4-AMINO-4-ARYLCYCLOHEXANONES AND THEIR KETALS

TRADUCTION NON-DISPONIBLE

English Abstract

ABSTRACT OF THE DISCLOSURE

A class of new 4-amino-4-arylcyclohexanones, their
ketals, and acid addition salts have been synthesized and
found to be useful for relieving pain in animals. Their
analgesic activity appears to be of high order, and in
addition some exhibit narcotic antagonist activity that is
useful in modifying the cardiovascular, respiratory, and
behavioral depression caused by other analgesics. Several
show mixed analgesic and narcotic antagonist activity.
Preferred compounds of the class are 4-(m-hydroxyphenyl)-4-
dimethylaminocyclohexanone ethylene ketal, and 4-(m-hydroxy-
phenyl)-4-(n-butylmethylamino)cyclohexanone ethylene ketal as
free bases and as their hydrochloride salts. Processes for
synthesis and intermediates are described. Unit dosage forms
and therapeutic treatments are disclosed. The compounds of the
invention have the formula:
Image
Formula 1


wherein X is oxo, and
Image

wherein the substituents R1, R2, R3, R4 and R5 can be hydrogen or
other substituents defined in the specification and n is zero or
one.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula:
Image

wherein Ar is thiophene, or Image wherein m is zero, one or
two, and Y is halogen, CF3, alkyl of 1 to 4 carbon atoms,
inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, cycloalkyloxy
of 3 to 6 carbon atoms, inclusive, alkylthio of 1 to 4 carbon
atoms, inclusive, or Image; R1 is alkyl of 1
to 8 carbon atoms, inclusive, R2 is alkyl of 1 to 8 carbon atoms,
inclusive, cycloalkylalkyl wherein cycloalkyl is of 3 to 6 carbon
atoms, inclusive, and alkyl is of 1 to 3 carbon atoms, inclusive,
cycloalkyl of 3 to 6 carbon atoms, inclusive, Image
or Image wherein Y' is halogen, CF3, alkyl of 1 to
4 carbon atoms, inclusive, or alkoxy of 1 to 4 carbon atoms,
inclusive, comprising (a) reacting a compound of the formula
Image with a diol of the formula:

Image

wherein n is zero or one and R1 is hydrogen or methyl; R5 is
hydrogen, phenyl, -CH2-alkenyl wherein alkenyl is of 2 to 4
carbon atoms, inclusive, or methyl; in the presence of acid in
an inert solvent to obtain a compound of the formula:

Image


(b) oxidation of the above compound to obtain a compound of the
formula:
Image

183

(c) reacting the above compound with hydrogen cyanide (HCN)
and an amine of the formula Image to obtain a compound of
the formula:
Image


(d) reacting the above compound with a Grignard Reagent of
the formula ArMgX in anhydrous organic solvent to obtain a
compound of the formula:
Image

(e) acid hydrolysis of the above ketal to prepare a compound
of the formula:
Image


wherein Ar, R1 and R2 are as defined hereinbefore.

2. A 4-amino-4-arylcyclohexanone of the following formula:

Image

wherein Ar, R1 and R2 are as defined in claim 1, whenever
prepared or produced by the process defined in claim 1 or
by the obvious chemical equivalent.

184

Description

S16

,. . .. . . . .
Thls applicat~on is . a dïvisi~n of, coPending
.
. ' Canadian applic~ n Serial No. 278,494, filed
May 16, 1977. : . . .

.
- . SUMMARY OF THE INVENTION . . .
.
. This invention pertains to some new organic chemical
compounds that are actlve as analgesics (Formula I), and
also to novel compounds useful as ;ntermediates in the
preparation of the compounds of Formula I, such as Formulae
Il, III~ IV, ~nd Vg and acid addition salts when the amino
~unctionality is present,


)~= ~=X

OCN . . II ~N\ III
C H 3 H
.
. . .- :
Ar . - NC
O=X
IY V
H2N . R~ R2

wherein Arg Rl, R2, and X are as de~ined below.
The invention is more particularly directed to some
new 4-amino-4-arylcyclohexanones~ their ketals~ and acid
addition salts thereof 9 two processes for preparing the
- same; and 2 me,thod and formulations for treating pain in
animals and humans.
. The new 4-àmino4-arylcyclohexanones and ketals are
represented by the general schematic formula:

-2 ~
~, .


3286
5 ~6

.,
R~
A r
X4 I C=X
\~/




N\ Formula I
Rl R2

where;n X is oxo, and
0 - CH2
R4
Cn
~ I \ Rs

-wherein n is zero or one and R4 is hydrogen or methyl; Rs
is hydrogena phenyl, -CH2-alkenyl wherein alkenyl is of 2
to 4 carbon atoms, inclusive9 or methyl 9 aryl is thiophene,
or ~ wherein m is zero, one or ~wo, and Y is
halogen, CFm, alkyl of l to 4 carbon atoms, inclusive,
alkoxy of l to 4 carbon atoms, inclusive9 hydroxy, cyclo-
alkyloxy of 3 to 6 carbon atoms9 inclusive, alkanoyloxy
of 2 to 4 carbon atoms, inclusive5 alkylthio of l to 4
carbon atoms, inclusive, or -0-(CH2), ~ where
Y' is halogen, CF3, alkyl of l to 4 carbon atomsn,~ inclusive,
or alkoxy of l to 4 carbon atoms, inclusive; R, is hydrogen,
or lower alkyl of l to 8 carbon atoms9 inclusive~ R2 is
hydrogen, lower alkyl of l to 8 carbon atoms, inclusive,
-CH2-alkenyl wherein alkenyl is of 2 to 8 carbon atoms, in-
ctusiYe, ac tyl, cycloalkylalkyl wherein cycloalkyl is of 3
to 6 carbon atoms, inclusive, and alkyl is of l to 3 carbon
a ~ms, inclusive,~-hydroxyethyl, carbethoxymethyl, cycloalkyl of
3 to 6 carbon atoms, lnclusive9 -(CH2) ~ , or
Y m




--3

32~6
~ S ~ 6

-(CH2 ~2 - ~ ; R3 is hydrogen, l.ower alkyl of
1 to S carbon atoms, lnclusive; and N can be a saturated
~ \R2
cycloalky1amino group N ~ ~)n' wherein n' is 3, 4, 5, or
6; or mono- or di-alkyl substituted cycloalkylamino wherein
each alkyl is of 1 to 3 carbon atoms9 inclusive; and the
acid addition salts thereof.
Rl and R2 taken together with the nitrogen atom to
which they are attached form a saturated cycloalkylamino
. group N ~ C)n. wherein n' is 3, 4, 5, or 6, and mono- or
di-alkyl substituted cycloalkylamino wherein each alkyl is
from 1 to 3 carbon atoms, inclusive.
The wavy l-ine (~ ) denotes the possibility of cis-trans
stereoisomerism with respect to substitution at the
4-position.
When R3 is lower atkyl9 the carbon atom to which R3
is attached (#.2) becomes asymmetric (possesses chirality
and the 2-substituted cyclohexanone can exist as two
enantiomers which can be resolved by known methods.
.. In compounds of the formula:

Ym~ '
~ . R3

~4 1 C= X
25 / \s 6/
~N\ VI
R, R2

wherein Ynl, Rl, R2, R3, and X are as defined above, since
the Y variable can be hydroxy, the compounds of the
invention incl~de 4-(meta-hydroxyphenyl)-4-aminocyclohex-

. - -4-

32~6
1516

anones, their ketals, and acid addition salts that are
particularly ;nteresting and especially preferred. They
exhibit excellent narcotic antagonist activity in addition
to their own analgesic effect. They are therefore pros-
pectively useful for antagonizing the toxic effects ofmorphine, meperidine, and codeine by 1nhibition of the
cardiovascular, respiratory, and behavioral depression
caused by these and other potent analgesics. These also
possess the additional useful property of low physical
dependence liability as measured by methods
described by E. L. Way, et al. 9 J. Pharmacol. Exp. Ther.,
167, 1 (1969), J. K. Sealens, et al.~ Arch. Int. Pharma-
., 190, 213 (1971), and S. E. Smits9 Res. Commun. inChem. Path. and Pharmac., 10, 651 (1975).
A preferred class of compounds for analgetic activity
are compounds of the formula:
. ' . ' ' , ' .

Y

Formula VII
N
Rl R2
2~ wherein X is oxo or
O CH2
__ __o - ~H2
R3 is hydrogen or lower alkyl of from 1 ~o 5 carbon atoms,
inclusive, Y is halogen, CF3, alkyl of 1 to 4 carbon atoms,
~nclusiYe, alkoxy of 1 to 4 carbon atoms9 inclusive, hydroxy
.

. , .
. .

. 3286
llQ~'5~6

or atkanoyloxy of 2 to 4 carbon atoms, inclusive, and Rl
is hydrogen, or lower alkyl of 1 to 8 carbon atoms, inclu-
sive, R2 is hydrogen, lower alkyl of 1 to 8 carbon atoms,
inclusive, -CH2-alkenyl wherein alkenyl is of 2 to 8
carbon atoms, inclusive, acetyl, cycloalkylalkyl wherein
cycloalkyl of 3 to 6 carbon atoms9 inclusive, and alkyl
is of 1 to 3 carbon atoms, inclusive, ~-hydroxyethyl, carb-
ethoxymethyl, cycloalkyl of 3 to 6 carbon atoms, inclusive,
-(CH2) ~ , or -(CH2)~--0 ~ , and R3
is hydrogen, lower alkyl of 1 to 5 carbon atmoms, inclus;ve,
R
and N / can be a saturated cycloalkylamino group N (C)
wherein n' is 3, 4, 5, or 6; or mono- or di-alkyl substi-
tuted cycloalkylamino wherein each alkyl is of 1 to 3
carbon atoms, inclusive; and the acid addition salts
lS thereof.
An especially preferred class of compounds for anal-
getic activity coupled with lower to moderate physical
dependence liability are compounds of the formula:



Y ~\~


- N YIII
: R, R2

wherein X i s oxo or
0--IH2
O--C H 2

R3 is hydrogen or lower alkyl of from 1 to 5 carbon atoms,

- -6-

1 3286
S16

inclusive, Rl is lower alkyl of from 1 to 8 carbon atoms,
incluslve, R2 is lower alkyl of from 1 to 8 carbon atoms,
inclusive, ~-hydroxyethyl, cycloalkylalkyl wherein cyclo-
alkyl is from 3 to 6 carbon atoms, inclusive, and alkyl is
from 1 to 3 carbon atoms, inclusive, acetyl or carbethoxy-
methyl, and Y ;s hydroxy, alkanoyloxy of 2 to 4 carbon
atoms, inclusive, alkoxy of 1 to 4 carbon atoms, ;nclusive,
or -O-(CH2)1 ~ wherein m is 0, 1, or 2 and Y'
is alkyl of 1 to 4 carbon atoms, inclusive, or alkoxy of
1 to 4 carbon atoms, inclusive.
It is accordingly a general object of this invention
to provide novel and useful analgesic agents, new and
appropr;ate formulations of the new compounds designed for
administration to humans and animals, e.g., cats, dogs,
cows, horses, suffering from pain, and a novel method for
treating and relieving pre-treatment pain in animals. Other
more limited objects of this invention, such as the new
syntheses of the desired ne.w active compounds and inter-
mediates, will be apparent to those skilled in the art as0 this description of the invention becomes more detailed
DETAILED DESCRIPTION OF TH~ INVENTION
In the foregoing schematic representation (see Formula
I, above) of the new 4-amino-4-arylcyclohexanones and
ketals of this invention, the variable X is defined as
oxo(=O) when a cyclohexanone itself is intended. Otherwise
the X variable represents an alkylene ketal which is pre-
ferably an ethylene ketal, i.e. 9 a spiro-1,3-dioxolane
group, but is also trimethylene ketal. For purposes of
consistency and perhaps simplicity the ethylene ketals are
named as 1- or 2-substituted ethylene.
,
-7-

)
3286
1106~Sl~

When the alkylene ketal has a trimethylene chain, the
chain carbons can be similarly hydrocarbon, optionally
substituted by lower-alkyl, lower alkenyl 9 phenyl, benzyl,
phenethyl, or other non-critical 9 non-interfering hydrocar-
bon groups. This group with two oxygens and the cyclohex-
anone carbon form a spiro-193-dioxane group. Thése are
conveniently designated as 2 substituted trimethylene.
As stated, the new 4-amino-4-arylcyclohexanones,
ketals, and acid addition salts of this invention9 repre-
sented by schematic Formula I, above, as limited bydefined variables, are active as analgesics. The compounds
have been discovered to in some way interfere with nerve
transmission or cortical awareness of normally painful
insults to the animal body. By and large this interfering
action has been observed to be physiologic, and no major
interference with other physiological activities of the
body has been observed. The new compounds can therefore
be used to treat and relieve pain regardless of origin in
animals and humans.
Certain compounds of this invention are extremely
potent and desirable analgesics. Many of them are compar-
ab7e to or exceed in potency the well-known analgesic
meperidine (N-methyl-4-phenyl-4-carbethoxypiperidine) and
are therefore preferred as pure analgetics. Among these
many preferred, newly preparedg and tested compounds are
4-(p-chlorophenyl)-4-dimethylaminocyclohexan-l-one,
ethylene ketal;
4-~p-fluorophenyl)-4-dimethylaminocyclohexan-l-one,
ethylene ketal;
4-(p-bromophenyl)-4-dimethylaminocyclohexan-l-one,

~ -8-

3286
5 1 6
.

ethylene ketal;
4~dlmethylamino-4-(p-tolyl)cyclohexan-l-one, ethylene
ketal;
4-(p-anisyl)-4-dimethylaminocyclohexan-l-one, ethylene
S ketal;
4-(p-tolyl)-4-dimethylaminocyclohexanone;
4-(p-bromophenyl)-4-dimethylaminocyclohexanone; and
4-(p-chlorophenyl)-4-dimethylaminocyclohexanone.
Other preferred compounds of this invention for low
physical dependence liability activity and analgetic
activity are
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexan-l-one,
ethylene ketal;
4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohexan-
lS l-one, ethylene ketal hydrochloride,
4-(m-hydroxyphenyl)-2-methyl-4-dimethylaminocyclohexan-
l-one and its ketals.
The (Y) variable substituent on the 4-phenyl ring can
any of a wide variety of non-interfering elemental atoms and
organic groups. Illustratively, Y can be halogen9 CF3,
alkyl of from l to 4 carbon atoms, inclusive; alkoxy of
from l to 4 carbon atoms, inclusive; alkylthio of from
l to 4 carbon atoms, inclusive; hydroxy; alkanoyloxy of 2 to
4 carbon atoms; -(CH2)1 ~ as defined above.
Specific examples of the foregoing general classes of
elemental atoms and organic groups include: chlorine, bromine,
~odine, fluorine, methyl, ethyl 9 propyl 9 butyl, isopropylg
isobutyl, methoxy, ethoxy, propoxy9 trifluoromethyl, methyl-
thio, ethylthio, tert-butylthioO benzyloxy, and acetoxy.
3n Representative CH2-alkenyl wherein alkenyl is of 2 to

3 286
1516
. , .
8 carbon atoms include such groups as ~-methyl-2-butenyl,
4-ethyl-2-hexenyl, 3-methyl-2-hexenyl, allyl, methallyl,
and the like. Cycloalkylalkyl may be cyclohe~ylmethyl,
cyclopropylmethyl, cyclopentylethyl and the like. The
foregoing are iust samples of such acceptable groups.
The characteristic -N \ group has been broadly
defined above, and it will be recognized by those skilled
in the art that any of a great variety of "amino" gr~ups
can be employed. For purposes of exemplification only,
some representative basic nitrogen groups are specified.
The methylamino embodiment was obtained in many of the
intermediates. Likewise, a 4-allylmethylamino group, a
butylmethylamino group, a (carbethoxymethyl)methylamino
group, a (2-hydroxyethyl)methylamino group, and a methyl
acetamido group are embodiments actually prepared in
final compounds.
Other representative "amino" embodiments consistent
with the general description include: lower-alkylamino,
dilower-alkylamino, lower-a1kenylamino, cycloaliphaticamino
of from 3 to Ç carbon atoms5 inclusive, (cycloaliphatic-
alkyl)amino of from 4 to 9 carbon atoms, inclusive, lower-
alkyl alkanamido of from 3 to 6 carbon atoms, inclusive,
pyrrolidinyl, l-piperidinyl, 4-alkylpiperidinyl, 3-alkyl-
pyrrolidinyl, and 3,4-dialkylhexamethyleneimino.
2~ The basic am;no nitrogen endows the new compounds of
~; this invention with the facility for preparation of acid
addition salts. In order to accomplish this transformation,
the free bases are merely reacted with a selected acid,
preferably in the presence of an organic solvent substan-
tlally inert to the basic compound9 the acid, and the acid

-10- .

32~h
i;S16

addition salt that is formed. Anhydrous conditions are
preferred. The salt usually precip;tates from an appro-
priate organic solvent or it can be recovered by evaporation
of solvent until crystallization occurs~ followed by
filtra~ion.
Acid addition salts suitable for physiological anal-
gesia are necessarily non-toxic to the animal to be
benefited. Hence, the anion of the acid addition salt
will be by definition relatively innocuous to the treated
animal at the therapeutic dosage admin;stered. The
beneficial action of the analgesic will not be vitiated by
side-effects ascribable to an inherently toxic anion.
Appropriate acid addition salts include those prepared
from suitable mineral acids, e.g., hydrochloric9 hydrobromic,
hydroiodic, nitric, sulfuric, and phosphoric acids; and
those prepared from organic acids, e.g. 9 acetic, propionic,
butyric, citric, lactic, benzoic, palmitic, succinic,
gluconic, mucic, tartar;c, pamoic, salicylic, cyclohexyl-
sulfamic, and p-toluenesulfonic acid. On occasion the
compounds or their acid addition salts in their crystalline
state are isolated as solvates, e.g., with a discreet
quantity of solvent, e.g., water, ethyl acetate, and the
like, associated physically, and thus removable without
effective alteration of the chemical entity ~ se.
Reference to Example 1 of this description of the
invention reveals a relatively involved multi-step procedure
for making the new 4-amino-4-arylcyclohexanones and ketals
of Formula I. This original procedure consists of eight
separate chemîcal conversions. Each step will be generally
described hereinbelow and the details are available in the

,

3 2~6


various Examples.
The synthesis begins with preparation of a dialkyl
4-cyano-4-arylpimelate via a Michael-type condensation
involving an arylacetonitrile and methyl acrylate. A sol-
vent medium, e.g., tert-butyl alcohol, is employed and a
basic catalyst, for example, 40% methanolic tetramethyl-
ammonium hydroxide (Triton B~). The reaction ~ixture is
heated at the reflux temperature for several hours, and
the desired dialkyl 4-cyano-4-arylpimelate first intermedi-
ate thus formed is recovered by conventional techniquessuch as solvent extraction and distillation.
The second intermediate, an alkyl 5-cyano-2-oxo-5-aryl-
cyclohexanecarboxylate, is prepared by heating a dialkyl
4-cyano-4-arylpimelate from Step 1 in the presence of a
strong base, e.g., an alkali metal, sodium hydride or
potassium tert-butoxide. An organic solvent medium such
as toluene or tetrahydrofuran is suitable and the desired
intermediate is recovered by conventional techniques of
solvent extraction and distillation. These intermediates
can be named as 2-carbalkoxy-4-cyano-4-arylcyclohexanones
as related in the Examples.
The third intermediate, a 4-cyano-4-arylcyclohexanone
is prepared by a conventional hydrolysis and decarboxylation
of the second intermediate alkyl 5-cyano-2-oxo-5-arylcyclo-
hexanecarboxylate. The desired degradation is accomplishedwith a strong mineral acid such as sulfuric acid. Aqueous
acetic acid is an appropriate and convenient solvent medium
for heating at the reflux temperatureO The desired inter-
; mediate is recovered by solvent extraction followed by
removal of the solvent, and purification9 for example by

- -12- ;

3~6
S16

,

recrystallization.
In the next step of the synthesis, the carbonyl func-
tion of the 4-cyano-4-arylcyclohexanone is protected by
convers;on to a ketal. Any alkylene ketal is suitable,
but an ethylene ketal readily obtainable with an ethylene
glycol in the presence of an acid catalyst such as p-tolu-
enesulfonic acid and an organic solvent medium is preferred
in the process embodiment. The ketalization reaction is
promoted by heating, conveniently at the reflux temperature
~0 and by azeotropic removal of the water formed. Ketals
other than ethylene ketal are obtained using, e.g. 9 1,3-di-
hydroxypropane. The alkylene chains constituting the
ketal function can be substituted with non-interfering
hydrocarbon groups such as lower-alkyl 9 phenyl, lower
2-alkenyl. These ketal intermediates are recovered with
appropriate organic solvents such as benzene and purified
by conventional techniquesO
Having protected the carbonyl functlon of the cyclo-
hexanone, the 4-cyano-group is converted to a carboxylic
- 20 group (saponification). This is readily accomplished by
he~ting the fourth intermediate~ above9 a 4-cyano-4-aryl-
cyclohexanone, alkylene ketalg with an alkali metal
hydroxide (preferably potassium hydroxide) in the presence
of a relatively high boiling solvent such as ethylene
glycol, followed by neutralization of the reaction mixture
in with a mineral acid9 e.g., hydrochloric acid. The thus
produced 4-carboxyl-substituted fifth intermediate is
readily recovered and purified by solvent extraction,
physical removal of the solvent, and recrystallization. It
is preferable that prior to saponification of the 4-cyano-


-13~


~ . , .

3286
Si6

4-arylcyclohexanone ethylene ketal wherein the aryl is
substituted by hydroxy, the hydroxy group ;s protected by
a readily removable group, e.g., benzyl. Introduction of
the protective 9roup can be accomplished by standard
g methods, using benzyl halide, e.g., benzyl chloride, and
base, e.g., sodium hydride.
-The sixth intermediate, which is d 4-isocyanato-
4-arylcyclohexanone, alkylene ketal, is prepared by a
modified Curtius rearrangement utili~ing an azide, (e.g.,
10diphenyl phosphonic azide (C6H50)2PON3) in a Inodification
of the procedure described by T. Shioiri~ K. Ninemiya and
S. Yamada, J. Amer. Chem. Soc., 94, 62039 (1972). Use of
an aprotic solvent medium, e.g., anisole, is preferred.
The reaction mixture is heated at about 100 C. but
reaction can start to occur at lower temperatures with the
evolution of nitrogen. The desired isocyanate is recovered
by removing volatile components, and then chromatographic
procedures followed by, if necessary9 recrystallization.
The next step in the synthesis provides a 4-methylamino
embodiment of the invention according to Formula I wherein
:
`X is an alkylene ketal. This step involves reduction of
the isocyanate group; chemical reducing agents, e.g.,
lithium ~luminum hydride, can be used. The reaction is
conventional and is promoted by heating. The desired pro-
duct is obtained treating the reaction mixture with an
alkali metal hydroxide so as to obtain the inorganic
aluminum salts as gelatinous precipitate which is removed
by filtration. Evaporation of the filtrate gives the amine
which is purified by conventional methods. Alternatively
the isocyanate may be reduced by catalytic hydrogenation.

.
-14-


-- . . . . . . . . . .

3286
516

Another embodiment of the invention9 the disubstituted
amino subject matter according to Formula I, are obtained
by adding an R2 group as defined onto the already described
~ethylamino group. Alkylations, acylations, and reduction
of acyl functions and the like are accomplished by usual
methods.
Alkylations with allyl halide, e.g., allyl bromide,
or ~-haloester, e.g., ethyl bromoacetate in polar aprotic
solvent, e.g., dimethylformamide, in the presence of
inorganic base, e.g., potassium carbonate proceed as des-
cribed in the literature. When converting the secondary
amine to the tertiary amine forms it is necessary to
first protect the hydroxy moiety (if it is present) by an
easily removable protecting group such as benzyl.
Preferred acylating agents are acyl chlorides (e.g.,
cyclopropanecarbonyl chloride, butyryl chloride) and
anhydrides of monobasic carboxylic acids (e.g., acetic
anhydride and the like).
Addition of R3 to the 2-position of 4-aryl-4-amino-
cyclohexanone is effected by reaction of equivalent amountsof the subject cyclohexanone and a strong base, e.g.,
lithium diisopropylamide, at 1OW temperature, e.g.~ -10
to -40 C. in an inert solvent9 e.g.9 tetrahydrofuran,
followed by reaction with the desired alkyl (R33 halide9
e.g., methyl iodide, n-propyl bromide and the like.
Isolation of the product is made using conventional pro-
cedures such as washing, chromatography, and recrystalliza-
t~on.
Stereochemistry of the R3 substituent in reference
to the 4-amino functionality is not exclusive; both the

~ -15-

32~6
d ~P 516

cis (Z) or trans (E) isomers are formed; the cis isomer
has been observed to form predominantly. Preferential
conformation with the phenyl group in an axial position
of the cyclohexane ring was ~ound in an x-ray study of
geminally-substituted cyclohexanes (e.g., l-acetoxy-
4-phenyl-4-acetoxymethylcyclohexane) as described in D.
Lednicer and D. J. DuChamp, J. Org. Chem., 39, 2311 (1974).
Reduction of the amide group resulting from acylation
can be accomplished by usual literature methods, e.g.,
using diborane or lithium aluminum hydride in appropriate
solvents.
Removal of the protecting group from a benzyloxy
substituted phenyl ring is effected by hydrogenolysis
under mild conditions over noble metal catalyst, e.g.,
,; 15 palladium on carbon, in solvent which mag contain mineral
acid, e.g., hydrochloric acid. The method is standard in
the art.
When a 4-amino-4-arylcyclohexanone, according to
Formula I and the invention, is desired, the ketal is
removed by prolonged action of an aqueous mineral acid
such as hydrochloric acid in the presence of methanol as
a solvent. i'Prolonged action" means as much as 48 hours'
time.
If an unsubstituted amino nitrogen is desired, the
best way to accomplish such objective is to heat the
4-isocyanato intermediate with an alkali metal hydroxide
particularly sodium hydroxide in the presence of ethylene
glycol at the reflux temperature followed by brief treat-
ment with acid. When a lower boiling solvent such as
methanol was used as the solvent medium, a dimeric urea

3286
S~6

~nstead of the primary amine was obtained.
During the course of developing this invention an
improved process of synthesis was discovered. It has been
found that many of the compounds of this invention can be
readily prepared by a Grignard reaction between a phenyl
Grignard reagent of the kind ~ MgX and a
4-dialkylamino-4-cyanocyclohexanome, ketal. In the fore-
going Formula the Y and m variables are as heretofore ---
defined, except that Y cannot be the unprotected hydroxy
nor the alkanoyloxy functionalities.
This process can also be used to prepare the 4-dialkyl-
amino-4-hydroxy-substitutedphenylcyclohexanone ketals if
the hydroxy function is protected by a protect;ng group,
e.g., tetrahydropyranyl 9 which can be removed under mild
hydrolytic conditions using aqueous acid, e.g., hydrochloric,
acetic, and the like.
The basis for the new synthesis was provided by the
teachings of Hauser, C. R. and D. Lednicer, J. Org. Chem.
249 p. 46 (1959) and Lednicer, D., and J. C. Babcock9 J.
Org. Chem. 27, p. 2541 (1962). These authors showed that
the nitrile group of an a-amino nitrile is displaced by the
organometallic reagent so that a different result obtains
than that taught by Whitmore, Frank C.9 Organic Chemistry,
at pp. 852-854 and p. 416 (published by D. YanNostrand Co.,
Inc., New York, 1951) where a Grignard reagent adds to
nitriles to produce imines. In this new and lmproved
process of this invention9 the phenyl ring attaches directly
to the 4-carbon of the cyclohexanone ring to which same
carbon the amino group is attached.
The indicated reaction takes place when the selected

-17~ ~

llO~'Si6 3286


Grignard reagent is heated dt the reflux temperature ;n an
organic solvent medium ;n the presence of a 4-amino-4-cyano-
cyclohexanone, ketal. A suitable organic solvent medium
is tetrahydrofuran, and it is preferable that it be anhy-
drous. Prolonged heating might be necessary; thosenitr;le displacements already successfully completed have
required from 18 hours to three days. In most cases, 15
to 24 hours would appear to be adequate reaction time.
The desired 4-dialkylamino-4-phenylcyclohexanone,
ketals are recovered in the usual way by decomposition of
the reaction mixture with aqueous ammonium chloride. The
, organic layer is recovered and further purification tech-
niques are applied such as solvent evaporation, washing,
drying, chromatography, and recrystallization.
- 15 The 4-dialkylamino-4-cyanocyclohexanone, ketal ante-
cedent compounds are obtained from 4-oxocyclohexanone,
monoketals by reaction with an alkali metal cyanide, e.g.,
potassium cyanide, and an amine acid addition salt as
- described. This reaction proceeds readily and no heating
is required. Room temperatures with stirring are suitable.
Recovery-purification methods are conventional.
The 4-oxocyclohexanone, monoketals are prepared by
methods known in the art, e.g., as described by M.
Haslanger and R. G. Lawton, Synthetic Commun., 4, 155 ;
(1974).
The foregoing improved method of synthesis provides
shorter synthesis to some compounds of the invention. Illus-
tratively the 4-tmeta-hydroxyphenyl)-4-dimethylaminocyclo-
hexanone, and 4-tm-hYd~oxY)-4-tn-butylmethylamino)cyclo-
hexanone ketal compounds of the invention have been prepared

- 1 8 -

' 3286
516
'
and found to possess unexpected narcotic antagonist
activity and, advantageously, low to moderate physical
dependence liability as well as the analgesic activity
observed w;th other compounds of the invention. It
s provides access to many compounds that would otherwise
require the complicated and time-consuming multiple reac-
~ion steps of the original synthesis.
j Preparation A p-tert-Butylphenylacetonitrile
A solution consisting of 4 ml. thionyl chloride and
1~ 10 ml. benzene is added to a solution consisting of 10.0 gm.
(0.061 mole) p-tert-butylbenzyl alcohol and 85 ml. benzene.
The reaction m-ixture is st;rred at 25 C. for 30 min. and
then heated at the reflux temperature for 4 hours. After
cooling, the benzene is removed by evaporation under
lS reduced pressure. The residue thus obtained is distilled
at 0.05 mm Hg. pressure, and 10.14 gm. (92% yield) of
benzyl chloride having a boiling range of 62 to 65 C.
is obtained. ~ -
Some 9.64 gm. (0.053 mole3 of this benzyl chloride
is mixed with 10.13 gm. potassium cyanide, 0.10 gm.
potassium iodide in 75 ml. water, and 150 ml. methanol and
heated at the reflux temperature for one (1) hour. After
removing the bulk of the methanol by evaporation under
reduced pressure, the residue thus obtained is extracted
with diethyl ether and the resulting ether solution is
washed first with water and then with brine. The washed,
ether solution is then concentrated by evaporation of the
ether, and the oil tilUS obtained is distilled at 0.03 mm
pressure. There is thus obtained 6.38 gm. (70X yield) of
p-tert-butylphenylacetonitrile having a boiling range

~ 1 9


, , . I

3286
516
.

between 79 and 84 C.
Analysis:
Calc'd. for C32H,sN:
C, 83.19; H, 8.73; N, 8.09.
Found: C, 82.56; H, 8.68; N, 7.34.
Example 1 Preparation of 4-(p-chlorophenyl)-4-dlmethyl-
aminocyclohexanone, ethylene ketal free base
and the hydrochloride thereof.
Part A Preparation of precursor9 the Dimethyl diester
of 4-(p-chlorophenyl)-4-cyanopimelic acid
A mixture consisting of 25.0 gm. (0.165 mole) p-chloro-
phenylacetonitrile9 77 ml. methyl acrylate, and 80 ml.
tert-butyl alcohol is heated to the reflux temperature. The
source of heat is removed, and a mixture consisting of 25
ml. of 40 percent methanolic tetramethylammonium hydroxide
(Triton B~) and 37 ml. tert-butyl alcoho1 is quickly added.
Heating at the reflux temperature is resumed and continued
for four (4) hours. The reaction mixture is allowed to
cool, and is then diluted with 300 ml. water and 100 ml.
benzene. The organic solvent and aqueous phases that form
are separated and the aqueous phase is discarded. The
organic phase is washed successively with 2.5 N hydrochloric
acid, water, and finally with brine. (The washed solution
is then dried over Na2S04)O The organic solvent is removed
by evaporation under reduced pressure5 and the residue thus
obtained is distilled under reduced pressure. The initial
pressure is 40 mm mercury at which pressure any remaining
methyl acrylate or other volatile components are eliminated.
The final pressure is 0.35 mm mercury9 and 38.06 gm. (71.4
yield) of the dimethyl ester of 4-(p~chlorophenyl)-4-cyano-

.
'20- .

,

3286
~L10~5:16

pimelic acid ~s obtained as an oil. The compoun~ has a
boiling point at 186 to 191 C.
Part B Preparation of f;rst intermediate, 2-Carbo-
methoxy-4-(p-chlorophenyl)-4-cyanocyclohex-
anone
A reaction mixture consisting of 34.97 gm. (0.108 mole)
dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimel lC acid,
(prepared in Part A, above), dissolved in 700 ml~ tetra-
hydrofuran with 24.4 gm. (0.218 mole) potassium tert-
butoxide added is heated at the reflux temperat~re for
4~ hours. After cooling, the reaction mixture is chilled
in an ice-bath and 175 ml. 2.5 N acetic acid is added. The
organic and aqueous phases separate and the organic phase
is recovered. It is diluted with 600 ml. benzene before
being washed successively with aqueous sodium bicarbonate,
water, and brine. The organic solvents are then removed
~y distillation under reduced pressure. There is thus
obtained 30.2 gm. (96% yiel~) of 2-carbomethoxy-4-(p-chloro-
phenyl)-4-cyanocyclohexanone havin~ a melting p~int at
1~9 to 143 C.
Analysis:
Calc'd. for Cl sHl 4Cl NO3:
C, 61.75; Hs 4.84; N, 4.80.
Found: C, 61.65; H9 5.02; Ng 4.850
Part C Preparation of second intermediate 4-(p-Chloro-
- ` phenyl)-4-cyanocyclohexanone
A reaction mixture consisting of 29.8 gm. (0.102 mole)
of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone
(prepared in Part B, aboYe), 660 ml. glacial acetic acid,
and 330 ml. lOX aqueous sulfuric acid is heated on 2 steam

-21-

3286
516

bath at about 100 C. for 24 hours. The m;xture is stirred
continuously. After cooling, the mixture is diluted with
1300 ml. water, and extracted-with benzene. The benzene
- phase is recovered and washed successively with water, with
aqueous sodium bicarbonate, and with brine. The benzene
is then removed by evaporation under reduced pressure to
give a solid residue. The solid residue is recrystallized
from diethyl ether to give 12.13 gm. (82% yield) of
4-(p-chlorophenyl)-4-cyanocyclohexanone having a melting
point at 94.5 to 97 C.
Analysis:
Calc'd. for C,3Hl2ClN0:
C, 66.81; H, 5.18; N, 5.99.
Found: C, 67.03; H, 5.16; N, 5.95.
Part D Preparation of third intermediate, 4-(p-chloro-
phenyl)-4-cyanocyclohexanoneg ethylene ketal
A reaction mixture consisting of 19.49 gm. (0.084
mole) of 4-(p-chlorophenyl)-4-cyanocyclohexanone (prepared
in Part C, above), 4.8 ml. (5.33 gm.) (0.086 mole) ethylene
glycol, 0.21 gm. (1.1 mmole) p-toluenesulfonic acid, and
150 ml. benzene is heated at the reflux temperature in a
reaction vessel equipped with a Dean and Stark trap for
six (6) hours. The reaction solution is then allowed to
cool before washing it successively with aqueous sodium
bicarbonate, with water, and with brine. The washed solu-
tion is then taken to dryness by evaporation of the benzene.
The solid residue thus obtained is crystallized from
cyc1Ohexane to give 21.87 gm. (79% yield) of 4-(p-chloro-
phenyl)-4-cyanocyclohexanone9 ethylene ketal having a melt-
ing point at 124 to 126.5 C.

