silica gel eluted with ether to yield the title compound.
Oxidation of the 4-piperidinol compounds of Example 7 by means of the
above procedure provides corresponding 4-piperidones having the formula below
wherein -Z-W and x are as defined in Example 7: ¦
0 ` I
_ 36 -
,i 1128936 ,
. EXAMPLE 9
l-(R6l substituted)-3-~2-benzyloxy-4-tZ-W)phenyl]-
¦ ~ enes
¦ The compounds tabulated below are prepared from appropriate l-R6'-
5 ¦ azacycloalkan-3-ones of Preparation Y and appropriate l-bromo-2-benzyloxy-4-
¦ (Z-W)benzenes according to the procedure of Example 4:
~l~Z_,~
¦ R6~ and x are as defined in Preparation Y and Z and W have the
following values: -
~,~ I . .. Z___ W
10 ¦ ( 3)2(C 2)6 H
¦ CH(CH3)CI~(CH3)(CH2)5 H
¦ (CH2)5 H
(CH2)13 H
¦ CH(CH3)(CH2)3 C6H5
15 ¦ CH(CH3)(CH2)3 4-FC6H4
CH(CH3)(CH2)2 - C6H5
CH(CH3)(CH2)2 4-ClC6H4
CH(CH3)(CH2)4 4-ClC6H4
¦ CH(CH3)(CH2)3 4-pyridyl
CH(CH3)(CH2)2 2-pyridyl
( 3)( 2)3 C6H5
OCH(CH3)(CH2)2 4-FC6H4
( 3)( 2)3 4-pyridyl
O(CH2)4 C6H5
- O(CH2)4 4-pyridyl
(CH2)10 3-pyridyl
0 4-ClC6H4
o 4-pyridyl
1121~36
Z W
(CH2)4 H
tCH2) 13 H
(CH2)6. 4-FC6H4
(CH2) 50 (CH2) 8 H
( 2) 4 2 C6H5
CH (CH3) (CH2) 2 C6H5
(cd2)4(cd2)5 4-pyridyl
'
. '
~lZ8936
~¦ ZXAKPL3 10
l-(R6~-Substituted)-3-~2-benzyloxy-4-(Z-W)phenyl]-
4-azacvcloalkanones
The compounds of Example 7 are subjected to the procedures of
Examples 7 and 8 to give the following compounds wherein x, R6', Z and W
are as defined in Example 9.
16'
0
. EXAMPLE 11
1-(R6'-Substituted)-3-[2-benzyloxy-4-(Z-W)phenyl]-
azacycloalkanes `
Following the procedure of Example 5, the compounds of Example 7
are converted to compounds having the formula below wherein x, R6', Z and W
: are as defined in Example 9.
~:~-W
- 39 -
1128936
EX~IPLE 12
l-Benzyl-3-~2-ben~yloxy-4-(1,1-dimethylheptyl3phenyl]-4-
(3-phenylpropylidene)piperidine
To a 15C. solution of 4.13 g. (12.0 mmols.) of triphenyl 3-phenyl-
propylphosphorane in 24 ml. of dimethyl sulfoxide ~from 5.1p g. (12.0 mmo~s.)
of triphenyl 3-phenylpropylphosphonium bromide and 12.0 mmols. of dimsyl sodium
in 24 ml. of dimethyl sulfoxide] is slowly added 4.97 g. tlO.O mmols.) of 1-
benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone in 10 ml.
of dimethyl sulfoxide. The reaction mixture is then allowed to warm to 25C.
and is then ~tirred at 25C. for 4 hours. It is then added to 500 ml. of ice
water-250 ml. ether. The ether extract is washed with two 250 ml. portions of
water, dried over magnesium sulfate and evaporated. The residue is purified
via column chromatography on 400 g. of silica gel eluted with 50% ether-
cyclohexane to yield the title compound.
lS Repetition of the above procedure but using the appropriate
4-plperidinone compounds of Examples 8 and lOand the appropriate triphenyl(R2)-
¦¦ pho-phonlu- ~ ide reactant (C6h5)3~ R2~(3r) affords the followiog compoaads.
32~ Z-W
which are hydrogenated according to the procedure of Example 5 to give compoundsfrom Example 8 having formula A and from Example 10, compounds having formula ~:
¦ ~ A aad
/ CH2 Z-W
R2~
;l 112B936
l6
~-W
wherein R6 is benzyl or R6' a,s defined in Example 10, and x, Z and W are as '
defined-in Examples 8 and 10.
R2' has the valueQ:
6 5 H
S CH2C6H5 CH3
(CH2) 3C6H5 C2H5
n-C5Hll CH2CH(CH3)2
The requisite,triphenyl(R2)phosphonium bromide reactants are prepared
by refluxing an equimolar mixture of triphenylphosphine and R2Br in a suitable
solvent, e.g., acetonitrile, for from 1-2 hours. The reaction mixture is
cooled and the product reco~ered by filtration if solid, or by evaporation of
solvent if a liquid.
11%8936
XA~PL~ 13
l-Benzyl-3-L2-benzyloxy-4-(1,1-dimethylheptyl)pheny~]-4-
~3-~henylpropyl)-4-piperidinol
To a 0 C. solution of 7.0 mmols. of 3-phenylpropylmagnesium bromide
in 7 ml. of tetrahydrofuran is 910wly added a aolution of 2.48 g. (5.0 mmols)
of l-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone in 10 ml.
of tetrahydrofuran. The resultant mixture is stirred for one hour and is then
added to 250 ml. of saturated ammonium chloride-250 ml. ether. The ether phase
is dried over magnesium sulfate and evaporated. The residue is purified via
column chromatography on 200 g. of silica gel eluted with 50% ether-cyclohexane
to yield the title compound.
The compounds of Examples 8 and 10 are converted to compounds tabula-
ted below by means of the above procedure and the appropriate Grignard reagent
wherein x, Z and W are as defined in Examples 8 and 10. R6 is benzyl (Exam21e
8 reactants) and R6' (Example 10 reactants). R2' has-the values given below.
~2l ~ W~,
CH3 n-C6H13
n~C3H7 C6H5
i-C3H7 (CH2)C6H5
t-C4Hg (CH2)3C6H5
36
_AMPLE 14
l-Ben~yl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-
_ (3-phenylpropyl)-1,2,5,6-tetrahydropyridine
To a -5C. solution of 3.0 g. (4.85 mmols.) of 1-benzyl-3-[2-
benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropyl)-4-piperidinol in
S ml. of pyridine is slowly added 2.89 g. (24.3 mmols.) of thionyl chloride.
The reaction mixture is then allowed to slowly warm to 250C and is stirred
12 hours longers. The reaction mixture is quenched by slow addition to 200 ml.
of cold 20% potassium carbonate. The quenched mixture is extracted with 250 ml~
of ether, the extract washed once with 200 ml. 20Z potassium carbonate, dried
over magnesium sulfate and evaporated. The residue is purified via column
chromatography on 300 g. silica gel eluted with 50% ether-cyclohexane to yield
the title compound.
In like manner, the compounds of Example 13 are dehydrated to com- ¦
pounds having the formula below wherein R6, R2' and -Z-W are as defined in
Zxa= e l3.
Catalytic hydrogenation of the 1,2,5,6-tetrahydropyridine compounds
thus produced over Pd/C affords the corresponding compounds of the formula
~1~ Z-U
wherein R6 is hydrogen or R6~ as defined in Example 13, other, of course, than
benzyl.
- 43
, 1128936
EXA~PLE 15
3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-4-(3-phenylpropyl)-4-piperidinol
l A mixture of 6.17 g. (10.0 mmols.) ofl-benzyl-3-[2-benzyloxy-4-(1,1-
¦ dimethylheptyl)phenyl]-4-(3-phenylpropyl)-4-piperidinol, 2.0 g. of 10
5 ¦ palladium-on-carbon and 50 ml. of ethanol is stirred under one atmosphere of
hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous
earth with ethyl acetate and the filtrate evaporated. The residue is purified
via crystallization from ether-pentane to yield the title compound.
Similarly, the compounds of Example 13 wherein R6 is benzyl are de-
la benzylated to afford compounds having the following formula wherein R2~, Z, W ¦
and x are as defined in Example 13: ¦
~Z-W
1128936
¦ EXAMPLE16
3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-4-(3-phenylpropyl)-
1,2,5,6-tetrahydropyridine
A mixture of 2.0 g. (4.57 mmols.) of 3-[4-(l,l-dimethylheptyl)-2-
hydroxyphenyl]-4-(3-phenylpropyl)-4-piperidinol~ 0.95 g. (5.0 mmols.) of p-
toluenesulfonic acid monohydrate and 100 ml. of toluene is heated under reflux
for 2 hours with a Dean Stark trap. The reaction mixture is cooled and added
to 100 ml. of 20% potassium carbonate-200 ml. dichloromethane. The dichloro-
methane extract along with two additional 200 ml. dichloromethane Pxtracts of
the basic phase is dried over magnesium sulfate and evaporated. The residue
is crystallized from ether-pentane to yield the title compound.
By means of the procedure of Example 15 and the above procedure,
; Example 13 compounds are converted to the following compounds wherein x,
R6, Rz~ s~d -Z are as deti~ed in rx~le l3.
li llZ8936
EXAMPLE 17
The following compound~ are prepared from the l-R6'-4-R2'-piperidone
of Preparation AA and the appropriate l-bromo-2-benzyloxy-4-(Z-W)benzene by
the procedures of Examples l, 4 and 5. In the formula below, x, R6' and R2' a e
as defined in Preparation Z, and Z-W is one of the follawing groups:
-C(CH3)2(CH2)5CH3
-cH(cH3)cll(c1~3)(cH2)4cH3
-cH(cH3~(cH2)4c6 5
-OCH(CH3)(C~l2)3c6 5
o (CH2) 4C6H5
. Of course, when R6' in the l-R6~-4-R2~-piperidone reactant is benzyl
. it is removed in the catalytic hydrogenation step to give R6' - hydrogen.
Il !