-22-


.

~286
S16

...
Analysis: ~
Calc'd. for C,5H, 6Cl N02:
C, 64.86; H, 5.81; N, 5.04.
Found: C, 64.77; H, 5.81i N, 4.92.
S Part E Preparation of fourth intermediate, 4-Carboxy-
4-(p-chlorophenyl)cyclohexanone, ethylene
ketal
A reaction mixture consisting of 21.87 gm. (0.079
mole) 4-(p-chlorophenyl)-4-cyanocyclohexanone, ethylene
ketal (prepared in Part D, above), 22.0 gm. (0.39 mole)
potassium hydroxide and 220 ml. ethylene glycol is heated
at the reflux temperature for 16 hours. After cooling and
diluting with water, the solutin is chilled in an ice-bath,
layered with diethyl ether and cautiously acidified with
concentrated hydrochloric acid. The ether layer is recov~
ered and the acidified aqueous solution is extracted two
more times with ether. The ether fractions are combined
and washed with brine before removing the ether by evapor-
ation. The residue thus obtained is recrystallized from
a mixture of methylene chloride and technical hexane to
give 19.26 9~. (82% yield) of 4-carboxy-4-(p-chlorophenyl)-
cyclohexanone, ethylene ketal having a melting point at
162.5 to 164.5 C.
Analysis
Calc'd. for ClsHl7C104:
C, 60.71; H9 5.78; Cl9 11.95.
Found: C, 61.01; ff9 5O77; Cl 9 12.12.
Part F Preparation of fifth intermediate 4-(p-Chloro-
phenyl)-4-isocyanatocyclohexanone, ethylene
~etal

.
-23-

~ S16 3286

To a mixture consisting of 15.79 gm. (0.0532 mole)
4-carboxy-4-(p-chlorophenyl)cyclohexanone, ethylene ketal
(prepared in Part E, above) 7.4 ml. (5.36 gm., 0.0532 mole)
triethylamine, and 135 ml. anisole is added 14.7 gm.
(0.053 mole) diphenylphosphor;c azide. This react;on
mixture is then heated at 90 to 100 C. in an oil bath
for two (2) hours. The volatile components are then
removed by evaporation under reduced pressure, and the
gummy residue thus obtained is chromato~raphed on a
1500 ml. column o~ silica gel. The column is eluted with
a mixture of ethyl-acetate and technical hexanes (in pro-
portion of 1:9) and 400-ml. fractions are collected. After
combining fractions 14 through 29 and removing the solvents
by evaporation under red~ced pressure, there is obtained
7.75 gm. of crude product. Recrystallization from petroleum
ether g;ves 6.72 gm. (43% yield) of 4-(p-chlorophenyl)-
4-isocyanatocyclohexanone, ethylene ketal having a melting
point at 76.5 to sn C .
Analysis:
Calc'd. for ClsHl6ClN03:
C, 61.33; H, 5.49; N, 4.77.
Found: C, 61.44; H9 5.50; N, 4.59.
Part G Preparation of sixth intermediate, 4-(p-Chloro-
phenyl)-4-methylaminocyclohexanonel ethylene
ketal
A solution consisting of 6.62 gm. (0.0226 mole)
4-(p-chlorophenyl)-4-isocyanatocyclohexanone, ethylene
ketal (prepared in Part F, above) in 50 ml. tetrahydrofuran
is mixed with a suspenslon of 1029 gmO ~0.045 mole)
l~thium aluminum hydride in 20 mlO tetrahydrofuran and the

-24-

3286
llQ~516

resulting reaction mixture is heated at the reflux temper-
ature for four (4) ho~rs. After cooling, followed by
chilling in an ice bath, 1.3 ml. water, 1.3 ml. 15% sodium
hydroxide, and finally another 3.9 ml. water are added
successively. A gelatinous precipitate forms which is
collected on a filter. The filtrate is saved, and the
volatile components are removed by evaporation under reduced
pressure. The residue thus obtained is recrystallized
from petroleum ether to give 5.78 gm. (91~ yield) of
4-(p-chlorophenyl)-4-methylaminocyclohexanone, ethyléne
ketal that has a melting point at 63.5 to 66.5 C.
Analysis:
Calc'd. for ClsH20ClN02:
C, 63.93; H, 7.15; Ng 4.97.
Found: ~, 64.14; H, 7.32; N, 5.15.
Part H Preparation of object compound, 4-(p-Chloro-
phenyl)-4-dimethylaminocyclohexanone, ethylene
ketal free base and the Hydrochloride thereof
A reaction solution consisting of 5.68 gm. (0.0201 mole)
4-(p-chlorophenyl)-4-methylaminocyclohexanone, ethylene
ketal (prepared in Part G, above), 22 ml. 37 percent
forma1in (aqueous formaldehyde), and 75 ml. methanol is
heated at the reflux temperature for four (4) hours, after
which heating the solution is allowed to cool and then
chi11ed in an ice-bath. Small portions of sodium borohy-
dride are cautiously added with stirring to a total of
2.89 gm. (0.076 mole). Stirring is continued for two (2)
hours at 25 C. when the solution is concentrated by
removing most of the solvent under reduced pressure. The
concentrate is diluted with a mixture of 100 ml. ~ethylene

-25-

. I . .

' ' 3286
S16

' chloride and 20 ml, water. The aqueous phase that
separates is discarded, and the organic phase is washed
successively with water and then with brine. The methylene
-~ ' chloride solvent is then removed by evaporation under'
'5 reduced pressure. The 'residue thus obtained is dissolved
in the formalin and methanol as initially, heat'ed at the
reflux temperature, cooled in an ice bath, and treated
again with the sodium borohydride as previously. Following
the same work-up as described, the crude 4-(p-chlorophenyl)-
4-dimethylaminocyclohexanone, ethylene ketal free base
obtained following the removal of the methylene chloride
is dissolved in a small amount of diethyl ether, and the
ether solution is treated with 3 N hydrogen chloride in
ether. A precipitate forms which is recrystallized from
methylene chloride and ethyl acetate to give 3.96 gm.
~59% yield) of object compound 4-(p-chlorophenyl)-4-di-
methylaminocyclohexanone9 ethylene ketal hydrochloride
having a melting point at 261 to 262 C. (with decompo-
sition).
' Analysis:
Calc'd. for Cl6H23C12N02:
C, 57.83, H, 6.98; N, 4.27.
Found: C, 58.10; H9 7.01; N9 4.41.
Example 2 Preparation of an object compound 4-(p-Chloro-
phenyl)-4-dimethylaminocyclohexanone
A reaction solutio'n consisting of 4.52 gm. (0.0136
mole) of 4-(p-chlorophenyl)-4-dimethylam;nocyclohexanone,
ethylene ketal-hydrochloride (prepared in Example 1, Part
H~ above~, 22.5 ml. 2.5 N hydrochloric acid, and 45 ml.
methanol is set aside at 25 CO for 48 hours. The methanol

. -~6~

3286
516

medium is substantially removed by evaporation under
reduced pressure to give a concentrate that is made
strongly basic by additions of 50% aqueous sodium hydroxide.
A precipitate forms which is collected on a filter and
dissolved in diethyl ether. This ether solution is washed
with brine to remove the residual water and the ether is
then removed by evaporation under reduced pressure. The
residue thus obtained is recrystallized from diethyl
ether to give 2.30 gm. (70% yield) of 4-(p-chlorophenyl)-
4-dimethylaminocyclohexanone having a melting point at
108 to 111 C.
Analysis:
Calc'd. for Cl4HlaClN0:
C, 66.79; H, 7.21; N9 5.57.
Found: C, 67.10; H, 7.36; N, 5.42.
Example 3 Preparation of 4-(p-Fluorophenyl)-4-dimethyl-
aminocyclohexanone, ethylene ketal free base
Pa~t A Preparation of precursor, the Dimethyl
diester of 4-cyano-4-(p-fluorophenyl)p;melic
acid
A reaction mixture consisting of 25.0 gm. (0.185 mole)
of p-fluorophenyl acetonitrile, 86 ml. methyl acrylate,
and 90 ml. tert-butyl alcohol is heated to the reflux
temperature. The source of heat is then removed and a
mixture consisting of 28.1 ml. of 40% methanolic tetra-
~ethylammonium hydroxide (Tribon B~) and 43 ml. tert-butyl
alcohol is quickly added. Heating at the reflux temperature
is resumed and continued for four (4) hours. The reaction
m~xture is allowed to cool and is then diluted with a mix-
ture of 300 ml. water and lOn mlO benzene. When the organic

-27-

3286
~ ~lQ~i'S16
,

.
aqueous phases forms, the aqueous phase is discarded and
the organic (benzene) phase is saved. It is washed
successively with 2.5 N hydrochloric acid, water, and
finally with brine. The benzene is then removed by evapor-
ation under reduced pressure, and the residue thus
obtained is distilled under reduced pressure in order to
removed any low-boiling by-products. The initial pressure
~s at 40 ~m mercury, and the final pressure is at 0.25 mm
mercury. There is thus obtained 50.99 gm. (72% yield) of
10 the dimethyl ester of 4-cyano-4-(p-fluorophenyl)pimelic
acid as an oil. Its boiling point is 179 to 181 C.
Part B Preparation of first intermediate, 2-carbo-
methoxy-4-cyano-4-(p-fluorophenyl)cyclohex-
anone
To a solution consisting of 42.71 gm. (0.139 mole) of
the dimethyl ester of 4-(p-fluorophenyl)-4-cyanopimelic
acid (prepared in Part A, above) and 900 ml. tetrahydrofuran
is added 31.3 gm. (0.28 mole) potassium tert butoxide. This
reaction mixture is heated at the reflux temperature for
four and one half (4~2) hours. It is allowed to cool. It
-is then chilled in ice and 225 ml. of 2.5 N aqueous acetic
acid is added. The organic layer that forms is recovered
and diluted with 750 ml. benzene. The benzene:tetrahydro-
furan solution is washed successively with sodium bicarbonate,
with water, and finally with brine. The solvents are then
removed by evaporation under reduced pressure to give 35.6
gm. (93X yield) of 2-carbomethoxy-4-cyano~4-(p-fluorophenyl)-
cyclohexanone as a gum.
- Part C Preparation of second intermediate, 4-Cyano-
4-(p-fluorophenyl)cycl~hexanone

-28-

~ 5 ~6 3286

,

A reaction mixture consi sti ng of 33~9 gm, ~0.l23 mole)
of 2-carbomethoxy-4-cyano-4-(p-fluorophenyl)cyclohexanone
(prepared ~n Part B, above), 900 ml. glac~al acetic acid,
and 450 ml. lO~ aqueous sulfuric acid is heated with
5 stirring on a steam bath for twenty-four ~24) hours. After
allowing the react;on mixture to cool, it is diiuted with
2000 ml. water and extracted thoroughly with benzene.
The benzene extracts are combined and washed successively
with water, with aqueous sodium bicarbonate, and finally
with brine. The benzene is then removed by evaporation
under reduced pressure, and the solid residue thus obtained
is recrystalli~ed from diethyl ether to afford 16.23 gm.
(67% yield) of 4-cyano-4-(p-fluorophenyl)cyclohexanone
having a melting point at 84 to 88 C.
Analysis:
Calc'd. for Cl3Hl2FN0:
C, 71.87; H, 5.57; N, 6.45.
Found: C, 71.64; H, 5.65; N, 6.30.
Part D Preparation of third intermediate, 4-Cyano-
4-(p-fluorophenyl)cyclohexanone, ethylene
ketal
A reaction mixture consisting of 16.23 gm. (0.075 mole)
of 4-cyano-4-(p-fluorophenyl)cyclohexanone (prepared in
Part C, abo~e), 6 ml. ethylene glycol, 0.6 gm. p-toluene-
; 25 sulfonic acid, and 250 ml. benzene is heated at the reflux
temperature in a reaction vessel fitted with a Dean and
Stark trap for six (6) hours. The reaction solution is
allowed to cool and then is washed successively with
~queous sodium bicarbonate, with water9 and finally with
brlne. The benzene and volatile components are then re-

5 1 6 3286


moyed by evaporation under reduced pressure and the solid
residue thus obtalned ~s recrystallized from technical
hexanes to give 18.17 gm. (94% yield) of 4-cyano-4-(p-fluoro-
phenyl)cyclohexanone9 ethylene ketal havlng a melting point
at 9l~ to 93.5~ C.
Analysis-

.




Calc'd. for ClsHl6FN02
C, 68.95; H, 6.17; N, 5.36.
Found: C, 68.4l; H-, 6.05; N, 5.35.
Part E Preparation of fourth intermediate, 4-Carboxy-
4-(p-fluorophenyl)cyctohexanone, ethylene
ketal
A reaction mixture consisting of 18.17 gm. (0.070 mole~
of 4-cyano-4-(p-fluorophenyl)cyclohexanone, ethylene
ketal (prepared in Part D, above), l5.0 gm. (0.38 mole)
sodium hydroxide, and 150 mlO ethylene glycol is heated
at the reflux temperature for about sixteen (16) hours
before it is allowed to cool, and is then diluted with
water. The aqueous solution is then chilled in an ice-
bath and layered with diethyl ether. The aqueous phase
is cautiously acidified with concentrated hydrochloric
acid. The ether layer is separated, and the aqueous
layer is extracted two times with diethyl ether. The
original ether layer and ether extracts are combined,
washed once with brine, and the ether is removed by
evaporation under reduced pressure. There is thus obtained
18.2 gm. (93% yield) of 4-carboxy-4-(p fluorophenyl)-
cyclohexanone, ethylene ketal as a solid that cannot be
recrystallized satisfa'ctorily (melting range ll7 to l22 C.).
Part F Preparation of f~fth inter~ed~ate, 4-(p-fluoro-

' -30-

.

.

1 ~U ~ S l6 3286


phenyl)-4~;socyanatocyclohexanone, ethylene
ketal
To a suspension consisting of 24 5 gm. (0.0875 mole)
of 4~c~rboxy-4-~p^fluorophenyl)cyclohexanone, ethylene
ketal (prepared in Part E, above~, 12.1 ml~ (8.8 gm.,
0.087 mole) of triethylamine~ and 220 ml. anisole there
is added 24.1 gm. diphenylphosphonic azide. Th~s reaction
mixture is then heated at 90 to 100 CO with stirring in
an oil bath for two ~2) hours. The reaction medium and
other Yolatile components are remoYed by evaporation under
reduced pressure. The gummy residue thus obtained is
chromatographed on a 1000 mlO column of silica gel. Elu-
tion was effected with a solvent system consisting of 1
percent ethyl acetate in methylene chloride.
The appropriate fractions are combined, and the
solvents.are removed by evaporation under reduced pressure
to give 8.49 gm. of 4-(p-fluorophenyl)-4-isocyanatocyclo-
hexanone, ethylene ketal that has the qualities of a gumf
Part G Preparation of sixth intermediate, 4-(p-fluoro-
20 - phenyl)-4 methylaminocyclohexanone, ethylene
ketal free base and hydrochloride thereof
A solution consisting of 10.11 gm. ~0.0365 mole) of
4-(p-fluorophenyl)-4-isocyanatocyclohexanone, ethylene
ketal (prepared in Part F9 above) and 80 ml. tetrahydro-
furan is added to a suspension consisting of 2.08 gm.
~0.055 mole? l~thium alum~num hydride and 30 ml. tetra-
hydrofuran, and this reactlon mixture is heated at the
reflux temperature wlth st~rring ~or four (4) hours. The
~ixture is allowed to cool, and ~s then chilled in an ice
bath. To the chilled mixture ~s added in sequence: 2.1 mlO

3286
`51~

water, 2.1 ml. 15% aqueous sodium hydroxlde, and another
6.3 ml~ water. A gelatinous material is obtained that is
removed by f~ltration. The fi1trate is recovered and
evaporated to dryness. The residue thus obtained is
d~ssolved in a small amount of diethyl ether and enough
3 N hydrogen chloride in diethyl ether is added to precipi-
tate all of the amine free base as the hydrochloride acid
addition salt. The precipitate is collected on a filter
and recrystallized from a mixture of methylene chloride
and ethyl acetate to giYe 9.34 gm. (56% yield) of 4-(p-
fluorophenyl)-4-methylaminocyclohexanone~ ethylene ketal
hydrochloride having a melting point at 262.5 to 263.5 C.
(with decomposition).
Analysis:
Calc'd. for C,5H2,ClFN02:
C, 59.69; H, 7.01; N, 4.64.
Found: C, 59.27; H, 7.21; N9 4.60.
Part H Preparation of object compound, 4(p-Fluoro-
phenyl)-4-dimethylaminocyclohexanone, ethylene
ketal free base
A solution consisting of the free base from 9.24 gm.
(0.0307 mole) of 4-(p-fluorophenyl~-4-methylaminocyclo-
hexanone, ethylene ketal hydrochloride (prepared in Part G,
above), 33 ml. of 37% formalin, and 110 ml. methanol is
heated at the reflux temperature for four (4) hours. The
m~xture is allowed to cool before chilling in an ice-bath
~nd slowly adding small portions of sodium borohydride until
a total of 4.4 gm. (0~115 mole) has been added. Stirring
~s cont~nued for two ~2~ hours at about 25 C. A substan-
tlal part of the volatile liquld components9 i.e., solvents

-32-

3 2~6


1s removed by evaporatlon under reduced pressure~ and
the concentrate thus obtained is d~luted with 200 ml.
methylene chloride and 50 mt. water. ~hen the organic
and aqueous phases have stabi1ized9 the organic phase is
recovered, washed with water and washed with brine. After
removing the methylene chloride solvent9 the residue thus
obtained is again reacted with sodium borohydride and
worked up as described immediately above. This time the
residue from removal of the methylene chloride solvent is
recrystallized from petroleum ether to give 7.29 gm. (89%
y~eld) of 4-(p-fluorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal having a melting point at 79.5 to 82 C.
Analysis:
Salc'd. for Cl6H22FN02:
~, 68.79; H, 7.94; N, 5.02.
Found: C, 69.16; H, 7.70; N, 4.91.
Example 4 Preparation of an object compound of 4-(p-Fluoro-
phenyl)-4-dimethylaminocyclohexanone
A solution consiting of 6.29 gm. (0.0226 mole) of
4-(p-fluorophenyl~-4-dimethylaminocyclohexanone, ethylene
ketal (prepared in Example 3, Part H), 32 ml. of 2.5 N
hydrochloric acid, and 64 ml. methanol is set aside at
25 C. for 48 hours. A substantial part of the methanol
is then removed by evaporation under reduced pressure,
and the concentrate is made strongly basic with 50% sodium
hydrox~de. A precipitate for~s which is collected on a
fllter and dissolved in diethyl ether. The ether solution
1s washed with water and f1nally with brine before removing
the ether by evaporation under reduced pressure. The
res1due thus obtain~d 1s recrystaltized from diethyl ether

o33 -

3286
11136~S16

to g~ve 3.97 gm. (75% yield) of 4-(p-fluorophenyl)-
4-d1methy1aminocyclohexanone having a melt~ng polnt at
~26 to 128 C.
Analysis:
Calc'd. for C~4HI~FNO:
C, 71.46; H, 7.71; N9 5.95.
Found: C, 71.45; H, 7.86; N, 5.83.
Example 5 Preparation ~f 4-(3,4-dimethoxyphenyl)-4-di-
methylaminocyclohexanone, ethylene ketal free
base
Part A Preparation of precursor, the dimethyl ester
of 4-cyano-4-(3,4-dimethoxyphenyl)pimelic
aoid
Following the procedure of Example l, Part A, but
substituting 25.0 gm. (0.141 mole) 3,4-dimethoxyphenyl
acetonitrile, 66 ml. methyl acrylateg and 70 ml. tert-
butyl alcohol for the 25.0 gm. p-chlorophenyl acetonitrile,
the 77 ml. methyl acrylate, and the 80 ml. kert-butyl
alcohol, using 21.5 ml. of the 40% methanolic tetramethyl-
ammonium hydroxide, and 32 ml. of the tert-butyl alcohol,
and final distillation at 0.20 mm pressure, there-is
prepared 32.22 gm. (65% yield) of the dimethyl ester of
4-cyano-4-(3,4-dimethoxyphenyl)pimelic acid as an oil
having a boiling range of 210 to 214 C.
Part B Preparation of first intermediate, 2-Carbo-
methoxy-4-cyano-4-(394-dimethoxyphenyl)-
cyclohexanone
Followlng the procedure o~ Example l, Part B, but
substitutlng 34.25 gm. (00098 mole) of the dimethyl
ester of 4-cyano-4-(3,4-d~methoxypheny7)pimel~c acid (pre-
.




~34~

328~
~la~1s~6
-




pdred in Part A, above) for the dimethyl ester of 4~(p-
- chlorophenyl)-4-cyanopimellc acld and using 640 ml. of the
tetrahydrofuran, 22.0 gm. (0.196 mole) of the potasslum
tert-butoxide and 155 ml. of the 2.5 N of the aqueous
acetic acid instead of the 700 ml. the 24.4 gm. (0.218
mole), and the 175 ml. respectively, there is prepared
29.2 gm. (94% yield) of 2-carbomethoxy-4-cyano-4-(3,4-di-
methoxyphenyl)cyclohexanone as crystals having a melting
ran~e of 110 to 113 C. An analytical sample recrystal-
lized from a mixture of ethyl acetate and cyclohexane
melts in the range of 112.5 to 114.5 C.
Analysis:
Calc'd. for ClsHl7N03:
C, 69.48; H9 6.61; N, 5.40.
Found: C, 69.73; H, 6.64; N, 5.16.
Part C Preparation of second intermediate, 4-Cyano-
4-(3,4-dimethoxyphenyl)cyclohexanone
Following the same procedure described in Example 1,
Part C, but substituting 29.0 gm. (0.0915 mole) of 2-carbo-
methoxy-4-~3,4-dimethoxyphenyl)-4-cyanocyclohexanone
(prepared in Part B, above) for the 29.8 gm. of 2-carbo-
methoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using
600 ml. acetic acid and 300 ml. 10 percent aqueous sulfuric
acid instead of the 660 ml. and 330 mlO 9 respectively~
Z5 heat~ng on the steam bath for 48 hours instead of 24
hours, and recrystallizing from a mixture of ethyl acetate
and hexane inste~d of diethyl etherp there is obtained
16.83 gm. (67% yield) of the desired 4~cyano-4-(3,4-di-
methoxyphenyl)cyclohexanone which has a melting point at
112.5~ to 114.5 C.

-35-

3286
~ 5 16

Analysis:
Calc'd. for Cl5HI7NO3:
C~ 69.48; H, 6.61; N, 5.40.
Found: C, 69.73, H, 6.64; N, 5 16.
Part D Preparation of third intermediate, 4-Cyano-
(3,4-dimethoxyphenyl)cyclohexanone, ethylene
ketal
Following the procedure of Example 1, Part D9 but
substituting 15.96 gm. (0.0616 mole) of 4-cyano-4-(3,4-di-
methoxyphenyl)cyc10hexanone (prepared in Part C, above)
for the 19.49 gm. of 4-(p-chlorophenyl)-4-cyanocyclohexa-
none; using 3.6 ml. ethylene glycol, 0.16 gm. p-toluene-
sulfonic acid, and 110 ml. benzene instead of the 4.8 ml.g
0.21 gm., and 150 ml., respectively; and recrystallizing
from diethyl ether instead of the cyclohexane there is
obtained 16.85 gm. (90% yield) of 4-cyano-4-(3,4-dimethoxy
phenyl~cyclohexanone, ethylene ketal having a melting
range at 93.5 to 96.5 C.
Analysis:
Calc'd. for C,7H2lN04:
C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.29; H, 7.019 N5 4.44.
Part E Prepar~tion of fourth intermediate9 4-Carboxy-
4-~3,4-dimethoxyphenyl)cyclohexanone, ethylene
ketal
Following the procedure of Example 1, Part E, but
subst~tuting 17.54 gm. (0.058 mole) of 4-cyano-4-(3,4-di-
methoxyphenyl)cyclohexanone9 ethylene ketal (prepared in
P~rt D, above) for the 21.87 gmO o~ 4-(p-chlorophenyl)-
4-cyanocyclohexanone9 ethylene ketal; and using 17.5 gm.

36
1. ,

~18@S1~ 3286
,

(0.31 mole) potassium hydrox~de and 175 ml. ethylene
glycol instead of the 22.0 gm. and 220 ml., respectively;
there is obtained, after removal of the ether, 19.0 gm.
(~9% yield) of 4-carboxy~4-(3,4-dimethoxyphenyl)cyclohex-
anone, ethylene ketal as a gum that gives a reasonably
expected infrared spectrum.
Part F Preparation of fifth intermediate, 4-Iso-
cyanato-4-(3,4-dimethoxyphenyl)cyclohexanone,
ethylene ketal
Following the procedure of Example 1, Part F, but
substituting 22.9 gm. ~0.0710 mole) of 4-carboxy-4-(3~4-di-
methoxyphenyl)cyclohexanone, ethylene ketal (prepared in
Part E, above) for the 15.79 gm. of 4-carboxy-4-(p-chloro-
phenyl)cyclohexanone, ethylene ketal, and us;ng 10.0 ml.
(7.26 gm., 0.073 mole) ~riethylam;ne, 215 ml. anisole, and
19.7 gm. d;phenylphosphon;c az;de instead of the 7.4 ml.,
the 135 ml., and the 14.7 gm. 9 respect;Yely~ there is
obtained after chromatographing on a 2000 ml. column of
silica gel and elution w;th 30 percent ethyl acetate in
technical hexane 6.44 gm. (28~ y;eld) of 4-isocyanato-
4-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal as
a waxy sol;d.
Part G Preparation of sixth ;ntermediate, 4-(3,4-Di-
methoxyphenyl)-4-methylaminocyclohexanone,
ethylene ketal hydroiodide
Following the procedure of Example 1 D Part G, but
substituting 6.44 gm. (0.020 mole) of 4-isocyanato-
4-(394-d1methoxyphenyl)cyclohexanone, ethylene ketal
(prepared ln Part F, above) for the 6.62 gm. of 4-~p-chloro-
phenyl)-4-isocyanatocyclohexanone9 uslng 95 ml. tetrahydro-


~ ~37-

3286
S16

furan and a suspension of 1.16 gm. (0.031 mole) lithlum
alum~num hydr~de ~n 11 ml. tetrahydrofuran lnstead Of the
50 ml., the 1.29 gm., and 20 ml., respectively, and add;ng
1.2 ml. water, 1.2 ml. of 15 percent sodium hydroxide, and
3.6 ml. water instead of the 1.3 mlO 9 1.3 ml., and 3.9 ml.,
respectively, there is obtained a residue from the filtrate
that is chromatographed on a 600 ml. column of silica gel
using ammonium hydroxide (NH40H)-saturated methylene chlo-
ride as solvent. After collecting and combining the
appropriate fractlons and removing the solvent by evapor-
ation under reduced pressure, the residue is dissolved
in methylene chloride. This solution is acidified with
10% aqueous hydriodic acid and the solvents are removed
by evaporation under reduced pressure. There is thus
obtained after recrystallization from a mixture of methylene
chloride and diethyl ether 5.0 gm. (57% yield) of 4-~3,4-
dimethoxyphenyl)-4-methylaminocyclohexanone, ethylene
ketal hydroiod;de having a melting point at 200.5 to
201.5 C.
Analysis:
Calc'd. for C " H26IN04:
C, 46.90; H, 6.02; N, 3.22.
Found: C, 46.82; H, 6.06; N, 3.27.
Part H Preparation of object compound, 4-(3,4-di-
methoxyphenyl)-4-dimethylaminocyclohexanone,
ethylene ketal
Following the procedure of Example 1, Part H, but
substituting the free base from 5.0 gm~ (0.0155 mole) of
4-(3,4-d1methoxyphenyl)-4-methylaminocyclohexanone, ethylene
3Q keta1 hydroiod~de (prepared in Part G9 above) for the

~38-

3 286
ll~f~S~6

5.68 gm. of 4-(p-chlorophenyl)-4-methylaminocyclohexanone,
ethylene ketal, us~ng 12.5 ml~ 37 percent formal~n and
43 ml. methanol ~nstead of the 22 mlO and 75 ml.,
respectiYely, and using 1.65 gm. (0.043 mole) sodium
S DOronydride instead of the 2.89 gm. there was obtained
the desired free base which is recrystal1i~ed as such from
technical hexane to give 3.40 gm. (92% yield) of 4-(3,4-
dimethoxyphenyl~-4-dimethylaminocyclohexanone, ethylene
ketal which has a melting range at 95 to 98.5 C.
Analysis:
Calc'd. for Cl 8 H2 7 NO4:
C, 67.26; H, 8.47; N, 4.36.
Found: C, 67.42; H, 8.65; N, 4.34.
Example 6 Preparation of an object compound, 4-(3,4-Di-
methoxyphenyl)-4-dimethylaminocyclohexanone
free base
Following the procedure of xample 2, but substituting
2.4 gm. (0.0075 mole) of 4 (3,4-dimethoxyphenyl)-4-dimethyl-
aminocyclohexanone, ethylene ketal free base (prepared in
Example 5, Part H, above) for the 4-(p-chlorophenyl)-
4-dimethylaminocyclohexanone, ethylene ketal hydrochloride,
12 ml. o~ 2.5 N hydrochloric acid for the 22.5 ml., and
24 ml. methanol for the 45 ml., there is prepared 1.48 gm.
~71% yield) of 4-(3,4-dimethoxyphenyl~-4-dimethylamino-
cyclohexanone as the free base, having a melting point
at 57 to 98.5 C.
Analysis.
Calc'd. for Cl6H23NO3:
C, 69.28; H, 8.36; N~ S.U50
~0 Found: C, 69.14; H, 8.44~ N~ 5.070

-39

~llC~; 32~6

Exam~Le 7 Preparati~n of 4-(p-Anisyl)-4-dimethylam~no-
cyclohexanone, ethylene ketal free base and
hydrochlorlde thereof
Part A Preparation of precursorS the dimethyl ester
of 4-cyano-4-(p-anisyl)pimelic acid
Following the procedure of Example 1, Part A5 but
substltuting 36.75 gm. (0.25 mole) p-anisyl acetonitrile,
116 ml. methyl acrylate, and 120 ml. tert-butyl alcohol
for the 25.0 gm. p-chlorophenyl acetonitrile, the 77 ml.
methyl acrylate, and the 80 ml. tert-buty1 alcohol, and
using 38 ml. of the 40% methanolic tetramethylammonium
hydroxide and 56 ml. tert-butyl alcohol 9 followed by final
distillation at 0.6 mm pressure, there is prepared 55.90 gm.
(70% yield) of the dimethyl ester of 4-cyano-4-(p-anisyl)-
pimelic ac;d as an oil having a boiling range of 205
to 210 C.
Part B Preparation of first intermediate, 2-Carbo-
methoxy-4-cyano-4-(p-anisyl)cyclohexanone
Following the procedure of Example 1, Part B9 but
substitutlng 53.94 gm. (0.169 mole) of the di~ethyl ester
of 4-cyano-4-(p-anisyl)pimelic acid (prepared in Part A,
above~ for the dimethyl ester of 4-(p-chlorophenyl)-4-cyano-
pimelic acid and using 1100 mlO of the tetrahydrofuran,
38.0 ml. (0.34 mole) of the potasslum tert-butoxide, and
270 ml. of the 2.5 N hydrochloric acid instead of the 700
ml., the 24.4 gm. (Q.218 mole)D and the 175 ml., respect-
~vely, there is prepared 46.2 gm. (95% yield) of 2-carbo-
methoxy-4-cyano~4-(p-anisyl )cyclohexanone as a gum.
Part C Preparation of second intermediate, 4-Cyano-
4- ~p-ani syl )cycl ohexanone

-40-

32~6


Following the procedure of Example 1, Part C, but
subst~tuting 41.5 gm. (0.145 mole) of 2-carbomethoxy-
4-cyano-4-(p-methoxyphenyl)cyclohexanone ~same as 2-carbo-
methoxy-4-cyano-4-~p-anisyl)cyclohexanone] (prepared in
Part B, aboYe) for the 29.8 gm. of 2-carbomethoxy-4-(p-
chlorophenyl)-4-cyanocyclohexanone, using 940 ml. glacial
acetic acid and 470 ml. 10 percent aqueous sulfuric ac;d
instead of the 660 ml. and 330 ml. respectively, and heat-
ing for 48 hours instead of 24 hours there is obtained
23.6 gm. (71% yield) of the expected 4-cyano-4-(p-anisyl)-
cyclohexanone which compound has a melting range at 84
to 86.5 C. ~n analytical sample recrystallized from
diethyl ether has a melting range at 77.5 to 79.5 C.
Analysis:
Calc'd. for Cl4HlsN02:
C, 73.34; Hg 6.59; N, 6.11O
Found: C, 73.21; H9 6.65; N9 6.U0.
Part D Preparation of third intermediate,`4-~yano-
4-(p-anisyl)cyclohexanone, ethylene ketal
Following the procedure of Example 1, Part D9 but
substituting 22.43 gm. (0.098 mole) of 4-cyano-4-~p-anisyl)-
cyclohexanone (prepared in Part C, above) for the 19.49 gm.
of the 4-(p-chlorophenyl)-4-cyanocyclohexanone, and using
5.6 ml. (6.15 gm., 0.099 mole) ethylene glycol, 0.24 gm.
p-toluenesulfonic acid, and 175 mlO benYene instead of
the 4.8 ml., the 0.21 gm., and the 150 ml., respectively,
there ;s obtained a residual solid that upon recrystalliza-
tion from a mixture of methylene chlor~de and technical
hexane instead of from cyclohexane gives 24.66 gm. (93%
yield) of ~he expected ~ntermedtate 4 cyano-4-~p-an~syl3-


-41-

3286
5~6

,
cyclohexanone, ethylene ketal that has a melting range at
101 to 103.5 C.
Analysis:
Calc'd. for Cl6HlgN03: !
C, 70~31; H, 7.01; N, 5.13
Found: C, 70.20; H, 7.01; N, 5.02~
Part E Preparation of fourth intermediate, 4-Carboxy-
4-(p-anisyl)cyclohexanone, ethy1ene ketal
Following the procedure of Example l, Part E, but
substituting 27.98 gm. (0.103 mole) of 4-cyano-4-(p-anisyl)-
cyclohexanone, ethylene ketal (prepared in Part D, above)
for the 21.87 gm. of 4-(p-chlorophenyl)-4-cyanocyclohex-
anone, ethylene ketal, and using 28.0 gm. (0.50 mole)
potassium hydroxide and 280 ml. ethylene glycol instead
of the 22 gm. and 220 ml., respectively, there is obtained
22.35 gm. (83% yi el d ) of 4-carboxy-4-(p-anisyl)cyclohex-
anone, ethylene ketal that has a meltlng point at 154 to
155.5Q C.
Analysis:
Calc'd. for Cl6H200s:
C, 65.74; H, 6.90.
Found: C, 65.42; H, 6.93.
Part F Preparation of fifth intermediate, 4-Iso-
cyanato-4-(p-anisyl)cyclohexanone9 ethylene
~ .ketal
Following the procedure of Example 19 Part F, but
subst1tuting lO.0 gmO (0.034 mole) of 4-carboxy-4-(p-anisyl)-
cyclohexanone, ethylene ketal (prepared in Part E, abo~e)
for the 15.79 gm. of 4-carboxy~4 (p-chlorophenyl)-4-cyano-
cyclohexanone, ethylene ketal~ and using 4.75 ml. (3.46 gm.,

-42~

32~6
11~ `516

0.034 mole) trlethylamine, 100 ml. anisole, and 9.42 gm.
diphenylphosphonic azide instead of the 7.4 ml., the
135 ml., and the 14.7 gm., respectively~ there is obtained
a residual gum that is chromatographed on a 1000 ml.
column of silica gel instead of 1500 ml., and elution is
e~fected with a solvent system consisting of 2.5 percent
ethyl acetate in methylene chloride instead of the mixture
of ethyl acetate and technical hexane. There is thus
obtained, after removal of the solvents by evaporation,
6.42 gm. of crude product that upon recrystallization
~rom technical hexane affords 6.11 gm. (62% yield) of
4-isocyanata-4-(p-anisyl)cyclohexanones ethylene ketal
melting at 70.5 to 72 C.
Analysis:
Calc'd. for Cl6Hl9N0*:
C, 66.41; H~ 6.62; N9 4.890
Found: C, 66.47; H, 6.61; N, 4.77.
Part G Preparation of sixth intermediate 4-(p-anisyl)-
4-methylaminocyclohexanone, ethylene ketal
p-toluenesulfonate
Following the procedure of Example 1, Part G, but
substituting 6.11 gm. of 4-isocyanato-4-~p-anisyl)cyclo-
hexanone, ethylene ketal (prepared in Part F, above) for
the 6.62 gm. of 4-(p-chlorophenyl)-4-isocyanatocyclohex-
anone, ethylene ketal; using 80 ml. tetrahydrcfuran and
1.22 gm. (0.032 mole) lithium aluminum hydride instead
~ of the 50 ml. and the 1.29 gm., respectively; and then
add~ng 1.22 ml. water~ 1.22 ml~ 15 percent aqueous sodium
hydroxide, and 3.66 ml. water ~nstead of the 1.3 ml.,
the 1.3 ml., and the 3~9 ml. respectively, there is obtained

- -43-

3286
`S~Ç~

a res~due from the fi 1 trate that is di ssol ved i n a small
amount of ether. To the ether solution ~s added 4.0 gm.
p-toluenesu1fonic acld dissolved in ether. The acid
add~tion salt that prec~pitates is collected on a filter
S and recrystallized from a solvent mixture of ethyl acetate
and methylène chloride. There is thus obtained 8.30 gm.
(88% yield) of the desired ;ntermediate 4-(p-anisyl)-
4-methylaminocyclohexanone, ethylene ketal p-toluenesulfon-
ate that has a ~elting point at 206 to 208 C.
Analysis:
Calc'd. for C23H3lN06S:
C, 61.44; H, 6.95; N, 3.120
Found: C, 61.27; H~ 6.95; N, 3.06.
Part H Preparation of object compound, 4-(p-anisyl~-
4-dimethylaminocyclohexanone, ethylene ketal
hydrochloride
Following the procedure of Example l, Part H, but
substituting the free base obtained from 8.30 gm. ~0.018
mole) of 4-(p-anisyl)-4-methylaminocyclohexanone, ethylene
ketal p-toluenesulfonate (prepared in Part G, above) for
the 5.68 gm. of the 4-(p-chlorophenyl)-4-methylaminocyclo-
hexanone, ethylene keta1, and using 20 ml. 37 percent
formalin, 60 ml. methanol, and 2.44 gm. sodium borohydride
instead of the 22 ml., 75 mlO, and 2.89 gm., respectively,
there is ~inally obtained a preclpitate of the hydrochloride
acid addition salt that is recrystallized from a mixture
of methylene chloride and ethyl acetate thus affording
4.61 gm. (78% yield) of the object compound 4-(p-anisyl)-
4-d~methylaminocyclohexanone, ethylene ketal hydrochloride
that has a melt~ng point at 203 to 204 Co
r

~44

3286


Analysis:
Calc'd. for C~7H26ClN03:
C, 62.28; H, 7.99; N, 4.27.
Found: C, 62.41; H, 8.20; N, 4.140
Example 8 Preparation of an object compound, 4-(p-anisyl)-
4-dimethylaminocyclohexanone free base
Following the procedure of Example 2, but substituting
4.61 gm. (0.014 mole) of 4-(p-anisyl)-4-dimethylaminocyclo-
hexanone, ethylene ketal hydrochloride (prepared in
Example 7, Part H, above) for the 4-(p-chlorophenyl)
4-dimethylaminocyclohexanone, ethylene ketal hydrochloride,
18.0 ml. of 2.5 N hydrochloric acid for the 22.5 ml., and
36 ml. methanol for the 45 ml. 9 there is prepared (after
recrystallization from technical hexane instead of diethyl
ether) 2.29 gm. (66% yield) of 4-(p-anisyl)-4-dimethyl-
aminocyclohexanone as the free base having a melting point
at 89 to 91 C.
Analysis:
Calc'd. for C, sH2 1 NO2:
C, 72.84, H, 8.56; N, 5.66.
Found: C, 73.18; H, 8.63; N, 5.55.
Exam~le 9 Preparation of 4-(o-chlorophenyl)-4-dimethyl-
aminocyclohexanone9 ethylene ketal hydroiodide
Part A Preparation of precursor, the Dimethyl ester
of 4-(o~chlorophenyl)-4-cyanopi~elic acid
Following the procedure of Example 1, Part A, but
subst~tuti~g b-chlorophenyl acetonitrile for p-chlorophenyl
aceton~tr~le and decreasing the final distillation pressure
, to 0.08 mm Hg, there ls prepared 39.11 gm. (73X yield) of
the dlmethyl ester of 4-(o-chlorophenyl)-4-cyanopimelic

-45-

~286
S

acid as an oil haYing a boiling range of 170 to 183 C.
Part B Preparation of first intermed1ate, 2-Carbo-
methoxy-4-cyano-4~(o-chlorophenyl)cyclohex-
anone
Following the procedure of Example 1, Part B, but
su~stituting 39.11 gm. (0.121 mole) dimethyl-4-(o-chloro-
phenyl~-4-cyanopimelate (prepared in Part A, above) for
the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic
acid, and using 780 ml. of the tetrahydrofuran, 27.4 gm.
(0.24 mole) of the potassium tert-butoxide, and 195 ml.
of the 2.5 N acetic acid instead of the 700 ml. 9 the
24.4 gm. t0.218 mole), and the 175 ml., respectivelys
there is prepared 33.4 gm. ~95% yield) of 2-carbomethoxy-
4-cyano-4-(o-chlorophenyl)cyclohexanone as a crystalline
solid having a melting range of 113 to 118 C.
Part C Preparation of second ;ntermediate, 4-(o-
chlorophenyl)-4-cyanocyclohexanone
Following the procedure of Example 1, Part C, but
substituting 33.4 gm. (0.115 mole) of 2-carbomethoxy-
20- 4-(o-chlorophenyl)-4-cyanocyclohexanone (prepared in Part
B, above) for the 29.8 gm. of the 2-carbomethoxy-~-(p-
chlorophenyl)-4-cyanocyclohexanone 9 USi ng 730 ml. glacial
acetic acid and 365 ml. 10 percent aqueous sul~uric acid
instead of the 660 ml. and 330 ml. 9 respectiYely~ and
heating for 48 hours instead of 24 hours there is obtained
a res~dual solid that is recrystallized from a mixture -
of methylene chloride and technical hexane thus affording
20.54 gm. (80% yield) of 4-(o chlorophenyl j-4-cyanocyclo-
hexanone having a melting point at 106 to 108 C.
~ :

,
-46-

3286
5 ~ 6

.
Calc'd. for Cl3HI2ClNO;
C, 66.81; H, 5.18; Ns 5 99.
Found: C~ 66.45; H, 5.13; N, 5586.
Part D Preparation of third lntermediate, 4-(o-
chlorophenyl)-4-cyanocyclohexanone, ethylene
ketal
Following the procedure of Example 1, Part D, but
substituting 20.54 gm. (0.092 mole) o~ 4-(o-chlorophenyl)-
4-cyanocyclohexanone (prepared in Part C, above) for the
19.49 gm. of the 4-(p-chlorophenyl)-4-cyanocyclohexanone,
and using 5.1 ml; (5.66 gm., 0.92 mole) ethylene glycol,
0.25 gm. p-toluenesulfonic acid, and 160 ml. benzene
instead of the 4.8 ml., the 0.21 gm., and the 150 ml.,
respectively, there is obtained 22.64 gm. (89% yield) of
the expected compound 4-(o-chlorophenyl)-4-cyanocyclohex-
anone, ethylene ketal having a melting range at 98.5
to 101 C.
Analysis:
Calc'd. for ClsHl6ClN02:
C, 64.86; H, 5.81; N5 5.04.
Found; C, 64.609 H, 5.79; N~ 5.20.
Part E Preparation of fourth intermedia~e, 4-carboxy-
4-(o-chlorophenyl~cyclohexanone, ethylene
ketal
Following the procedure of ~xample 1, Part E, but
substitutin~ 22.54 gm. (0.081 mole) of 4-(o-chlorophenyl)-
4-cyanocyclohexanone9 ethylene ketal (prepared in Part D,
above) for the 21.87 gm. of 4-(p-chlorophenyl)-4-cyano-
cyclohexanone, ethylene ketal and using 23.0 gm. (~.41 mole)
potassium hydrox~de and 230 mlO ethylene glycol instead
,
-47~

3286
`516

of the 22.0 gm. and the 220 ml., respectively, there is
obtained 18.49 gm. (77% yield) of 4 carboxy-4-(o-chloro-
phenyl)cyclohexanone, ethylene ketal having a melt~ng
po~nt at 195 to 197 C.
Analysis:
Calc'd. for C,sHl 7Cl 04
C, 60.71; H, 5.78~
Found: C, 61.11; H, 5.96.
Part F Preparation of fifth intermediate, 4-(o-Chloro-
phenyl)-4-isocyanatocyclohexanone, ethylene
ketal
Following the procedure of Example l, Part F, but
substituting 18.49 gm. (0.0625 mole) of 4-carboxy-4-(o-
chlorophenyl)cyclohexanone9 ethylene keta1 (prepared in
Part E, above) for the 15.79 gm. of 4-carboxy-4-(p-chloro-
phenyl)cyclohexanone, ethylene ketal and using 8.7 ml.
(S.3 gm., 0.063 mole) triethylamine~ 150 ml. anisole,
and 17.4 gm. diphenylphosphonic azide instead of the
7.4 ml., the 135 ml., and the 14.7 gm.9 respectively, there
is obtained 15.49 gm. (85% yield) of 4-(o-chlorophenyl)-
4-isocyanatocyclohexanone, ethylene ketal as an oil.
Part G Preparation of sixth intermediate, 4-(o-chloro-
phenyl)-4-methylaminocyclohexanone, ethylene
ketal
Following the procedure of Example 19 Part G, but
substituting 15.49 gm. (0.053 mole) of 4-(o-chlorophenyl)-
4-~socyanatocyclohexanone, ethyle~e ketal (prepared in
Part F9 above) for the 6.62 gm. of the 4tP-chloroPhenYl)-
4-~socyanatocyclohexanone, ethylene ketal; using 120 ml.
tetrahydrofuran, 3.04 gm. ~0008 mole) l~thium aluminum

-48~

3286
llC~6

:
hydride~ and S0 ml. tetrahydrofuran, respectively; and
addlng 3.0 ml. water, 3.0 ml. of the 15 percent aqueous
sodium hydroxide, and 9.0 ml. water instead of the 1.3 ml.,
the 1.3 ml., and the 3.9 ml., respectively, there is
obtained 14.27 gm. (96~ yield) of 4-(o~chlorophenyl)-4-
methylaminocyclohexanone, ethylene ketal as a noncrystal-
line gum.
Part H Preparation of object compound, 4-(o-chloro-
phenyl)-4-dimethylaminocyclohexanone, ethylene
ketal hydroiodide
Following the procedure of Example 1, Part H, but
substituting 14.27 gm. (0.051 mole~ of the 4-(o-chloro-
phenyl)-4-methyiaminocyclohexanone, ethylene ketal prepared
in Part G, above, for the 5.68 gm. of the 4-(p-chloro-
lS phenyl)-4-methylaminocyclohexanone, ethylene ketal and
using 55 ml. of the 37 percent formalin, 190 ml. methanol,
and 7.25 gm. (0.191 mole) of the sodium borohydrlde
instead of the 22 ml., the 75 ml. 9 and the 2.89 gm.,
respectively, there is obtained the free base product from
the final removal of methylene chloride, after recycling.
This is then dissolved in a small amount of methylene
chloride and washed with 10 percent hydriodic acid.
After removing the methylene chloride by evaporation under
reduced pressure, the residue is recrystallized from a
mixture of methanol and diethyl ether to afford 2.7 gm.
of the object compound 4-(o-chlorophenyl)-4-dimethylamino-
cyclohexanone, ethylene ketal hydroiodide having a melting
r~nge of 208 to 213 C.
Analysis:
Calc'd. for Cl6H23ClIN02:
.~ .
-49-

32~6

C, 45.35; H, 5.47; N, 3.31
Found: C, 45.58; H, 5.65; N, 3.18
Example 10 Preparation of an ob~ect compound, 4-(o-Chloro-
phenyl)-4-dimethy1aminocyclohexanone
~ollow~ng the procedure of Example 2, but substituting
10.0 gm. (0.034 mole) of 4-(o-chlorophenyl)-4-dimethylamino-
cyclohexanone, ethylene ketal (prepared in Example 9,
Part H, above) for the 4.52 gm. of the 4-(P-chloropheny1)-
4-dimethylaminocyclohexanone, ethylene ketal hydrochloride,
and using 50 ml. 2.5 N hydrochloric acid and 100 ml.
methanol instead of the 22.5 ml. and the 45 ml., respect-
ively, there is prepared 2.25 gm. (26.3% yield) of 4-(o-
chlorophenyl)-4-dimethylaminocyclohexanone having a melting
point at 81 to 84 C.
Analysis:
Calc'd. for Cl4Hl7ClN0:
C, 66.79; H, 7.21; N9 5.57.
Found: C, 66.98; H, 7;54; N, 5.810
Example 11 Preparation of 4-(m-anisyl)-4-dimethylamino-
cyclohexanone, ethylene ketal hydrochloride
Part A Preparation of precursor, the Dimethyl ester
of 4-(m anisyl)-4-cyanopimelic acid
Follow;ng the procedure of Example 1, Part A, but
substituting 25.0 gm. (0.17 mole) m-anisyl acetonitrile
for the 25.0 gm. of the p-chlorophenyl acetonitrile and
us~ng 79 ml. methyl acrylate, 27 ml. of the 40~ methanolic
tetramethylammonium hydroxide with 38 ml. tert-butyl
alcohol, înstead of the 77 ml., the 24 ml., and the
37 ml., respectivelyD and decreasing the final d~stillation
pressure to 0.07 mm Hg~ there is prepared 30.34 gm. (56~

~50~

3~86
ll~G~

yield) of the dimethyl ester of 4-(m-anisyl)-4-cyanopimelic
acid as an oil having a boiling range from 180 to 187 C.
Part B Preparation of first intermediate, 4-(m-anisyl)-
2-carbomethoxy-4-cyanocyclohexanone
Fol lowi ng the procedure of Example 19 Part B, but
subst~tuting 30.34 gm. (0.0951 mole) of ~he dimethyl ester
of 4-(m-anisyl)-4-cyanopimelic acid (prepared in Part A,
above) for the 34.97 gm of the d;methyl ester of 4-~p-
chlorophenyl)-4-cyanopimelic acid and using 620 ml. of the
tetrahydrofuran, 21.3 gm. (0.19 mole) of the potassium
tert-butoxide, and 150 ml. of the 2.5 N glacial acetic
acid instead of the 700 ml.9 the 24.4 gm. (0.218 mole),
and the 175 ml., respectively, there is prepared 29.1 gm.
(99% yield) of 4-(m-anisyl)-2-carbomethoxy-4-cyanocyclo-
, hexanone as a gum.
Part C Preparation of second intermediate, 4-(m-
anisyl)-4-cyanocyclohexanone
Following the same procedure as described in Example
1, Part C, but substituting 29.1 gm. (OolOl mole) of
4-(m-anisyl)-2-carbomethoxy-4-cyanocyclohexanone (prepared
in Part B, above) for the 29.8 gm. of 2-carbomethoxy-
4-(p-chlorophenyl)-4-cyanocyclohexanone 9 there is obtained
14.93 gm. (~4% yield) of 4 (m~anisyl) 4-cyanocyclohexanone
- having a melting range at 72~ to 76 C~
Calc'd. ~or Cl4Hl5ND2-
C, 73.34; H9 6.59& Ns 6.11.
Found: C, 73.68; H, 6.769 N9 6.210
Part D ~reparation o~ third intermediate, 4-(m-
~0 an~sy1)-4-cyanocyclohexanone9 ethylene ketal

-51-

3286
~ 5 ~6

Follow~ng the procedure of Example 1, Part D, but
substituting l4.93 gm. (0.065 mole) of 4-(m~anisyl)-
4-cyanocyclohexanone (prepared in Part C, abvoe) for the
19.49 gm. of the 4-(p-chlorophenyl)-4~cyanocyclohexanone,
using 4.0 ml. ethylene glycol, 0.l6 gmO p-toluenesulfonic
acld, and llO ml. benzene instead of the 4.8 ml., the
0.21 gm., and the 150 ml., respectively, and recrystalliz-
ing from technical hexane instead of cyclohexane, there
is obtained 16.24 gm. (92% yield) of 4-(m-anisyl)-4-cyano-
cyclohexanone, ethylene ketal me1ting at 70 to 72 C.
Analysis:
Calc'd. for C~6H~gN03:
C, 70.31; H, 7.0l; N, 5.13.
Found: C, 70.09; H, 7.07; N, 4.96.
Part E Preparation of fourth intermediate 4-(m-anisyl)-
4-carboxycyclohexanone, ethylene ketal
Followbng the procedure of Example l, Part E, but
substituting 16.24 gm. (0.059 m4le) of 4-(m-anisyl)-
4-cyanocyclohexanone, ethylene ketal (prepared in Part D,
above~ for the 21.87 gm. of the 4-carboxy-4-(p-chloro-
phenyl)cyclohexanone, ethylene ketal and using 7.83 gm.
(0.19 mole) sodium hydroxide and llO ml. ethylene glycol
instead of the 22.0 gm. (0.39 mole~ potassium hydroxide
and 220 ml., respectively, there is obtained, without
recrystallization, l7.31 gm. (99% yield) of 4-(m-anisyl)-
4-carboxycyclohexanone, ethylene ketal having a melting
range at 102 to 107 C.
Part F Preparation of fifth intermediate, 4-(m-anisyl)-
4-isocyanatocyclohexanone9 ethylene ketal
Follow~ng the procedure of Fxample t, Part F, but

~52-

3286
1~@~5~6

substituting the 17.31 gm. (O.OS9 mo7e) of 4-(m-anisyl)-
4-carboxycyclohexanone, ethylene ketal (prepared in Part
E, above) for the 15.79 gm. of the 4-carboxy-4-(p-chloro-
phenyl)cyclohexanone, ethylene ketal and using 6.0 ml.
S (8.23 gm., 0.059 mole3 triethylamine, 160 ml. anisole,
and 16.31 gm. diphenylphosphonic azide instead of the
7.4 ml., the 135 ml. 7 and the 14.7 gm., respectively,
there is obtained after elution of the silica gel column
with a l.S percent mixture of ethyl acetate in methylene
chloride, 4.07 gm. of 4-(m-anisyl)-4-isocyanatocyclohex-
anone ethylene ketal.
Part G Preparation of sixth intermediate, 4-(m-anisyl)-
4-methylaminocyclohexanone, ethylene ketal
hydroch1oride
Following the procedure of Example 1, Part G, but
substituting 4.07 gm. ~0.014 mole) of 4-(m-anisyl)-
4-isocyanatocyclohexanone, ethylene ketal (prepared in Part
F, above~ for the 6.62 gm. 4-(p-chlorophenyl)-4-isocyanato-
cyclohexanone, ethylene ketal and using 80 ml. tetrahydro-
furan, 0.76 gm. (D.02 mole) lithium aluminum hydride, and
10 ml. tetrahydrofuran instead of the 50 ml., the 1.29 gm.,
and the 20 ml., adding 0.76 ml. water, 0.76 ml. of 15 per-
cent aqueous sodium hydroxide, and 2.28 ml. water instead
of the 1.3 ml., the l.3 ml., and the 3.9 ml., respectively,
~ 25 there is obtained a corresponding residue from the filtrate
t ~ that is dissolved in a small amount of diethyl ether. The
t`~ ether solution is acidified with an equivalent amount of
3 N hydrogen chloride in ether. The hydrochloride acid
- add~tion salt that precipitated is collected on a filter
and recrystallized from a m~xture Qf methylene chlor~de

-53-

`
3286
llQ~16

and ethyl acetate to afford 3.10 gm. (71X y~eld) of
.: . 4- (m-an~ syl ) ~4-methylaminocyclohexanone, ethylene ketal; hydrochloride hav~ng a melting po;nt at 238 to 239 C.
Analysis:
Calc'd. for C~6H24ClN03:
C, 61.23; H, 7.71; N, 4.46.
Found: C, 60.07; H, 7.52; N, 4.29.
Part H Preparation of object compound, 4-(m-anisyl)-
4-(dimethylamino)cyclohexanone, ethylene
ketal hydrochloride
Following the procedure of Example 1, Part H, but
substituting the free base from 3.10 gm. (0.0099 mole) of
4-(m-anisyl)-4-methylaminocyclohexanone ethylene ketal
hydrochloride (prepared in Part G, above) for the 5.68 gm.
15 of the 4-(p-chlorophenyl)-4-methylaminocyclohexanone, --
ethylene ketal and using 7.5 ml. of 37 percent formalin,
22.5 ml. methanol, and adding 0.91 gm. sodium borohydride
.. . .
;~ instead of the 22 ml., the 75 ml., and the 2.89 gm.
~: respectively, there is obtained a hydrochloride precipitate
that upon recrystallization from a mixture of methylene
chloride and ethyl acetate gives 2.21 gm. (68% yield) of
` 4-(m-anisyl)-4-(dimethylamino)cyclohexanone, ethylene
ketal hydrochloride having a melting point at 184 to
185-5 C.
; 25 Lnalysis:
Calc'd. for Cl7H26ClN03:
C, 62.28; H, 7.99, N~ 4.27.
Found: C9 62.11; H, 8.24; N, 4.21,
Example 12 Preparation of an obiect compound, 4-tm-anisYl)-
4-dlmethylamlnocyclohexanone

-54

3286


Following the procedure of Example 2, but substitut~ng
1.71 gm. (0,0052 mole) of 4-(m-anisyl)~4~dlmethylam~no-
cyclohexanone, ethylene ketal hydrochloride (prepared in
Example 11, Part H, above) for the 4-(p~chlorophenyl)-
4-dimethylaminocyclohexanone, ethylene ketal hydrochloride,
7.5 ml. of 2.5 N hydrochloride acid for the 22.5 ml., and
15 ml. methanol for the 45 ml., there is prepared (after
recrystallization from petroluem ether instead of diethyl
ether) 0.54 gm. (45% yield) of 4-(m-anisyl)-4-dimethyl-
aminocyclohexanone as the free base having a melting point
at 57 to 59 C.
Analysis:
Calc'd. for C~sH2~No2:
C, 72.84; H, 8.56; N9 5.66.
Found: C, 72.88, H, 8.47; N, 5.72.
Example 13 Preparation of 4-Dimethylamino-4-(p-tolyl)-
cyclohexanone, ethylene ketal hydrochloride
Part A Preparation of precursor, the Dimethyl ester
of 4-cyano-4-(p tolyl)pimelic acid
Following the procedure of Example 1, Part A, but
substituting Z5.0 gm. (0.191 mole) p-tolyl acetonitrile for
the 25.0 gm. of the p-chlorophenyl acetonitrile and using
89 ml. methyl acrylate, 90 mlO tert-butyl alcohol, 29 ml.
of 40 percent methanolic tetramethylammonium hydroxide, and
43 ml. tert-butyl alcohol instead of the 77 ml., the 80 ml.,
th2 25 ml., and the 37 ml. 9 respectively, and decreasing
the final distillation pressure to 0.07 mm mercury, there
ls prepared 42.44 gm. ~73X yield) of the dimethyl ester
of 4cyano-4-(p tolyl)pimel~c-acid as an oil having a
bolling range of 170 to 180 C.

~55-

3~86
lir~s~6

Part B Preparat~on of flrst ~ntermedlate, 2-carbo-
methoxy-4-syano-4-(p-tolyl)cyclohexanone
Follow~ng the procedure of Example 19 Part B, but
sllbst;tuting 42.44 gm. (0.14 mole) of the dimethyl ester
of 4-cyano-4-(p-tolyl)pimelic acid (prepared ;n Part A,
above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyano-
pimelic acid and using 900 ml . of the tetrahydrofuran,
31.5 gm. (0.28 mole) of the potassium tert-butoxide, and
225 ml. of the 2.5 N aqueous acetic acid instead of the
700 ml., the 24.4 gm. (0.218 mole), and the 175 ml.,
respectively, there is prepared 39.3 gm. (99~ yield) of
2-carbomethoxy-4-cyano-4-~p-tolyl)cyclohexanone as a gum.
Part C Preparation of second intermediate, 4-Cyano-
4-(p-tolyl)cyclohexanone
Following the procedure of Example 1, Part C, but
substituting 39.3 gm. (0.145 mole) of 2-carbomethoxy-4-cyan~
4-(p-tolyl)cyclohexanone (prepared in Part B, above) for
the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-
4-cyanocyclohexanone and us;ng 960 ml. glacial acetic
acid and 480 ml. of 10 percent aqueous sulfuric acid
instead of the 660 ml. and 330 ml., respectively, there
is obtained after recrystallization from a mixture of di-
ethyl ether and petroleum ether 22.84 gm. (74% yield) of
4-cyano-4-(p-tolyl)cyclohexanone having a melting range
at 79 to 82 C.
Analysls:
Calc'd. for Cl4HlsN0:
C, 78.84; H9 7.09; N, 6.570
Found: C, 78.96; H, 7.079 N, 6.53.
Part D Preparation of third intermediate, 4-Cyano-

5 6 -

- 3286
516

4~(p-tolyl)cyclohexanone, ethylene ketal
Followlng the procedure of Example 1, Part D, but
substitutlng 22.74 gm. (0.107 mole) of 4-cyano-4-(p-tolyl)-
cyclohexanone (prepared in Part C, above) for the 19.49 gm.
of the 4-~p-chlorophenyl)-4-cyanocyclohexanone and using
6.3 ml. (7.0 gm., 0.113 mole) ethylene glycol, 0.28 gm.
p-toluenesulfonic acid, and 190 ml. benzene instead of
the 4.8 ml., the 0.21 gm., and the 150 ml., respectively,
there is thus obtained 25.29 gm. (92% yield) of 4-cyano-
4-(p-tolyl)cyclohexanone, ethylene ketal having a melting
range at 107.5 to 110 C.
Analysis:
Calc'd. for C16HlgN02:
C, 74.68i H, 7.44; N9 5.44.
Found: C, 75.04; H, 7.40; N, 5.48.
; Part E Preparation of fourth intermediate, 4-Carboxy-
4-(p-tolyl)cyclohexanone, ethylene ketal
Following the procedure of Example 1, Part E, but
substituting 25.29 gm. (0.0985 mole) of 4-cyano-4-(p-tolyl)-
cyclohexanone, ethylene ketal (prepared in Part D, above)
for the 21.87 gm. of the 4-(p-chlorophenyl)-4-cyanocyclo-
hexanone, ethylene ketal and using 25.0 gm. (0.45 mole)
potassium hydroxide and 250 ml. ethylene glycol instead
of the 22.0 gm. and the 220 ml., respectively, there is
obtained ~3.04 gm. (85~ yield) of the expected compound
4-carboxy-4-(p-tolyl)cyclohexanone 9 ethylene ketal having
a melting range of 72 to 74 C.
Analysis:
Calc'd. for C16H2~04:
C, fi9.54; H~ 7.30.

3286

~ 5 1 6
Found: C, 69.79; H, 7.310
Part F Preparation of fifth lntermediate, 4-Isocyana-
to-4-(p-tolyl)cyclohexanone, ethylene ketal
Following the procedure of Example 1, Part F, but
substituting 22.94 gm. (0.083 mole) of 4 carboxy-4-(p-
tolyl)cyclohexanone, ethylene ketal (prepared in Part E,
above) for the 15.79 gm. of the 4-carboxy-4-(p-chloro-
phenyl)cyclohexanone, ethylene ketal using 12.6 ml. (9.15
gm., 0.092 mole) triethylamine9 270 ml. anisole, and
24.5 gm. di~henylphosphonic azide for the 7.4 ml.9 the
135 ml.9 and the 14.7 gm. 5 respective1y, and chromatograph-
ing over a 2000 ml. column instead of a 1500 ml. column,
there is obtained 19.0 gm. (84% yield) of 4-isocyanato-
4~(p-tolyl)cyclohexanone9 ethy1ene ketal as an oilO
Part G Preparation of sixth intermediate, 4-Methyl-
amino-4-(p-tolyl)cyclohexanone, ethylene
........
ketal
Following the procedure of Example 1, Part G, but
substituting 19.07 gm. (0.0675 mole) of 4-isocyanato-
4-(p-tolyl)cyclohexanone9 ethylene ketal (prepared in Part
F, above) for the 6.62 gm. of the 4-(p-chlorophenyl)-
4-isocyanatocyclohexanone, ethylene ketal, using 325 ml.
tetrahydrofuran~ 4.0 gm. ~0.105 mole) lithium aluminum
hydride9 and 40 ml. tetrahydrofuran; and adding 4.0 m~.
water, 4.0 ml. of 15 percent sodium hydroxide, and 12 m1.
water instead of the 1.3 mlO 9 1 . 3 mlO 9 and 3.9 ml., res-
pectively, there is obtained 14075 gmO (57% yield) of
4^methylamino 4-(p-tolyl)eyclohexanone9 ethylene ketal
having a melting range at 56 to 60 CO
~ r~

58

3286
11~0516

Calc'd. ~or C~6H23N~2:
C9 73.53; H, 8.87, N, 5.36.
Found: C, 73.19; H, 9.01; N9 5.46.
Part H Preparation of object compound, 4-Dimethyl-
S am1no-4-(p-tolyl)cyclohexanone, ethylene
ketal hydrochloride
Following the procedure of Example 1, Part H, but sub-
stituting 7.0 gm. (0.027 mole) of 4-methylamino-4-(p-tolyl)-
cyclohexanone, ethylene ketal (prepared in Part G, above)
for the 5.68 gm. of the 4-(p-chlorophenyl)-4-methylaminocy-
c1Ohexanone, ethylene ketal and initially using 29.2 ml. of
37 percent formalin, 100 mlO methanol, and 3.96 gm. (0.104
mole~ sodium borohydride instead of the 22 ml., the 75 ml.,
and the 2.89 gm., respectively, there is obtained the free
base; this on further treatment as in Exa.mple 1, Part H gives
a hydrochloride acid addition salt precipitate that is re-
crystallized from a solvent mixture consisting of methylene
chloride and ethyl acetate thus affording 6.27 gm. (76%
yield) of the desired, object compound 4-dimethylamino-4-
(p-tolyl)cyclohexanone, ethylene ketal hydrochloride salt
which rnelts at 228 to 229 CO
Analysis: Calc'd. for Cl7H2 6Cl N02:
C, 65.47; H, 8.40; N9 4.49.
Found: C9 65.57; H, 8.309 N9 4.60.
Example 14 Preparation of an object compound9 4-dimethyl-
am~no-4-(p-tolyl)cyclohexanone
Following the procedure of Example 29 but substltuting
6.27 gm. (0~02 mole) of 4~dimethyl~mlno~4~p-tolyl)cyclo-
hexanone9 ethylene ketal hydrochloride ~prepared in Example
13, Part H, above) for the 4-(p-shlorophenyl)-4~dimethyl-

-5~-

~ S~6 3~86

aminocyclohexanone, ethylene ketal hydrochloride, 31 ml.
2.5 N hydrochloric acid for the 22.5 mlO 9 and 62 ml.
methanol for the 45 ml., there is prepared (after recrystal-
lization from petroleum ether instead of diethyl ether)
2.54 gm. (55% yield) of 4-dimethylamino-4-(p-tolyl)-
cyclohexanone having a melting point at 65 to 67.5 C.
Analysis:
Calc'd. for ClsH2lNo:
Cg 77.88; H9 9.15; N, 6.06.
Found: C, 77.72; H, 9.14; N, 6.24.
Example 15 Preparation of 4-Dimethylamino-4-(o-tolyl)-
cyclohexanone, ethylene ketal hydroiodide
Part A Preparation of precursor, the Di~ethyl ester
of 4-cyano-4-(o-tolyl)pimelic acid
Following the procedure of Example 1, Part A, but
substituting 25.0 gm. (0.191 mole) o-tolyl acetonitrile
for the 2~.0 gm. of the p-chlorophenyl acetonitrile and
using 89 ml. methyl acrylate5 90 ml. tert-butyl alcohol,
29 ml. of 40 percent methanolis tetramethylammonium
2a hydroxide, and 43 ml. tert-butyl alcohol instead of the
77 ml., the 80 ml., the 24 ml. 9 and the 37 ml., respect-
ively, and decreasing the final distillation pressure to
0.03 mm mercury, there is prepared 21.76 gm. (37% yield)
of the dimethyl ester of 4-cyano-4-(o-tolyl)pimelic acid
as an oi 1 having a boiling range between 168 to 175 C.
Part B Preparation of first intermediate, 2-Carbo-
methoxy-4-cyano-4-(o-tolyl)cyclohexanone
Following the procedure of Example 1, Part B, but
substituting 21.76 gm. (0.0715 mole) of the dimethyl ester
of 4-cyano-4-(o-tolyl)pimelic acld (prepared in Part A,


,

32~6
S16

above) for the 34.97 gm, of the dimethyl ester of 4-~p-
chlorophenyl)-4-cyanopimelic ac~d and us~ng 460 ml. of
the tetrahydrofuran, 16.3 gm. (0.145 mole) of the potass1um
tert-butoxide, and 115 ml. of the 2.5 N aqueous acetic
ac~d instead of the 700 ml., the 24.4 gm. and the 175 ml.,
respectively, there is prepared 18.0 gm. (93% yield) of
; 2-carbomethoxy-4-cyano-4-(o-tolyl)cyclohexanone as a
crystalline solid having a melting range at 107 to 113 C.
Part C Preparation of second intermediate, 4-Cyano-
4-(o-tolyl)cyclohexanone
Following the procedure of Example 17 Part D~ but
substituting 18.Q gm. (0.0663 mole) of the 2-carbomethoxy-
4~cyano-4-(o-tolyl)cyclohexanone (prepared in Part B,
above), for the 29.8 gm. of the 2-carbomethoxy-4-~p-chloro-
phenyl)-4-cyanocyclohexanone, using 440 ml. of the acetic
acid and 220 ml. of the 10 percent aqueous sulfuric acid
instead of the 660 ml., and the 330 ml. 9 respectively, and
heating for 48 hours instead of 24 hours there is prepared
4-cyano-4-~o-tolyl)cyclohexanone which upon recrystalliza-
tion from a mixture of diethyl ether and technical hexane
affords ll.OS gm. of the compound having a melting range
at 86.5 to 89 C.
Analysis:
Calc'd. for Cl4HlsN0:
2S C, 78.84; H, 7.09; N9 6.57
Found: C, 78.85j H, 7.29; N9 6.55~
Part D Preparation of third intermediate, 4-Cyano-
4-(o-tolyl )cyclohexanone9 ethylene ketal
Following the procedure-of Example 1, Part D, but
subst~tutlng 10.95 gm. ~0.0513 mole) of 4-cyano-4-(o-tolyl)-

-61~

.