,, I
Il ~128936
EXAMPLE 18
3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-~-methyl-
1,2,5,6-tetrahydropyridine __
To a 25 C. solution of l,0 g. (3.32 mmoles) of 3-[4-(1,1-dimethyl-
heptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine in 15 ml. of acetonitrile
is added 1.32 ml. (17.6 mmoles) of 37% formaldehyde solution. After stirring
for one hour the reaction i5 cooled to 0 C. and 332 mg. (5.3 mmole) of sodium
cyanoborohydride added. The reaction mixture is allowed to warm to Z5 C. over
a one hour period while the pH is maintained at 7 by the addition of acetic
acid. The reaction mixture is evaporated, made basic with 2N potassium hydrox-
ide and extracted with 200 ml. of dichloromethane. The organic extract is
dried over magnesium sulfate and evaporated. The residue is crystallized from
ether-pentane to yield 350 mg. of the title compound.
M.P.: 126-127 C.
PMR: ~CDCl 0.85 (m, terminal methyl), 1.25 (s, gem dimethyl), 2.5
(m, C-5 or C-6 methyl), 2.68 (s, N-CH3), 2.94 (m, C-5 or C-6 methyl), 3.62 (m,
C-2 methylene), 5.98 (m, vinyl proton), 6.80 (m, two ArH) and 7.05 (d, ~=8Hz,
ArH).
l I~: (CHC13) 3546, 3175, 1689, 1624 and 1565 cm
20 ¦ MS: m/e 315 (M ), 300, 272, 257, 230, 187.
The hydrochloride salt, prepared by neutralization of the compound
in ether with ethanolic hydrogen chloride, is obtained as a crystalline solid,
M.P. 179 C. (from ethanol-ether).
Analysis: Calc~d for C21H33N0-HCl: C, 71.67; H, 9.73; N, 3.98,
Cl, 10.07 %
Found: C, 71.54; H, 9.48; N, 3.94;
Cl, 10.22 %
1128936
By means of this procedure, the followlng compounds are prepared from~
appropriate azacycloal~enes of Example 3 and appropriate aldehydes. In the
formula belo~, x, Z and W are as defined in Example 3 and R6 has the values
given belo~.
~-W
' n-C3H7
i C3H7
6 13
(CH2) 3C6~15
( 2)4C6H5
furfuryl
2-thienylmethyl
tetrahydrofurfuryl
2-tetrahydrothienylmethyl
C3H5CH2
C4 7CH2
' C6HllCH2
5 gC 2
Hydrogenation of these compounds according to the procedure of
Example 2 but using 5% palladium-on-carbon in place of 10% palladiumron-carbon
affords the corresponding saturated compounds.
Il 1128936
EXA~IPLE 19
3~[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-
__ methylpiperidine
A mixture of 600 mg. (1.98 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-
hydroxyphenyl]-piperidine, 0.78 ml. of 37% formaldehyde, 1.98 ml. of lN hydro-
chloric acid and 150 mg. of 5% palladium-on-carbon is hydrogenated under 55
p.s.i. of hydrogen for 1.5 hours. The reaction mixture is filtered through
diatomaceous earth and concentrated under reduced pressure. The residue is
diluted with 75 ml. of saturated sodium bicarbonate and extracted with two 75
ml. portions of dichloromethane. The combined extract is washed with 75 ml. of
saturated sodium chloride, dried over magnesium sulfate and evaporated to yield
567 mg. (90%) of the title compound as an oil.
PMR: ~CDCl 0.80 (m, terminal methyl), 1.25 (s, gem dimethyl), 2.37
(s, N-methyl), 3.05 (m) and 6.75 (m, ArH).
IR: (CHC13) 3390, 1629 and 1575 cm
MS: m/e 317 (M ), 302 and 233.
Neutralization of the compound in ether with ethanolic hydrogen
chloride gives the hydrochloride salt, ~.P. 198-199 C. (from ether-ethanol).
Reductive alkylation of compounds of Example 6 according to the above
procedure but using the appropriate aldehyde affords the following compounds
wherein x, Z and W are as defined in Example 6:
lR2
C2H5 2-thienylmethyl
i-C4H9 C3H5CH2
6 13 C5II9CH2
(CH2)3C6H5 furfuryl
~l ~128936
EXA~PLE ~0
3-[4~tl,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-
~2-propynyl)piperidine
A mixture oE 0.900 g. (2.97 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-
hydroxyphenyl~piperidine, 481 mg. (3.49 mmoles) of anhydrous potassium carbon-
ate and 353 mg. (2.97 mmoles) of 1-bromo-2-propyne in 20 ml. of ethanol is
heated at reflux for 22 hours. The reaction mixture is then evaporated and
dissolved in 100 ml. of saturated sodium bicarbonate and 200 ml. of dichloro-
met~ane. The organic extract is washed with two 150 ml. portions of saturated
sodium chloride, dried over magnesium sulfate and evaporated. The residue is
purified via column chromatography on 100 g. silica gel eluted with 2~
methanol-dichloromethane. The product is crystallized from pentane (117 mg.,
11.5%).
M.P.: 91-93 C.
PMR: ~CDCl 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 2.41
(t, J=2Hz, acetylenic methine), 3.57 (d, J=2Hz, acetylenic methylene) and 6.85
(m, ArH).
IR: (CHC13) 3356, 1637 and 1582 cm
MS: m/e 341 (M ), 326, 257 and 256.
Neutralization of the product in ether with ethanolic hydrogen
chloride gives the HCl salt, M.P. 180-181 C. (from ethanol-ether).
Similarly, the azacycloalkanes of Example 6 are alkylated to give th~
following co~p mdc wherein x, Z snd U are as defined in Rxawple 6 and R6 is:
R6 6_ - R6
CH2-C^H CH(C3H7)C-CI~ (CH2)2-C--CH
(CH2)3-C_CH C_C-(CH2)3CH3 C--CH
( 2)2C_C CH3 CH2 C-C-(CH2)2C~3 C(CH3)~C2H5)C_CH
i 1128936
EXAMPLE 21
3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-(2-propynyl)-
1,2,5,6-tetrahydropyridine
A mixture of 1.0 g. (3.33 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-
hydroxyphenyl]-1,2,5,6-tetrahydropyridine, 539 mg. (3.90 mmoles) of anhydrous
potassium carbonate and 395 mg. t3.32 mmoles) of 1-bromo-2-propyne in 23 ml. of
ethanol is heated at reflux for 20 hours. The reaction mixture is evaporated
and dissolved in 100 ml. of saturated sodium bicarbonate and 200 ml. of di-
chloromethane. The organic extract is washed with two 150 ml. portions of
saturated sodium chloride, dried over magnesium sulfate and evaporated. The
residue is crystallized from pentane to yield 161 mg. of the title compound.
M.P~: 116-117 C.
PMR: ~CDCl 0.86 (m, terminal methyl3, 1.24 (s, gem dimethyl), 2.23
(t, J-2Hz, acetylenic methine), 2.45 (m, C-5 methylene), 2.78 (t, J=6Hz, C-6
methylene), 3.33 (m, C-2 methylene), 3.48 (d, J=2Hz, acetylenic methylene),
5,93 (m, vinyl proton), 6.9 (m, two ArH), and 7.05 ~d, J=8Hz, ArH).
IR: (CHC13) 3571, 3333, 1637 and 1572 cm
MS: m/e 339 (M ), 324, 300, 254 and 187.
Neutralization of the compound in ether with ethanolic hydrogen
chloride gives the hydrochloride salt, M.P. 158 C. (from ether-ethanol).
Analysis: Calc~d for C23H33NO-HCl: C, 73.48; H, 9.12; N, 3.72 %
Found: C, 73.37; H, 8.91; N, 3.73 ~
The following compounds are prepared in like manner by the above
procedure from appropriate alkynyl bromides and compounds of Example 3:
R,6
~ (~Z-W
wherein x, Z and W are as defined in Example 3 and R6 is:
CH2C-CH ( 2)4 ~ (CH ) -C-C-CH
( 2)2 ~ CH(C3H7)-C-CH C-CH
- 51 -
1128936
EXAM~LE 22
3-[4-~1,1-Dimethylheptyl)-2-hydroxyphenyl]-1-N-
(2-propenyl)piperidine
A mixture of 900 m8. (2.97 mmoles) of 3-~4-(1,1-dimethylheptyl)-2-
hydroxyphenyl]piperidine, 481 mg. ~3.48 mmoles) of anhydrous potassium car-
bonate and 359 mg. (2.97 mmoles) of allyl bromide in 20 ml. of ethanol is heate
at reflux for 23 hours. The reaction mixture is concentrated under reduced
pressure and the residue dissolved in 250 ml. of saturated sodium bicarbonate
and 200 ml. of dichloromethane. The organic extract is washed once with 100
ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated
under reduced pressure to an oil. The oil is purified via column chromatograph~
on 125 g. of silica gel eluted with 25% cyclohexane-ether to yield 172 mg.
(15%) of 3-[4-(1~1-dimethylheptyl)-2-allyloxyphenyl]-1-~-(2-propenyl)-piperi-
dine as an oil and 411 mg. (40%) of the title compound as an oil.
Title Compound: PMR: ~CDCl 0.85 (m, terminal methyl), 1.25 (s, gem dimethyl),
3.1 (m, allyl methylene and C-2 or 6 methylene), 5.0-5.4 and 5.5-6.1 (m, three
vinyl protons) and 6.8 (m, ArH).
IR: (CHC13) 1681, 1653, 1626 and 1597 cm
MS: m/e 343 (M ), 328, 316, 302, 259 and 258 cm 1
Neutralization of the title compound with ethanolic hydrogen chlorid
gives the hydrochloride salt as a glass.
Bis Allyl ComPound: PMR: ~cDscl 0.80 (m, terminal methyl), 1.22 (s, gem dimeth
- yl), 2.98 and 3.10 (bs, allyl methylenes), 4.09 (dd, J=8 and 6Hz, one H of C-2
methylene), 4.50 (dd, J-16 and 8Hz, one H of C-2 methylene), 4.9-5.4 and 5.5-
6.1 (m, six vinyl protons), 6.69 (d, J=2Hz, ArH), 6.71 (dd, J=8 and 2Hz, ArH)
and 7.00 (dj J=8Hz, ArH).