. .

~ 516 . 3286


cyclohexanone (prepared in Part C, above) for the 19.49 gm.
(0.084 mole) of the 4-(p-chlorophenyl) 4-cyanocyclohexanone
and using 3.1 ml. (3.44 gm., 0.044 mole) ethylene glycol,
0.14 gm. p-toluenesulfonic acidg and 90 ml. benzene
~nstead of the 4.7 ml., the 0.21 gm.9 and the 150 ml.,
respectively, there is thus obtained a residual solid that
is recrystallized from a mixture of diethyl ether and
petroleum ether thus affording 11.22 gm. (85% yield) of
4-cyano-4-(o-tolyl)cyclohexanone, ethylene ketal having
a melting range at 65.5 to 68.5 CO
Analysis:
Calc'd. for Cl6HlgN02:
C, 74.68; H, 7.44; N, 5.44.
Found: C, 74.56; H, 7.50; N, 5.29.
Part E Preparation of fourth intermediate, 4-Carboxy-
4-(o-tolyl)cyclohexanone, ethylene ketal
Following the procedure of Example 1~ Part E, but
substituting 11.22 gm. (0.044 mole) of 4-cyano-4-(o-tolyl)-
cyclohexanone, ethylene ketal (prepared in Part D~ above)
for the 21.87 gm. of the 4-(p-chlorophenyl)-4-cyanocyclo-
hexanone, ethylene ketal and using 11.0 gm. (0.20.mole)
potassium hydroxide and 110 ml. ethylene glycol instead of
the 2..0 gm. and 220 ml., respectively, there is obtained
7.70 gm. ~63.3% yield) of 4-carboxy-4-(o-tolyl)cyclohexa-
none, ethylene ketal having a melting range at 174
to 177 C.

Calc'd. for ClsH2 D04:
C, 69~54; H, 7.30.
Found: C, 69.43; H, 7.62.

-62-

516 3286


Part F Preparatlon of f~fth intermediate, 4-Iso-
-
cyanato~4-(o-tolyl)cyclohexanone, ethylene
ketal
Following the procedure of Example l, Part F, but
substitut1ng 7.70 gm. (0.028 mole) of 4-carboxy 4-(o-tolyl)-
cyclohexanone, ethylene ketal (prepared in Part E, above)
for the 15.79 gm. of the 4-carboxy-4-(p-chlorophenyl)-
cyclohexanone, ethylene ketal and using 4.3 ml. (3.12 gm.,
0.031 mole) triethylamine, 90.0 ml. anisole, and 8.4 gm.
diphenylphosphonic azide instead ~f the 7.4 ml., the 135 ml.,
and the 14.7 gm., respectively, followed by chromatographic
separation on a 400 ml. column of silica gel instead of
the 1500 ml. column and elution with 2 percent ethyl
acetate in methylene chloride instead of ethyl acetate and
technical hexane, there is obtained 6.09 gm. ~79.6% yield)
of 4-isocyanato-4-(o-tolyl)cyclohexanone, ethylene ketal
as a gum.
Part G Preparation of sixth intermediate, 4-Methyl-
amino-4-(o-tolyl)cyclohexanone, ethylene
ketal hydrochloride
Following the procedure of Example l, Part Gj but
substituting 6.09 gm. (0.022 mole) of 4-isocyanato-4-(o-
tolyl)cyclohexanone, ethylene ketal (prepared in Part F9
above) for the 6.62 gm. of the 4-(p-chlorophenyl)-4-iso-
cyanatocyclohexanone ethylene ketal 9 using 105 ml. tetra-
hydrofuran, 1.28 gm. (0.034 mole) 1ithium aluminum hydride,
and 70 ml~ tetrahydrofuran instead of the 50 ml., the
1.29 gm., and the 20 ml., respectively9 there is obtained
a corresponding resldue from the filtrate that is dissolved
~n a small amount of diethyl ether and the solution is

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- 3286
lla~sl6

acidifled wtth ~ust enough 3 N hydrogen chloride in ether
to pre~p1tate the hydrochloride satt which is collected
on a filter and recrystallized from a mixture of methylene
chloride and ethyl acetate to afford 4.03 gm. (59.7% yield)
of the desired 4~methylamino-4-~o-tolyl)cyclohexanone,
ethylene ketal hydrochloride having a melting point at
231 to 233 C~
Analysis:
Calc'd. for Cl 6 H24ClN02-~zH20:
0 Ct 62.62; H, 8.21; N, 4.57.
Found: C, 62.78; H, 8.01; Ng 4.72.
Part H Preparation of object compound, 4-Dimethyl-
amino-4-(o-tolyl)cyclohexanone, ethylene ketal
hydroiodide
A solution of the free base from 3.93 gm. (0.013 ~ole)
of 4-methylamino-4-(o-tolyl)cyclohexanone, ethylene ketal
- hydrochloride (prepared in Part G, above) with 14.4 ml. of
37 percent formalin in 50 ml. methanol is heated at the
reflux temperature for four (4) hours. The refluxed solu-
tion is allowed to cool, and it is then chilled in an ice-
bath. Small portions of sodium borohydride are added
cautiously with stirring to a total of 1095 gm. (0.051 mole).
Stirring is continued for two (2) hours at 25 C., after
which the bulk of the solvent is removed under reduced
pressure. The concentrate thus obtained is dispersed in
a mixture of 200 ml. methylene chloride and 25 ml. water.
A methylene chloride phase separates upon discontinuance of
agitation. It ls recovered and washed with water and brine
before the methylene chloride is removed by evaporation
under reduced pressure. The residue thus obta;ned is

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3286
llO~'Si6

recycled through the same reaction and work up. A portion
(1.68 g.) of th;s second residue is dissolved in methylene
chloride and washed with 10 percent hydriodic acid. The
methylene chloride phase is separated, the solvent removed
S by evaporation under reduced pressure and the residue thus
obtained is recrystallized from a mixture of methylene
chloride and ether to afford 2.03 gmD (37.1% yield) of the
desired object compound, 4-dimethylamino-4-(o-tolyl)cyclo-
hexanone, ethylene ketal hydroiodide having a ~elting point
at 182 to 183.5 C.
Analysis:
Calcid. for Cl7H26IN02 H20:
C, 48.45; H, 6.70; N, 3.33.
~ound: C, 48.77; H, 6.54; N, 3.41.5 Example 16 Preparat;on of an object compound, 4-Dimethyl-
amino-4-(o-tolyl)cyclohexanone free base and
the hydroiodide thereof
Following the procedure of Example 2, but s`ubstituting
2.0 gm. (0.0073 mole) of 4-dimethylamino-4-(o-tolyl)cyclo-
hexanone, ethylene ketal hydroiodide (prepared in Example15, Part H, above) for the 4-(p-chlorophenyl)-4-dimethyl-
aminocyclohexanone, ethylene ketal hydrochloride and using
10 ml. of the 2.5 N hydrochloric acld and 20 ml. of the
methanol instead of 22.5 ml~ and 45 mlO 9 respectively,
there is obtained 4-dimethylamino 4-(otolyl)cyclohexanone
free base as the residue. This residue is dissolved in
50 ml. methylene chloride and shaken with 10 ml. 10 percent
aqueous hydriodic acid. The methylene chloride layer is
s~parated and the solvent removed by evaporation under
reduced pressure. The residue thus obtained is recrystal-


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3286
516

l~zed from a mixture of methanol and diethyl ether. There
1s thus obta~ned 0.94 gm. (35.8% y~eld) of 4-dimethylamino-
4-(o-tolyl)cyclohexanone hydroiodide having a melting range
of 162 to 16~ C.
S Analysis:
Calc'd. for ClsH22IN0:
C, 50.15; H, 6.17; N, 3.90.
Found: C, 49.86; H, 6.37; N, 4.00.
Example 17 Preparation of 4-Dimethylamino-4-phenylcyclo-
hexanone, ethylene ketal hydrochloride
Part A Preparation of precursor, the Dimethyl ester
of 4-cyano-4-phenylpimelic acid
Following the procedure of Example 1, Part A, but
substituting 20.26 gm. (0.25 mole) of phenyl acetonitrile
lS for the 25.0 gm. of p-chlorophenyl acetonitrile and using
116 ml. methyl acrylate, 120 ml. tert-butyl alcohol 9 38 ml.
of the 40 percent methanolic tetramethylammonium hydroxide,
and 56 ml. tert-butyl alcohol instead of the 77 ml., the
80 ml., the 24 ml., and the 37 ml. quantities stated,
respectively, and increasing the final distillation pres-
sure to 0.45 mm of mercury, there is prepared 55.15 gm.
~70% yield) of the dimethyl ester of 4-cyano-4-phenylpimelic
acid as an oil having a boiling range from 183 to 186 C.
Part B Preparation of first intermediate, 2-~arbo-
methoxy-4-cyano-4-phenylcyclohexanone
Followiny the procedure of Example 1, Part B, but
substituting 2.0 gm. (0.0069 mole) of the dimethyl ester
of 4-cyano-4-phenylpimelic acid (prepared in Part A,
abo~e) for the 34.97 gm~ of the dimethyl ester of 4-(p-
chlorophenyl)-4-cyanoplmelic acid and using 45 ml. of the

~66~

3286
S~ -

tetrahydrofuran, 1.57 gm. (0.014 mole) of the potassium
tert-butox~de, and 10 ml. of the 2.5 N acet~c ac~d ~nstead
of the 700 ml., the 24.4 gm., and the 175 ml., respect~vely,
there is thus obtained a residue which upon recrystalliza-
tion from technical hexane gives 1.07 gm~ (60% yield) of
the desired 2-carbomethoxy-4-cyano-4-phenylcyclohexanone
havlng a melting point at 79.5 to 81.5 C.
- Analysis:
Calc'd. for ClsHlsN03:
C, 70.02; H9 5.883 N, 5.44.
Found: C, 6~.77; H, 5.88; N, 5.54.
Part C Preparation of second ;ntermediate, 4-Cyano-
4-phenylcyclohexanone
~ollowing the procedure of Example 1, Part C, but
substituting 44.7 gm. (0.174 mole) of 2-carbomethoxy-
4-cyano-4-phenylcyclohexanone (prepared as in Part B,
above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chloro-
phenyl)-4-cyanocyclohexanone and using 1200 ml. of the
glacial acetic acid9 and 600 ml. of the 10% aqueous sul-
furic acid instead of the 660 ml. and the 330 ml.,
respectively, and finally recrystallizing the residual
solid from a mixture of ethyl acetate and hexane, there
is obtained 25.75 gm. (75~ yield) of the desired 4-cyano-
4-phenyicyclohexanone having a melting range from 112 to
115.5 C.
Part D Preparation of third intermediate, 4-Cyano-
4-phenylcyclohexanone 9 ethylene ketal
Follow~ng the procedure of Example 1, Part D, but
substituting 10.0 gm. (0.05 mole) of 4~cyano-4-phenyl-
cyclohexanone (prepared in Part CD aboYe) for the 4-(p-


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32~6
S16

,
chlorophenyl)-4-cyanocyclohexanone and using 2.85 ml.
(3.17 gm., 0.051 mole) of the ethylene glycol, 0.12 gm.
of the p-toluenesulfonic acid, and 90 ml. of the benzene
solvent instead of the 4.8 ml., the 0.21 gm., and the
150 ml., respectively, there is obtained 11.27 gm. ~92%
y~eld) of the desired 4-cyano-4-phenylcyclohexanone,
ethylene ketal as crystals having a melting range of 120
to 122.5 C.
Analysis:
Calc'd. for Cl5HI7NO2:
C, 74.05; H, 7.04; N, 5.76.
Found: C, 74.10; H, 6.98; N, 5.77.
Part E Preparation of fourth intermediate, 4-Carboxy-
4-phenylcyclohexanone, ethylene ketal
Following the procedure of Example-l, Part E, but
substituting 11.27 gm. (0.0464 mole) of 4-cyano-4-phenyl-
cyclohexanone, ethylene ketal (prepared in Part D9 above)
for the 21.87 gm. of the 4-(p-chlorophenyl) 4-cyanocyclo-
hexanone, ethylene ketalg and using 11.3 gm. ~0.2 mole)
of the potassium hydroxide, and 90 ml. of the ethylene
glycol instead of the 22.0 gm. and 220 ml., respectively,
there is obtained 10.51 gm. (86% yield~ of the desired
4-carboxy-4-phenylcyclohexanone, ethylene ketal as
crystals having a melting range from 736 to 140.5 C.
Analysis:
Calc'd. for CI~Hl80~:
C, 68.68; H, 6.920
Found: C, 68.27; H, 6.90~
Part F Preparation of`f~fth inte~mediate, 4-Iso-
cyanato-4-phenylcyclohexanone, ethyl ne ketal

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3286
516

~ollowlng the procedure of Example lg Part F, but
substituting 2.62 gm. (0.01 mole) of 4-carboxy-4-phenyl-
cyclohexanone ethylene ketal (prepared in Part E, above)
for the 15.79 gm. of the 4-carboxy-4-(p~chlorophenyl)-
cyclohexanone, ethylene ketal and using 1.38 ml. (1.01 gm.,
0.01 mole) of the triethylamineg 25 ml. of the anisole,
2.75 gm. of the diphenylphosphonic azide9 and a 400 ml.
silica gel column instead of the 7.4 ml. (5.36 gm.9 0.532
mole~, the 135 ml., the 14.7 gm.9 and the 1500 ml. column,
respectively, there is obtained 1.94 gmO (75% yield) of
the desired 4-isocyanato-4-phenylcyclohexanone9 ethylene
ketal which has a melting range from 47 to 50 C.
Anal~
Calc'd. for ClsHl7N03:
C, 69.48; H, 6.61; N9 5.40.
Found: C, 69.56; H, 7.01; N, 5.39.
Part G Preparation of sixth intermediate, 4-Methyl-
amino-4-phenylcyclohexanone, ethylene ketal
hydrochloride
A solution consisting of 0.96 gm. (0.0037 mole) of
4-isocyanato-4-phenylcyclohexanone, ethylene ketal. (pre-
pared in Part F, above) and 15 ml. tetrahydrofuran is
added to a well-stirred suspension prepared by dispersing
0.20 gm. (0.0053 mole) lithium aluminum hydride in 5 ml.
tetrahydrofuran. The resulting reaction mixture is heated
at the reflux temperature with stirring for four (4)
hours. The mixture is then allowed to cool before chilling
~t in an ice-bath. To the chilled mixture is added 0.2 ml~
water, 0.2 ml. 15% aqueous sodium hydroxide, and a further
0.6 ml. water. A gelatinous prec~pitate forms and the whole

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3 286
11(}~?516

preparation is poured onto a filter. The filtrate is
collected and the volatile components are removed by
evaporation under reduced pressure. The residue thus
obtained is dissolved in a small amount of diethyl ether
and 3 N hydrogen chloride in ether is added to the solution
to give the desired, insoluble acid addition saltO A~ter
collecting the crude salt on a filter and recrystallizing
it from a mixture of methylene chloride and ethyl acetate,
there is obtained 0.82 gm. (78% yield) of 4-methylamino-
4-phenylcyclohexanone, ethylene ketal hydrochloride having
a melting point at 243 to 245 C.
Analysis:
Calc'd. for ClsH22ClN02
C, 63.48; H, 7.82, N, 4.94.
Found: C, 63.51; H, 7.89; N, 5.00.
Part H Preparation of object compound, 4-Dimethyl-
amino-4-phenylcyclohexanone, éthylene ketal
hydrochloride
A reaction solution consisting of the free base from
1.0 gm. (0.00354 mole) 4-methylamino-4-phenylcyclohexa-
none, ethylene ketal hydrochloride (prepared as in Part
G, above), 3.5 ml. 37% formalin, and 12 ml. methanol is
heated at the reflux temperdture for four (4) hours. This
reaction mixture is allowed to cool to room temperature
before chilling it in an ice-bath. Small portions of
sodium borohydride are cautiously added with stirring, to
a total amount of 0.48 gm. (0.125 mole)O Stirring is
continued at 25 C. for two (2) hours 9 and then the
volatile solvents are removed b~ evaporation under reduced
pressure. The residue thus obtained ~s dlspersed In a

~70-
.

3286
~ 5 1~
mixture of 50 ml. methylene chloride and lO ml. water
and the llqu~ds are allo~ed to separate. The methylene
chloride phase is recovered and washed wlth water and
then with br~ne. After remov~ng the methylene chloride
solvent by eYaporat~on under reduced pressure, the residue
~s dissolved in a small amount of ether. A solution o~
hydrogen chloride in ether (3 N) is added so as to produce
the hydrochloride acid addition salt which precipitates
out. The precipitate is collected on a filter and
recrystallized from a mixture of methylene chloride and
ethyl acetate to give 0.72 gm. (68% yield) of the desired
final product, 4-dimethylamino-4-phenylcyclohexanone,
ethylene ketal hydrochloride having a melting range from
226 to 22g C. An analytical sample is obtained by
recrystallization from methylene chloride and ethyl
acetate having a melting range from 236 to 238 C.
Analysis:
Calc'd. for Cl6H24ClN02:
C, 64.52; H, 8.12; N, 4.70.
Found: C, 64.47; H, 7.85; N9 4.920
Examp1e 18 Preparation of 4-Dimethylamino-4-phenylcyclo-
hexanone
Following the procedure of Example 2, but substituting
l3.66 gm. (0.052 mole~ 4-dimethylamino-4-phenylcyclohex-
anone, ethylene ketal (prepared in Example 17, Part H,
above) for the 4.52 gm. of the 4-(p-chlorophenyl)-4-dimethyl-
aminocyclohexanone, ethylene ketal hydrochloride and using
70 ~l. 2.5 N hydrochloric acid and 14 ml. me~hanol instead
of the 22.5 ml. and 45 ml.9 respectively9 there is prepared
7.76 gm. (69% y~eld) of 4-dlmethylam~no-4-phenylcyclo-

32~6
S~6

hexanone having a melting point at 98 to 99.5 C. An
analytical sample has a melting range at 100 to 103Q C.
Analysis:
Calc'd. for Cl4HlgN0: .
C, 77.38; H, 8.~1; N~ 6.45
Found: C, 77.39i H, 8.86; N, 6.41.
Example 19 Part A
Following the procedure of Example 1, Part A, but
substituting the primary reactant p-bromophenyl acetoni-
trile for the p-chlorophenyl acetonitrile and modifying
other factors of the procedure as noted in Table Ag there
is prepared the corresponding precursor dimethyl ester of
4-(p-bromophenyl)-4-cyanopimelic acid as an oil.
Example 20 Part A
Followlng the procedure of Example 1, Part A9 but
substituting the primary reactant m-chlorophenyl aceto-
nitrile for the p-chlorophenyl acetonitrile and modifying
other factors of the procedure as noted in Table A, there
is prepared the corresponding precursor dimethyl ester of
20 - 4-(~-chlorophenyl)-4-cyanopimelic acid as an oil.
Example 21 Part A
Following the procedure of Example 1, Part A, but
substituting the primary reactant 3,4-dichlorophenyl
acetonitrile for the p-chlorophenyl acetonitrile and
modifying other factors of the procedure as noted in Table
A, there is prepared the corresponding precursor dimethyl
ester of 4-(3,4-dichlorophenyl)-4-cyanopimelic acid as an
o~l.
Example 22 Part A
Following the procedure of Example ls Part A~ but

-72O

328~


substituting the primary reactant 2,4 dichlorophenyl
acetonitr~le for the p-chlorophenyl acetonitrile and
modifying other factors of the procedure as noted in
Table A, there is prepared the corresponding precursor,
dimethyl ester of 4-(2,4-dichlorophenyl)-4-cyanopimelic
acid as an oil.



' -:




-73-

3286
16

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-74-

~ 5 16 3286


Example 19 Part B
Following the procedure of Example 1, Part B, but
substituting the precursor, dlmethylester of 4-(p-bromo-
phenyl)-4-cyanop~melic acld (prepared in Part A, above)
for the 34.97 gm. of the dimethyl ester of 4-(p-chloro-
phenyl)-4-cyanopimelic acid and modifying other factors
of the procedure as noted in Table B, there is prepared the
corresponding first intermediate 4-(p-bromophenyl)-2-carbo-
methoxy-4-cyanocyclohexanone as crystals having a melting
range at 164 to 166 C.
Ana1ysis:
Ca1c'd. for ClsHI4BrNO3:
C, 53.59; H, 4.20; N, 4.51.
Found: C, 53.49; H, 4.46; N, 4.29.
Example 20 Part B
Following the procedure of Example 1, Part B, but
substituting the precursor, dimethyl ester of 4-(m-chloro-
phenyl)-4-cyanopimelic acid (prepared in Part A, above) for
the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-
4-cyanopimelic acid and modifying other factors of the pro-
cedure as noted in Table B, there is prepared the corres-
ponding first intermediate, 2-carbomethoxy-4-(m-chloro-
phenyl)-4-cyanocyclohexanone as crystals having a melting
po~nt at 123.5 to 125.0 C.
Analysis:
Calc'd. for Cl5HI~ClNO3:
C, 61.75; H~ 4.84; N, 4~800
Found; C, 61.52; H, 4.96; N9 4.86.
Example 21 Part B
Followlng the procedure of Example 1, Part BD but

-75

3286
lla~s~6


substituting the precursor, dimethyl ester of 4-(3,4-d1-
chloropheny1)-4~cyanop1melic actd (prepared in Part A,
above) for the 34~97 g~. of the dimethyl ester of 4-(p-
chlorophenyl)-4-cyanopime1ic acid and modifying other
factors of the procedure as noted in Table B, there is
prepared the corresponding first intermiedate 2-carbo-
methoxy-4-(3,4-dichlorophenyl)-4-cyanocyclohexanone as
crystals having a melting.range at 82 to 87 C. An
analytical sample recrystallized from diethyl ether has a
melting point at 112 to 113 C.
Analysis:
Calc'd. for Cl5H,3Cl2N03:
C, 55.23; H, 4012; N, 4.30.
Found: C, 55.47; H, 4.07; N, 4.48.
Example 22 Part B
Following the procedure of Example 1, Part B, but
substituting the precursor, dimethyl ester of 4-(2,4-di-
chlorophenyl)-4-cyanopimelic acid (prepared in Part A,
above) for the 34.97 gm. of the dimethyl ester of 4-(p-
Z0- chlorophenyl)-4-cyanopimelic acid and modifying other
factors of the procedure as noted in Tab1e B, there is
prepared t-he corresponding first intermediate 2-carbo-
methoxy-4-(2,4-dichlorophenyl)-4-cyanocyclohexanone as
a gum.




-760

3286
S ~6

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77
_

3286
Sl~

Exa,~ple 19 Part C
Followlng the procedure o~ Example 1, Part C, but
substitut~ng the f~rst lntermediate 4-(p bromophenyl)-
2-carbomethoxy~4-cyanocyclohexanone, (prepared in Part B,
above~ for the 29.8 gm. of the 2-carbomethoxy-4-(p-chloro-
phenyl)-4-cyanooyclohexanone and modifying other factors
of the procedure as noted in Table C, there is prepared
the correspondtng second intermediate 4-tp-bromophenyl)-
4-cyanocyclohexanone as crystals having a melting range
at 110 to 113 C.
Analysis:
Calc'd. for Cl3Hl2BrN0
C, 56,13, H, 4.35; N9 5.04.
Found: C, 56.35; H, 4.34; Ns 5.06.
Example 20 Part C
Following the procedure of Example 1, Part C, but
substituting the first intermediate, 2-carbomethoxy-
4-(m-chlorophenyl)-4-cyanocyclohexanone (prepared in Part
B~ above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-
chlorophenyl.)-4-cyanocyclohexanone and mod;fying other
factors of the procedure as noted in Table C, there is
prepared the corresponding second intermediate9 4-(m-chloro-
phenyl)-4-cyanocyclohexanone as crystals having a melting
range at 71 to 73.5 C.
Calc'd. for Cl3Hl2ClN0
. C, 66.81; H, 5.18i N7 5.99.
Found: C9 66.91; H, 5.11; N9 5.95O
Example 21 Part C
Follow~ng the procedure of Example li Part C, but

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.

3286
~ 5 ~6

subst~tuting the first ~ntermediate, 2-carbo~ethoxy-
4-(3,4-dichlorophenyl)-4-cyanocyclohexanone, (prepared
ln Part B, above) for the 29.8 gm. of the 2-carbomethoxy-
4~(p-chlorophenyl)-4-cyanocyclohexanone and modifying
other factors of the procedure as noted in Table C, there
is prepared the corresponding second intermediate,
4-(3,4-dichlorophenyl)-4-cyanocyclohexanone as crystals
having a melting point at l56 to l57.5 C.
Analysis:
Calc'd. for Cl3HllCl2N0:
C, 58.22; H, 4.14; N~ 5.22.
Found: C, 58.61; H, 4.37; N, 5.50.
Example 22 Part C
Following the procedure of Example l, Part C, but
substituting the first intermediate 2-carbomethoxy-4-(2,4-
dichlorophenyl)-4-cyanocyclohexanone (prepared in Part B,
above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chloro-
phenyl)-4-cyanocyclohexanone and modifying other factors
of the procedure as noted in Table C, there is prepared
the corresponding second intermediate 4,(2,4-dichlorophenyl)-
4-cyanocyclohexanone as crystals having a melting range
at 119 to 122.5 C.
Analysis:
Calc'd. for Cl3HllCl2N0:
C, 58.22; H, 4.l4; N9 S.Z2.
Found: C, 58.21; H, 3.g5; N9 5.41.




-79-

3286
11Ç)~516

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a~ ~ d ~ O
S. C ~ C _
_ ~1.~ 0 E C
_ ~ o O
a
~ ~ C ~ O a
o ~ a o
Cn~
~.,in X
C ~ OU ~ ~ .~
._ OEn~ ~ 0 0 O -- IU
o ~ ~ ~
~ ~ ~g ~ ~ E
o s t~ ~,c cn
V Io ~ . N al S.
~Q~ OO O ~ a
1~ 3 ~ ~ 0! 3 C~


-80-


,

3286


Example 19 Part D
Following the procedure of Example 1, Part D, but
substituting the second intermediate9 4-(p-bromophenyl)-
4-cyanocyclohexanone (prepared in Part C, above) for the
19.49 gm. of the 4-(p-chlorophenyl)-4-cyanocyclohexanone
and modifying other factors of the procedure as noted
in Table D, there is prepared the corresponding third
intermediate, 4-(p-bromophenyl)-4-cyanocyclohexanone,
ethylene ketal as crystals having a melting range at 127
to 131 C.
Analysis:
Calc'd. for Cl sHl 6BrN02:
C, 55.91; H, 5.00; N~ 4.35.
Faund: C, 55.78; H, 5.13; N, 4.39.
Example 20 Part D
Following the procedure of Example 1, Part D, but
substituting the second intermediate, 4-(m-chlorophenyl)-
4-cyanocyclohexanone (prepared in Part C, above) for the
19.49 gm. of the 4-(p-chlorophenyl)-4-cyanocyclohexanone
and modifying other factors of the procedure as noted in
Table D, there is prepared the corresponding third
intermediate, 4-(m-chlorophenyl~-4-cyanocyclohexanone,
ethylene ketal as crystals having a melting range at
68 to 71 C.
Analysis:
Calc'd. for Cl5HI 6Cl N02:
C, 64.86; H, 5.81; N, 5.04.
Found: C, 64.94; H, 5.91; ND 4.81
Example 21 Part D
Fotlowing the procedure of Example 1, Part D, but

-81-

32~6
`S16

substltuting the second intermediate, 4~(3,4-dichloro-
phenyl)~4 cyanocyclohexanone, (prepared ~n Part C, above)
for the 19.4g gm~ of the 4~(p-chlorophenyl)-4-cyanocyclo~
hexanone and modifylng other factors of the prosedure
as noted in Table D, there is prepared the corresponding
third intermediate, 4-(3,4-dichlorophenyl)-4-cyanocyclo-
hexanone, ethylene ketal as crystals having a melting
range at 120.5 to 123 C.
Analysis;
Calc'd. for C~sHlsCl2N02: ,
C, 57.51; H, 4.84; N, 4.49.
Found: C, 57.44; H, 5.05; N9 4.50.
Example 22 Part D
Following the procedure of Example 1, Part D, but
substituting the second intermedlate, 4-(2,4-dichloro-
phenyl)-4-cyanocyclohexanone (prepared in Part C, above)
for the 19.49 gm. of the 4-(p-chlorophenyl)-4-cyanocyclo-
hexanone and modifying other factors of the procedure as
noted in Table D, there is prepared the corresponding
third intermediate, 4-(2,4-dichlorophenyl)-4-cyanocyclo-
hexanone, ethylene ketal as crystals having a meltin~
range at 109.5 to 112.0 CO
Ana~ysis:
Calc'd. for ClsHlsCl2N02:
C, 57.71; H, 4.84; N, 4.49.
Found: C~ 57.709 H~ 4.81; N9 4.71O




~82

3~86


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e
a) ~~
_~ ~ e a~
Q r~ In O r- O ~ L ~ ~ C r
E C~J ~ O ~ ~ O
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LLI ~' E ~ ~ c I



~~C~ ~t m ~ N
Q ~IS~ r .- O O d-
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1~ C~ ~ ~) O 1
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, LIJ ~

S E
0 a
Q~ _ r- O
r u~ 00 r
Q ~ ~L~) i O C ~ ~ I~
E O~ O ~ ~ a~ --
o~ J o o a c~ ~ o a~
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~ l~ o o - o o
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a~ x
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cn
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~ . ~
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a~ ,- 4- ~
E
C E
~~ o a_
s-. - ~ c ^ o
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a~ ~ co _ E 1
t~ O O ~~ O L
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s_ ~1 ~ c
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~~ ~ ~ _a~ ~ ~ c
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~~ o o a~ o
1~_ 3 ~ ~ 3 ~ ~ 3 C~

-83




:

~ 5 ~ 6 32~6


Example 19 Part.E
Following the procedure of Example 1, Part E, but
substituting the third intermediate9 4-(p-brumophenyl)-
4-cyanocyclohexanone, ethylene ketal, (prepared in Part
D, above) for the 21.87 gm. of the 4-(p-chlorophenyl)-
4-cycnocyclohexanone, ethylene ketal and modifying other
factors of the procedure as noted in Table E, there is
prepared the corresponding fourth intermediate, 4-(p-bromo-
phenyl)-4-carboxycyclohexanone, ethylene ketal as crystals
having a melting range at 176 to 178 C.
Ana1ysis:
Calcld. for C,5Hl7BrO4:
C, 52.80; H, 5.02.
Found: C, 53.40; H, 4.92.
lS Example 20 Part E
Following the procedure of Example 1, Part E, but
substituting the third intermediate, 4-(m-chlorophenyl)-
4-cyanocyclohexanone, ethylene ketal, (prepared in Part
D, above) for the 21.87 gm. of the 4-(p-chlorophenyl)-
20 - 4-cyanocyclohexanone, ethylene ketal and modifying other
factors of the procedure as noted in Table E, there is
prepared the corresponding ~ourth intermediate, 4-carboxy-
4-(m-chlorophenyl)cyclohexanone 9 ethylene ketal as
crystals having a melting point at 14C to 141.5 C.
Analysis:
Calc'd. for ClsHl 7 ~104:
C, 60.71; H, 5.78.
Found: C, 60.51; H, 5.780
~ e~ Part E
Follow~ng the procedure of Example 1, Part E, but

~4~

3286
S~6

substituting the third intermediate, 4-~3,4-dichloro-
phenyl)-4-cyanocyclohexanone, ethylene ketal (prepared
in Part D, above) for the 21.87 gm. of the 4~(p-chloro-
phenyl)-4-cyanocyclohexanone, ethylene keta1 and modifying
other factors o~ the procedure as noted in Table E, there
~s prepared the corresponding fourth intermediate, 4-car
boxy-4-(3,4-dichlorophenyl)cyclohexanone, ethylene ketal
as crystals having a melting range at 119 to 121.5 C.
- Analysis:
Calc'd. for ClsHl6cl2o4
C, 54.39; H, 4.87~
Found: C, 54.69; H, S.ll.
Example 22 Part D
Following the procedure of Example 1, Part E, but
substituting the third intermediate, 4-(2,4-dichloro-
phenyl)-4-cyanocyclohexanone, ethylene ketal (prepared
in Part D, aboYe) for the 21.87 gm. of the 4-(p-chloro-
phenyl)-4-cyanocyclohexanone, ethylene ketal and modifying
other factors of the procedure as noted in Table E, there
is prepared the corresponding fourth intermediate, 4-car-
boxy~4-(2,4-dichlorophenyl)cyclohexanone, ethylene ketal
as crystals having a melting range at 192 to 195.5 C.
Analysis:
Calc`d. for Cl sHl 6cl 24
C, 54.39; H, 4.87.
Found: C, 54.63; H, 5.03.




8 5 ~

3286
llQC~S16

a~ c~ '~ ~ a,~
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~ o o o ~, . ~ ~ .
E N .C O >~ ~N O
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al E
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E ~ o ~ ~ L aJ a-
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LLI ~ F ~5 ~ Q


~ r--
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C~.1~ O C~.l S ~>~ L C C e:t ~
E o ~ Q~s o s ~cS co
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s^ a) ,--
al c ~ ~
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LLI rIr~~ ~ . ~ . ~. . aJ ~D O
~ O O~ X O S L :~ L C C U~
LL~~ O~ ' -Cl O ~ ~V S O S ~ . C~J
J~ rt~ OO ~ O V S ~ r-- ~ X C~
a:~ x r-~' ~7 ~ O ~ ~ ~ S aJ ~ r~ `~
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a~ ~ o ~
a~ ~ E ~ c
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v~ o s ~
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_ C~ ~ o o _ ~ o ~
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O'~ V
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LL 3 ~ 3 ~ S 3 1

-86 -

32~6
S16

Example l9 Part F
Following the procedure of Example 1, Part F, b~t
substituting the fourth intermediate, 4-(p-bromophenyl)-
4-carboxycyclohexanone, ethylene ketal, (prepared ;n
Part E, above) for the 15.79 gm~ of the 4-carboxy-4-(p-
chlorophenyl)cyclohexanone, ethylene ketal and modifying
other factors of the procedure as noted in Table F, there
is prepared the corresponding fifth intermediate, 4-(p-
bromophenyl)-4-isocyanatocyclohexanone, ethylene ketal
as crystals having a melting range at 87 to 89 C.
Analysis;
Calc'd. for Cl5Hl6BrN03:
C, 53.27; H, 4.77; N, 4.14.
Found: C, 53.43; H, 4.89; N, 4.02.
Example 20 Part F
Following the procedure of Example 1, Part F, but
substituting the foruth intermediate, 4-carboxy-4-(m~
chlorophenyl)cyclohexanone, ethylene ketal (prepared in
~art E, above) for the 15.79 gmO of the 4-carboxy-4-~p-
chlorophenyl)cyclohexanone, ethylene ketal and modifying
other factors of the procedure as noted in Table F, there
is prepared the corresponding fifth intermediate, 4-(m-
chlorophenyl~-4-isocyanatocyclohexanone, ethylene ketal
as a gum having an I.R. maximum at about 2290 cm.~l.
Example 21 Part F
Following the procedure of Example 1, Part F, but
substitut~ng the fourth lntermediate~ 4-carboxy-4-(3,4-
d~chlorophenyl)cyclohexanone, ethylene ketal (prepared
ln Part E, above) for the 15579 gm. of the 4-carboxy-
4-(p-chlorophenyl)cyclohexanone5 ethylene ketal and modify-

; 8 7 ~ .