IR: (CHC13) 3521, 3226, 1653, 1629 and 1565 cm
MS: m/e 383 (M ), 368, 342, 298 and 257.
l 1128936
EXAM~LE 23
3-[4-~1,1-Dimethylheptyl)-2-llydroxyphenyl]-1-N-
(2-propenyl~ 2~5~6-tetrahydropyridine
A`mixture of l.0 g. (3.32 mmoles~ of 3-[4-(1,1-dimethylheptyl)-2-
hydroxyphenyl]-1,2,5,6-tetrahydropyridine, 539 mg. (3.90 mmoles) of anhydrous
potassium carbonate and 401 mg. (3.32 mmoles) of allyl bromide in 23 ml. of
ethanol is heated at reflux for 23 hours. The reaction mixture is concentrated
under reduced pressure and the residue dissolved in 250 ml. of saturated sodium
bicarbo~ate and 200 ml. of dichloromethane. The organic extract is washed
once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate
and evaporated to an oil. The oil is purified via column chromatography on
125 g. of silica gel eluted with 5% methanol-dichloromethane to yield 372 mg.
(29%) of 3-[4-(l,l-dimethylheptyl)-2-allyloxyphenyl]-1-N-(2-propenyl)-1,2,5,6-
tetrahydropyridine as an oil and 247 mg. (22%) of the title compound, M.P. 109
110 C. (from ether-pentane).
Title Compound: P~R: ~cDScl 0.85 (m "terminal methyl), 1.25 (s, gem dimethyl),
3.23 (m, allyl methylene), 5.0-5.4 and 5.5-6.1 (m, four vinyl protons), 6.82
(m, ArH) and 6.97 (d, J=8Hz, ArH).
IR: (CHC13) 3425, 1631 and 1572 cm
MS: m/e 341 (M ), 326, 300, 272 and 256.
Neutralization of the title compound with ethanolic hydrogen
chloride gives the hydrogen chloride salt as a glass.
Bis Allyl Compound: PMR: ~cTMcl 0.82 (terminal methyl), 1.25 (s, gem dimethyl)
3.03 and 3.12 (two m, allyl methylenes), 3.9-5.4 and 5.5-6.1 (m, seven vinyl
protons), 6.71 (d, J=2Hz, ArH), 6.72 (dd, J=8 and 2Hz, ArH) and 7.13 (d, J=8Hz,
ArH).
IR: (CHC13) 3521, 3215, 1653, 1629 and 1565 cm
MS: mle 381 (M ), 3669 340, 312, 284, 271 and 260.
112~936
EXAMPLE 24
l-N-Cyclopropylmethyl-3-[4-tl,l-dimethylheptyl)-2-
hydroxyphenyl]-1,2,5,6-tetrahydropyridine
To a solution of 596 mg. (1.98 mmoles) of 3-[4-(1,1-dimethylheptyl)-
2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine in 2.25 ml. of toluene and 4.5 ml.
of pyridine is added 180 ~1 (3.96 mmoles) of cyclopropanecarboxylic acid
chloride in 2.25 ml. of toluene. The reaction mixture is stirred for one hour
at 25C. and for 0.5 hour at 80C. Another 180 ~1 (3.96 mmoles) portion of
cyclopropanecarboxylic acid chloride is added and the heating at 80C. con-
tinued for 2 hours. The reaction mixture is cooled and added to 300 ml. of
saturated sodium chloride. The quenched mixture is extracted with two 75 ml.
portions of dichloromethane. The extract is washed once with 50 ml. of satu-
rated sodium chloride, dried over magnesium sulfate and evaporated to yield
an oil. A solution of this oil in 100 ml. of ether is added dropwise to a
mixture of 3.0 g. (78.9 mmoles) of lithium aluminum hydride in 150 ml. of
ether. The reaction mixture is refluxed for 17 hours, cooled in ice and de-
composed by the addition of 3 ml. of water, 3 ml. of 15~ sodium hydroxide and
9 ml. more of water. After stirring for 30 minutes at 25C. the quenched
reaction mixture is filtered and the filtrate evaporated to a solid. Recry-
stallization from dichloromethane and pentane gives 296 mg. (42%) of the title
compound.
MP: 118C.
PMR: ~CDCl 0.2 and 0.5 (m, cyclopropane), 0.84 (m, terminal methyl ),
1.28 (s, gem dimethyl), 2.40 (m, C-5 or 6 and C-l methylene), 2.75 (t, J=6Hz,
C-5 or 6 methylene), 3.26 (m, C-2 methylene), 5.80 (m, vinyl H),6.75 (m, two
ArH) and 6.96 (d, J=8Hz, ArH).
MS: m/e 355 (M ), 340, 314, 300 and 270.
~eutralization of the title compound in ether with ethanolic hydro-
gen chloride gives the hydrochloride salt of the title compound as a foam.
-53a-
, llZ8936
In a similar manner the following compound~ were prepared:
l-N-cvclopropylmethyl-3-[4-(l~l-dimethyiheptyl)-2-hydroxyphenyl]-
plperidine as an oil (515 mg., 73X) from 3-[4-(1,1-dlmethylheptyl)-2-hydroxy-
phenyl]piperidine (600 mg., 1.98 mmoles) and cyclopropane carboxylic acid
chloride t360 yl, 7.82 mmoles).
PMR ~CTMCl 0.25 and 0.55 (m, cyclopropane), 0.82 (terminal methyl) .
1.25 (s, gem dimethyl), 2.39 (d, J-6Hz, C-l methylene), 6.61 (dd, J-8 and 2Hz,
ArH), 6.79 (d, J=2Hz, ArH) and 6.95 (d, J=8Hz, ArH).
IR: (CHC13) 1639 and 1580 cm 1.
MS: mle 357, 342, 316, 302 and 273.
Neutralization of the title compound in ether with ethanolic hydrogen
chloride gives tbe hydrochloride salt of the title compound as a foam.
l-N-Cyclobutylmethyl-3-t4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-
1,2,5,6-tetrahydropyridine (198 mg., 39%) from 3-~4-(1,1-dimethylheptyl)-2-
hydroxyphenyl]-1,2,5,6-tetrahydropyridine (412 mg., 1.37 (mmoles) and cyclo-
butane carboxylic acid chloride (586 ~1, 5.48 mmoles).
MP: 116-117C. ~from dichloromethane-pentane~.
PMR: ~CDCl 0.85 (m, terminal methyl), 1.25 ~s, gem dimethyl),
2.40 and 2.80 (m, C-5, 6 and 1 methylenes), 3.48 (bs, C-2 methylene), 5.90
(m, vinyl H), 6.82 (m, ArH) and 7.02 (d, J=8Hz, ArH).
IR: (CHC13) 3571, 3279, 1634 and 1572 cm
MS: m/e 369 (M ), 354, 314, 300 and 284.
Neutralization of the title compound in ether with ethanolic hydrogen
chloride affords the hydrochloride salt of the title compound as a foam.
-53b-
i! I
llZ8936
l-N-Cyclobutylmethyl-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyll-
piperidine as an oi.l (427 mg., 86%) from 3-[4-(1,1-dlmethylheptyl)-2-hydroxy-
phenyl]piperidine (415 mg., 1.37 mmoles) and cyclobutanecarboxylic acid chlorid ,
(586 ~1, 5.48 mmoles).
PMR: ~CDCl 0.82 (m, terminal methyl), 1.25 (s, gem dimethyl),
6.60 (dd, J-8 and 2Hz, ArH), 6.76 (d, J=2Hz, ArH) and 6.82 (d, J=8Hz, ArH).
IR: (CHC13) 1637 and 1575 cm
MS: m/e 371 (M ), 356, 316 and 302.
~eutralization of the title compound in ether with ethanolic hydrogen
chloride produces the hydrochloride salt of the title compound as a foam.
-53c-
1128936
EXAMPLE 25
l-AcetYl-3-~2-acetoxY-4-(l,l-dimethylheptyl)phenYl]piperidine
To a solution of 2.0 g. of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl] _
piperidine in 20 ml. of pyridine at 10 C. is added 20 ml. of acetic anhydride
and the mixture stirred under nitrogen for 18 hours. It is then poured onto
ice/water and acidified with dilute hydrochloric acid. The product is isolated
by extraction with ethyl acetate (2 x 100 ml.). The combined extracts are
washed with brine, dried (MgS04) and evaporated to give the product as an oil.
In like manner, the compounds of formulae I and II wherein R6
is hydrogen and Rl is hydrogen are converted to their diacyl derivatives.
Replacement of acetic anhydride by propionic, butyric or valeric acid anhydride
affords the corresponding diacyl derivatives.
When R is other than hydrogen, the above procedure produces the
monoacyl derivative of the phenolic hydroxy group.
llZ8936
EXAMPLE 26
3-[2-(4-~lorpholinobutyryloxy)-4-(1,1-dimethylheptyl)phenyl]-
Dil~eridine
Dicyclohexylcarbodiimide tO.227 g., 1.1 mmole) and 4-N-piperidyl-
butyric acid hydrochloride (0.222g., 1.0 mmole) are added to a solution of 3-
[4-(l,l-dimethylheptyl)-2-hydroxyphenyl3piperidine (0.303 g., 1.0 mmole) in
methylene chloride (25 ml.) at room temperature. The mixture is stirred for
18 hours and is then cooled to 0 C. and filtered. Evaporation of the filtrate
affords the title product as its hydrochloride salt.
Similarly, the reactant of this example and the remaining phenolic
compounds of this invention are converted to the basic esters of the phenolic
hydroxy group by reaction with the appropriate basic acid reagent. Esters
wherein the Rl moiety has the following values are thus prepared:
-COCH2NH2
-CO(CH2)2N(C4H3)2
-CO(CH2)2-N-(methyl)piperazino
-COC(CH3)2(CH2)2-PiPeridin
-CO(CH2)3N(C2H5)2
-COCH(CH3)(cH2)2-morpholino
~C(cHZ)3-pyrrolo
-CO(CH2)3-pyrrolidino
-COCH2-pyrrolo
-CO(CH2)3-piperidino
CO (CH2) 4NH2
-CO(cH2)3NH(c3H7)
-CO (CH2) 2-N-butylpiperazino
Careful neutralization of the hydrochloride salts affords the free
basic esters which are converted to other acid addition salts according to the
procedure of Example 18 In this manner, the hydrobromide, sulfate, acetate,
malonate, citrate, glycolate, gluconate, succinate, sulfosalicylate and
tartrate salts are prepared.
_ 55 -
~ I
l~Z8936
EXAMP~E 27
General Hydrochloride Salt Formation
Excess hydrogen chlorite is passed into a solution-of the appropriate
compound of formulae I-II and the resulting precipitate separated and recrys-
tallized from an appropriate solvent, e.g. methanol-ether (1:10).
The remaining compounds of formulae I-II are converted to their
hydrochlorides in like manner.
Similarly, the hydrobromide, sulfate, nitrate, phosphate, acetate,
butyrate, citrate, malonateJ maleate, fumarate, malate, glycolate, gluconate,
lactate, salicylate, sulfosalicylate, succinate~ pamoate, tartrate and embonate
salts are prepared.
I ~
1128936
EXAMPLE 28
3-~4-(1,1-Dimethylheptyl~-2-hydroxyyhenyl]piperidine
2~-0-hemisuccinate Ester Sodium Salt
To a 0 C. solution of 0.606 g. t2.0 mmoles) of 3-[4-(1,1-dimethyl-
heptyl)-2-~ydroxyphenyl~piperidine in 3 ml. of ~ichloromethane is added 0.244 g
(2.0 mmoles) of 4-N,N-dimethylaminopyridine. To the resultant solution is
slowly added 0.200 g. (2.0 mmoles) of succinic anhydride in one ml. of dichloro
methane. The reaction mixture is stirred for 4 hours at 0 C. and then 2.00
ml. of lN hydrochloric acid is slowly added. The reaction mixture is stirred
5 minutes longer and then added to 100 ml. water-100 ml. dichloromethane. The
dichloromethane extract is dried over magnesium sulfate and evaporated. The
residue is dissolved in 5 ml. of ethanol and 2.00 ml. of lN sodium hydroxide in
ethanol added. Addition of ether causes crystallization. Recrystallization
from ethanol-ether yields the title compound.
Replacement of sodium hydroxide by potassium hydroxide in the above
procedure affords the potassium salt.
By means of this procedure, the remaining compounds described herein
are converted to their hemisuccinate esters.
- 57
1~28936
EXA~LE 29
3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]piperidine
2~-0-Phos~hate Ester Monosodium Salt
. __ ._ . . . . .
To a 0 C. slurry of O.lZ6 g. (3.14 mmoles) of potassium hydride in
3 ml, of dimethylformamide is added a solution of 0.953 g. (3.14 mmoles) of 3-
[4-(1,1-dimethylheptyl)-2-hydroxyphenyl~piperidine in 3 ml. of dimethyl-
formamide. After gas evolution ceases (~10 min.) 0.932 g. (3.14 mmoles) of
dibenzylphosphochlridate is slowly added. The reaction mixture is stirred for
l one hour and then added to 200 ml. ether-100 ml. water. The ether extract is
washed with two lO0 ml. portions of water, dried over magnesium sulfate and
e~aporated to a residue. The residue is mixed with 1.0 g. of 5% platinum on
carbon and 25 ml of ethanol and stirred under one atmosphere of hydrogen for
3 hours. The reaction mixture is filtered through diatomaceous earth and 3.14
l ml. of l~ sodium hydroxide in ethanol slowly added to the filtrate. Addition
15 ¦ of ether causes crystallization of the product. Recrystallization from
ethanol then yields the title compound.
Similarly, the remaining compounds described herein are converted
to their phosphate ester monosodium salts and, by replacement of sodium
hydroxide with potassium hydroxide, to their corresponding potassium salts.
l, ~
i llZ8936
EXAMPLE 30
One hundred mg. of 3-~4-(1,1-dlmethylheptyl)-Z-hydroxyphenyl~-
piperidine are intimately mixed and ground with 900 mg. of starch. The mixtur
is then loaded into telescoping gelatin capsules sueh that each capsule con-
tains 10 mg. of drug and 90 mg. of starch.
EXAMPLE 3~
A tablet base is prepared by blending the ingredients listed below:
Sucrose 80.3 parts
Tapioca starch 13.2 parts
Magnesium stearate 6.5 parts
Sufficient l-benzyl-3-~2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-tetra
hydropyridine is blended into this base to provide tablets containing 0.1, 0.5
1, 5, 10 and 25 mg. of drug.
EXAMPLE 3~
Suspensions of l-benzyl-3-~4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-
1,2,5,6-tetrahydropyridine are prepared by adding sufficient amounts of drug t
0.5~ methylcellulose to provide suspensions having 0.05, 0.1, 0.5, 1, 5 and 10
mg. of drug per ml.
~128936
PREPARATION A
2-~3-Benzyloxyphenyl)-2-methylpropionitrile
To a solution of 1500 ml. of dimethylsulfoxide saturated with methyl
bromide is simultaneously added a solution of 294 g. (1.32 mole) of 2-(3-
benzyloxyphenyl~acetonitrile in 200 ml. dimethyl sulfoxide and a solution of420 ml. of 50% aqueous sodium hydroxide. Methyl bromide is continuously bub-
bled through the reaction mixture during the above addition (30 minutes) and
then for 1.5 hours longer while the reaction temperature is maintained at
<50 C. with ice cooling. The reaction mixture is added to 2 liters of water-
2 kg. ice and the resultant mixture extracted four times with 1 liter of ether.The combined ether extracts are washed twice with one liter of water, once
with one liter of saturated sodium chloride, dried over magnesium sulfate and
evaporated to yield 325 g. (98%) of product as an oil.
PMR: ~cTDMcl 1.70 (s, methyl), 5.12 ts, methylene), 6.8-7.5 (m, ArH)
and 7.45 (s, PhH).
IR: (CHC13~ 2247, 1616 and 1603 cm
MS: m/e 251 (M ), 236, 160 and gl.
llZ8936
PREPARATION B
2-~3-~enzylox~Phenyl)-2-methylpropionaldehyde
To a 15 C. solution of 325 g. (1.25 mole) of 2-(3-benzyloxyphenyl)-
2-methylpropionitrile in 1.85 ~iters of tetrahydrofuran is added 1.6 moles of
diisobutylaluminum hydride as a 1.3 M solution in hexane (reaction temperature
is maintained at 15-18 C.). The reaction mixture is allowed to warm to room
temperature and is stirred 2 hours longer. It is then quenched by addition to
a solution of 170 ml. of concentrated sulfuric acid in 670 ml. of water
(temperature <30 C.). The resultant mixture is allowed to warm to room
temperature and is then stirred an additional 2 hours. The organic layer is
separated and the aqueous phase extracted once with one liter of ether. The
combined organic phase is washed with 500 ml. of water and 500 ml. of
saturated sodium chloride, dried over magnesium sulfate and evaporated to
yield 315 g. (99%) of the title product.
PMR: ~CDCl 1.43 (s, methyls), 5.08 (s, methylenes), 6.8-7.5 (m,
ArH), 7.4 (s, PhH) and 9.55 (s, aldehyde).
i! ,
1128936
PREPARATION C
2-(3-Benzyloxyphenyl)-2-methyl-cis-oct-3-ene
I To a 15C. solution of 1.~ moles of dimsyl sodium (from sodium hydrid~
¦and dimethyl sulfoxide) in 2 liters of dimethyl sulfoxide is added, portionwise,
1768 g. (1.8 moles) of pentyltriphenylphosphonium bromide. The resultant slurry
is stirred 15 minutes at 15-20C. and then 3.5 g. (1.24 moles) of 2-(3-benzyl-
oxyphenyl)-2-methylpropionaldehyde is slowly added (reaction temperature ~30C.) .
The resultant mixture is stirred for 4 hours at room temperature and is then
¦ added to 6 liters of ice water. The quenched reaction is extracted four times
lO ¦ with one liter portions of 50% ether-pentane. The combined extract is washed
twice with one liter of water and once with onè liter of saturated sodium
chloride and is then dried over magnesium sulfate and evaporated to yield an
oil. Crystallization of this oil in 50% ether-pentane (to remove triphenyl-
phosphine oxide), filtration and evaporation of the filtrate gives 559 g. of
15 oil. The crude o~l is purified via column chromatography on 2 kg. of silica
gel eluted with 20% hexane-dichloromethane to yield 217 g. (57~) of 2-(3-
benzyloxyphenyl)-2-methyl-cis-oct-3-ene.
PMR: ~CDCl 0-75 (bt, J=6Hz, terminal methyl), 1.1 (m, two side-
chain methylenes), 1.43 (s, gem dimethyl), 1.60 (m, alIylic methylene), 5.09
(s, benzylic methylene), 5.28 (dt, J=12 and 6Hz, vinyl H?, 5. 70 (dd, J=12 and
lHz, vinyl H), 6.7-7.5 (m, ArH) and 7.42 (s, PhH).
IR: (CHC13) 1610 and 1587 cm
MS: m/e 308 (M ), 293, 274, 265, 251, 239, 225, 217 and 91.
-61~-
~128936
Similarly, l-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene (13.5 g.,
707O) i9 prepared from 15.75 g. (0.062 mol.) of 2-(3-benzyloxyphenyl)-2-methyl-
propionaldehyde and 37.5 8- (0,0899 mol.) of hexyltriphenylphosphonium bromide.
The product is an oil.
PM~: ~CDCl 0.78 (m~ terminal sidechain methyl), 1.40 (s, gem
dimethyl), 4.97 (s, benzyl ether methylene), 5.23 (m, vinyl H), 5.57 (d, J=ll
Hz, vinyl H) and 6.6-7.4 (m, ArH and PhH).
IR: (CHC13) 1608 and 1582 cm l,
MS: m/e 322 (M ), 307, 279, 274, 265 and 231.
. . .