-` llQ~`516 . 3286


ing other factors of the procedure as noted in table F,
there ls prepared the correspondlng fifth intermediate,
4-(3,4-dichlorophenyl)-4-isocyanatocyclohexanone, ethylene
ketal as an oil having an I.R. maximum at about 2250 cm.~'.
Example 22 Part F
Following the procedure of Example 1, Part F, but
substituting the fourth intermediate, 4-carboxy-4-(2,4-
dichlorophenyl)cyclohexanone, ethylene ketal ~prepared
in Part E, above) for the 15.79 gm. of the 4-carboxy-
4-(p-chlorophenyl)cyclohexanone, ethylene ketal and modi-
fying other factors of the procedure as noted in Table F3
there is prepared the corresponding fifth intermediate,
4-(2,4-d;chlorophenyl)-4-isocyanatocyclohexanone, ethylene
ketal as crystals having a melting range at 85 to 89.5 C.
Analysis:
Calc'd. for Cl sHl 5Cl 2NO3:
C, 54.89; H~ 4.61i N, 4.27.
Found: C, 55.02; H5 4.61; N, 4.36.




-8~-

3286
516

U
'~' ~ +~ C L O S_
E N _ O . . ~ ~ E c o ~ ~ L a~ -
t0 N ~ ~ ~ ~ C~ 1~1 ~ OJ GJ I aJ ~~ ~ C OQ t--.
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. ~ ~ a aJ Q aJ
.

,
r~
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CL ~ O 1~ . ~ r 0 ~ ~ r~
E r- . . ~ ~ O >~ O
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X ~ ~ O . O ~ ~.) ~ ~ -- I (~
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a1 ,t, c a
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s_ o ~ s. ~~ ~ N
a ~~ ~ c~
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-89~

3286
~ 5 1 6

Example l9 Part G
Follow~ng the procedure of Example 1, Part G, hut
substltuting the fifth intermediate, 4-~p-bromophenyl)-
4-isocyanatocyclohexanone, ethylene ketal (prepared in Part
F, above) for the 6~62 gm. of the 4-(p-chlorophenyl)-4-iso-
cyanatocyclohexanone, ethylene ketal, modifying other
factors of the procedure as noted in Table G, and ;nclud-
ing the additional step of dissolving the residue from
the filtrate into a small amount of diethyl ether and
treating this solution with sufficient 3 N hydrogen
chloride in ether to form the hydrochloride acid addition
salt, there is- prepared the corresponding sixth inter-
mediate, 4-(p-bromophenyl)-4-methylaminocyclohexanone,
ethylene ketal hydrochloride as crystals having a melting
point at 266 to 267 C.
Analysis:
Calc'd. for ClsH2~BrclNo2:
C, 48.99; H, 5.76; N, 3.81.
Found: C, 48.59; H, 5.46; N, 3.63.
Example 20 Part G
Following the procedure of Example l, Part G~ but
substituting the fifth intermediate, 4-(2,4-dichloro-
phenyl)-4-isocyanatocyclohexanone, ethylene ketal (pre-
pared in Part F, above) for the 6.62 gm. of the 4-(p-
chlorophenyl)-4-isocyanatocyclohexanone9 ethylene ketal,
modifying other factors of the procedure as noted in Table
G. and ~ncluding the additional step of dissolving the
residue from the filtrate into a small amount of diethyl
ether and treat~ng this solution with sufficient 3 N
hydrogen chlor~de in ether to form the hydrochloride acid

- -90-

32~6
516

add~t~on salt, there ls prepared the correspondtng sixth
fntermed1ate, 4-(m~chlorophenyl) 4-methylam~nocyclohexa-
none, ethylene ketal hydrochloride as crystals having a
melttng range at 252 to 254 C.
Analysis:
Calc'd~ for Cl5H2lC12N02:
C, 56,61, H, 6.65; N, 4,40.
Found. C, 56~74; H, 6.68; N, 4.64.
Example 21 Part G
Following the procedure of Example 19 Part G, but
substituting the fifth intermediate, 4-(3,4-dichloro-
phenyl)-4-isocyanatocyclohexanone, ethylene ketal (prepared
in Part G, above) for the 6.62 gm. of the 4-(p-chloro-
phenyl)-4-1socyanatocyclohexanone, ethylene ketal, modify-
ing other factors of the procedure as noted in Table G,
and ~ncluding the additional step of dissolving the residue
from the filtrate into a smal1 amount of diethyl ether
and treating this solution with sufficient 3 N hydrogen
chloride in ether to form the hydrochloride acid addition
~0 salt, there is prepared the corresponding sixth inter-
mediate, 4-(3,4-dichlorophenyl)-4-methylaminocyclohexanone,
ethylene ketal hydrochloride as crystals having a melting -
range at 225 to 227 C.
Analysis:
Calc'd. for ClsH2ocl3No2o
C, 51.08; H~ 5.72; N9 3.97.
Found: C, 51.49; H, 5.91; N9 4.200
Example 22 Part G
Foll~w~ng the procedure of Example 1, Part G, but
subst~tuting the ftfth 1ntermediate9 4-~2,4-d~chlorophenyl)-



,

'S ~ 6 . 3286

4~isocyanatocyclohexanone, ethylene ketal ~prepared ~n
Part F, above) for the 6.62 gm. of the 4-(p chlorophenyl)-
4-~socyanatocyclohexanone, ethylene ketal, modify~ng
other factors o~ the procedure as noted in Table G, and
including the additional step of dissolv~ng the residue
from the filtrate into a small amount of diethyl ether
and treat;ng this solution with sufflcient 3 N hydrogen
chloride in ether to form the hydrochloride acid addition
salt, there is prepared the corresponding sixth inter-
mediate, 4-(2,4-dichlorophenyl)-4-methylaminocyclohexanone,
ethylene ketal hydrochloride as crystals having a melting
range at 201 to 2.305 C.
Analysis:
Calc'd. for ClsH2ocl3No2~l/3H2o
C, 50.22, H, 5.62; N9 3.91.
Found: C, 50.42; H, 5.92; N, 3.80.




-92-

32~6


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~ ~ ~. a~ _.
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+ i
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3 ~: ~ ~ ~n 1~ ~ ~ C~ 3 1:~

-93-

.328B
06}'51~i
,
Example 19 Part H
Follow~ng the procedure of Example l, Part H, but
subst~tuting the free base from the sixth intermediate,
4-(p-bromophenyl)~4-methylaminocyclohexanone, ethylene
ketal hydrochloride, (prepared in Part G, above) for the
4.68 gm. of the 4-(p-chlorophenyl)-4-methylaminocyclohex-
anone, ethylene ketal free base, and modifying other
fact~rs of the procedure as noted in Table H, there is
prepared the corresponsing object compound, 4-(p-bromo-
phenyl)-4-dimethylaminocyclohexanone, ethylene ketal
hydrochloride as crystals having a melting point at 254
to 255.5 C.
Analysis:
Calc'd. ~r Cl6H23BrClN02:
C, 51.01; H, 6.14, N, 3.72.
Found: C, 51.29; H, 6.30; N, 3.85.
Example 20 Part H
Following the procedure of Example 1, Part H, but
substituting the free base from the sixth intermed;ate,
20- 4-(m-chlorophenyl)-4-methylaminocyclohexanone, ethylene
ketal hydrochloride, (prepared in Part G, above) for the
5.68 gm. of the 4-(p-chlorophenyl)-4-methylaminocyclohex-
anone, ethylene ketal free base and modifying other
factors of the procedure as noted in Table H, there is
prepared the corresponding object compound, 4-(m-chloro-
phenyll-4-dimethylaminocyclohexanone, ethylene ketal
hydrochloride as crystals having a melting range at 224
to 227 C.
Analysis:
Calc'd. for C,6H23Gl2N02:

. -94-

-3286
516

C, 57.83; H, 6.98; N, 4.22~
Found; C, 57.71; H, 7.03, N, 4.310
Example ?l Part H
Follow~ng the procedure of Example 1, Part H, but
substituting the free base from the sixth intermediate~
4-(3,4-dichlorophenyl)-4-methylaminocyc10hexanone,
ethylene ketal hydrochloirde (prepared in Part G, above)
for the 5.68 gm. of the 4-(p chlorophenyl~-4-methylamino-
cyclohexanone, ethylene ketal free base and modifying
other factors of the procedure as noted in Table H, there
is prepared the corresponding object compound, 4-(3,4-di-
chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal
as crysta1s haYing a melting range at 77~ to 81 C.
Analysis:
Calc'd. for C~6H2lC12N02:
C, 58.19, H, 6.41; N, 4.24. .
Found: C, 58.30; H, 6.38; N1 4.48.
Example 22 Part H
Following the procedure of Example 1, Part H, but
substituting the free base from the sixth intermediate,
4-(2,4-dichlorophenyl)-4-methylaminocyclohexaone, ethy1ene
ketal hydrochloride, (prepared in Part G, above) for the
5.68 gm. of the 4-(p-chlorophenyl)-4-methylaminocyclohex-
anone, ethylene ketal free base and modifying other factors
of the procedure as noted in Table H, there is prepared
the corresponding object compound9 4-(2,4-dichlorophenyl)-
- 4 dimethylaminocyclohexanone~ ethylene ketal hydrochloride
as crystals hav1ng a melting range at 229.5 to 232 C.
Analys~s:
Calc'd. for Cl6H22C13N020~H200

-95- -

3286
5~6

C, 51.14; H, 6.17; N, 3~73
~ound: C, 51.47; H, 6.28; N, 3~99




- 9 6 -

3286
16

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-97-

3286
516

.
Example 23
Follow~ng the procedure as described in Example 2, but
separately substituting the object compound, 4-(p-bromo-
phenyl~-4~dlmethylaminocyclohexanone, ethylene ketal hydro-
chloride (prepared in Example 19, Part H, above) for the
4.52 gm. of the 4-(p-chlorophenyl)-4-dimethylaminocyclo-
hexanone, ethylene ketal hydrochloride and modifying
other factors of the procedure as noted in Table J, there
is prepared the corresponding further object compound,
4-(p-bromophenyl)-4-dimethylaminocyclohexanone as crystals
having a melting range at 115 to 118 C.
Analysis:
Calc'd. for Cl4Hl8BrN0:
C, 56.76; H, 6.12; N, 4.73.
Found: C, 56.79, H, 6.14; N, -1.91.
Example 24
Following the procedure as described in Example 2, but
substituting the object compound, 4-(m-chlorophenyl)-4-di-
methylaminocyclohexanone, ethylene ketal hydrochloride
(prepared in Example 20, Part H, above) for the 4.52 gm.
of the 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal hydrochloride and modifying other factors
of the procedure as noted in Table J~ there is prepared
the corresponding further object compound, 4-(m-chloro-
phenyt)-4-dimethylaminocyclohexanone~ as crystals having
a melting range at 93 to 95 C.
Analysis:
Calc'd. for Cl 4Hl 8Cl N0:
C, 66.79; H~ 7.21; N9 5.59O
Found: C, 67.35D HD 7.33; N9 5.87.

-98~

~ S~6 3286


Example 25
Following the procedure as described in Example 2,
but substituting the ob~ect compound9 4-(3,4-dich10ro-
phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydro-
chloride (prepared in Example 21, Part H9 above) for the
4.52 gm. of the 4-(p-chlorophenyl)-4-dimethylaminocyclo-
hexanone, ethylene ketal hydrochloride and modifying other
factors of the procedure as noted in Table J, there is
prepared the corresponding further object compound,
4-(3,4-dichlorophenyl)-4-dimethylaminocyclohexanone as
crystals having a melting range at 88.5 to 91 C.
Analysis:
Calc'd. for Cl4HI7Cl2NO:
C, 58.75; H, 5.99; N, 4.99.
15Found: C, 59.02; H, 6.14; N, 5.22.
Example 26
Following the procedure as described in Example 2,
but substituting the object compound, 4-(2,4-dichloro-
phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydro-
20 - ch10ride (prepared in Example 22, Part H, above) for the
4.52 gm. of the 4-(p-chlorophenyl)-4-dimethylaminocyclo-
hexanone, ethylene ketal hydrochloride and modifying other
factors of the procedure as noted in Ta~le J, there is
prepared the corresponding further object compound,
4-(2,4-dichlorophenyl)-4-dimethylaminocyclohexanone, as
crystals having a melting range at 116.5 to 120 C.
Analysis:
Calc'd. for C~ 4HI 7Cl ~N0:
C, 58.75; H, 5.99; N9 4.900
30Found: C, 58.84; H, 6025; N, 4087.

_99_

516 3286


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- 1 00 -


j

3286
S16

Exam~ 2? Prep~ration of 4-dimethylamino-4-(2-thienyl)-
cyclohexanone, ethylene ketal
Part A Preparation of Dimethyl 4-(2-thienyl)-
4-cyanopimelate
S A mixture of S.0 9. (0.40~ mole) of 2-thiophene
acetonitrile and 19 ml. of methyl acrylate in 20 ml. t-
butyl alcohol is brought to reflux. The heat is removed
and there is added quickly 6.5 ml. of 40% methanolic Triton
B~ in 9 ml. t-butyl alcohol. Following 4 hours heating
at reflux the mixture is allowed to cool and diluted with
water and benzene~ The organic layer is separated, washed
in turn with 2;5 N hydrochloric acid, water and brine and
taken to dryness. The residue is distilled first at 40
mm Hg to remove low-boiling by-products 9 then at O.OS mm
H~ to afford the product as an oil. There is obtained
7.70 9. (73%) of pimelate, boi1ing point 162-18~ C.
Part B Preparation of 4-(2-thienyl)-4-cyano-2-carbo-
methoxycyclohexanone
To a solution of 8.80 9. (0.0298 mole) of dimethyl-
4-(2-thienyl~-4-cyanopimelate (prepared in Part A~ above)
in 200 ml. THF there is added 6.70 9. (0.06 mole) pf
potassium tert-butoxide. Following 4.5 hours' heating at
reflux the mixture is cooled in ice and treated with 47 ml.
2.5 N acetic acid. The organic layer is separated and
diluted with benzene. That solution is washed in turn with
aqueous sodium bicarbonate (NaHC03), water and brine and
taken to dryness. There is obtained 8.0 9. t99%) of
4-(2-th~enyl)-4-cyano-2-carbomethoxycyclohexanone as a
crystalline mater1al, m.p. 76-78 C.
Analysls:

-10

32~6
516

Calc'd. for C~3H,3NO3S:
C, 59.30; H, 4.98; N, 5.32.
Found: C, 59.16; H, 5.13; N, 5.19.
Part C Preparat10n of 4-(2-thienyl)-4-cyanocyclo-
S hexan~ne
A mixture of 8.0 g. (0.0304 mole) of 4-(2-thienyl)-
4-cyano-2-carbomethoxycyclohexanone in 200 ml. acetic acid
and 100 ml. 10% aqueous sulfuric acid is heated on the
steam bath with mechanical stirring for 24 hours. The mix-
ture is then allowed to cool, diluted with water and
extracted thoroughly with benzene. The organic layer is
washed in turn with water, aqueous sodium bicarbonate and
brine and taken to dryness. The residual solid is recrys-
tallized from methylene chloride:Skellysolve B to afford
4.10 9. (66% yield) of 4-(2-thienyl)-4-cyanocyclohexanone,
m.p. 117.5-119 C.
Analysis:
Calc'd. for C1lHllNOS: -
O, 64.36; H, 5.40; N, 6.82.
20Found: C, 64.75; H, 5.49; N, 6.85.
Part D Preparation of 4-(2-thienyl)-4-cyanocyclohex-
anone, ethylene ketal
A mixture of 4.0 9. (0.0195 mole) of 4-(2-thienyl)-
4-cyanocyclohexanone, 1.2 ml. (1.32 9.9 0.02 mole) ethylene
glycol and 0.05 9. p-toluenesulfonic acid in 35 ml. benzene
ls heated at reflux under a Dean-Stark trap for 6 hours.
The solution is then allowed to cool 9 washed in turn with
aqueous sodium bicarbonater water and brine and taken to
dryness. The residual solid is recrystallized from benzene
to g~ve 4.38 9. (9OX yield) of 4-(2-thienyl)-4-cyanocyclo-

-102-

3286
1~ S~6

hexanonet ethylene ketal, m.p. 90.5-92 C.
Analysis:
Calc`d~ for Cl3H,sN02S:
C, 62.62; H, 6.06; N, 5.62.
Found: C, 62.47; H, 5.9~; N, 5.71.
Part E Preparation of 4-carboxy-4-(2-thienyl)cyclo-
hexanone, ethylene ketal
A mixture of 4.98 9. (0.02 mole) of 4-cyano-4-(2-thi-
enyl)cyclohexanone ethylene ketal and 0.70 9. (0.02 mole~
of sodium hydroxide in 40 ml. ethylene glycol is heated
overnight at reflux. The mixture is allowed to cool and
diluted with water. The solution is then cooled in ice,
covered with ether and cautiously acidified. The organic
layer is separated and the aqueous layer is washed twice
more with ether. The extracts are combined, washed once
with brine and taken to drynessO The residual solid is
recrystallized from methylene chloride:Skellysolve B to
afford 4.64 9. (82% yield) of 4-carboxy-4-(2-thienyl)cyclo-
hexanone, ethylene ketal, m.p. 125-127 C.
Analysis:
Calc'd. for Cl3Hl604S:
C, 58.19; H, 6.01.
Found: C, 58.38; H, 5.93O
Part F Preparation of 4-isocyanato-4~(2 thienyl~cyclo-
hexanone, ethylene ketal
To a mixture of 4.64 g. (0.017 mole) of 4-carboxy-4-(2-
thienyl)cyclohexanone ethylene ketal and 2.4 ml . (1.75 9.,
0.017 mole) triethylamine in 60 mlO anisole there is added
4.68 9. diphenylphosphonic azideO The mixture is then
stirred in an oil bath at 90-100 CO for 2 hours; the solvent

-103-

3286
llO~S16

1s removed under oil pump vacuum. The residua1 gum is
chromatographed on 400 ml. sllica gel (elution with 5%
ethyl acetate:Skellysolve B). The appropriate fractions
are combined to give 1.28 9. (28%) of crude isocyanate as
a mobile oil; (~nfrared absorptîon; vmax 2280 cm ~
Part G Preparati on of 4-methylami no-4- ( 2-thienyl)-
cyclohexanone, ethylene ketal hydrochloride
A solution of 2.21 9. (8.3 mmole) of 4-isocyanato-
4-(2-thienyl)cyclohexanone ethylene ketal in 40 ml. tetra-
hydrofuran (THF) is added to a suspension of 0.32 9.(8.4 mmole) of lithium aluminum hydride (LAH) in 5 ml. THF.
Following 4 hours' stirring under reflux the mixture is
cooled in ice. There is then added in turn 0.32 ml. water,
0.32 ml. 15% NaOH and 0.96 ml. water. The inorganic gel
is collected on a filter and the filtrate taken to dryness.
A solution of the residue in a small amount of ether is
treated with a just-sufficient amount of 3 N hydrogen
chloride in ether. The precipitated salt is recrystallized
from methylene chloride:ethyl acetate to afford 0.84 9.
~35~ yield) of 4-methylamino-4-(2-thienyl)cyclohexanone,
ethylene ketal hydrochloride, m.p. 211-214 C.
Analysis: -
Calc'd. for Cl3H20ClNO2S:
C, 53.87; H9 6.96; N, 4.83.
Found: C, 53.47i H9 6.81; N9 5.04.
Part H Preparation of object compound, 4-dimethyl-
~mtno-4-(2-thienyl)cyclohexanone, ethylene
ketal
A solution of the free base from 0.84 9. (2.9 mmole)
of 4-methylamino-4-(2-thienyl)cyclohexanone ethylene ketal

104-

3286
llQ6~S16

hydrochloride and 2.2 ml. 37% formalin in 6.6 ml~ methanol
ls heated at reflux for 4 hours. The m{xture ls cooled in
ice and treated cautiousiy in small portion with 0.27 g. ~-
(7.1 mmole) sodium borohydride. Following 2 hours' stirr-
ing at room temperature the bulk of the solvent is removed
in vacuum. The residue is taken up in methylene chloride
and water. The organic layer is washed with water and
brine and taken to dryness. The residue is recycled twice
through the same reaction conditions and workup. The solid
which is finally obtained is recrystallized twice from
ether (cooling in Dry-Ice:acetone) to afford 0.14 9.
(18X yield) of 4-dimethylamino-4-(Z-thienyl)cyclohexanone,
ethylene ketal, m.p. 99-103 C.
Analysis:
Calc'd. for Cl4H2,N02S:
C, 62.88; H, 7.92; N, 5.24.
Found: C, 62.75i H, 8.21i N, 5.49.
Example 28 Preparation of 4-dimethylamino-4-(2-thienyl)-
cyclohexanone
Following the procedure of Example 2, but substituting
the appropriate quantity of 4-dimethylamino-4-(2-thienyl)-
cyclohexanone ethylene ketal (prepared above in Example
27H) for the 4-(p-chlorophenyl)-4-dimethylaminocyclohex-
anone, ethylene ketal hydrochloride there is prepared
(after recrystallization from methanol-water) the title
compound in 64X yield, m.p. 102-103 C.
Aralysis:
Calc'd. for C,2HI7NOS:
C~ 64.53; H, 7.67; N9 6~27.
Found: C, 64.41; H, 7.769 N9 5.94.

-105-

3286
~ 5 16

Example 29 Alternate preparation of 4~methylamino-~-(2-
thienyl)cyclohexanone ethylene ketal hydro-
chloride
- Part A Preparation of precursor, 4-(2-thienyl)-
4-ethoxycarbonylaminocyclohexanone ethylene
ketal
To a solution of 2.68 9. (0.010 mole) of 4-carboxy-
4-(2-thienyl~oyclohexanone ethylene ketal and 1.39 ml.
triethylamine in 40 ml. ethanol there is added 2.75 g.
diphenylphosphonic azide. Following 5 hours' heating at
reflux the bulk of the solvent is removed in vacuum. The
residue is dissolved in ~ater and ether:benzene. The
organic layer is washed in turn with water, ice cold 2.5 N
hydrochloric acid, water, saturated sodium bicarbonate and
brine and taken to dryness. The residual solid is recrys-
tallized from cyclohexane to give 1.58 9. (51% yield) of
4-(2-thienyl)-4-ethoxycarbonylaminocyclohexanone ethylene
ketal, m.p. 113-117 C.
Analysis:
Calc'd. for ClsH2lN04S:
C, 57.85; H, 6.80, N, 4.50.
Found: C, 57.50; H, 6.79; N~ 4.55.
Part B Preparation of 4-methylamino-4-(2-thienyl)-
cyclohexanone ethylene ketal hydrochloride
To a suspension of 2.0 g~ of lithium aluminum hydride
in 50 ml. of THF (tetrahydrofuran) is added a solution of
11.58 9. ~.037 mole) of 4-(2-thienyl)-4-ethoxycarbonylamino-
cyclohexanone ethylene ketal (prepared in Part A, above)
ln 150 ml. of THF. The reactlon mixture ~s heated at
reflux temperature for 5 hours~ and then is cooled. To

-106O

3286
5~6

thls cooled reactlon mixture are added, in order, 2 ml.
H20, 2 ml. 15% NaOH, and 6 ml. H20. The ~norganic gel
wh~ch accumulates is filtered off and the ~iltnate is taken
to dryness. The residue is dissolved in ether and a just-
S suffic~ent volume of 2.5 N HC1 in ether ;s added to givethe title compound. Recrystal1izati.on is effected from
methylene chloride-ethyl acetate to give 7.25 9. of the
4-methylamino-4-(2-thienyl)cyclohexanone ethylene ketal
hydrochlorlde, m.p. 212-214 C.
Example 30 Preparation of 4-(p-t-butylphenyl)-4-dimethyl-
aminocyclohexanone
Part A 4-p-t-butylphenyl-4-isocyanatocyclohexanone
ethylene ketal
Following the procedure of Example 1, Parts A-F, but
initially substituting p-t-butylphenylacetonitrile (pre-
pared as in the "Preparation" above) for p-chlorophenyl-
acetonitrile, and substituting appropriate quantities of
each appropriate corresponding intermediate subsequently
in each step, there is obtained a 71% yield of 4-p-t-
20 . butylphenyl-4-isocyanatocyclohexanone ethylene ketal, on
elution from a silica gel colum.n with a 2:1 mixture of
ethyl acetate in methylene chloride, and recrystallization
from Skellysolve B, m.p. 103-105.5 C.
e~
Calc'd. for ClgH25NO3:
C, 72.35i H, 7.99; N, 4.44.
Found: C, 72.66; H, 8.03, N, 4.50.
Part B Preparat~on of 4-(p-t-butylphenyl)-4-methyl-
aminocyclohexanone ethylene ketal
Follow~ng the procedure of Example 1, Part G, but

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3286


substituting an appropriate q~antity of 4-(p-t-butyl-
pheny1)-4-isocyanatocyclohexanone ethylene ketal for 4-p-
chlorophenyl-4-isocyanatocyclohexanone there is obtained
4-(p-t-butylphenyl)-4-methylaminocyclohexanone ethylene
5ketal which as a m.p. 118.5-121 C. (94% yield).
Analysis:
Calc'd. for ClgH29N02:
C~ 75.20; H, 9.63; N, 4.62.
Found: C, 75.32; H, 9.92; N, 4.l5.
Part C Preparation of 4-(p-_-butylphenyl)-4-dimethyl-
amlnocyclohexanone ethylene ketal
Following the procedure of Example 19 Part H, but
substituting 4-methylamino-4-(p-t-butylphenyl1cyclohexa-
none ethylene ketal (Part B, above) for 4-(p-chlorophenyl)-
l~ 4-methylaminocyclohexanone ethylene ketal there is
obtained 4-~p-t-butylphenyl)-4-dimethylaminocyclohexanone
ethylene ketal in 90% yield9 m.pO l03.5-107 C.
Analysis:
Calc'd. for C2CH3,N0~:
C, 75.66; H, 9.84; N, 4.4l.
Found: C, 75.4g; H, 9.73; N9 4.68.
Part D Preparation of 4-(p-t-butylphenyl)-4-dimethyl-
aminocyclohexanone
Following the procedure of Example 29 but substitut-
ing 4-(p-t-butylphenyl)-4-dimethylaminocyclohexanone
ethylene ketal (Part C, above) for 4-(p-chlorophenyl)-
4-dimethyla~inocyclohexanone ethylene ketal hydrochloride
there Is obtained a 60% yield of the 4-(p-t-butylphenyl)-
4-dimethylaminocyclohexanone after recrystallization from
petroleum ether, m.p. 82.5-87 C.

-108-

S~i
'

Analysls:
Calc'd. for C,8H2,N0:
C, 79.07; H, 9.96; N, 5.12.
Found: C, 78.85; H, 10.05; N, 4.85.
Example 31 Preparation of 4-(m-tolyl)-4-dimethylamino-
cyclohexanone
Part A Preparation of 4-(m-tolyl)-4-isocyanatocyclo-
hexanone ethylene ketal
Following the procedure of Example 15, parts A-F,
but initially substituting m-tolylacetonitrile for o-tolyl-
acetonitrile and subsequently substituting each inter-
mediate appropriately and in appropriate quantities, there
is obtained a 90% yield of 4-(m-tolyl)-4-isocyanatocyclo-
hexanone ethylene ketal as an oil. (Infrared absorption
v at 2250-2270 cm~') eluted from a silica gel column with
methylene chloride instead nf 2~ ethyl acetate in methylene
chloride.
Part B Preparation of 4-(m-tolyl)-4-methylamino-
cyclohexanone ethylene ketal hydrochloride
Following the procedure of Example 15, Part G, but
substituting 4-isocyanato-4-(m--tolyl)cyclohexanone ethylene
ketal for 4-isocyanato-4-(o-tolyl)cyclohexanone ethylene
ketal there is obtained a 58% yield of 4-(m-tolyl)-4-methyl-
aminocyclohexanone ethylene ketal hydrochloride, m.p.
219-221 C.
Analysis:
Calc'd. for C,6H~4ClN02:
C, 64.52i ~, 8.12; N, 4~70G
Found: C, 64.35; H, 8.18; N, 4.93.
Part C Preparation of 4-(m-tolyl)~4-dlmethylamino-

-109- . ,

5~6 3286
..

,
cyclohexanone ethylene ketal hydroiodide
Follow~ng the procedure of Example 159 Part H, but
substituting 4-(m-tolyl)-4-methylaminocyclohexanone
ethylene ketal hydrochloride for 4-(o-tolyl)-4-methylamino-
5 cyclohexanone ethylene ketal hydrochloride there is ob-
tained an 85% yield of 4-(m-tolyl)-4-dimethylaminocyclo-
hexanone ethylene ketal hydroiod;de, m.p. 214-215.5 C.
Analysis:
Calc'd. for C~7H26IN02:
C, 50.62; H, 6.50; N, 3.47.
Found: C, 50.60; H, 6.58; N, 3.59.
Part D Preparation of the object compound 4-(m-
tolyl)-4-dimethylaminocyclohexanone hydro-
iodide salt
Following the procedure of Example 16, but substitut-
ing 4-(m-tolyl)-4-dimethylaminocyclohexanone ethylene
ketal hydroiodide for the 4-(o-tolyl)-4-dimethylamino-
cyclohexanone ethylene ketal hydroiodide there is obtained
the 4-(m-tolyl~-4-dimethylaminocyclohexanone hydroiodide
salt in 75% yield after recrystallization from methylene
chloride:ethyl acetate; m.p. 172-174.5 C.
Analysis:
Calc'd. ~or ClsH22INo:
C, 50.15~ H, 6.17i N, 3.90.
Found: C, 49.91; H, 6.22; N, 4.14.
Example 32 Preparation of 4-amino-4-phenylcyclohexanone,
ethylene ketal hydrochloride
A reaction mixture consisting of 21.9 gm. (0.085 mole)
4-isocyanato-4-phenylcyclohexanone ethylene ketal (pre-
pared as ln Example 179 Part G)9 10.9 gm. sodium hydroxide,

- 1 1 0-

5 ~6


and 210 m1. ethylene glycol is heated at the reflux
temperature for s;xty-six (66) hours. A solution results
wh~ch is cooled in an ice-water bath. A small amount of
~ce is added to the solution followed by 23 ml. of concen-
trated hydrochloric ac;d which is added dropwise withstirring. After five minutes, the acidified solution is
made strongly basic by adding 50% aqueous sodium hydroxide.
The basic solution is diluted ~ith 800 ml. waterO The
strongly basic, dilute aqueous solution is then extracted
four times with 200 ml. portions of diethyl ether. The
extracts are combined and washed with water and with brine,
before removing the ether by evaporation under reduced
pressure. The residue thus obtained is dissolved in 50 ml.
of diethyl ether and the oily solution is treated with an
equivalent of 3 N hydrogen chloride in diethyl ether. A
precipitate forms which is collected on a fi-lter and re-
crystallized from a mixture of methylene chloride and
ethyl acetate. There is thus obtained 15.2 gm. (52% yield)
of 4-amino-4-phenylcyclohexanone, ethylene ketal hydro-
Z0 chloride which has a melting point at 226 to 228 C.
(with deco~position). A second crop of crystals weighs
1.60 gm. and has a melting range from 222 to 226 C. An
analytical sample has a melting point at 248 to 249 C.
Analysis:
Calc'd. for C~ 4 H2 oCl NO2:
C, 62.33; H, 7.47; N9 5.19.
Found: C, 61.93; H9 7.58; N, 5.53.
Example 33 Preparation of 4-(N-allyl-N-methylamino)-
4-phenylcyclohexanone9 ethylene ketal hydro-
chloride

32~6
llUC~S16

A reaction mlxture consist~ng of the free base from
2.46 gm. (0.0087 mole) of 4-methylamino-4-phenylcyclo-
hexanone ethylene ketal hydrochloride (prepared in Example
17, Part G, above), 1.05 gm. (0.75 ml.) allyl bromide,
1.28 gm. potassium carbonate, 10.0 ml. dimethylformamide,
and 40.0 ml. benzene is heated at the reflux temperature,
with stirring, for eighteen ~18) hours. After cooling,
this mixture is washed with water and then with brine
before the volatile solvents are removed by evaporation
under reduced pressure. The residue thus obtained is
dissolved in diethyl ether and 0.6 N hydrogen chloride
in diethyl ether is added in order to form the hydrochlo-
ride salt. The hydrochloride thus formed, precipitates
and is collected on a filter. The filter cake is recrys-
tallized from a mixture of methylene chloride and ethyl
acetate and there is thus obtained 1.82 gm. (65% yield)
of 4-(N-allyl-N~methylamino)-4-phenylcyclohexanone, ethylene
ketal hydrochloride having a melting range from 163 to
167 C
_alysis:
Calc'd. for Cl8H26ClN02:
C, 64.94; H, 8.17i N7 4.21.
Found: ~, 65.33; H, 7.93; N9 4.03.
Example 34 Preparation of 4-(N-allyl-N-methylamino)-
4-phenylcyclohexanone hydroiodide
A reaction solution consisting of 1.82 gm. (0.0058
mole) of 4-(N-allyl-N-methylamino)~4-phenylcyclohexanone,
ethylene ketal hydrochloride (prepared in Example 33,
above), 8.0 ml. of 2.5 N hydrochloric acid and 16.0 ml.
methanol 1s set aside in a stoppered reaction vessel at

-112-

~ 5 ~ 6 3286


25 C. for sixty-six (66) hours. After removing most of
the solvent by evaporatlon under reduced pressure, the
concentrate thus obtained is extracted with methylene
ch1Oride. The methylene chlor~de solution is washed
S f1rst with saturated aqueous sodium bicarbonate, then with
water, and finally with 10% hydroiodic acid. The methylene
chloride solvent is then removed by evaporationS and the
residue obtained is recrystallized two times from a mix-
ture of methylene chloride and ethyl acetate. There is
thus obtained 0.88 gm. (42% yield) of 4-(N-allyl-N-methyl-
amino)-4-phenylcyclohexanone hydroiodide having a melting
point at l82 to 183 C.
Analysis:
Calc'd. for CI~H22INO:
C, 5l.76; H, 5.97; N, 3:77.
Found; C, 5l.73; H, 5.96; N, 3.84.
Example 35 Preparation of 4-[[(ethoxycarbonyl)methyl]-
methylamino~-4-phenylcyclohexanone, ethylene
ketal, p-toluenesulfonate
A reaction mixture consisting of 8.77 gm. (0.031 mole)
of 4-methylamino-4-phenylcyclohexanone, ethylene ketal
hydrochloride (prepared as in Example 179 Part G, above),
5.l6 gm. (3.42 ml.) ethyl bromoacetate, 4.29 gm. potassium
carbonate, and 120 ml. dimethylformamide is heated in an
oil bath to 100 C. and then held at that temperature with
st~rring for ei~hteen (18) hours~ After removing the
solvent medium by evaporation under reduced pressure, the
residue obtained is dissolved in a mixture of 25 ml. water
and l50 ml. benzene. The benzene layer is allowed to
separate from the water and is recoveredO It is washed

-ll3-

S16 3286


with water and then with brine. The benzene is then re-
moved by evaporation under reduced pressure. The res1due
thus obtained is d~ssolved in diethyl ether and to the
ether solution is added 5.9 gm. p-toluenesulfonic acid
dissolved in the minimum possible amount of diethyl ether.
A gummy precipitate forms which is recrystallized two times
from a mixture of methylene chloride and ethyl acetate.
There is thus obtained 10.0 gm. (63% y;eld) of 4-[[(ethoxy-
carbonyl)methyljmethylamino~-4-phenylcyclohexanone,
ethylene ketal, p-toluenesulfonate having a melting range
from 108 to 115 C. An analytical sample melts from
115 to 117 C.
Analysis:
Calc'd. for C26H3sN0~S:
C, 59.86; H, 6.76, N, 2.68.
Found: C, 60.90; H, 7.16; N, 2.58.
Example 36 Preparation of 4-[(2-hydroxyethyl)methyl-
amino]-4-phenylcyclohexanone, ethylene ketal
hydrochloride
A solution consisting of 4.52 gm. (0.0136 mole) of
4~[[(ethoxycarbonyl)methyl]methylamino]-4-phenylcyclohex-
anone, ethylene ketal, p-toluenesulfonate (prepared in
Example 35~ above), and 100 ml. tetrahydrofuran is added
to a suspension of 0.52 gm. lithium aluminum hydride in
Z5 10 ml. tetrahydrofuran. This reaction is heated at the
reaction mixture is heated at the reflux temperature for
four (4) hours, after which heating it is allowed to cool
and then chilled in an ice bath. To the chilled solution
1s added 0.52 ml. water followed by 0.52 ml. of 15% aqueous
sod~um hydroxide, and finally followed by another 1.56 ml.

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516

water. A gel forms and the gelatinous l~quld is poured
through a filter. The filtrate is collected and the
l~quids removed by evaporation under reduced pressure. The
res~due thus obtained is chromatographed on a 400 ml.
column of silica gel and the chromatogram is developed by
elution with a 3% solution of methanol in methylene chlo-
rlde which has been saturated with ammonia. The fractions
containing the prospective product, as determined by thin
layer chromatography, are combined and the solvents re-
moved by evaporation under reduced pressure. The residuethus obtained is dissolved in diethyl ether and then
hydrogen chloride saturated diethyl ether is added. A
precipitate forms which ;s collected on a filter and
recrystallized from a mixture of methylene chloride and
15ethyl acetate. There is thus obtained 2.56 gm. (58% yield)
of 4-~(2-hydroxyethyl)methylamino]-4-phenylcyclohexanone
ethylene ketal hydrochloride having a melting range from
184 to 186 C. A second crop of crystals obtained by
removing so~e of the solvent mixture from the mother
liquors by evaporation under reduced pressure weighs 0.56
gm. and has a melting range from 176 to 182 C.
Analysis:
Calc'd. for C,7H2 6Cl N03:
C, 62.28; H9 7.99; N9 4.27.
25Found: C, 62.14; H9 8.21; N~ 4.100
Example 37 Preparation of 4-~(2-hydroxyethyl)methylamino]-
4-phenylcyclohexanone
A reaction mixture consisting of 1.50 gm. (0.0046
mole) of 4-[(2-hydroxyethyl)methylamino]-4-phenylcyclo-
hexanone, ethylene keta19 hydrochloride (prepared in

-115

~ S 1~ 3286


Example 36, above), 3 ml. of 2.5 N hydrochloric acid,
and 30 ml. acetone is stirred at 25 C. for eighteen (18)
hours. After removing most of the acetone by evaporation
under reduced pressure, the concentrate thus obtained is
basified with sodium bicarbonate. The basic mixture is
then extracted three times with 25 ml. portions of methyl-
ene chloride. The methylene chloride extracts are com-
bined and the solvent is removed by evaporation under
reduced pressure. The residue thus obtained is recrystal-
lized two times from a mixture of acetone and technical
hexane to give 0.71 gm. (62% yield) of 4-[(2-hydroxyethyl)-
methylamino]-4-pheny1cyclohexanone having a melting range
from 139 to 141 C.
Analysis:
Calc'd. for ClsH2lN0~:
~C~ 72.84; H, 8.56; N, 5.66.
Found: C, 72.80; H, 8.68; N, 5.56.
Example 38 Preparation of 4-~ethylacetamido-4-phenylcyclo-
hexanone, ethylene ketal
A reaction solution consisting of the free base from
1.08 gm. (0.0038 mole) of 4-methylamino-4-phenylcyclo-
hexanone, ethylene ketal hydrochloride (prepared in Example
17, Part G, above), 6.0 ml. pyridine9 and 2.0 ml. acetic
anhydride is set aside for eighteen (18) hours at 25 C.
and then poured into ice:water. The ice:water mixture is
then extracted three times with 25 ml. portions of methylene
chloride. The combined methylene chloride extracts are
first washed with ice-cold 2.5 N hydrochloric acid,
followed by a washing with water~ and finally a washing
with saturated aqueous sodium bicarbonate. The methylene

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516

chlor~de is then removed by ~VapQrat~on under reduced
pressure, and the res~due thus obtained ls chromatographed
on a 100 ml. column of silica gel. The chromatogram is
developed with a solvent mixture consisting of 15% ethyl
acetate in methylene chloride. The appropriate fractions
are combined, and the solvents are removed by evaporation
under reduced pressure. The residue thus obtained is
recrystallized from a mixture of methylene chloride and
technical hexane to give 0O57 gm. (52% yield) of 4-methyl-
acetamido-4-phenylcyclohexanone, ethylene keta1 having
a melting point at 98 to 99.5 C.
Analysis:
Calc'd. for Cl7H23N03:
- C, 70.56; H, 8.01; N, 4.84.
15Found: C, 70.78; H, 7.93; N, 4.98.
Example 39 Preparation of 4-Methylamino-4-phenylcyclo-
hexanone hydrochloride
A reaction mixture con~sisting of 1.0 gm. (0.0035 mole)
of 4-methylamino-4-phenylcyclohexanone, ethylene ketal,
hydrochloride (prepared in Example 17, Part G, above) 2.0
ml. of 2.5 N hydrochloric acid, and 20 ml. acetone is
stirred continuously for eighteen (18) hours, at 25 C.
The reaction mixture is then made basic by adding solid
sodium bicarbonate, and most of the solvent is removed
by evaporation under reduced pressure. The concentrated
material thus obtained is ectracted four times with 20 ml.
portlons of methylene chloride. The extracts are combined
and the methylene chloride is removed by evaporation under
reduced pressure. A gummy residue is obtained that is
dissolved in diethyl ether. The e~her solution is treated

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S16

w~th hydrogen chloride ln ether. A preclp~tate forms
whlch is collected on a filter and recrystallized from
a mixture of methylene chloride and ethyl acetateO There
Is thus obtained 0.53 gm. (74% yield) of 4-methylamino-
4-phenylcyclohexanone hydrochloride having a melting
range from 218 to 220 C.
Analysis:
Calc'd, for Cl3Hl3ClN0:
C, 65.12; H, 7.56; N, 5.84.
Found: C, 64.35; H, 7.64; N, 5.85.
Example 40 Preparation of 4-(m-hydroxyphenyl)-4-(methyl
n-butylamino)cyclohexanone
Part A 4-Cyano-4-(m-hydroxyphenyl)cyclohexan-1-one
To an ice-cooled solution of 10.0 9. (0.044 mole)
of 4-cyano-4-(m-anisyl)cyclohexan-1-one (prepared in
Example 11, Part C), in 125 mlO methylene chloride there
is added dropwise 13 ml. of boron tribromide. Following
4 hours stirring in the cold the mixture is pourèd onto
ice and diluted with 50 ml. chloroform. The organic layer
is washed with water, aqueous sodium bicarbonate and
brine, and taken to dryness. The residual solid is
recrystallized from acetone:Skellysolve B to give 7.60 9.
of 4-cyano-4-(m-hydroxyphenyl)cyclohexan-1-one, m.p.
130-133 C.
Analysis:
Calc'd. for Cl3Hl3N02:
C, 72.54; H, 6.0g, N9 6.510
Found: C, 72.50; H, 6.14; N, 6.350
Part B 4-Cyano-4-(m-hydroxyphenyl)cyclohexan-1-one,
ethylene ketal

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~ 5 1~

A m~xture of 8.80 g. (0.041 mole) of 4-cyano-4-(m-
hydroxyphenyl)cyclohexan-l-one, 2.50 ml. ethylene glycol
and 0.26 9. p-toluenesulfonic acid in 170 ml. benzene is
heated at reflux under a Deane-Stark trap ~or 4 hours.
The mixture is then allowed to cool, washed with aqueous
sodium bicarbonate and taken to dryness. The residual
solid is recrystallized from methylene chloride:Skellysolve
B to give 9.~5 9. of 4-cyano-4-(m-hydroxyphenyl)cyclohex-
an-l-one, ethylene ketal, m.p. lO9-ll0.5 C.
Analysis:
Calc'd. for C,sHl7N03:
C, 69.48; H, 6.61; N, 5.32.
Found: C, 59.23; H, 6.69; N, 5.32.
Part C 4-Cyano-4-(m-benzyloxyphenyl)cyclohexan-
1-one, ethylene ketal
To a solution of 9.85 9. of 4-cyano-4-(m-hydroxy-
phenyl)cyclohexan-l-one, ethylene ketal (prepared in Part
B, above) in 40 ml. DMF and ~0 ml. benzene there is added
1.85 9. of a 50% dispersion of sodium hydride in mineral
oil. The mixture is stirred for 15 mins. at roam temper-
ature and l hour at reflux. Benzyl chloride (6.53 9.)
is then added, the mixture heated for an additional 4
hours and allowed to cool. The reaction mixture is washed
in turn with water and brine and taken to dryness. The
res1dual solid ;s recrystallized from ether:petroleum
ether to give l1.70 9. of 4-cyano-4-(m-benzyloxyphenyl)-
cyclohexan-l-one, ethylene ketal, m.p. 67-69 C.
Analysis:
Calc'dO for C22H~3N03:
C, 75.62; H, 6.63; N, 4.01

- 1 1 9 - .

3286
~ 5 ~6

Found: C, 75.34; H, 6.66; N, 4.01O
pdrt D 4-(m-benzyloxyphenyl~cyclohexan-1-one-
4-carboxylic acid, ethylene ketal
A mixture of 7.00 9. (0.020 mole) of 4-cyano-4-(m-
benzyloxyphenyl)cyclohexan-l-one, ethylene ketal ~prepared
in Part C, above) and 1.20 g. sodium hydroxide in 50 ml.
ethylene glycol is heated at reflux for 17 hours. The
solution is allowed to cool, diluted to 300 ml. with water
and covered with 100 ml. ether. The aqueous layer is
acidified with 5 ml. concentrated hydrochloric acid and
the organic layer separated. The aqueous layer is then
extracted with 100 ml. portions of ether and methylene
chloride. The organic layer and extracts are combined,
washed with water and brine and taken to dryness. There
is obtained 7.22 9. of 4-(m-benzyloxyphenyl)cyclohexan-
l-one-4-carboxylic acid, ethylene ketal, m.p. 108-110.5
C. A small sample is recrystallized from ether to give
the analytical sample, m.p. 118~5-120~5 C~
Analysis:
Calc'd. for C22H240s:
C, 71.72; H, 6.57.
Found: C9 71~80; H, 6.89.
Part E 4-(m-benzylcxyphenyl)-4-(methylam;no)cyclo-
hexan-l-onea ethylene ketal
2S A mixture of 7~22 9~ (0.020 mole) of 4-(m-benzyloxy-
phenyl)cyclohexan-l-one-4-carboxylic acid9 ethylene ketal~
(prepared in Part D9 above) 5O52 9~ of diphenylphosphoryl-
azide and 2.8 ml. triethylamine in 50 ml~ anisole is
heated ~n an oil bath at 90 for 2 hours. The bulk of the
solvent ~s then removed in vacuum and the residue chromato-


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3286
~ 5 1 6

graphed over 600 ml. silica gel. The column is eluted
with 2% ethyl acetate in methylene chloride and those
fractions which contain product as determined by tlc are
comb~ned. There is obtained 4.97 g. of the i~termediate
isocyanate as an oil.
A solution of this oil (isocyanate) in 80 ml. THF
is added to a suspension of 0.78 9. lithium aluminum
hydr;de in 10 ml. THF. Fo1lowing 6 hours heating at re-
flux the mixture is cooled in an ;ce bath and treated in
turn with 0.7 ml. water, 0.7 ml. l5% sodium hydroxide
and 2.4 ml. water. The inorganic gel is separated on a
filter and the filtrate taken to dryness. The residual
solid is recrystallized from petroleum ether to afford
3.3l 9. of 4-(m-benzyloxyphenyl)-4-(methylamino)cyclo-
hexan-l-one, ethylene ketal, m.p. 64-66 C.
Analysis:
Calc'd. for C22H27N03:
C, 74.75; Hg 7.70i N, 3.960
Found: C, 75.03; H, 7.53; N, 3.93.
Part F 4-(Methyl-n-butylamino)-4-(m-benzyloxy-
phenyl)cyclohexan-l-one, ethylene ketal
To an ice cold solution of 3.3l 9. (9.4 mmole) of
4-methylamino-4-(m-benzyloxyphenyl)cyclohexan-l-one,
ethylene ketal (prepared in Part E, above) and 1.30 ml.
triethylamine in 40 ml. THF there is added dropwise l.0 9.
(l.lO ml.~ butyryl chloride. Following 6 hours' standing
~n the cold the bulk of the solvent is removed in vacuum.
The residual is diluted with ice-water and ether. The
organic layer is separated and washed in turn w~th water,
saturated sodium bicarbonate and brine. The solution is

-l2l-

3286
~ 5 ~6

taken to dryness to give the amide as a gum. Infrared
spectrum is consistent with the structure assigned tab-
sorption at 1660 cm~l). A solution of the crude amide
thUS obtained in 80 ml. THF is added to a suspension of
0.50 9. lithium aluminum hydride in 10 ml. THF. Following
6 hours' heating at reflux the mixture is cooled in ice
and treated in turn with 0.50 ml. water, O.S0 ml. l5%
sodium hydroxide and l.5 ml. water. The inorganic gel is
collected on a filter and the filtrate taken to dryness.
There is obtained 3.50 9. of 4-(methyl-n-butylamino)-
4-(m~enzyloxyphenyl)cyclohexan-l-one, ethylene ketal as
an amorphous gum which shows a single spot on thin
layer chromatography (tlc).
Part G 4-(Methyl-n-butylamino)-4-(m-hydroxyphenyl)-
cyclohexan-l-one, ethylene ketal hydrochlo-
ride
A mixture of 3.56 9. of the crude tertiary amine
(prepared in Part F, above), 3.6 ml. 3 N ethereal hydrogen
chloride and l.78 9. lO% palladium on charcoal in l50 ml.
ethyl acetate is shaken in an atmosphere of hydrogen for
18 hours. The catalyst and some precipitated prod~ct
are then collected on a filter. The collected solid is
washed thoroughly with chloroform. The combined filtrate
and washes are then taken to dryness. The residual solid
is recrystallized from methylene chloride:acetone to give
2.00 9. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl~-
cyclohexan-l-one, ethylene ketal hydrochloride, m.p.
208-210 C.; m.m.p. (mixed melting point) with authentic
material (prepared in Example 42) 208-2lO C.
Part H Preparation of 4-(m-hydroxyphenyl)-4-(methyl-

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3286
51~

n-butylamino)cyclohexanone
Followiny the procedure of Example 2, but substitut-
ing 4-(m-hydroxyphenyl)-4-(methyl-n-butylamlno)cyclohexan-
l-one, ethylene ketal hydrochloride (prepared in Part G,
above) for the 4-(p-chlorophenyl)-4-dimethylaminocyclo-
hexanone, ethylene ketal hydrochloride there is obtained
the object compound 4-(m-hydroxyphenyl)-4-(methyl-n-
butylamino)cyclohexanone. Recrystallization from ether:
petroleum ether gives an analytical sample, m.p. 89-91 C.
Analysis:
Calc'd. for Cl7H2sN02:
C, 74.14; H, 9.15~ N, 5.08.
Found: C, 74.32; H, 9.04i N, 5.26.
Example 41 Alternative preparation for a preferred com-
pound 4-(p-Chlorophenyl)-4-dimethylaminocyclo-
hexanone, ethylene ketal free base and the
hydrochloride thereof
Part A Preparation of precursor Cyclohexane-1,4-di-
one, ethylene monoketal
A reaction mixture consisting of 10 gm. (0.085 mole)
4-hydroxycyclohexanone, 4.75 ml. ethylene glycol, 0.20 gm.
p~toluenesulfonic acid, and 100 ml. benzene is heated at
the reflux temperature in a reaction vessel fitted with a
Dean and Stark trap for 2 hours. After the reaction mix-
ture has cooled, it is washed first with water and then
with brine. The benzene is then removed by evaporation
under reduced pressure giving the intermediate 4-hydroxy-
cyclohexanone ethylene monoketal as a viscous oil weighing
14.12 gm. The 4-hydroxycyclohexanone ethylene monoketal
is dissnlved in 100 ml. methyler.e chloride and added with

~ -123

32~6
Sl~

stirring to a suspension consisting of 55.0 gm. chromium
triox~de (predried for 24 hours under reduced pressure
over phosphorous pentoxide), one liter dry methylene
chloride, and 52.8 gm. 3,5-dimethylpyrazo1e. After con-
tinued stirring for ten (10) min. this dark reaction mix-
ture is poured onto a two liter column of silica gel.
When the reaction mixture has been completely adsorbed,
the chromatogram is developed with a 1:1 mixture of ethyl
acetate and technical hexane ~Skellysolve B - a mixture
of isomeric hexanes haYing a boiling range between 60
and 70 C.). The appropriate fractions as determined by
TLC are collected and combined9 after which the solvents
are removed by evaporation under reduced pressure. The
crystals thus obtained are recrystallized from technical
hexane, and there is thus obtained 10.82 gm. (~1% yield)
of the desired cyclohexane - l,4-dione, ethylene monoketal
having a melting point at 68 to 69 C. [The literature
value is 71.5 to 72.5 C.]
Part B Preparation of first intermediate 4-Cyano-
4-dimethylaminocyclohexanone, ethylene
ketal
A reaction mixture consisting of 3.0 gm. (0.019 mole)
of the cyclohexane-1,4-dione, ethylene monoketal prepared
in Part A, above, 3.0 gm. potassium cyanide, 4.5 gm. di-
methylamine hydrochloride~ 3.0 ml. methanol, and 25 ml.
saturated aqueous dimethylamine is stirred at 25 C. for
48 hours. The reaction mixture is then extracted succes-
sively with five 40 ml.-portions of diethyl ether. The
ether extracts are comblned and the ether is removed by
evaporation under reduced pressureO The residue thus

- 1 2 4

3286
S~6

obtalned is dissolved in methylene chloride. Some small
amount of water present ls separated, and the organic sol.
vent portion is conserved for removal of the methylene
chloride by evaporation under reduced pressure. The residual
solid thus obtalned is recrystallized from technical hex-
ane to give 3.6 gm. (78% yield) of the desired intermediate
4-cyano-4-dimethylaminocyclohexanone ethylene ketal having
a melting point at 79 to 81 C.
Analysis: Calc'd. for CI~Hl7N202:
C, 62.83; H, 8.63; N, 13.33.
Found: C, 62.92; H9 8.66; N, 13.58.
Part C Preparation of object compound, 4-(p Chloro-
phenyl)-4-dimethylaminocyclohexanone, ethylene
ketal hydrochloride
To a Grignard reagent prepared from 2.73 gm. of p-chloro-
bromobenzene, 0.35 gm. magnesium and 30 ml. tetrahydrofuran
(THF), is added 1.50 9. (0.071 mole) of 4-cyano-4-dimethyl-
aminocyclohexanone ethylene ketal (prepared in Part B) în 40
ml. of THF. The reaction mixture is heated for three (3)
days at the reflux temperature. It is then cooled, chilled
in an ice bath and 20 ml. saturated ammonium chloride in ben-
zene added. The organic phase is separated. It is washed
initially with water and then with brine. Finally, the sol-
~ents are removed by evaporation under reduced pressure. The
residue thus obtained is dissolved in diethyl ether and 4 N
ethereal hydrogen chloride is added until precipitation is
somplete. The salt thus obtained is collected on a filter as
a gummy material. It is suspended in methylene chloride and
one N aqueous sodium hydroxide is addedO The organic layer
is separated and the methylene chloride is removed by

-125-

32~6
~ '5 ~ 6

evaporation under reduced pressure. The residue thus
obta~ned is added onto a 200 ml. column of s~1ca gel,
the chromatogram is developed with methylene chlor;de
contaln;ng 4X methanol and 20-ml. fractions are collected.
The solvent is removed by evaporation under reduced pres-
sure and the residue is dissolved in diethyl ether. The
ether solution is treated with 4 N ethereal hydrogen chlo-
ride until precipitation ~f the desired 4-(p-chlorophenyl)-
4-di~ethylaminocyclohexanone ethylene ketal hydrochloride
is complete. The precipitate is collected on a filter
and crystallized from a mixture of methylene chloride and
ethyl acetate to give 0.80 gm. (34% yield) of pure 4-(p-
chlorophenyl)-4-dimethylaminocyclohexanone ethylene ketal
hydrochloride having a melting point at 252 to 254 C.
Example 42 Alternative preparation for a preferred com-
pound 4-(m-hydroxyphenyl)-4-(methyl-n-butyl-
amino)cyclohexanone9 ethylene ketal hydrochlo-
ride
Part A 4-(methyl-n-butylamino)-4-cyanocyclohexan-
l-one, ethylene ketal
A mixture of 2.05 9. (15 mmole) of 1,4-cyclohexane-
dione ethylene monoketal (prepared as in Example 41, Part
A), 2.05 9. potassium cyanide, 5.40 9. methyl-n-butylamine,
in 8 ml. water and 12 ml. 2.5 N hydrochloric acid is
stlrred at room temperature for 5 days. The mixture is
then extracted thoroughly with 5 portions, of 40 ml. each9
methylene chloride. The extracts are combined and taken
to dryness. To a solution of the residual gum in 50 ml.
ether there is added sufficient 3 N ethereal hydrogen
chlor~de to precipitate all the bas;c material. That

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` 32~6
11(~C~516

prec~p;tate is recrystallized ~rom methylene chlor;de:
ethyl acetate to give 2.65 9. of 4-(methyl-n-butylamino)-
4-cyanocyclohexan-1-one, ethylene ketal (hydrochloride
salt), m.p. 114-120 C.
Analysis:
Calc'd. for C~4H2 5Cl N202-1~H~0:
C, 53.23; H, 4.93; N, 8~870
Found: C, 53.62; H, 8.67; N, 8.71.
A suspension of the salt in 50 ml. of methylene chlo-
ride is shaken with 40 ml. 1 N sodium hydroxide. The
organic layer is separated and taken to dryness to give
2.49 g. of the 4-(methyl-n-butylamino)-4-cyanocyclohexan-
l-one, ethylene ketal as an oil.
Part B 4-(methyl-n-butylamino)~4-(m-hydroxyphenyl)-
cyclohexan-l-one, ethylene ketal hydrochlo-
ride
To the Grignard reagent prepared from the tetrahydro-
pyranyl ether of 4.80 9. of m-bromophenol, 0.81 9. mag-
nesium and 60 ml. THF there is added a solution of 2.49
g. 4-(methyl-n-butylamino)-4-cyanocyclohexan-1-one,
ethylene ketal (prepared in Part A, above) in 25 ml. THF.
Following 24 hours' heating at reflux the mixture is
cooled in an ice bath and treated with 25 ml. each satur-
ated aqueous ammonium chloride and benzene. The organic
layer is washed with water and brine and taken to dryness.
The residue is dissolved in 25 mi. ether and treated with
~ust sufficient 3 N ethereal hydrogen chloride to pre-
c~pitate the basic material. This gum is dissolved in
40 ml. water. Following 5 mins. standing at room temper-
ature the solution is neutralized with solid sodium bicar-


~127-

~ 5 16 3286


.
bonate. The mixture is then extracted wlth 3 portions
(40 ml. each) of methylene chloride. The extracts are
then taken to dryness. The residual gum is chromatographed
on a 1" x 48" column o~ tlc grade silica gel (elution with
7.5% met~anol in chloroform). Those fractions which
conta1n product (as determined by tlc analysis) are
comb;ned and taken to dryness. The residual gum is con-
verted to the hydrochloride salt and this is recrystallized
from methylene chloride:acetone. There is obtained 152
mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyljcyclo-
hexan-l-one, ethylene ketal hydrochloride, m.p. 206-208 C.
Analysis:
Calc'd. for ClgH~oClN03:
C, 64.11; H, 8.51; N, 3.94.
Found: C, 64.46; H, 8.44; N, 3.75.
Example 43 Preparation of 4-(m-hydroxyphenyl)-4-dimethyl-
aminocyclohexanone, ethylene ketal
A reaction solution consisting of 5.0 gm. (0.029 mole)
~-bromophenol, 5.0 gm. dihydropyran, 0.30 gm. p-toluene-
sulfonic acid, and 80 ml. anhydrous diethyl ether is
stirred at 25 C. for four (4) hours. The mixture is
washed successively with 25 ml. portions of 1 N aqueous
sodium hydroxide, with water, and with brine. The thus
washed organic layer is taken to dnyness by removing the
solvent by evaporation under reduced pressure. There is
thus obtained 7.42 gm. of m-(tetrahydropyranyl-2-oxy)-
bromobenzene which is converted to the corresponding
Grignard reagent by dlssolving in 60 ml. of tetrahydro-
furan and adding the solution to 0.70 gm. magnesium. To
this Grignard is added 1.50 gm. (0.0071 mole) of 4-cyano-

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,, , 11~516


4-dimethyla~inocyclohexanone ethylene ketal (prepared
in Example 41, Part B, ~bove) dlssolved in 30 ml. tetrahydro
furan. This reaction mixture is heated at the reflux
temperature for 22 hours. After cooling, the mixture is
treated with 10 ml. saturated ammonium chloride in benzene.
The organic solvent portion is ;n;tially washed with water
and then with brine. The organic solvent is then removed by
evaporation under reduced pressure. The residue thus ob-
tained is dissolved in diethyl ether and treated with 4 N
ethereal hydrogen chloride until precipitation of the hydro-
chloride salt is complete. The salt is collected on a fil-
ter and then suspended in 25 ml. water containing 1 ml.
2.5 N hydrochloric acid. The acidified mixture is stirred
at 25 C. for one hour, when sodium bicarbonate (solid) is
added until the pH is 8. This slightly basic mixture is
extracted thoroughly with diethyl ether. The ether extracts
are combined and the ether removed be evaporation under
reduced pressure. The residue thus obtained is transferred
to a column of the grade silica gel 1" in cross section by
-48" in length. The chromatogram is developed with a solvent
medium cor,sist;ng of 0.5~ ammonia and 7.5% methanol in
chloroform, and 20-mlO fractions are collected. Those
~ractions which contain product (as determined by tlc anal-
ysis) are combined. The solvent is removed by evaporation
2~ under reduced pressure to give 0.96 gm. (48X yield) of crude
4-(m-hydroxyphenyl3-4-dimethylaminocyclohexanone, ethylene
ketal having a melting point at 169 to 175 C. An analyt-
ical sample is obtained by recrystallization from a mixture
of ethyl acetate and cyclohexane. The melting point is
175 to 177 C.

-1~9-


32~6
5 ~6

Analysis:
Calc'd. for Cl6~J~3N03:
C, 69.28; H, 8.36; N, 5.05.
Found: C, 69.08; H, 8.13, N? 5.02.
Example 44 Preparation of 4-(m-hydroxyphenyl)-4-dimethyl-
aminocyclohexanone
A reaction mixture consisting of 1.92 gm. (0.0069 mole)
of 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene
ketal (prepared in Example 43, above), 15 ml. 2.5 N hydro-
chloric acid, and 30 ml. methanol is stirred continuously
for three (3) days (72 hours). The bulk of the solvent is
then removed by evaporation under reduced pressure, and
solid sodium bicarbonate is added until the pH is brought
to 8. This basic mixture is then extracted with six 20 ml.
portions of chloroform. The extracts are combined and the
chloroform removed by evaporation under reduced pressure.
The residue thus obtained is recrystallized from a mixture
- of acetone and technical hexane to give 0.48 gm. (30%
yield) of 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone
having a melting point at 127 to 130 C.
An~
Calc'd. for C~4HI9NO2:
C, 72.07; H, 8.21; N, 6.01.
Found: C, 72.02; H, 8.13; N, ~.87.
Example 45
Part A
Foltowing the procedure of Example 409 Part F, but
separately subst~tuting acetyl chloride9 29?-dimethylpro-
p~onyl chloride, cyclohexanecarbonyl chloride, cyclopentane-
carbonyl chlor~de and 2-cyclopentylacetyl chlorlde for

-130-

- 3286
~ 5 ~ 6

n-butyryl chloride there are prepared the corresponding:
4-(m-benzyloxyphenyl)-4-(ethylmethylamino)cyclohex-
anone ethylene ketal,
4-(m-benzyloxyphenyl)-4-(pivalylmethylamino)cyclo-
S hexanone ethylene ketal,
4-(m-benzyloxyphenyl)-4-(N-cyclohexylmethyl-N-methyl-
amino)cyclohexanone ethylene ketal, and
4-(m-benzyloxyphenyl)-4-(N-cyclopentylmethyl-N-methyl-
amino)cyclohexanone ethylene ketal, respectively.
Part B
Following the procedure of Example 40, Part G, but
substituting the compounds obtained in Part A (above) for
4-(methyl-n-butylamino)-4-(m-benzyloxyphenyl)cyclohexanone
ethylene ketal there are obtained
4-(m-hydroxyphenyl)-4-(ethylmethylamino3cyclohexanone
ethylene ketal hydrochloride,
. 4-(m-hydroxyphenyl)-4~(pivalylmethylamino)cyclohexa-
none ethylene ketal hydrochloride,
4-(m-hydroxyphenyl)-4-(N-cyclohexylmethyl-N-methyl-
amino~cyclohexanone ethylene ketal hydrochloride, and
4-(m-hydroxyphenyl)-4-(N-cyclopentylmethyl-N-methyl-
amino)cyclohexanone ethylene ketal hydrochloride, respect-
ively.
Part C
Following the procedure of Example 44 but substituting
the compounds prepared in Part B (above) for the 4-(m-
hydroxyphenyl)-4-(dimethylamino)cyclohexanone ethylene
ketal there are prepared the object compounds
4-(m-hydroxyphenyl)-4-(ethylmethylamino)cyclohexanone,
4-(m hydroxyphenyl)-4-(pivalylmethylamino)cyclnhexa-

-l31-

32~36
S~6

none,
4-(m-hydroxyphenyl)-4-(N-cyclohexylmethyl-N-methyl-
amino)cyclohexanone, and
4-(m-hydroxyphenyl(-4-(N-cyclopentylmethyl-N-methyl-
amino)cyclohexanone, respectively.
Example 46 Preparation of 4-(p-hydroxyphenyl)-4-(methyl-
- n-butylamino)cyclohexanone
Part A
Following the procedure of Example 40, Parts A-E,
but initially substitut;ng 4-p-anisyl-4-cyanocyclohexanone
(prepared in Example 7, Part C) for the 4-m-anisyl-4-cyano-
cyclohexanone a-nd subsequently substituting the appropriate
intermediates in appropriate quantities there is obtained
4-methylamino-4-(p-benzyloxyphenyl)cyclohexanone ethylene
ketal.
Part B
Following the procedure of Example 40, Part F, but
substituting the appropriate quantity of 4-(p-benzyloxy-
phenyl)-4-methylaminocyclohexanone ethylene ketal for
4-(m-benzyloxyphenyl)-4-methylaminocyclohexanone ethylene
ketal there is obtained 4-(n-butylmethylamino)-4-(e-benzyl-
oxyphenyl)cyclohexanone ethylene ketalO
- Part C
Following the procedure of Example 40, Part G, but ;`
substituting 4-(p-benzyloxyphenyl)-4-(n-butylmethylamino)-
cyclohexanone ethylene ketal (prepared in Part B, above)
for 4-(m-benzyloxyphenyl~-4-(n-butylmethylamino)cyclohex-
anone ethylene ketal there is obtained 4-(p-hydroxyphenyl)-
4-(n-butylmethylamino)cyclohexanone ethylene ketal hydro-
chlor~de.