- 62 -
1 1128936
PREPARATION D
2-(3-Hydroxyphenyl)-2--methyloc-tane
A mixture of 65 g. (0.211 mole) of 2-(3-benzyloxyphenyl)-2-methyl-
cis-oct-3-ene and 7.5 g. of 10~ palladium-on-carbon in 100 ml. of ethanol is
hydrogenated for one hour on a Parr apparatus at 50 p.s.i. hydrogen pressure.
Additional 7.5 g. portions of 10% palladium-on-carbon are added after one and
two hours of reaction and the reaction continued for 12 more hours. The reac-
tion mixture is filtered through diatomaceous earth with ethanol and the fil-
trate evaporated to an oil. The oil is purified via column chromatography on
lb one kg. of silica gel eluted with 50~ hexane-dichloromethane to yield 105 g.
(78~) of 2-(3-hydroxyphenyl)-2-methyloctane.
PMR: ~CDCl 0.85 (bt, terminal methyl), 1-1.9 (m, methylenes), 1.29
(s, gem dimethyl), 4.98 (s, phenol H) and 6.6-7.4 (m, ArH).
IR: (CHC13) 3571, 3311 and 1592 cm
MS: mte 220 (M ), 205 and 135.
In like manner, 2-(3-hydroxyphenyl)-2-methylnonane is prepared in
82~ (7.8 g.) yield from 13.0 g. (0.0406-mol.) of 1-benzyloxy-3-(1,1-dimethyl-
oct-2-enyl)benzene. It is obtained as an oil having the characteristics:
PMR: ~CDCl 0.85 (m, terminal methyl), 1.27 (s, gem dimethyl), 5.25
(bs, OH) and 6.6-7.4 (m, ArH).
IR: (CHC13) 3571, 3279, 1563 and 1527 cm 1.
MS: m/e 234 (M ), 219, 191, 178, 164, 149, 135 and 121.
Il llZ8936
PREPARATION E
2-(4-Bromo-3-hYdroxYphenyl)-2-methYloctane
To a 0 C. solution o~ 110 g. (0.50 mole) of 2-t3-hydroxyphenyl)-2-
methyloctane in 200 ml. of carbon tetrachloride is added dropwise a solution of
80 g. (0.50 mole) of bromine in 90 ml. of carbon tetrachloride (reaction temr
I perature ~30 C. with cooling). The reaction mixture is stirred an additional
15 minutes and is then evaporated to yield 150 g. (100%) of 2-(4-bromo-3-
hydroxyphenyl)-2-methyloctane.
PMR: ~CDCl 0.85 (bt, terminal methyl), 0.8-1.9 (m, methylenes),
1.28 (s, gem dimethyl), 5.4 (bs, phenolic H), 6.78 (dd, J-8 and 2Hz, C-6 ArH),
7.02 (d, J=2Hz, C-2 ArH) and 7.37 (d,J=8Hz, C-5 ArH).
In like manner, 2-(4-bromo-3-hydroxyphenyl)-2-methylnonane is
prepared in 82% (8.5 g.) yield as an oil from 7.8 g. (0.033 mol.) of 2-(3-
hydroxyphenyl)-2-methylnonane:
PMR: ~TMSl 0.86 (m, terminal methyl), 1.27 (s, gem dimethyl), 5.50
(bs, OH), 6.83 (dd, J-8 and 2Hz, ArH), 7.08 (d, J=2Hz, ArH) and 7.43 (d, J=8
Hz, ArH).
IR: (CHC13) 3279, 1613 and 1587 cm
NS: m/e 314, 312 (M ), 212, 210, 185 and 187.
l 1128936
PR~PARATION F
2-(3-B~nzyloxy-4-bromophenyl)-2-meth~loctane
To a -18 C. slurry ~f 23~0 g. (0.575 mole) of potassium hydride in
400 ml. o N,~-dimethylformami~e is added over a 45 minute period a solution
of 150 g. (0.5 mole) of 2-(4-bromo-3-hydroxyphenyl)-2-methyloctane in 400 ml.
of N,N-dimethylformamide (reaction temperature < -15 C.). The reaction mix-
ture is stirred 15 minutes longer after which a solution of 98.3 g. (0.575
mole) of benzyl bromide in 200 ml. of N,N-dimethylformamide is added. The
mixture is then warmed to room temperature and stirred 30 minutes longer. It
is quenched by addition to 6 liters of ice water. The quenched mixture is
extracted six times with 500 ml. of ether. The combined extract is washed
twice with one liter portions of water and once with one liter of saturated
sodium chloride, dried over magnesium sulfate and evaporated to a quantitative
yield of the title product.
PMR: ~TcDcl 0.85 (bt, terminal methyl), 0.8-2.0 (m, methylenes~, 1.22
(s, gem dimethyl), 5.17 (s, benzylic methylene) and 6.7-7.6 (two multiplets,
ArH and PhH).
IR: (CHC13) 1592 and 1575 cm
MS: m/e 390, 388 (M ), 375, 373, 354, 352, 305, 303 and 91.
And, 2-(3-benzyloxy-4-bromopheny~2-methylnonane is prepared in 95~
(10.4 g.) yield from 2-(3-hydroxy-4-bromophenyl)-2-methylnonane (8.5 g., 0.027
mol.), sodium hydried (0.744 g., 0.031 mol.) and benzyl bromide (5.3 g., 0.031
mol.) as an oil.
PMR: ~CDCl 0.87 (terminal methyl), 1.23 (s,gem dimethyl), 5.18 (s,
benzyl ether methylene), 6.8 (dd, J=8 and 2Hz, ArH), 6.97 (d, J=2Hz, ArH) and
7.43 (m, ArH and PhH).
IR: (CHC13) 1600 and 1575 cm 1.
MS: m/e 404, 402 (M ), 305, 303, 91.
;
1128936
The compounds eabulated below are prepared according to the
procedures of Preparations C-F from appropriate reactants:
ll
¦ C(CH3)2(CH2)2 H
C(CH3)2(CH2)10
C(CH3)2(CH2)4 C6 5
~ C(CH3)2(Ca2)4 4-pyridyl
- C(CH3)2(CH2)3 2~pyridyl
C(cH3)2(cH2)lo C6 5
10 CH(CH3)(CH2)2 C6 5
CH(C2Hs)(cH2)2 4 ClC6H4
CH(C2Hs)(CH2)4 4 FC6 4
(CH2)5 H
( 2)13 H
. (CH2)4 C6H5
(C~2)8 ~ ~
- 66 -
1128936
l PREPARATION G
¦ 3-Benzylox,y-4-bromophen
¦ To a 0 C. slurry of 1.l g. (42.5 mmoles) of potassium hydride in
¦ 35 ml. of N,N-dimethylformamide is slowly added a solution of 7.22 g. (38.2
¦ mmoles) of 4-bromoresorcinol. The resultant mixture is stirred for 30 minutesand then 4.54 ml. (38.2 mmoles) of benzyl bromide is slowly added. The reac-
I tion mixture is stirred 3 hours longer at 0 C and then added to 200 ml. of
- ¦ cold water and 200 ml. of ether. The ether extract is washed twice with 200
¦ ml. portions of water, dried over magnesium sulfate and evaporated to an oil.
The crude oil is purified via column chromatography on 400 g. of silica gel
eluted with 25% ether-pentane to yield ~in order of elution) 2.2 g. (16~) of
2,4-dibenzyloxybromobenzene, 0.21 g. (2~) of 5-benzyloxy-2-bromophenol and
3.52 g. (33%) of 3-benzyloxy-4-bromophenol.
5-Benzyloxy-2-bromophenol:
PMR: ~CDScl 4.98 (s, benzyl ether), 5.46 (bs, OH), 6.40 (dd, J=8
and 2Hz, ArH), 6.60 (d, J=2Hz, ArH), 7.17 (d, J=8Hz, ArH) and 7.33 (s, PhH).
IR: (CHC13) 3521, 3221, 1610 and 1600 cm
MS: m/e 280, 278 (M ), 189, 187 and 91.
3-Benzyloxy-4-bromophenol:
PMR: ~CDCl 5-00 (s, benzyl ether methylene), 5.33 (bs, OH), 6.21
(dd, JD8 and 2Hz, ArH), 6.38 (d, J=2Hz, ArH) and 7.30 (m, ArH and PhH).
IR: (CHC13) 3546, 3257, 1603 and 1585 cm 1
MS: m~e 280, 278 (M ) and 91.
1128936
li
PREPARATION H
2-Benzyloxy-4-[2-C5-phenylpentyloxy)]bromobenzene
A mixture of 3.50 g. (12.5 mmoles) of 3-benzyloxy-4-bromophenol, 3.48
g. tl4-4 mmoles) of 2-(5-phenylpentyl)methanesulfonate and 5.17 g. (37.5
mmoles) of anhydrous potassium carbonate in 20 ml. of N,N-dimethylformamide is
heated at 85 C. for 6 hours. It is then cooled and added to 200 ml. of water
and 200 ml. of ether. The organic extract is washed twice with 150 ml. portionc
of water, dried over magnesium sulfate and evaporated to an oil. The oil is
purified via column chromatography on 400 g. of silica gel eIuted with 2:1
pentane:methylene chloride to yield 4.39 g. (82%) of the desired product as an
oil.
PMR: ~CDCl 1.21 (d, J=6Hz, sidechain methyl), 1.7 (m, sidechain
methylenes), 2.60 (m, sidechain benzyl methylene), 4.25 (m, sidechain methine),
5.00 (s, benzyl ether methylene), 6.22 (dd, J=8 and 2Hz, C-5 ArH), 6.39 (d,
J-2Hz, C-3 ArH) and 7.30 (m, Pha and C-6 ArH).
IR: (CHC13) 1587 cm
MS: 426, 424 (M ), 280, 278 and 91.
The following compounds are similarly prepared from the appropriate
mesylate Ca3S03-Z-W.
Br ~ O-(sl~2)-~
~128936
(:llk2)
(CH2)4 4-FC6H4
(CH2)8 C61~5
l (CH2) 10 4-ClC6H4
5 1 ( 3)( 2)8 C6H5
l CH(CH3)CH2 4-FC6H4
¦ . ( 3)2(CH2)3 C6H5
CH2CH(CH3)CH2 C6U5
l CH(CH3)(CH2)10 H
10 ¦ ( 3)2(C 2)5 H
¦ (CH3)2(C~I2)7 H
¦ (CH2)13 H
(CH2)13 C6H5
CH(CH3)(CH2)6 4-FC6H4
. ( 3)2( 2)10 4-FC6H4
(CH2)12 C6H5
( 2 5)( 2)3 4-ClC6H4
(C 3)2(CH2)6 H
(CH2)2C(CH3)2(cH2)2 H
. (CH2)6 C6H5
(C 2)12 H
CH(C~13)(Ca2)3 4-pyridyl
(C 2)2 4-pyridyl
. CH(CH3)(CH2)3 2-pyridyl
(CH2)5 3-pyridyl
(CH2)10 2-pyridyl
C (C2 5)(Cd2)2 4-pyridyl
I
- 69 _
! l~Z8936
PREPARATION I
3-(3-Benzyloxy)benz~loxypropane
Sodium (0.2 mole) i8 dissolved in n-propylalcohol (1.0 mole) and the
reaction mixture then cooled ln an ice-bath. Then 0.2 mole of 3-benzyloxybenzy
chloride is added with constant stirring over a half-hour period. The ice-bath
is removed and the temperature gradually raised to reflux. After 4 hours at
reflux, the excess alcohol is removed by distillation under reduced pressure.
The residue is treated with water to dissolve the salt present and then extrac-
ted with diethyl ether. The extract is washed with water, dried (MgS04) and
evaporated to give the title product.
In those instances where the alcohol reactant is not readily availabl
or is a solid at normal temperatures, a modification of this procedure is used.
The appropriate alcohol is dissolved in acetone and heated with the halide reac
tant in the presence of powdered potassium carbonate for 6-8 hours. The reac-
tion mixture is then cooled, water added and the ether recovered as describedabove.
The following compounds are prepared in like manner from appropriate
alcohols:
. [~ CH2-0-(alk2)-W
(alk2) W (alk2) W
(CH2)2 H __ C6H5
(CH2)4 H __ 4-pyridyl
(C 2)12 H CH(CH3)(CH2)2 C6H5
(CH2) C6 s 2 C6H5
! CH(CH3)CH2 H (CH2)5 4-FC6H4
(CH2)2CH(CH3) C6H5 CH2CH(c2 5) 2
Bromination of the ethers according to the method of Preparation E
affords the corresponding 2-bromo-5-(Z-W substituted)phenol benzyl ethers.
_ 70 -
,
1~28936
l l
I
PREPARATION J
2-~3-MethoxyPhenyl)-5-phenylpentane
A solution of l-bromopropylben~ene (51.7 g.) in ether (234 ml.) is
added dropwise over a 2-hour period to a refluxing mixture of magnesium (7.32
g.) in ether (78 ml.). The reaction mixture is refluxed for 30 minutes
longer and then a solution of 3-methoxy-acetophenone (41.6 g.) in ether (78
ml.) is added dropwise and the mixture heated to reflux for 1.5 hours. The
¦ reaction is quenched by addition of saturated ammonium chloride (234 ml.), the
¦ ether layer is separated and the aqueous phase extracted with ether (3 x 200
l~ ¦ ml.). The combined ether extracts are dried over magnesium sulfate and concen-
¦ trated under vacuum to yield an oil. The oil is hydrogenated in a mixture con-
¦ taining ethanol (300 ml.), concentrated hydrochloric acid (2 ml.) and 5%
¦ palladiumron-carbon (5 g.). The catalyst is filtered off and the ethanol
¦ removed under vacuum. rne residue is distilled under vacuum to give the
ti~le product.
,~ . I
Il 1128936
P~l'ARATI0~ K
2-(3-Hydroxyphenyl)-5-phenylpentane
A mixture of 2-(3-methoxyphenyl)-5-yhenylpentane (18.4 g.) and
pyridine hydrochloride (94 g.) under nitrogen is heated to 190 C. for 2 hours
with vigorous stirring. The reaction mixture is cooled, dissolved in 6N hydro-
chloric acid (200 ml.) and diluted with water to 600 ml. The aqueous solution
is extracted with ethyl acetate (4 x 100 ml.), the ethyl acetate extracts
dried over sodium sulfate and concentrated under vacuum to yield the crude
product. The product is purified by silica gel chromatography.
The following compounds are prepared from appropriate reactants by
the method of Preparation J and that of the above preparation:
.' I
~Z-W ' ' I
~(CH3)(CH2)2 C6H5
( 2 5)( 2)2 4-ClC6H4
CH(C2H5)(CH2)4 4 FC6H4
(CH2)5 H
(CH2)11 H
(C 2)13 H
(CH234 C6H5
(CH2) 8 H
Bromination of the above compounds according to the procedure of
Preparation E affords the corresponding 4-bromo derivatives, e.g. 2-(4-bromo-
3-hydroxyphenyl)-5-phenylpentane.
_ 7~ _
li~8936
PREPARATION L
Etllyl 3-(3-Benzyloxyphenyl~crotonate (Wlttig Reaction)
A mixture of 3-benzyloxyacetophenone (29.4 g., 0.13 mole) and
carbethoxymethylenetriphenylphosphorane (90.5 g., 0.26 mole) is heated under a
nitrogen atmosphere at 170 C. for 4 hours. The clear melt is cooled to room
temperature, triturated with ether and the precipitate of triphenyl phosphine
oxide removed by f iltration. The f iltrate is concentrated under vacuum to an
oily residue which is chro~atographed over silica gel (1500 g.) and eluted
with benzene:hexane solutioas of increasing benzene concentration beginning witl-
40:60 and ending with 100% benzene. Concentration of appropriate fractions
gives the product as an oily residue.
- 73 -
llZ8936
PREPAR~TION ~1
3-~3-Benzyloxyphenyl)butYl TosYlate
A solution of ethyl 3-(3-b~nzyloxyphenyl)crotonate (17.8 g., 60
mmole) in ether (250 ml.) is added to a mixture of lithlum aluminum hydride
(3.42 g., 90 mmole) and e~her (250 ml.). Aluminum chloride (0.18 g., 1.35
mmole> is added and the mixture refluxed for 12 hours and then 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 inorganic salts which precipitate
are filtered off and the filtrate is then concentrated in vacuo to give the
3-(3-benzyloxyphenyl)butanol as an oil.
Tosyl chloride (11.1 g., 58.1 mmole) is added to a solution of 3-(3-
benzyloxyphenyl)-l-butanol (14.5 g., 57 mmole) in pyridine (90 ml.) at -45 C.
The reaction mixture is held at -35 C. for 18 hours and is then diluted with
cold 2N hydrochloric acid (1500 ml.) and extracted with ether (5 x 200 ml.).
The combined extracts are washed with saturated sodium chloride solution (4 x
250 ml.) and then dried (Na2S04). Concentration of the dried extract affords
the product as an oil.
.
28936
PREPARATION N
3-(3-Benzyloxyphenyl~-l-phenoxybutane
A solution of phenol (4.56 g.,48.6 mmole) in dimethylformamide (40 ml.
is added under a nitrogen atmosphere to a suspension of sodium hydride (2.32 g.
48.6 mmole) of 50% previously washed with pentane) in dimethylformamide (70
ml.) at 60 C. The reaction mixture is stirred for one hour at 60-70 C.,
after which a solution of 3-(3-benzyloxyphenyl)butyl tosylate (18.9 g.,46 mmole
in dimethylformamide (80 ml.) is added. The reaction mixture is stirred at
80 C. for a half hour and is then cooled to room temperature, diluted with
cold water (2500 ml.) and extracted with ether (4 x 400 ml.). The combined
extract9 are washed successively with cold 2N hydrochloric acid (2 x 300 ml.)
and saturated sodium chloride solution (3 x 300 ml.) and then dried (Na2S04).
P~e val of the solvent under reduced pressure affords the product as an oil.
The oily residue is dissolved in benzene and filtered through silica gel (lOO
g.). Concentration of the filtrate under reduced pressure gives the product
as an oil.
Repetition of Preparations L through N but using the 3-benzyloxy
derivatives of benzaldehyde, acetophenone or propiophenone, the appropriate
carbethoxy (or carbomethoxy) alkylidenetriphenylphosphorane, and the appro-
priate alcohol or phenol affords the following compounds.
O-(all~z)n-W
I` !
~:IZ8~31i ''
alkl) (alk2~ w
(CH2)3 1 (CH2)3 H
(CH2)3 1 (CH2)5 H
(CH2)5 1 (CH2)8 H
(CH2)6 . 1 (CH2)7 H
(CH7)3 1 (CH2)7 H
(CH2)3 1 (C 2)10
I (CH2)10 1 (CH2)2 H
. C(CH3)2(CH2)2 1 (CH2)4 H
.' 10 ' (CH2)4 1 CH2 C6H5
(CH2)6 ~~ C6H5
(C 2)13 H
(CH2)6 ~~ H
(CH2)6 1 CH2 4-ClC6H4
15 (CH2)6 ~~ 4-FC6H4
. CH (CH3) (CH2) 2 -- C6H5
CH(cH3)(cH2)3 ~~ C6H5
CH(CH3)(CH2)6 -~ H
( 2)3 4-pyridyl
(CH2)3 ~~ 3-pyridyl
(CH2)3 1 CH(CH3) 2-pyridyl
CH(CH3?(CH2)2 1 (CH2)4 4-pyridyl
CH(C2Hs)(cH2)21 CH(CH3) 2-pyridyl
(CH2)4 1 (CH2)5 4-pyridyl
(CH2)8 1 (CH2)5 4-pyridyl
Bromination of the products according to the procedure of Prepara-
tion E affords the corresponding 2-bromo-5-[(alkl)-0-(alk2)n-U]phenol-
b Qzyl ether
` llZ8936
PREP~RATI0~ 0
4-(3-Hydroxypheny~ (4-pyr-idyl)pentane
A mixture of 3-(3-methoxyphenyl)butyl triphenylphosphonium bromide
(17.5 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecar-
boxaldehyde (3.79 g., 35.4 mmoles) ln tetrahydrofuran (40 ml.). rne resulting
mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39
mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0-5 C.