-132-

3286
CPS16

Part D
Follow~ng the procedure of Example 44, but substitut-
ing 4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone
ethy1ene ketal hydrochlorlde ~prepared in Part C, above)
for the 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone,
ethylene ketal there is obtained 4-(p-hydroxyphenyl)-4-(n-
butylmethylamino)cyclohexanone.
Example 47
Part A
Following the procedure of Example 42, Part A, but
substituting an appropriate quantity of diethylamine for
n-butylmethylamine there is obtained 4-cyano-4-diethylamino-
cyclohexanone ethylene ketal.
Part B
Following the procedure of Example 42, Part B, but
substituting the appropriate quantities of the compound
prepared above in Part A for 4-(methyl-n-butylamino)-
4-cyanocyclohexanone, ethylene ketalg-and of the tetrahydro-
pyranyl ether of p-bromophenol for the corresponding ether
of m-bromophenol, there is obtained 4-(p-hydroxyphenyl)-
4-diethylaminocyclohexanone ethylene ketal hydrochloride.
Part C
.
Following the procedure of Example 44 but substituting
an appropriate quantity of the compound prepared above
(Part B) for 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone
ethylene ketal there is obtained 4-(p-hydroxyphenyl)-4-di-
ethylaminocyclohexanone.
Example 48
Following the procedure of Example 19 Part A; Example
3, Part A; and Example 17, Part A9 but separately substituting

-133-

S16 32~6


(2-bromo-S-~ethoxyphenyl)acetonitr~l e 9
(3-bromo-4-phenethyl)acetonitrile,
(5-brom~-4-anisyl)acetonitrile,
CS-bromo-3-(n-propoxy)phenyl~acetonitrile,
(3-chloro-4-fluorophenyl)acetonitrile,
(3-chloro-6-methoxyphenyl)acetonitrile,
(2,6-dichlorophenyl)acetonitrile,
(3,5-diisopropylphenyl)acetonitrile,
(4,5-dimethoxyphenyl)acetonitrile,
(o-ethylphenyl)acetonitrile, for (p-chlorophenyl)-
acetonitrile, there are prepared the corresponding:
dimethyldiester of 4-(2-bromo-5-methoxyphenyl)-4-cyano-
pimelic acid,
4-(3-bromo-4-phenethyl)-4-cyanopimelic acid,
4-(5-bromo-4-anisyl)-4-cyanopimelic a-cid,
4-(5-bromo-3-n-propoxyphenyl)-4-cyanopimelic acid,
4-(3-chloro-4-fluorophenyl)-4-cyanopimelic acid,
4-(3-chloro-6-methoxyphenyl)-4-cyanopimelic acid9
4-(2,6-dichlorophenyl)-4-cyanopimelic acid,
4-(3,5-diisopropylphenyl)-4-cyanopimelic acid,
4-t4-5-dimethoxYphenyl)^4-cyanopimelic acid,
4-(o-ethylphenyl)-4-cyanopimelic acid, respectively.
_ample 49
Followi~g the procedure of Examples 19 4, and 17,
Parts B, C, D9 E, F, G, and H9 but substituting as indicated
a priori the intermediates prepared in Example 48, above,
and those intermediates thus sequentially prepared, there
are prepared finally the corresponding:
4-(2-bromo-5-methoxyphenyl)-4-dimethylaminocyclohex-
anone, ethylene ketal free base and the HCl salt thereof,

-134-

~ 5 1 6 3286


4-(3-bromo-4-phenethyl)-4-d~methylaminocyclohexanone,
ethylene ket~l free base and the HCl salt thereof,
4-(5-bromo-4-anisylj-4-dimethylaminocyclohexanone,
ethylene ketal free base and the HCl salt thereof,
4-(5-bromo-3-n-propoxyphenyl)-4-dimethylaminocyclo-
hexanone, ethylene ketal free base and the HCl salt thereof,
4-(3-chloro-4-fluorophenyl)-4-dimethylaminocyclohex-
anone ethylene ketal free base and the HCl salt thereof,
4-(3-chloro-6-methoxyphenyl)-4-dimethylaminocyclo-
hexanone ethylene ketal free base and the HCl salt thereof,
4-(2,6-dichlorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal free base and the HCl salt thereof,
4-(3,5-diisopropylphenyl)-4-dimethylam;nocyclohexanone,
ethylene ketal free base and the HCl salt thereof,
4-(4,5-dimethoxypher,yl)-4-dimethylaminocyclohexanone,
ethylene ketal free base and the HCl salt thereof,
4-(o-ethylphenyl)-4-dimethyiaminocyclohexanone,
ethylene ketal free base and the HCl salt thereof,
Example 50
Part A
-
Following the procedure of Example 41, Part A, but
separately substituting trimethylene glycol (1,3-propane-
diol), 2,2-dimethyl-1,3-propanediol [prepared as described
in J. Amer. Chem. Soc. 70, 946 (1948)], 2-phenyl-1,3-propane-
diol, 2-allyl-1,3-propanediol, for the ethylene glycol,
there are prepared the corresponding precursors:
cyclohexane-1,4-dione, trimethylene monoketal,
cyclohexane-1,4-dione, (2,2-dimethyltrimethylene)mono-
ketal,
cyclohexane 1,4-dione, ~2-phenyltrimethylene)monoketal,

~ -135-


. . .

3286
S16

.. .
cyclohexane,-1,4-d;one, (2-al1yltrimethylene)mono-
ketal, respectively.
Part B
Following the procedure of Example 41, Part B, but
substituting cyclohexane-1,4-dione, tr;methylene monoketal,
cyclohexane-1,4-dione, (2,2-dimethyltrimethylene)monoketal,
cyclohexane-1,4-dione, (2-phenyltrimethylene)monoketal, and
cyclohexane-1,4-dione, (2-allyltrimethylene)monoketal for
the cyclohexane-1,4-dione, ethylene monoketal, there are
prepared the corresponding intermediates:
4-cyano-4-dimethylaminocyclohexanone9 trimethylene
ketal,
4-cyano-4-dimethylaminocyclohexanone, (2,2-dimethyl-
trimethylene) ketal,
lS 4-cyano-4-dimethylaminocyclohexanone, (2-phenyltri-
methylene) ketal, and
4-cyano-4-dimethylaminocyclohexanone, (2-allyltri-
methylene) ketal respectively. ..
Part C
Following the procedure of Example 41, Part C, but
separately substituting each intermediate prepared in Part
B, above for the 4-cyano-4-dimethylaminocyclohexanone,
ethylene ketal, there are prepared the corresponding object
compounds: .
4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, tri-
methylene ketal hydrochloride,
4-~p-chlorophenyl)-4-dimethylaminocyclohexanone,
(2,2-dimethyltrimethylene~ ketal hydrochloride,
4-(p-chlorophenyl)-4-dimethylaminocyclohexanone,
(2-phenyltrimethylene) ketal hydrochloride~

-136-

3286
Sl~

..
and 4-(chlorophenyl)-4-dimethylaminocyclohexanone,
(2-allyltrimethylene) ketal hydrochloride, respectively.
Example 51
Part A
Following the procedure of Example 42, Part A, but
separately substituting each intermediate prepared in
Example 50, Part A, for the cyclohexane-1,4-dione ethylene
monoketal there are prepared the corresponding intermediates:
4-cyano-4-n-butylmethylaminocyclohexanone, trimethylene
ketal,
4-cyano-4-n-butylmethylaminocyclohexanone, (2,2-di-
methyltrimethylene) ketal,
4-cyano-4-n-butylmethylaminocyclohexanone, (2-phenyl-
trimethylene) ketal, and
4-cyano-4-n-butylmethylaminocyclohexanone, (2-allyl-
trimethylene) ketal, respectively.
Part B
Following the procedure of Example 42, Part B, but
separately substituting each intermediate prepared in Part
A (above) for 4-cyano-4-(methyl-n-butylamino~cyclohexanone,
ethylene ketal, there are prepared the corresponding object
compounds:
4-(m-hydroxyphenyl)-4-n-butylmethylaminocyclohexanone,
trimethylene ketal hydrochloride,
4-(m-hydroxyphenyl)-4-n-butylmethylaminocyclohexanone,
(2,2-dimethyltrimethylene) ketal hydrochloride,
4-(m-hydroxyphenyl)-4-n-butylmethylaminocyclohexanone,
(2-phenyltrimethylene) ketal hydrochloride 9 and
4-(m-hydroxyphenyl)-4-n-butylmethylaminocyclohexanone,
(2-allyltrimethylene) ketal hydrochloride, respectively.

-137-

. .. 3286
S16

.
Example 52
Following the procedure of Example 42, Part A, but sep-
arately substituting diethylamine, di-n-propylamine, N-allyl-
N-ethylamine, di-n-butylamine, n~butylethylamine9 and
N-methyl-N-cyclopropylamine, for n-butylmethylamine, there
are prepared the corresponding intermediates:
4-cyano-4-diethylaminocyclohexanone, ethylene ketal,
4-cyano-4-di-n-propylaminocyclohexanone, ethylene ketal,
4-cyano-4-(N-allyl-N-ethylamino)cyclohexanone, ethylene
ketal,
4-cyano-4-di-n-butylaminocyclohexanone, ethylene
ketal,
4-cyano-4-(n-butylethylamino)cyclohexanone, ethylene
ketal, and
4-cyano-4-(N-methyl-N-cyclopropylamino)cyclohexanone,
ethylene ketal, respectively.
Example 53
- Following the procedure of Example 42, Part B, but
separately substituting each intermediate prepared as in
Example 52, for the 4-cyano-4-n-butylmethylaminocyclohex-
anone, ethylene ketal, there are prepared the corresponding
object compounds:
~-(m-hydroxyphenyl)-4-diethylaminocyclohexanone,
ethylene ketal hydrochloride,
4-(m-hydroxy?henyl)-4-di~n-propylaminocyclohexanone,
ethylene ketal hydrochloridep
4-~m-hydroxyphenyl)-4-(N-allyl-N-ethylamino)cyclo-
hexanone, ethylene ketal hydrochloride~
4-(m-hydroxyphenyl)-4-di-n-butylaminocyclohexanone,
ethylene ketal hydrochloride,

~138-

~ 5 ~ 6 3286


4-(m-hydroxyphenyl)-4-(n-butylethylamino)cyclohexanone,
ethylene ketal hydrochloride, and
4-(m-hydroxyphenyl)-4-(N-methyl-N-cyclopropylamino)-
cyclohexanone, ethylene ketal hydrochloride, respectively.
Example 54
Following the procedure of Example 44, but separately
substituting each compound prepared in Example 53 for the
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene
ketal, there are prepared the corresponding:
4-(m-hydroxyphenyl)-4-diethylaminocyclohexanone,
4-(m-hydroxyphenyl)-4-di-n-propylaminocyclohexanone,
4-(m-hydroxyphenyl)-4-(N-allyl-N-ethylamino)cyclo-
hexanone,
4-(m-hydroxyphenyl)-4-di-n-butylaminocyclohexanone,
4-(m-hydroxyphenyl)-4-(n-butylethylamino)cyclohexanone,
and 4-(m-hydroxyphenyl)-4-(N-methyl-N-cyclopropylamino)-
cyclohexanone, respectively.
~xample 55 Preparation of 4-(m-trifluoromethylphenyl)-
4-dimethylaminocyclohexanone ethylene ketal
hydrochloride
A Grignard reagent is prepared using 4.79 gm. (0.024
mole) m-trifluoromethylbromobenzene, 0.59 gm. magnesium-
and 50 ml. tetrahydrofuran; to this is added 1.50 gm.
(.0071 mole) 4-cyano-4-dimethylaminocycloh~xanone ethylene
ketal (prepared in Example 41, Part B9 dissolved in 40 ml.
tetrahydrofuran. This reaction mixture is heated at the
reflux temperature for 17 hours. It is then cooled, chilled
~n ice, and 20 ml. saturated aqueous ammonium chloride and
benzene are addéd. The organic solution is then separated,
~nitially washed with water, and then washed with brine.

139-

S16 3286


The solvents are then removed by evaporat~on under reduced
pressure. The residue thus obtained is dissolved in diethyl
ether, and 4 N ethereal hydrogen chloride ls added until
prec1pitation of the hydrochloride salt as a gum is complete.
S The supernatant liquid is decanted and the remaining gum
is disso1ved in methylene chloride. One N aqueous sodium
hydrox;de is added. The organic layer is then separated
and the methylene chloride is removed by evaporation under
reduced pressure. The residue thus obtained is transferred
onto a 200 ml. column of silica gel and the chromatogram
is developed with methylene chloride containing 3% metahnol.
The appropriate fractions, as determined by TLC, are col-
lected and combined. The solvent is removed by evaporation
under reduced pressure, and the gummy residue thus obtained
is dissolved in diethyl ether. The ether solution is
treated with 4 N ethereal hydrogen chloride until precipi-
tation of the hydrochloride salt is complete. The precipi-
tate is collected on a filter and then recrystallized
from a mixture of methylene chloride and ethyl acetate to
gi~e 0.63 gm. (24% yield) of 4-(m-tri~luoromethylphenyl)-
4-dimethylam.nocyclohexanone ethylene ketal hydrochloride
having a melting point at 231 to 232 C.
Analysis:
Calc'd. for Cl7H23ClF3NO20
C, 55.81; H, 6.33i N, 3.83.
Found: C, 55.63; H, 6.66i Ng 3.94.
Example 56 Preparation of 4-(p-trifluoromethylphenyl)-
4-dimethylaminocyclohexanone, ethylene ketal
hydrochloride
Following substantially the same procedure as described

-140-

~ 5 1 6 3286


in Example 55, but substituting 4.79 gm. (0.024 mole)
p-trifluoromethylbromoben2ene for the 4.79 gm. (0.024 mole)
m-trifluoromethylbromobenzene, there is prepared 0.90 gm.
(34% yield) of 4-(p-trifluoromethylphenyl)-4-dimethylamino-
cyclohexanone, ethylene ketal hydrochloride having a melt-
ing point at 243 to 244 C.
Analysis:
Calc'd. for Cl7H23ClF3N02 ~H20:
C, 54.47; Hj 6.45; N, 3.74.
Found: C, 54.56; H, 6.24; N~ 4.13.
Example 57 Preparation of 4-(p-chlorophenyl)-2-methyl-
4 dimethylaminocyclohexanone
A solution cons;sting of 0.51 gm. (0.005 mole) diiso-
propylamine in 10 ml. tetrahydrofuran is chilled in an ice:
methanol bàth and 3 ml. of 1.68 N butyllithium in pentane
is added. To this mixture is then added a solution con-
sisting of 1.25 gm. (0.005 mole) 4-(p-chlorophenyl)-4-di-
methylaminocyclohexanone (prepared in Example 2) in 20 ml.
tetrahydrofuran. After 5 min. stirring, 1.42 gm. methyl
iod.de is added. This reaction is stirred for another
30 min. in the cold, and then it is allowed to warm up to
25 C. Striring is continued for 2~ hours, when 20 ml.
saturated aqueous ammonium chloride is added. Benzene is
also added. The organic solvents are removed by evaporation
under reduced pressure. The residue thus obtained is
transferred to a chromatographic column containing 200 ml.
silica gel. The chromatogram is developed wi~h 2 liters
of a mixture of 3% methanol in methylene chloride followed
by 2 liters of a mixture of S% methanol in methylene chlo-
ride. The appropriate fractions as determined by TLC are

-141-

3286
~ 6

comb~ned. The solvent is removed by evaporation under
reduced pressure giving the desired 4-(p-chlorophenyl3-
2-methyl-4-dimethylaminocyclohexanone. The compound is
recrystallized from diethyl ether to give an analytical
sample having ~ melting point at 110 to 111 C. This is
recognized to be the c~s isomer by NMR spectroscopy.
Analysis:
Calc'd. for ClsH20clNo:
C, 67.78; H,- 7.59; N, 5.27.
Found: C, 67.75; H, 7.59; N, 5.56.
The corresponding trans isomer is obtained by combining
the later series of fractions in the same manner. It is
recrystallized from a mixture of diethyl ether and technical
hexane to give 0.52 gm. of the isomer having a melting point
at lO3 to lO5 C.
Analysis:
Calc'd. for CL SH2 ~C1 NO:
C, 67.78; H, 7.59; N, 5.~7.
Found: C, 68.03; H, 7.61; N, 5.11.
Following the same procedure, but substituting, e.g.,
ethyl iodide, n-propyl iodide, n-butyl iodide, and n-pentyl
iodide, for methyl iodide, there are prepared the correspond- -
ing:
4-(p-chlorophenyl)-2-ethyl-4-dimethylaminocyclohexa-
none,
4-(p-chlorophenyl)~4-dimethylamino-2-n-propylcyclo-
hexanone,
2-n-butyl-4-(p-chlorophenyl)-4-dimethylaminocyclo-
hexanone,
4-(p-chlorophenyl3-4-d~methylamino-2-n-pentylcyclohex-

~l42-

3286
~ 5 1 6

anone, respectively.
Example 58 Preparation of 2-methyl-4-d;~ethylamlno-4-(p-
tolyl)cyclohexanone
A solution consisting of 1.02 gm. (O.OlO mole) diiso-
propylamine ;n 20 ml. tetrahydrofuran was chilled ;n an
ice:methanol bath before 6 ml. of l.68 N butyll;thium in
pentane is added. To this mixture is then added a solution
consisting of 2.31 gm. (.010 mole) o~ 4-dimethylamino-4-(p-
tolyl)cyclohexanone (prepared in Example l4) and 40 ml.
tetrahydrofuran. Five minutes later~ 2.82 gm. methyl iodide
is added, and the mixture is stirred for 45 min. in ~he cold.
It is allowed to warm to 25 C. and stirring is continued
for 5 hours, when the react;on mixture ;s diluted with a
mixture of water and benzene. The organic layer is separated
and washed first with water and then with brine. The organic
solvents are removed by evaporation under reduced pressure,
and the residual waxy solid thus obtained is transferred
to a column of the grade silica gel l" by 48". The chrom-
.. . ~
atogram is developed with a solvent medium consisting of
7.5~ methanol in chloroform and 20-ml. fractions are collected.
The fractions which contain product (as determined by TLC)
are combined. The solvent is removed by evaporation under
reduced pressure, and the residue thus obtained is recrystal-
l~zed from diethyl ether. There is thus obtained l.Ol gm.
2~ (39% yield) of the object compound 2-methyl-4-dimethylamino-
4-(p-tolyl)cyclohexanone having a melting point at 102 to
104.5 C. NMR suggests assignment o~ cis relationship of
2-methyl to 4-N(CH3 )2
Analysis:
Calc'd. for C~6H23N0:

-143-

32~6
~ 5 1 6

C, 78.32; H, 9.45; N, 5.71
Found: C, 78.03; H, 9.51; N5 5.65.
Exam~le 59
Following the procedure of Example 589 but separately
S substituting 4-(p-chlorophenyl)-4-diethylaminocyclohexanone,
4-(p-chlorophenyl)-4-dipropylaminocyclonexanone,
4-(p-chlorophenyl)-4-di-n-butylaminocyclohexanone, and
4-(p-chlorophenyl)-4-~N-methyl-N-cyclopropylamino)-
cyclohexanone, for the 4-dimethylamino-4-(p-tolyl)cyclo-
hexanone, there are prepared the corresponding objectcompounds:
4-(p-chlorophenyl)-4-diethylamino-2-methylcyclohex-
anone,
4-(p-chlorophenyl)-4-dipropylamino-2-methylcyclohex-
anone,
4-(p-chlorophenyl)-4-di-n-butylamino-2-methylcyclohex-
anone, and
4-(p-chlorophenyl)-4-(N-methyl-N-cyclopropylamino)-
2-methylcyclohexanone, respectively. 20 Example 60 Preparation of 4-(m-hydroxyphenyl)-4-n-propyl-
methylaminocyclohexanone ethylene ketal hydro-
chloride
Following the procedure of Example 40, Parts F and G,
but substituting the appropriate quantity of propionyl
chloride for butyryl chloride, and the appropriate inter-
mediate subsequently, the title compound is obtained as
a crystalline solid (m.p. 204-207 CO).
Anal~sis:
. Calc'd. for C,aH2aO3NCl:
C, 63.23; H, 8.25i N~ 4.10.

-l44- -

S:16 3286


Found: C, 63.13i H, 8.42; N, 3.95.
Example 61 Preparation of 4-(m-hydroxyphenyl )-4-(methyl-
n-pentylamino)cyclohexanone ethylene ketal
hydrochloride
Following the procedure of Example 40, Parts F and G3
but substituting the appropriate quantity of valeryl chlo-
ride ~pentanoyl chloride) for butyryl chloride, and the
appropriate intermediate subsequently, the title compound
is obtained as a gum.
Analysi$: -
Calc'd. for C20H3203NC1 ~2H20:
C, 63.68; H, 8.78; N, 3.70.
Found: C, 63.61; Hg 8.92; N, 3.50.
Example 62 Preparation of 4-~m-hydroxyphenyl)-4-(N-methyl-
N-~-phenylethylamino)cyclohexanone ethylene
ketal hydrochloride
Following theprocedure of Example 40, Parts F and G,
but substituting the appropriate quantity of phenylacetyl
chloride for n-butyryl chloride, and the appropriate inter
mediate subse~uently, the title compound is obtained as an
amorphous solid. The NMR and mass spectra are consistent
with the assigned structure.
Anal~sis:
Calc'd. for C23H3003NClo
C9 71.20; H9 7.80; N9 3.61.
Found: C, 66.64; H~ 7.47; N, 3.46.
Example 63 Preparation of 4-(m-hydroxyphenyl)-4~ butyl-
methylamino)cyclohexanone ethylene ketal hydro-
chloride
Following the procedure of Example 40, Parts F and G,

~145-

3286
lla~sl6

.
but substituting the appropriate quantity of 2-methylpro-
panoyl chlorlde for n-butyryl chlorlde, and the appropriate
~ntermediate subsequently, the title compound is obtained
as a crystalline solid (m.p. 203-204 C.). -
Analysis:
Calc'd. for ClgH3003NCl: r
C, 64.12; H, 8.57; N, 3.94.
Found: C, 64.14; H, 8.66; N, 4.30.
Example 64 Preparation of 4-(m-hydroxyphenyl)-4-(N-methyl-
N-cyclopropylmethylamino)cyclohexanone ethylene
ketal hydrochloride
Following the procedure of Example 40, Parts F and G,
but substituting the appropriate quantity of cyclopropane-
carbonyl chloride for n-butyryl chloride, and the appropriate
intermediate subsequently, the title compound is obtained
as a crystalline solid (m.p. 214-215 C.).
Analysis:
Calc'd. for Cl9H2ao3Ncl:
C, 64.48; H, 7.97; N9 3.96.
Found: C, 64.21; H, 8.08; N, 3.86.
~xample 65
Part A 4-(m-benzyloxyphenyl)-4-(N-methyl-N-ethylamino)-
cyclohexanone ethylene ketal hydroiodide
Following the procedure of Example 40, Part F, but
substituting the appropriate quantity of acetyl chloride for
n-butyryl chloride, there is obtained a material which is
dissolved in methytene chloride and this solution is washed
with 20% aqueoùs hydrogen iodide. The solid which remains
when the solution is taken to dryness is recrystallized
from methylene chloride:ethyl acetate to give crystalline

146-

~ 5 16 3286


4 (m-benzyloxyphenyl)-4-(N-methyl-N-ethylamlno)cyclohex~rlnne
ethylene ketal hydro~od1de, m.p. 195-196.5 C.
Analysis:
- Calc'd. fnr C24H32IN0:
C, 56.60; H, 6.33; N, 2.75.
~ound: C, 56.$3; H, 6.48; N, 2.93.
Part B
Hydrogenolysis of the compound prepared in Part A,
over inert catalyst, gives the corresponding 4-(m-hydroxy-
phenyl)-4-(N-methyl-N-ethylamino)cyclohexanone ethylene ketal.
Example 66
Part A 4-(m-benzyloxyphenyl)-4-(N-methyl-N-~-phenoxy-
ethylamino)cyclohexanone, ethylene ketal
hydrochloride
Following the procedure of Example 40, Part F but sub-
stituting phenoxyacetyl chloride for n-butyryl chloride
there is obtained the title compound. Recrystallization
from methylene chloride-ethyl acetate gives the product,
m.p. 173-174 C.
Analysis:
Calc'd. for C30H34ClN04:
C, 70.92, H, 6.75; N9 2.76.
Found: C, 70.81; H, 7~08; N, 2.62.
Part B
Hydrogenolysis of the compound prepared in Part A, over
inert catalyst, gives the corresponding 4-(m-hydroxyphenyl)-
4-(N-methyl-N-~-phenoxyethylamino)cyclohexanone, ethylene
ketal.
Example 67 4-(m-acetoxyphenylj-4-dimethylaminocyclohexan-
l-one

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3286
S16

.. .
To a solution of 0.96 g. (4~1 mmole) of 4-(m-hydroxy- -
phenyl)-4 dimethylaminocyclohexan-l-one (prepared in Exam~le
44) in 20 ml. THF there is added 0.46 g. (0.63 ml.) tri-
ethylamine and 0.46 9. (0.42 ml.) acetic anhydride. Follow-
ing 6 hours standing at room temperature the mixture is
concentrated in vacuum and the residue diluted with ice:
water. The precipitated gum is extracted with methylene
chloride. The extract is washed with saturated sod;um
bicarbonate and brine and taken to dryness. The residue is
chromatographed over a 1" x 48" column of TLC grade silica
gel. These fractions shown by TLC to contain product are
collected and taken to dryness. The solid which remained
is recrystallized from petroleum ether to give 0.30 g. of
4-(m-acetoxyphenyl)-4-dimethylaminocyclohexan-1-one, m.p.
15~1-53 C.
Analysis:
Ca~c'd. for Cl6H21N03:
C, 69.79; H, 7:69; N, 5.09.
Found: C, 69.47; H, 7.89; N, 5.21.
Exa~ple 68
Following the procedure of Example 67, but substituting
4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohexanone
(prepared in Example 40, Part H) for 4-(m-hydroxyphenyl)-
4-(dimethylamino)cyclohexanone there is obtained the desired
4-(m-acetoxyphenyl)-4-(methyl-n-butylamino)cyclohexanone
as the hydrochloride.
Qnalysis:
Calc'd. for C,9H2,N03~HClo2/3H20:
C, 62.36; H, 8.17; N~ 3.82.
30Found: C, 62.07; H, 7.81; N9 3.800

-148

~ 3~86
S~L6

Example 69 Preparation of 4-phenyl~ pyrroi~d~nyl)-
cyclohexanone, ethylene ketal 9 hydrochlor1de
A reaction mixture consisting of the free base from
2.69 gm. (0.01 mole) of 4-amino-4-phenylcyclohexanone,
ethylene ketal hydrochloride (prepared in Example 32, above)
2.16 gm. of l,4-dibromobutane9 2.76 gm. potassium carbonate,
and 15.0 ml. ethanol is heated at the reflux te~perature,
with stirring, for eighteen (18) hours. The volatile compo-
~ents are then substantially removed by evaporation under
reduced pressure, and the concentrate thus obtained diluted
with water. A precipitate forms which is collected on a
filter and dissolved in diethyl ether. The ether solution
is treated with an equivalent of 3 N hydrogen chloride in
diethyl ether. A precipitate that forms is collected on a
filter and recrystallized from a mixture of methylene chlo-
ride and ethyl acetate. There is thus obtained 1.57 gm.
(49% yield) of 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone,
ethylene ketal hydrochloride having a melting range from
238 to ~39.5 C.
Analysis:
Calc'd. for Cl8H26ClN02:
C, 66.75; H, 8.09; N, 4.33.
Found: C, 66.38; H, 8.25; N, 4.30.
Example 70 Preparation of 4-phenyl-4-(1-pyrrolidinyl)cyclo-
hexanone
A reaction solution consisting of 1.57 gm. (0.0049
mole) 4-phenyl-4-(1-pyrrolidinyl~cyclohexanone, ethylene
ketal hydrochloride (prepared in Example 69, above), 7.0 ml.
of 2.5 N hydrochlorlc acid, and 14.0 mlO methanol is set
as~de at 25 C. for sixty-six (66) hours. After cooling

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516

and removing most of the liquid and volatiles by evaporation
under reduced pressure, the residue is made strongly basic
with 50% aqueous sodium hydroxide. A precipitate that forms
i~ collected on a filter and then recrystallized from
petroleum ether. There is thus obtained 0.77 gm. ~65% yield)
of 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone having a melting
point at 75 to 76.5 C.
Analysis:
Calc'd. for Cl6HzlNO:
C, 78.97; H9 ~.70; N, 5.76.
Found: C, 79.03; H9 8.73i N, 5.75.
Example 71 Preparation of 4-phenyl-4-(1-piperidinyl)-
cyclohexanone, ethylene ketal hydrochloride
A reaction mixture consist;ng of the free base from
2.88 gm. (0.011 mole) of 4-amino-4-phenylcyclohexanone
ethylene ketal hydrochloride (prepared in Example 32, above),
3.47 gm. 1,5-diiodopentane, 2.95 gm. potassium carbonate,
and 25 ml. ethanol is heated at the reflux temperature, with
stirring, for eighteen (18) hours. After cooling and
-removing most of the liquid and volatiles by evaporation
under reduced pressure, the residue thus obtained is dis-
persed in a mixture of 100 ml. of diethyl ether and 10 ml.
of water. The ether layer is allowed to separate and is
recovered. It is washed with water and with brineg before
removing the ether by evaporation under reduced pressure.
The residue thus obtained is dissolved in diethyl ether
and an amount of 3 N hydrogen chloride in diethyl ether is
added so as to form the hydrochloride acid addition salt
wh~ch precipitates. The salt is collected on a filter and
then recrystallized from a mixture of methylene chloride and

-150-

32~6
`516
.
ethyl acetate. There is thus obtained 2.26 gm. (61% yield)
of 4-phenyl-4~ piperidinyl)cyclohexanone, ethylene ketal
hydrochlor~de having a melting range from 228 to 231 C.
An analytical sample has a melting point at 234 to 235.5 C.
Analysis:
Calc'd. for Cl9H28ClN02:
C, 67.54i H, 8.35; N, 4.14.
Found: C, 67.24i H, 8.12; N, 3.97.
Example 72 Preparation of 4-phenyl-4-(1-piperidinyl)cyclo-
hexanone
A reaction solution consisting of 2.26 gm. (0.0067
mole) of 4-phenyl-4-(1-piperidinyl)cyclohexanone, ethylene
ketal hydrochloirde (prepared in Example 71, above), 10 ml.
of 2.5 N hydrochloric acid and 20 ml. methanol is set aside
in a stoppered reaction vessel at 25 C. for four (4) days.
After removing most of the solvent by evapration under
reduced pressure, the residue is made strongly basic with
50% aqueous sodium hydroxide; A precipitate forms which
is collected on a f;lter and recrystallized two times from
a mixture of acetone and technical hexane. There is thus
obtained 0.94 gm. (55% yield) of 4-phenyl-4-(1-piperidinyl)-
cyclohexanone having a melting range from 114 to 117 C.
Analysis:
Calc'd. for Cl7H23N0:
C, 79.33; H, 9.01; N9 5.44.
Found: C, 79.16; H, 9.15; N9 5.31.
Example 73
Part A
__ ,
Following the procedure of Example 32 but substituting
the approprlate quantity of 4-isocyanato-4-(m-methoxyphenyl3-

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. 3286
'516

cyclohexanone ethylene ketal (prepared in Example 11, Part
F, above) for 4-phenyl-4-isocyanatocyclohexanone ethylene
ketal there is obtained 4-amino-4-(m-methoxyphenyl)cyclo-
hexanone, ethylene ketal hydrochloride (alternate name:
4-amino-4-(m-anisyl~cyclohexanone, ethylene ketal hydro-
chloride).
Part B
Fo710wing the procedure of Example 69 but substituting
the appropriate quantity of 4-amino-4-(m-methoxyphenyl)-
cyclohexanone ethylene ketal hydrochloride (prpeared in PartA, above) for the 4-amino-4-phenylcyclohexanone, ethylene
ketal hydrochloride there is obtained 4-(1-pyrrolidinyl)-
4-(m-methoxyphenyl)cyclohexanone ethylene ketal hydrochloride.
Part C
Following the procedure of Examp`le 70 but substituting
an appropriate quantity of 4-(m-anisyl)-4-(1-pyrrolidinyl)-
cyclohexanone ethylene ketal hydrochloride (prepared in Part
B, above) for 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone
ethylene ketal hydrochloride there is obtained 4-(m-anisyl)-
4-(~pyrrolidinyl)cyclohexanone.
Part D
Following the procedure of Example 40, Part A, but
substituting an appropriate quantity of 4-(m-anisyl)-4-(1-
pyrrolidinyl)cyclohexanone (prepared in Part C, above) for
the 4-cyano-4-(m-anisyl)cyclohexanone there is obtained
4-(m-hydroxyphenyl)-4-(1-pyrrolidnyl)cyclohexanone.
. . Part E
Following the procedure of Example 409 Part B, but
substituting an appropriate quantity nf 4-(m-hydroxyphenyl)-
4-(1-pyrrolidinyl)cyclohexanone (prepared ln Part D, above)

~ -152-

il~3f~S16 3 286


~or 4-cyano-4-tm-hydroxyphenyl)cyclohexanone there is ob-
tained 4-(m-hydroxyphenyl)-4-(1-pyrrolidinyl)cyclohexanone,
ethytene ketal.
Part F
Following the procedure of Example 67, Part A, but
substituting an appropriate quantity of 4-(m-hydroxyphenyl)-
4-(1-pyrrolid;nyl)cyclohexanone (prepared in Part D, above)
for 4-(m-hydroxyphenyl)-4-(dimethylamino)cyclohexanone
there is obta;ned 4-(m-acetoxyphenyl)-4~ pyrrolidinyl)-
cyclohexanone.
Example 74
Part A
Following the procedure of Example 32 but separately
substituting the appropriate quantity of each of the 4-iso-
cyanato intermediates prepared in Examples 1-27 (Parts F)
and Example 31, Part A, for 4-isocyanato-4-phenylcyclo-
hexanone ethylene ketal there is obtained, respectively,
each corresponding 4-aryl-4-aminocyclohexanone, ethylene
ketal hydrochloride.
Part B
Fotlowing the procedure of Example 69 but separately
substituting each amino compound prepared in Part A above
for 4-phenyl-4-aminocyclohexanone ethylene ketal hydrochlo-
chloride and 2-methyl-1,4-dibromobutane for 1,4-dibromo-
butane there is prepared, respectively9 each corresponding
4-aryl-4-t3-methyl-1-pyrrolidinyl)cyclohexanone ethylene
ketal hydrochloride.
Part C
Each product compound prepared in Part B, above, can
be hydrolyzed to the corresponding ketone, following the

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3286
S~6
,
procedure of Example 70 but substituting an appropriate
quantity of each ethylene ketal hydrochloride (Part B,
abo~e) for 4-(phenyl)-4-tl-pyrrolidinyl)cyclohexanone
ethylene ketal hydrochloride.
Example 75
Part A
Following the procedure of Example 71 but separately
substituting appropriate quantities of each amino compound
prepared in Example 74, Part A, for 4-phenyl-4-aminocyclo-
hexanone ethylene ketal hydrochloride, and 3-ethyl-1,5-di-
iodopentane for the l,5-diiodopentane there are prepared,
respectively, the corresponding 4-aryl-4-(4-ethyl-1-piper-
idinyl)cyclohexanone ethylene ketal hydrochlorides.
Part B
Following the procedure of Example 72 but separately
substituting an appropriate quantity of each ketal prepared
in Part A, above, for 4-phenyl-4-(1-piperidinyl)cyclohex-
anone, ethylene ketal hydrochloride there are obtained,
respectively, the corresponding 4-aryl-4-(4-ethyl-1-piper-
idinyl)cyclohexanones.
xample 76
Following the procedure of Example 42, Part B, but
separately substituting the appropriate quantity of each
intermediate prepared in Example 509 Part B, for the 4-cyano-
4-(methyl-n-butylamino)cyclohexanone ethylene ketal there
are prepared the corresponding compounds:
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone tri-
methylene ketal (m.p. 147-1~0 C.)
Analysis:
Calc'd. for Cl7H2sNO~:

-15~-

,

3 286


C, 70.07; H, 8.65; N, 4.81.
Found: C, 69.67; H, 8.45; N, 5.07.
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone
(2,2-dimethyltr;methylene) ketal
S Analys;s:
Calc'd. for ClgH29N03:
C, 71.44; H, 9.15; N, 4.39.
Found: C, 70.76; H, 9.22; N, 4.57.
4-(m-hydroxypheny1)-4-dimethylaminocyclohexanone,
(2-phenyltrimethylene) ketal
Anal ys i s:
Calc'd. for C 2 3 H 2 9 N0 3 :
C, 75.17; H, 7.95; N, 3.81.
Found: C, 74.79; H, 8.04; N, 4.09.
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone,
(2-allyltri0ethylene) ketal
Analysis:
Ca)c'd. for C20H2gN03:
C, 72.47; H/ 8.82; N, 4.23.
Found: C, 72.15; H, 9.01; N, 4.42.
Example 77
Part A
Following the procedure of Example 429 Part A, but
substituting the appropriate quantity of allylmethylamine
for methyl-n-butylamine, stirring at room temperature for
2 days and extracting the reaction mixture with diethyl
ether there is obtainedg on recrystallization from petroleum
ether, crystalline product, 4-cyano-4-(N-methyl-N-allyl-
am~no)cyclohexanone ethylene ketal 9 m.pO 47-5Q C. (Mass
spec. m/e+ (M ) = 236).