Following completion of addition, the mlxture is stirred for one hour at 0-5
C. and then concentrated under reduced pressure. The concentrate is diluted
with water t200 ml.) and then acidified with 6N HCl. The aqueous acid solution
is extracted with benzene (4 x 50 ml.). It is then made basic and extracted
with ethyl acetate (3 x 50 ml.). Evaporation of the combined extracts after
drying (MgS04) affords 4-(3-methoxyphenyl)-1-(4-pyridyl)-1-pentene as an oil.
Catalytic hydrogenation of the thus-produced pentene derivative in
ethanol at 45 p.s.i. in the presence of Pd/C (1 g. of 10%) and concentrated HCl
(1 ml.) affords the title product.
The pentane derivative thus obtained is demethylated by heating a -
mixture of the compound (25 mmoles) and pyridine hydrochloride (35 g.j under a
nitrogen atmosphere at 210 C. for 8 hours. The hot mixture is poured into
water (40 ml.) and the resulting solution made basic with 6N sodium hydroxide.
Water and pyridine are removed by distillation in vacuo. Ethanol (50 ml.) is
added to the residue and the inorganic salts which precipitate are filtered
off. The filtrate is concentrated in vacuo and the residue chromatographed on
silica gel using as eluting agents 5% ethanol/benzene (4 liters), 10% ethanol/
benzene (1 liter), 13% ethanoltbenzene (1 liter~ and 16% ethanol/benzene ~5
liters). The product is isolated by concentration of appropriate fractions of
the eluate.
112~
1,
The 3-(3-methoxyphenyl)butyltriphenylphosphonium bromide is prepared !
by refluxing a mixture of l-bromo-3-(3-methoxyphenyl)butane (78.5 mmoles) and
triphenyl phosphine (78.5 mmoles) in xylene (60 ml.) for 18 hours. The reac-
tion mixture is then cooled t~ room temperature and filtered. The filter
cake is washed with ether and the product dried in a vacuum desiccator.
Repetition of this procedure but using the appropriate bromo-(3-
methoxyphenyl)alkane and the appropriate aldehyde or ketone affords the
following compounds.
OH
:' ' ' ~Z-W
. Z W_
(CH2)3 2-pyridyl
(C~2)4 4-pyridyl
: CH(CH3)CH(CH3)CH2 3-pyridyl
CH(CH3)CH(CH3)CH2 4-pyridyl
CH(C2Hs)(cH2)2 4-pyridyl
(CH2)10 4-pyridyl
Bromination of the above compounds according to the ~ethod of
Preparation E gives the corresponding 2-bromo-5-(Z-W)-phenols.
1128936
l ll
PREPARATION P
3-Methoxy-a-methylstyrene Oxide
To a solution of dimethylsulfoxonium methylide (69.4 mmoles) in
l dimethyl sulfoxide (65 ml ) at room temperature is added solid 3-dimethoxy-
5 ¦ acetophenone (8.33 g., 55.5 mmoles). The reaction mixture is stirred for onehour at 25 C., for one-half hour at 50 C. and is then cooled. The mixture is
diluted with water (50 ml.) and added to a mixture of ice water (200 ml.)--
ether (250 ml.)--low boiling petroleum ether (25 ml.). The organic extract is
washed twice with water (250 ml.), dried (MgS04) and evaporated to an oil which
is fractionally distilled.
PREPARATION Q
2-(3-Methoxyphenyl)-2-hydroxyp-ropyl-2--ph-enylethyl Ether
A mixture of dry 2-phenylethanol (30 ml., 251 mmoles) and sodium
metal (690 mg., 30 mmoles) is heated at 110 C. for 30 minutes. The resulting
15 ¦ LM solution of sodium 2-phenylethoxide is cooled to 60 C., 3-methoxy-~-methyl-
styrene oxide (1.69 g., 10.3 mmoles) added and the reaction heated 15 hours at
60 C. The reaction mixture is cooled and added to a mixture of ether and
water. The ether extract is dried over magnesium sulfate and evaporated.
Excess 2-phenylethanol is removed by vacuum distillation (b.p. ~65 C., 0~1 mm. .
The residue is purified via column chromatography on silica gel 60 (300 g.) and
eluted in 15 ml. fractions with 60X ether-pentane.
llZ8936
PREPARATION R
2-~3-Methoxyphenyl~propyl 2~PhenYlethyl Ether
To a 0 C. solution pf 2-(3-methoxyphenyl)-2-hydroxypropyl 2-phenyl-
ethyl ether (498 mg., 1.74 mmole) in pyridine (2 ml.) is added dropwise
phosphorous oxychloride ~477 ml., 5.22 mmole). The reaction is allowed to war
to 20 C. over a 1.5 hour period. It is then stirred for 1.5 hours at 20 C.
: and then added to ether (150 ml.) and 15% sodium carbonate (100 ml.). The
organic phase is separated and washed with 15% sodium carbonate (3 x 50 ml.),
dried over magnesium sulfate and evaporated to an oil. The oil is dissolved
in absolute ethanol (15 ml.), 10% palladium-on-carbon (100 mg.) added and the
mixture stirred under one atmosphere of hydrogen gas. When hydrogen uptake
ceases the reaction is filtered through diatomaceous earth and the filtrate
evaporated to an oil. The oil is purified via preparative layer chromatograph~
on silica gel plates, eluted twice with 6:1 pentane:ether to yield the title
compound.
.
1~8936
, I
PREPARATION ~
2-(3-Hydroxyphenyl)pro-pyl 2-Phenylethyl Ether
A ~ixture of 2-(3-methoxyphenyl)propyl Z-phenylethyl ether (176 mg.,
0.65 mmole), pyridine (0.4 ml.; 4~96 mmole) and dry pyridine hydrochloride
(4 g., 34.6 ~mole) is heated at 190 C. for 6 hours. The reaction mixture is
I cooled and added to a mixture of water (100 ml.) and ether (150 ml.). The
ether extract is washed once with water (50 ml.) and, along with a second
ether-extract (50 ml.) of the aqueous phase, is dried over magnesium sulfate
and evaporated to an oil. The oil is purified via preparative layer chroma-
tography on silica gel plates, eluted six tlmes with 30~ ether-pentane to
yield the title product.
The following compounds are prepared from appropriate alkanols by
the methods of Procedures Q and R:
OH
--CH O
. CH3
. ' (alk2) W
-(CH2)7- H
-(CH2)6- C6H5
-(CH2)5- H
-CH (CH3) CH2
-CH (CH3) (CH2)5 H
-(CH2)- 6 4
-(CH2)2- 4-pyridyl
-(CH2)2- 4-ClC6H4
-(CH2)2CH(cH3) (CH2)3- H
-CH (CH3)CH2- H
( 3) 2C 2 H
(CH2) 10 H
-CH2- C6H5
l~ Z8936
PREPARATION T
3-Methoxy-~-methylstyrene Oxide
To a -78 C. solutian of diphenylsulfonium ethylide (1.0 mole) in
tetrahydrofuran (one liter) is slowly added 3-methoxybenzaldehyde (1.0 mole).
The reaction mixture is stirred at -78 C. for 3 hours and then allowed to warm
to room temperature. It is then added to ether-water and the ether phase sepa-
rated. The ether phase is was~d with water, dried (MgS04) and evaporated.
Fractional distillation of the residue gives the title product.
- 82 -
1128936
PREPAR~TION U
3-(3-Hydroxyphenyl)-2-propylbutyl Ether
To a solution of sodium butoxide in butanol (0.5 liters of lM) is
added 3-methoxy-~-methylstyrene oxide (6,33 mole). The mixture is heated for
18 hours at 70 C. and is then cooled and ~dded to a mixture of ether-water.
The ether solution is separated, dried (MgS04) and evaporated to give the crude
product 2-(3-methoxyphenyl)-3-hydroxy-2-propylbutyl ether. It is purified by
colu~n chromatography on silica gel with ether-pentane elution.
By means of the procedure of Preparation R the title product is
produced.
Similarly, the follo~-ing are prepared from appropriate alcohols:
CN~
CH2 O- (alk2)-W
(alk2) W
. (CH2)2 H
(CH2)7 H
(CH2)3 C6H5
(CH2)2 4-FC6H4
(CH2)2 4-pyridyl
CH(C~13)(CH2)2 H
CH(C2H5)(CH2)3 H
CH(CH3)CH2 C6H5
CH2 H
(CH2)2 4-ClC6H4
1 1128936
¦ PREPARATION V
l l-Bromo-3-~3-methoxyphenyl)butane
¦ A solution of phosphoraus tribromide (5.7 ml., 0.06 mole) in ether
¦ t30 ml.) is added to a solution of 3-(3-methoxyphenyl)-1-butanol (30.0 g.,
¦ 0.143 mole) in ether (20 ml.) at -5 C. to -10 C. and the reaction mixture
¦ stirred at -5 C. to -10 C. for 2.5 hours. It is then warmed to room
temperature and stirred for an additional 30 minutes. The mixture is poured
over ice ~200 g.) and the resulting mixture extracted with ether (3 x 50 ml.).
The combined extracts are washed with 5~ sodium hydroxide solution (3 x 50 ml.) ,
saturated sodium chloride solution (1 x 50 ml.) and dried (Na2S04). Removal of
the ether and vacuum distillation of the residue affords the title product.
The following compounds are prepared from 3-methoxybenzaldehyde, 3-
methoxyacetophenone and 3-methoxypropiophenone and the appropriate carbethoxy-
alkylidene triphenylphosphorane by the procedures of Preparations L, M and
the above procedure. OCH3
~ Z-Br
(CH2)3
(CH2)4
CH(C2H5)CH2
CH(CH3)CH2
CH(CH3)(CH2)3
128936
PREPAR~TION W
l-Substituted-4-piperidones
A mixture of ethyl acryla~e (3 moles) and the appropriate amine
~6'NH2 (1 mole) in dry ethanol (200 ml.) is stirred and refluxed for 48 hours.
The reaction mixture i9 then fractionally distilled to give the corresponding
N~di~(2~CarbethXYethyl)-R6'-amirle [~6'-N-(CH2-CH2-COoC2H5)2].
- The disubstituted amine (l mole) is then cyclized by treatment with
metallic (bird shot) sodium (49.5 g.) in xylene (one liter) and the mixture
warmed to 50 C., care being taken to exclude moisture. Additional base is
added drop-wise to maintain the reaction. The reaction mixture is stirred at
50 C. for 3-4 hours following addition of the base and then cooled. Water
(one liter) is cautiously added, the aqueous phase separated, extracted with
ether (4 x 200 ml.)-and then acidified with concentrated hydrochloric acid.
The acid solution is saturated with potassium carbonate and the oil which
separates extracted with ether. The ether solution ls dried (K2C03) and
evaporated. The residue is refluxed with 20% HCl (2 liters) for 3-4 hours
and the mixture then evaporated to dryness under reduced pressure to give the
desired l-substituted-4-piperidone.
By means of this procedure (substantially that of Beckett, et al.,
J. Med, Pharm. Chem., 1, 37-58, 1959), the following compounds are prepared.
1128936
¦ __ __
n C3H7
l i-C3H7
5 ¦ n-C~Hg
sec-C4Hg
t-C4H9
l n-C5Hll
I n-C6H13
I (CH2) 3C6H5
I (ca2)4C6H5
C3H5
l furfuryl
¦ tetrahydrofurfuryl
15 ¦ tetrahydrothienylmethyl
l . (CH2) 2C6a5
. - CH(CH3)C6H5
- ¦ CH(CH3)CU2C6H5
!
1128936
I
PREPARATION X
l-R~'-Substituted-Azacycloalkan-3-ones
A mixture of the appropriate N-(R6'-substituted)glycine ethyl ester
and the appropriate ~-halo ester BrCH2(CH2)xCH2COOC2H5 (1 mole) is allowed to
stand at room temperature for 24 hours. It is then diluted with ether,
filtered and the ethereal solution evaporated.
The ~,~'-dicarbethoxydialkyl-R6~-amineS [H5C20oc-cH2-NR6 -CH2(cH2)x-
CH2COOC2H5] are then cyclized by heating a mixture of equimolar amounts of the
di-ester and sodium ethoxide at from 120-130 C. under conditions which allow
distillation of by-product ethanol. When removal of alcohol is complete, water
is added to the reaction mixture and the resulting mixture extracted with
ether. The aqueous solùtion is then acidified with hydrochloric acid and
refluxed until the solution gives no color reaction with ferric chloride.
Evaporation of the solution affords the ~Cl salt of the l-R6'-substituted-3-
pyridone. Careful neutralization with potassium carbonate gives the freeketone.
In this manner the l-R6~-substituted azacycloalkan-3-ones listed
below are prepared from appropriate N-R6'-glycine ethyl esters and appropriate
~-bromoalkanoic acid ethyl esters,
(~0
x R6'
0 cyclohexylmethyl
l cyclopentylmethyl
1 cyclohexylmethyl
2 cyclobutylmethyl
3 cyclohexyl=ethyl
!
1128936
C~2 6 5
0 CH3
O n-C3H7
~CH2)~C6 5
0 cyclobutylmethyl
0 cyclopropylmethyl
0 furfuryl
0 2-tetrahydrothienylmethyl
1 CH3
1 t-C4H9
1 i C6H13
1 furfuryl
1 tetrahydrofururyl
1 2-tetrahydrothienylmethyl
. 1 (CH2) 2C6H5
' 1 (CH2) 4C6H5
1 cyclobutylmethyl
1 cyclopropylmethyl
. 2 CH3
2 i-C3H7
2 n-C5Hll
2 cyclopropylmethyl
2 (CH2)3C6H5
2 tetrahydrofurfuryl
2 CH2C6H5
3 CH3
3 sec-C4H9
3 n-C6H13
3 (C~2)3C6 5
3 cyclopropylmethyl
3 2-2-tetrahydrothienylmethyl
3 CH2C6 5
1 n-C3H7
C3 7
0 2-thienylmethyl(thenyl)
1 2-thienylmethyl(thenyl)
( 3) 6 5
2 CH(CH3)CH2C6H5
- 88 -
l~Z8936
The N-R6'-glycine ethyl esters not described in ~he art are prepared
by reacting 2 moles of the appropriate amine in anhydrous ether at 0-10C.
with one mole of ethyl bromoacetate. The mixture is stirred for 3 hours then
allowed to stand overnight. T~e pr~cipitate is filtered off, the ether evap-
orated and the residue vacuum disti~led.
1 il28936
PREPARATION Y
Repetition of the procedure of Preparation X but using the appropriat
N-(R6~-substituted)-~-alanine ethyl ester in place of the N-(R6'-substituted)-
glycine ethyl ester affords co~pounds having the formula
2 CH3
2 n C6H13
2 (CH2)3C6H5
2 cyclopropyl
2 cyclopropylmethyl
2 2-tetrahydrothienylmethyl
2 furfuryl
3 C2H5
3 tetrahydrofurfuryl
3 cyclopropyl
3 (CH2)4C6H5
~lZ8936
PREPARATION Z
l_Benzyl_4 (3-phenylpropyl)-3-piperidone
To a 0 C. solution of 7,0 mmols. of 3-phenylpropylmagnesium bromide
in 7 ml. of tetrahydrofuran i9 slowly added a solution of 0.95 g. (5.0 mmols.)
of 1-benzyl-4-piperidone in 10 ml. of tetrahydrofuran. The resultant mixture
is stirred for one hour and is then added to 250 ml. of saturated ammonium
chloride-250 ml. ether. The ether phase is dried over magnesium sulfate and
evaporated. The residue is purified via column chromatography on 200 g. of
¦ silica gel eluted with 50% e~her-cyclohexane to yield 1-benzyl-4-(3-phenyl-
10 ¦ propyl)piperidinol.
The thus-prepared piperidinol (6.18 g., 20 mmols.) is then added to ¦
2N hydrochloric acid (250 ml.) and the mixture refluxed for 6 hours. It is
then evaporated under reduced pressure and the residue taken up in 500 ml. of
l saturated sodium bicarbonate-300 ml. of ether-100 ml. of dlchloromethane. The
15 ¦ organic phase is separated, dried (MgS04? and evaporated to an oil which is
purified by column chromatography on 400 g. of silica gel eluted with 50% ethe~-
cyclohexane to give the product l-benzyl-4-(3-phenylpropyl)-1,2,5,6-tetrahydro
pyridine.
l Hydroboration and subsequent oxidation of the thus-produced 1,2,5,6-
tetrahydropyridine according to the procedure of Example 5 gives 1-benzyl-4-
(3-phenylpropyl)-3-piperidinol.
Oxidation of the 3-piperidinol compound by the procedure of Example ¦
6 yield~ the desired 1-benzyl-4-(3-phenylpropyl)-3-piperidone.
The following compounds are prepared in like manner from appropriate
- 25 Grignard reagents R2~gBr and the appropriate l-(R6~-substituted)azacycloalkan-
3-one:
(~0
1128936 ll
1 CH3 CN3
1 CH3 n~C3H7
1 CH3 n-C6H13
1 n~C3H7 5 11
1 - i-C3H7 C2E15
1 t-C4Hg n-C4Hg
1 i C6H13 CH3
1 THF CH3
1 THF n-C6H13
1 CH2C6H5 CH3
1 CH2C6H5 n~C3H7
. 1 tCH2)4C6H5 i C3H7
1 (CH2)2C6H5 CH3
1 CH2C6H5 (CH2)3C6H5
. 1 C3H5 CH3
1 C3H5 n-C4Hg
. 1 C3H5CH2 CH3
, 1 C3H5CH2 n-C6H13
1 C3H5CH2 ( 2)2C6 5
1 C3H5 C6H5
.1 CH3 C6H5
1 t-C4Hg C6H5
1 furfuryl CH3
25 . 1 furfuryl (CH2)4C6H5
1 furfuryl n C5Hll
1 THTM ~H3~
1 THTM sec-C4Hg
1 THTM (CH2)3C6H5
1 THTM (CH2)4C6H5
1 THF C6H5
0 CH3 CH3
0 CH3 i-C3H7
O n-C3H7 i-C6H13
0 CH3 C6H5
O n-C3H7 (CH2)3C6H5
0 (CH2)2C6H5 C2 5
1, 1
~128936
x 6 2
0 C3H5 n-C3H7
0 C3H5 (C 2)2C6H5
C3H5ÇH2 CH3
O fur~lryl C2H5
: 0 THT~ CH3
0 THTM C6H5
2 CH3 CH3
2 CH3 n-C5Hll
2 i-C3H7 (CH2)3C6H5
5 11 CH3
2 CH2C6H5 CH3
. 2 CH2C6H5 n-c4H9 .
2 (CH2)4C6H5 CH3
3 5 C2H5
2 C3H5 (CH2)3C6H5
2 C3H5 C6H5
. 2 (CH2)3C6H5 CH3
. 2 THF CH3
2 THF C6H5
0 C 2C6 5 CH3
2 6 5 n-C6H13
CH2C6H5 C6H5
3 CH3 CH3
. 3 CH3 i-C3H7
3 CH3 n-C6H13
3 CH3 (CH2)3C6H5
3 SeC-C4H9 CH3
3 SeC-C4H9 C6H5
3 SeC_C4Hg i-C3H7
3 n-c6Hl3 3
3 n-c6Hl3 5 11
3 C3H5CH2 CH3
3 C3H5CH2 n-c4H9
3 C3H5CH2 ( 2)2 6 5
3 C3H5CH2 C6H5
3 THTM C6H5
llZ8936
R ' R '
3 THTM (CH2) 3C6H5
3 CH2C6H5 CH3
3 CH2C6H5 n-C4Hg
3 (CH~)4C6H5 CH3
3 ~THF CH3
C3 5 i-C3H7
C3 5C 2 3 7
C3H5CH2 (CH2) 3C6H5
n C6H13 CH3
. . THF ~ tetrahydrofurfuryl
THTM = 2-tetrahydrothienylmethyl
_94~_