-155-

3 286
5~

- Analysls:
Calc'd. for Cl3H20N202:
C, 66.07; H, 8.53; N, 11.86.
Found: C, 66.85; H, 8.65; N, 11.69.
Part B
.
Following the procedure of Example 42, Part B, but
substituting 4-cyano-4 (N-methyl-N-allylamino)cyclohexanone
ethylene ketal (prepared in Part A) for 4-cyano-4-(methyl-
n-butylamino)cyclohexanone ethylene ketal, and purifying
by high-pressure liquid chromatography followed by recrys-
talli~ation there is obtained the object compound 4-(m-
hydroxyphenyl)-4-(N-allyl-N-methylamino)cyclohexanone
ethylene ketal.
Analysls:
Calc'd. for ClaH2sNo3-2/3Hzo:
C, 68.54; H, 8~40; N9 4.44.
Found: C, 68.62; H, 8.45; N, 4.32.
Example 78
Part A
Following the procedure of Example 1, Parts A-H, but
in;tially substituting l-naphthylacetonitrile for p-chloro-
phenylacetonitrile and subsequently substituting each inter-
mediate appropriately there is obtained 4-(1-naphthyl)-
4-dimethylaminocyclohexanone ethylene ketal, m.p. 132-135 C.
Analysis:
Calc'd. for C2 oH~ sNO2:
; C, 77.13; H, 8.09; N, 4.50.
Found: C9 76.939 H, 8.40; N9 4.48.
Part B
- 30 Following the procedure of Example 2 but substituting

.
- 1 5 6 - .

3 286
516

the product from Part A for 4-(p-chlorophenylj-4-dimethyl-
aminocyclohexanone ethylene ketal hydrochlor~de there is
obtained 4 (1-naphthyl)-4-dimethylaminocyclohexanone.
Analysis:
Calc'd. ~or Cl~H2lN0 1/4H20
C, 79.52; H, 7.97; N, 5.15.
Found: C, 79.76; H, 8.04; N, 5.22.
Example 79
.
Following the procedure of Example 44, but separately
substituting the appropriate quantities of the final com-
pounds prepared in Examples 60 through 64 for 4-(m-hydroxy-
phenyl)-4-dimethylaminocyclohexanone, ethylene ke~al there
are prepared
4-(m-hydroxyphenyl)-4-(n-propylmethylamino)cyclohex-
anone (m.p. 116-118 C.)
Analysis:
Calc'd. for Cl6H23N02:
C, 73.53; H, 8.87; N9 5.36.
Found: C, 73.29; H, 8.96; N, 5.67.
4-(m-hydroxyphenyl)-4-(n-pentylmethylamino)cyclohexanone,
4-(m-hydroxyphenyl)-4-~N-~-phenylethyl-N-methylamino)-
cycl ohexanone,
4-(m-hydroxyphenyl)-4-(i-butylmethylamino)cyclohexanone,
and 4-(m-hydroxyphenyl)-4-(N-cyclopropylmethyl-N-methyl-
amino)cyclohexanone,
Example 80
Following the procedure of Example 67, but substituting
4-(m-hydroxyphenyl)-4-(N-~-phenyle~hyl-N-methylamino)-
cyclohexanone,
4-(m-hydroxyphenyl)-4-(n-propylmethylamino)cyclQhexanone9

157-

" ` 3286
S~6

4-(m-hydroxyphenyl)-4-(n-pentylmethylamino)cyclohex-
anone,
4-(m-hydroxyphenyl)-4-(isobutylmethylamino)cyclohex-
anone, and
4-(m^hydroxyphenyl)-4-(cyclopropylmethylmethylamino)-
cyclohexanone prepared in Example 79 (above) for 4-(m-
hydroxyphenyl)-4-dimethylaminocyclohexanone there are
obta;ned, respectively, 4-(m-acetoxyphenyl)-4-tN-~-phenyl-
ethyl-N-methylamino)cyclohexanone,
4-(m-acetoxyphenyl)-4-(N-propylmethylamino)cyclohexa-
none,
4-(m-acetoxyphenyl)-4-~n-pentylmethylamino)cyclohex-
anone,
4-(m-acetoxyphenyl)-4-(isobutylmethylamino)cyclohexa-
none, and
4-(m-acetoxyphenyl)-4-(cyclopropylmethylamino)cyclo-
hexanone.
Example 81
Following the procedure of Example 67 but substituting
propionic anhydride and butyric anhydride for acetic
anhydride there are prepared
4-(m-propionoxyphenyl)-4-dimethylaminocyclohexanone,
4-(m-n-butyroxyphenyl)-4-dimethylaminocyclohexanone.
Example 82
Following the procedure of Example 68 but substituting
propionic anhydride and n-butyric anhydride for acetic
anhydride, there are obtained
4-(m-propionGxyphenyl)-4-(methyl-n-butylamino)cyclo-
hexanone, and
4-~m-n-butyroxyphenyl)-4-(methyl-n-butylamino)cyclo-

-158-

llU~S16.


hexanone, respectively.
Example 83 Preparatlon of 4-phenyl-4-d~ethylaminocyclo-
hexanone hydrochloride
Part A
Following the ~rocedure for Example 47, Part B, but
substituting bromobenzene for the tetrahydropyranyl ether
of m-bromophenol, there is obtained 4-phenyl-4-diethylamino-
cyclohexanone ethylene ketal.
Part B
tollowing the procedure of Example 44, but substituting
an appropriate quantity of the compound prepared in Part A
(above) for 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone
ethylene ketal, there is obtained the 4-phenyl-4-diethyl-
aminocyclohexanone as the hydrochloride salt, m.p. 175-
177.5 C.
Analysis:
Calc'd. for Cl6H24NOC1 ~2H20:
C, 66.07; H9 8.66; N, 4.81.
Found: C, 65.78; H, 8.88i N~ 4.98.
Example 84 Preparation of 4-dimethylamino-4-(3-hydroxy-
4-methylphenyl)cyclohexanone ethylene ketal
Part A
Following the procedure of Example 42~ Part B, but
substituting the appropriate quantities of 4-cyano-4-di-
methylaminocyclohexanone ethy1ene ketal, prepared in Example
41, Part B, and of the tetrahydropyranyl ether of 3-hydroxy-
4-methylbromobenzene for the corresponding ether of m-bromo-
phenol, there ~s obtained 4-(3-hydroxy-4-methylphenyl)-
4-d~methylaminocyclohexanone ethylene ketal which is re-
erystalllzed from chloroform/ethyl acetate; m.p. 196-200 C.

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3286
516

Analysis:
Calc'd. for C~7H25N03~H20:
C, 67.96; H, 8.72; N, 4.66.
Found: C, 68.28; H, 8.73; N, 4.90~
The compounds of the Formula I have analgetic activity
and can be used for the relief of pain without loss of con-
sciousness. The compounds can be used to treat the pain of
headache, muscle spasm, arthritis and other musculoskeletal
conditions, e.g., bursitis, relieve mild to moderate post-
operative and postpartum pain; dysmenorrhea and pain of
traumatic origin. Additionally, the compounds of Formula
I can be administered for the treatment of severe pain, e.g.,
pain associated with adenocarcinoma, amputation of a limb,
and third degree burns over a major portion of the body
lS in animals and humans.
Additionally selected compounds of Formula I have a~tiv-
ity as narcotic antagonists. They can be used to counteract
or prevent excessive central nervous system depression and
respiratory depression resulting from the administration of
morphine ur other morphine like drugs, e.g., hydromorphone,
oxymorphone, methadone and meperidine. The compounds are also
capable of inducing an abstinence syndrome in narcotic ad-
dicted subjects, i.e., induce withdrawal effects for
diagnostic purposes.
The dosage of the compound of the Formula I for analgetic
purpose~ is from about 0.01 to about 7 mg~/kg. body weight of
the patient. The compounds of the Formula I are conveniently
prepared in 5,lO,25,50,75,lOOand 200 mg. dosage units for ad-
~inistration for 1 to 4 times a day. Preferred unit dosages
are from 0.05 to 4 mg./kg. body weight of the patient.

- 1 6 0 -

11(~¢~516 32~6


The co~pounds are administered orally, parenterally
and rectally for systemic actionO
The compos;t;ons of the present lnvention are presented
for administration to humans and animals in unit dosage
forms, such as tablets, capsules, pills, powders, granules,
sterile parenteral solutions or suspensions, and oral solu-
tions or suspensions, and oil-water emulsions containing
suitable quantities of a compound of Formula I or its
pharmacologically acceptable salts.
Pharmaceutical dosage unit forms are prepared in
accordance with the subsequent general specific descriptions
to provide from about 0.5 mg. to about 500 mg. of the
essential active ingredient per dosage unit form (pre-
ferred 2.5 - 300 mg.).
Oral pharmaceutical dosage forms are either solid or
li~uid. The solid dosage forms are tablets, capsules,
granules, and bulk powders. Types of oral tablets are,
for example, compressed (including chewable and lozenge),
tablet triturates, enteric-coated, sugar-coateds film-
coated, and multiple compressed. Capsules are either hard
or scft elastic gelatin. Granules and powders are either
effervescent or non-effervescent.
Pharmaceutically acceptable substances utilized in
compressed tablets are binders9 lubricants, diluents, dis-
integrating agents~ coloring agents, flavoring agents, flow~nducing agents, and wetting agents. Tablet triturates
(either molded or compressed) utilize diluents and binders.
Enter~c-coated tabletsl, due to their enteric-coating, resist
the action of stomach acid and dissolve or disintegrate in
the alkaline intestine. Sugar-coated tablets are compressed

-161-

3286
~ 5 1 6

tablets to which usual1y four different layers of pharma-
ceutically acceptable substances have been applied. Film-
coated tablets are compressed tablets which have been
coated with a water soluble cellulose polymer. Multiple
compressed tablets are compressed tablets made by more than
one compression cycle utilizing the pharmaceutically accept-
able substances previously mentioned. Coloring agents are
utilized in the above dosage forms. Flavoring and sweeten-
ing agents are utilized in compressed tablets, tablet
triturates, sugar coated, mult;ple compressed and chewable
tablets. Flavoring and sweetening agents are especially
useful in the formation of chewable tablets and lozenges.
Examples of binders include glucose solution (25-50%),
acacia mucilage (l0-20%), gelatin solution ~l0-20%), sucrose
and starch paste. Lubricants include, for example, talc,
starch, magnesium or calcium stearate, lycopodium and
stearic acid. Diluents include, for example, lactose, su-
crose, starch, kaolin, salt, mannitol and dicalcium phosphate.
Disintegrating agents include, for example, corn starch,
potato starch, bentonite, methylcellulose, agar and carboxy-
methylcellulose. Coloring agents include, for example, any
of the approved certified water soluble FD and C dyes,
mixtures thereof, and water insoluble FD and C dyes suspended
on alumia hydrate. Sweetening agents include, for example,
sucrose, lactose, mannitol, and artificial sweetening agents
such as sodium cyclamate and saccharin9 and any number of
spray dried flavors. Flavoring agents include natural
flavors extracted from plants such as fruits and synthetic
blends of compounds which produce a pleasant sensation. Flow
~nduc~ng agents include, for example9 silicon dioxide and

-l62-

32~6
6;?516

talc. Wettlng agents include, for example, propylene
glycol monostearate, sorb~tan monooleate, diethylene glycol
monolaurate and polyoxyethylene laural ether. Enteric-
coatings include, for example, fatty acids, fats, waxes,
shellac, ammoniated shellac and cellulose acetate phthal-
ates. Pharmaceutically acceptable substances for the first
layer, an undercoating, of sugar-coated tablets, include,
for example, dextrin and gelatin. The second layer, an
opaque zone, includes, for example, starch, talc, calcium
carbonate, magnesium oxide and magnesium carbonate. The
third layer, a translucent zone, includes, for example9
sucrose The fourth layer, a glaze, includes, for example,
beeswax, carnauba wax, or a mixture of these waxes. Film
coatings include, for example, hydroxyethylcellulsoe, sodium
carboxymethylcellulose, polyethylene glycol 4000 and cellu-
lose acetate phthalate.
Hard gelatin capsules, sizes 5 through 1000, are made
largely from gelatin and may be either clear or colored.
These capsules may be filled with either a powder or coated
pellets (sustained release).
The diluents utilized in powder filled capsules are
the same as those illustrated above for tablets. Pharma-
ceutically acceptable substances utilized for coating pellets
include, for example, stearic acid, palmitic acid, glyceryl
myristate, cetyl alcohol, fats9 waxes9 polymeric substances
sensitive to small changes in p~ of the gastrointestinal
tract, polyvinyl alcohol, ethyl cellulose and mixtures of
beeswax, carnauba wax or bayberry wax with glyceryl mono-
stearate.
Soft elastic gelatin capsules contain sufficient

-1 63q

~ 5 16 3286


glycerin so that they are permanently flex;ble. Pharma-
ceutically acceptable liquid diluents used in soft elastic
gelatin capsules are those which do not dissolve or harm
the capsule and which are non-toxic? including, for example,
corn o;l 9 cottonseel oil, polysorbate 809 DMA and triacet;n.
Pharmaceutically acceptable substances utilized in
non-effervescent granules, for solution andlor suspension,
include diluents, wetting agents, flavoring agents and
coloring agents. Examples of diluents, wetting agents,
flavoring agents and coloring agents include those prev;ously
exemplified.
Pharmaceutically acceptable substances utilized in
effervescent granules and powders include organic acids,
a source of carbon dioxide, diluents, wetting agents,
flavoring agents and coloring agents.
Examples of organic acids include, for example, citric
acid and tartaric acid. Sources of carbon dioxide include,
for example, sodium bicarbonate and sodium carbonate. Exam-
ples of sweetening agents include, for example, sucrose,
calcium cyclamate and saccharin. Examples of diluents~
wetting agents and coloring agents include those previously
exemplified.
Bulk powders have the compound of the Formula I uniformly
dispersed throughout a pharmaceutically acceptable powdered
carrier diluent. Examples of the diluent include those
previously exemplified.
The individual oral solid pharmaceutical dosage forms9
tablets and capsules, are packaged individually, unit-dose,
or in quantity. multiple-dose containers, for example,
bottles of 50, 100, 500, 1000, or SOOOO
.




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32~6
S16

The amount of compound of the Formula I analog per
dose unit is adjusted so that it provides the patient with
an effective amount. The exact dose depends on the age,
weight and condition of the patient or animal as is known
in the art. For example, tablets and capsules are given
~n sufficient number and frequency to obtain the desired
pharmacological effect.
The sustained release tablets and capsules provide an
effective amount upon ingestion and continue to release a
sufficient amount of the active material to keep the concen-
tration at an effective level for increased periods of
time, for example, 12 hours.
Non-effervescent granules and powders are packages in
predetermined amounts, such that when reconstituted with a
specified quantity of an appropriate liquid vehicle 9
usually distilled water, a solution and/or suspension results,
pro~iding a uniform concentration of the compound of the
Formula 1 after shaking, if necessary. The concentrat-,on of
the solution is such that a teaspoonful (5 ml.), a table-
spoonful (one-half ounce or 15 ml.) or a fraction or a
m,ultiple thereof will provide an effective amount to produce
the desired pharmacological effect. The exact dose depends
on the age, weight and condition of the patient or animal,
as is known in the art.
Ef~ervescent granules and powders are packaged ei~her
in unit-dose, for example, tin foil packets, or in bulk,
for example, in 4 oz. and 8 oz. amounts, such that a specific
amount, either a unit-dose or, for example~ a teaspoonful,
tablespoonful or a fraction or a multiple thereof of bulk
granules, when added to a specific amount of liquid vehicleS

-165-

PS16


for example, water, yields a ccntainer of liquid dosage
form to be ingested. The concentratlon of the active
materlal in the granules is adjusted so that a specified
amount when mixed with a spec;fic amount of water yields
an effective amount of the active ma~erial and ~roduces the
desired pharmacological effect. The exact amount of
granules to be used depends on age, weight and condition
of the patient as is known in the art.
Liquid oral dosage forms include, for exa~ple, aqueous
solutions, emulsions, suspensions, solutions and/or sus-
pensions reconstituted from non-effervescent granules and
effervescent preparations reconstituted from effervescent
~ranules. Aqueous solutions include, for example, elixirs
and syrups. Emulsions are either oil-in-water (o/w) or
water-in-oil (w/o).
Elixirs are clear, sweetened, hydroalcoholic prepara-
tions. Pharmaceutically acceptable substances utilized in
elixirs include, for example, solvents. Syrups are con-
centrated aqueous solutions of a sugar, for example, sucrose,
20 - and may contain a preservative. An emulsion is a two-phase
system in which one liquid is dispersed in the form of small
globules throughout another liquid. 0/w emulsions are much
preferred for oral administration over w/o emulsions. Phar-
maceutically acceptable substances utilized in emulsions are
non-aqueous liquids, emulsifying agents and preservatives.
Syspensions utilize pharmaceu~ical1y acceptable suspending
agents and preservatives. Pharmaceutically acceptable sub-
stances utilized in non-effervescent granules, to be recon-
stituted into a liquid oral dosage form, lnclude, for
example, diluents, sweeteners 9 and wetting agents. Pharma-

-1 66-

32~6
S16

ceutically acceptable substances utllized in effervescent
granules, to be reconst~tuted into a liquld oral dosage
form, include, for example, organic acids and a source of
carbon dioxide. Coloring and flavoring agents are utilized
~n all of the aboYe dosage formsO
Solvents include9 for example, glycerin, sorbitol,
ethyl alcohol and syrup. Examples of preservat;ves include
glycerin, methyl and propylparaben, benzoic acid, sodium
benzoate and alcohol. Examples of non-aqueous liquids
utili~ed in emulsions include, for example, mineral oil and
cottonseed oil. Examples of emulsifying agents include for
example, gelatin, acacia, tragacanth, bentonite, and sur-
factants such as polyoxyethylene sorbitan monooleate.
Suspending agents include, for example, sodium carboxy-
~5 methylcellulose, pectin, tragacanth, Veegum and acacia.Diluents include, for example, lactose and sucrose. Sweet-
ening agents include, for example9 sucrose7 syrups, glycerin,
and artificial sweetening agents such as sodium cyclamate
and saccharin. Wetting agents include, for example, propyl-
ene glycol monostearate, sorbitan monooleate, diethylenegiycol monolaurate and polyoxyethylene lauryl ether. Organic
acids include, for example, citric and tartaric acid.
Sources of carbon dioxide include, for example, sodium
bicarbonate and soidum carbonate. Coloring agents include,
for example, any of the approved9 certified water soluble
FD and t dyesa and mixtures thereof. Flavoring agents
includie, for example, natural flavors extracted from plants
such as fruits, and synthetic blends of compounds which
produce a pleasant taste sensation~
The concentratlon of the compound of the Formula I

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3286
$16

throughout the solutlons must be unlform. Upon sh~lk~n~l
the concentratlon of the compound of the Formula 1 throughout
the emulsions and suspensions must be uniform.
The concentration of the compound of the Formula I is
adjusted so that a teaspoonful (5 ml.), a tablespoonful
(one-half ounce or 15 ml.) or a fraction or multiple thereof,
will provide an effective amount to produce the desired
pharmacological effect. The exact dose depends on the age,
weight and condition of the patient or animal as is known
in the art.
The liquid oral dosage forms may be packaged, for
example, in unit-dose sizes of 5 ml. (teaspoonful), 10 ml.,
15 ml. (tablespoonful) and 30 ml. (one ounce), and multiple
dose containers9 including, for example9 2 oz., 3 oz., 4 oz.,
6 oz., 8 oz., pint, quart, and gallon sizes.
Non-efferYescent granules are pac~aged in predetermined
amounts such that when reconstituted with a specified
quantity of an appropriate liquid vehicle, usually distilled
water, a solution and/or suspension results providing a
uniform concentration of the compound of the Formula I after
shaking, if necessary. The concentration of the solution is
such that a teaspoonful (5 ml.), a tablespoonful (one-half
ounce or 15 ml.) or a fraction or multiple thereof will
provide an effective amount to produce the desired pharma-
cological effect. The exact does depends on the age, weisht,and condition of the patient or animal as is known in the
art.
Effervescent granules are packaged either in unit-dose,
for example, tin foil packets or in bulk9 for example, in
4 oz. and 8 oz. amounts such that a specific amount, ei~her

-1~8-

110U$16 32~6


a unit-dose or for example, a teaspoonful, tablespoonful or
a fract~on or multiple thereof of bulk granules when added
to a specific amount of liquid vehicle, for example, water
yields a container of liquid dosage form to be ingested.
The concentration of the compound of the Formula I in the
granules is adjusted so that a specified amount when mixed
with a specific amount of water yields an effective amount
of the active material to produce the desired pharmacological
effect. The exact amount of granules to be used depends on
age, weight and condition of the patient as it known in
the art.
Parenteral administration includes intravenous, sub-
cutaneous, intramuscular, and the like.
Preparations for parenteral administration include
sterile solutions ready for injection, sterile dry soluble
products ready to be combined with a solvent just prior to
use, including hypodermic tablets, sterile suspensions
ready for injection, sterile dry insolbule products ready
to be combined with a vehicle just prior to use and sterile
emulsions. The solutions may be either aqueous or non-
aqueous.
Pharmaceutically acceptable substances utilized in
parenteral preparations include aqueous vehicles, non-
aqneous vehicles, antimicrobial agents, isotonic agents,
buffers, antioxidants9 local anesthetics9 suspending and
dispersing agents, emuls~fying agents, sequestering or
chelattng agents and other pharmaceutical necessities.
~ xamples of aqueouls vehlcles include Sodium Chloride
In~ection, Ringers In~ection, Isotonic (5 percent) Dextrose
~n~ection, Steri1e Water for Injectionj Dextrose and Sodium

- -169-

~,

.

~ 5 1~ 3286


Chloride InJection and Lactated Ringers Injection. Non-
aqueous parenteral vehicles ~nclude flxed olls of vegetable
origln, for example, cottonseed oil, corn oil, sesame oil
and peanut oil. Antimicrobial agents in bacteriostatic t
5 or fungistatic concentrations must be added to parenteral
preparations packaged in multiple-dose containers (vials)
which ;nclude phenol or cresols, mercur;als, benzyl alcohol,
chlorobutanol, methyl and propyl p-hydroxybenzoic acid
esters~ thimerosal, benzalkonium chloride and benzethonium
lO chloride. Isotonic agents include, for example, sodium
chloride and dextrose. Buffers include, for example, phos
phate and citrate. Antioxidants include, ~or example,
sodium bisulfiate. Local anesthetics include, for example,
procaine hydrochloride. Suspending and dispersing agents
15 include, for example, sodium carboxymethylcellulsoe, hydroxy-
propyl methylcellulose and polyvinylpyrrolidone. Emulsifying
agents include, for example, Polysorbate 80 (Tween 80). A
sequestering or chelating agent of metal ions include, for
example, EDTA (ethylenediaminetetraacetatic acid)O Pharma-
20 ceutical necessities include, for example, ethyl alcohol,
polyethylene g1ycol and propylene glycol for water miscible
vehicles and sodium hydroxide, hydrochloric acid, citric
acid or lactic acid for pH adjustment.
The concentration of the pharmaceutically active
25 ingredient is adjusted so that an injection, for example,
0.5 ml.~ l.n ml., 2.0 ml., and 5.0 ml. or an intraarterial
or intravenous infusion, for example, 0.5 ml.~min., l.0
ml./min., l.0 ml./min., and 2~0 ml./min. provides an
effectlve amount to produce the desired pharmacological
30 effect. The exact dose depends on the age, weight and

..
-170- -

328
110(~6

condition of the patient or animal as ls known in the
art.
The un~t-dose parenteral preparations are packaged,
- for example, in an ampul or a syringe with a needle. The
multiple-dose package, for example, is a vial.
All preparations for parenteral administration must be
sterile, as is known and practiced in the art.
Illustratively, intravenous or intraarterial infusion
of a sterile aqueous solution containing an active material
is an effective mode of administration. Another embodiment
is a sterile aqueous or oily solution or suspension con-
taining an active material injected as necessary to produce
the desired pharmacological effect.
Pharmaceutical dosage forms for rectal administration
are rectal suppositories, capsules, tablets for systemic
effect.
Rectal suppositories are used herein mean solid bodies
for insertion into the rectum which melt or soften at body
temperature releasing one or more pharmacologically or
therapeu~ically active ingredients.
Pharmaceutically acceptable substances utilized in
rectal suppositories are bases or vehicles and agents to
raise the melting point.
Examples of bases or vehicles include, for example,
cocoa butter (theobroma oil), glycerin-gelatin, carbowax,
(polyoxyethylene glycol) and appropriate mixtures of mono-,
di- and triglycerides of fatty ac~ds. Combinations of the
various bases may be used. Agents to raise the melting point
of suppositorles include9 for example, spermaceti and wax.
Rectal suppositories may be prepared e~ther by the compressed

~171-

~ 3286


method or by molding. The usual we~ght of a rectal
suppository is about 2.0 gm.
Tablets and capsules for rectal adm1nistration are
manufactured utilizing the same pharmaceut1cally acceptable
~ubstance and by the same methods as for formulations for
oral administration.
Rectal suppositories, tablets or capsules are packaged
either individually, in unit-dose, or in quantityt, multiple
dose, for example, 2, 6, or 12.
The pharmaceutically therapeutically active compounds
of the Formula I are administered orally, parenterally or
rectally in unit-dosage forms or multiple-dosage forms.
Unit-dose forms as used in the specification and claims refers
to physically discrete units suitable for human and animal
subjects and packaged individually as is known in the art.
Each unit-dose contains a predetermined quantity of the
therapeut;cally active compound sufficient to produce the
desired therapeutic effect, in association with the required
pharmaceutical carrier, vehicle or diluent. Examples of
unit-dose forms include ampuls and syringes (parenteral),
individually packaged tablet or capsule (oral-solid) or
individually packaged teaspoonful or tablespoonful (oral-
liquid). Unit-dose forms may be administered in fractions
or multiples thereof. A multiple-dose form is a plurality
of identical unit-dosage forms packaged in a single container
to be administered in segregated unit-dose form. Examples
of multiple-dose forms include vials (parenteral), bottles
of tablets or capsules (oral-solid) or bottles of pints or
gallons (oral-liquid). Hence, multiple dose form is a
multiple of unit-doses which are not segregated in packaging.

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32~6
'516

The spec~ficat;ons ~or the unit-dosage form and the multiple-
dosage form are dictated by and directly dependent on (a)
the unlque characteristics of the therapeutically act;ve
compound and the particular therapeutic ef~ect to be
S achieved and (b) the limitations inherent in the art of
compounding such a therapeutically active compound for ther-
apeutic or prophylactic.
In addition to the administration of a compound of
Formula I as the principal active ingredient of compositions
for the treatment of the conditions described herein, the
said compound can be included with other types of compounds
to obtain advantageous combinations of properties. Such
combinations include a compound of Formula I with other
analgesics such as aspirin, phenacetin acetaminophen, pro-
poxyphene, pentazocine, codeine, meperidi-ne, oxycodone,
mefenamic acid, and ibuprofen; muscle relaxants such as
methocarbamol, orphenadrine, carisoprodol, meprobamate,
chlorphenesin carbamate, diazeoam, chlordiazepoxide, and
chlorzoxazonei analeptics such as caffeine, ~ethylphenidate
and pentylenetetrazol; corticosteroids such as methylpred-
nisolone, prednisone, prednisolone and dexamethasone; anti-
histamines such as chlorpheniramine, cyproheptadine, pro-
methazine and pyrilamine.
Example 85 Capsules
One thousand two-piece hard gelatin capsules for oral
use9 each containing 0.5 mg. of 4-(methyl-n-butylamino)-
4-tm-hydroxyphenyl)cyclohexan-1-one ethylene ketal hydro-
chloride are prepared from the following types and amounts
of mater1als:
4-~nlethyl-n butylamino)~

-~73

~ 6 32~6


4-(m-hydroxyphenyl)cyclo-
hexan-l-one ethylene ketal
hydrochloride 0.5 gm.
Lactose l50 gm.
Corn Starch 25 gm.
Talc 20 gm.
Magnesium stearate 2.0 gm.
The materials are thoroughly mixed and then encap-
sulated in the usual manner.
The foregoing capsules are useful for the treatment
of headache in adult humans by the oral administration of
l capsule every 4 hours.
Using the procedure above, capsules are similarly
prepared containing 4-(methyl-n-butylamino)-4 (m-hydroxy-
phenyl)cyclohexan-l-one ethylene ketal hydrochloride in 50,
75, lO0, and 200 mg. amounts by substituting 50, 75, 100,
and 200 gm. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)-
cyclohexan-l-one ethylene ketal hydrochloride for the 25 gmO
used above.
Exam~e 86 Capsules
One thousand two-piece hard gelatin capsules for oral
use, each containing 100 mg. of 4-(methyl-n-butylamino)-
4 (m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydro-
chloride and 325 mg. of aspirin9 are prepared from the
following types and amounts of ingredients:
4-(methyl n-butylamino)-
4-(m-hydroxyphenyl)-
cyclohexan-l-one ethylene
ketal hydrochloride lO0 gm.
Asp~rin 325 gm.

-174-

32~6
llQ~5~6

Talc 35 ym.
Magnesium stearate 2.5 gm.
The ingredients are thoroughly mixed and then encap-
sulated ln the usual manner.
The forego;ng capsules are useful for the treatment of
headache in adult humans by the oral administration of 1
capsule every 6 hours.
Example 87 Tablets
One thousand tablets for oral useS each containing
200 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclo-
hexan-l-one ethylene ketal hydrochloride are prepared from
the following types and amounts of materials:
4-(methyl-n-butylamino)-4-
(m-hydroxyphenyl)cyclohexan-
l-one ethylene ketal hydro-
chloride 200 gm.
Lactose 125 gm.
Corn Starch 65 gm.
Magnesium stearate 2.5 gm.
Light liquid petrolatum 3 gm.
The ingredients are thoroughly mixed and slugged. The .-
slugs are broken down by forcing through a number sixteen
screen. The resulting granules are then compressed into
tablets, each tablet containing 200 mg. of 4-(methyl-n-
butylamino)-4-(m-hydroxyphenyl)cyclohexan-1-one ethylene
ketal hydrochloride.
The foregoing tablets are useful for treatment of
arthritic pain in adult humans by oral administration of
1 tablet every 4 hours.
Example 88 Ta~lets

-175

llQC~S16


One thousand oral tablets, each containing 100 mg. of
4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-
l-one ethylene ketal h~drochloride and a total of 400 mg.
of chlorphenesin carbamate are prepared from the following
types and amounts of materials:
4-(methyl-n-butylamino)-4-
(m-hydroxyphenyl)cyclohexan-
l-one ethylene ketal hydro-
chloride 100 gm.
Chlorphenesin Carbamate 400 gm.
Lactose 50 gm.
Corn starch 50 gm.
Calcium stearate 2.5 gm.
Light liquid petrolatum 5 gm.
The ingredients are thoroughly mixed and slugged. The
slugs are broken down by forcing through a number sixteen
screen. The resulting granules are then compressed into
tablets, each containing 100 mg. of 4-(methyl-n-butylamino)-
4-(m-hydroxyphenyl)cyclohexan-1-one ethylene ketal hydro-
chloride and 400 mg. of chlorphenesin carbamate.
The foregoing tablets are useful for treatment of low
back pain by the oral administration of 1 tablet every six
hours.
Example 89 Oral Syrup
Qne thousand ml. of an aqueous suspension for oral
use, containing in each 5 ml. dose, 100 mg. of 4-(methyl-
n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-1-one ethylene
ketal hydrochloride is prepared from the followint types
and amounts of ~ngredients:
4-(methyl-n-butylamino)-4

-176-

3286


~(m-~hydroxyphenyl)cyclohexan-
l-one ethylene ketal hydro-
chloride 20 gm.
~ C~tric acid 2 gm.
Benzoic acid l gm.
Sucrose 700 gm.
Tragacanth 5 gmO
Lemon oil 2 ml.
Deionized water q.s. lO00 ml.
The citric acid, benzoic acid, sucrose, tragacanth,
and lemon oil are dispersed in sufficient water to make
850 ml. of solution. The 4 (methyl-n-butylamino)-4-(m-
hydroxyphenyl)cyclohexan-l-one ethylene ketal hydrochloride
is stirred into the syrup until uniformly distributed.
Suffic;ent water ;s added to make 1000 ml.
The composition so prepared is useful in the treatment
of headache ;n adult humans at a dose of l teaspoonful 4
times a day.
Example 90 Parenteral solution
A sterile aqueous solution for intramuscular use,
containing in l ml. 25 mg. of 4-(methyl-n-butylamino)-
4-(m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydro-
chloride is prepared from the following types and amounts
of mater1als: '
4-(methyl-n-butylamino)-4-
(m-hydroxyphenyl)cyclohexan-
l-one ethylene ketal hydro-
chlor;de 25 gm.
L~doca;ne hydrochlor;de 4 gm.
3G Methylparaben 2.5 gm.

-177-

32~6
516

Propylparaben 0.17 gm.
Water for ~njection q.s. 1000 ml.
~ he ~ngredients are dissolved in the water and the
so1ution sterilized by filtration. The sterile solution
; 5 is filled into vials and the vials sealed.
Example 91 Suppository, rectal
One thousand suppositories, each weighing 2.5 gm. and
containing 100 mg. of 4-(methyl-n-butylamino)-4-(m hydroxy-
phenyl)cyclohexan-l-one ethylene ketal hydrochloirde are
prepared from the following types and amounts of
ingredients:
4-(methyl-n-butylamino)-4-
(m-hydroxyphenyl)cyclohexan-
l-one ethylene ketal hydro-
chloride 100 gm.
Propylene glycol 162.5 gm.
Polyethylene glycol 4000 q.s. 2500 gm.
The 4-(methyl-n-butylam;no)-4-(m-hydroxyphenyl)cyclo-
hexan-l-one ethylene ketal hydrochloride is added to the
propylene glycol and the mixture milled until the powders
are finely divided and uniformly dispersed. The poly-
ethylene glycol 4000 is melted and the propylene glycol
dispersion added slowly with stirring. The suspension is
poured into unchilled molds at 40 C. The composition is
allowed to cool and solidify and then removed from the mold
and each suppository foil wrapped.
The suppositories are useful in the treatment of
headache by the insertion rectally of 1 suppository every
5~X hours.
Example 92

-178-

32~6
~5~6

Compositions are similarly prepared following ~he
procedure of the preceding Examples 85 through ~l substi-
tut~ng an equlmolar amount each of
4-(p-chlorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal free base;
4-(p-chlorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal hydrochloride;
4-(p-chlorophenyl)-4-dimethylaminocyclohexanone;
4-(p-fluorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal free base;
4-(p-fluorophenyl)-4-d;methylaminocyclohexanone,
ethylene ketal hydrochloride;
4-(p-fluorophenyl)-4-dimethylaminocyclohexanone;
4-(p-anisyl)-4-dimethylaminocyclohexanone, ethylene
ketal free base;
4-(p-anisyl)-4-dimethylaminocyclohexanone, ethylene
ketal hydrochlonide;
4-(p-anisyl)-4-dimethylaminocyclohexanone free base;
4-(o-chlorophenyl)-4-dimethylaminocyclohexanone,
20 ethylene ketal free base; - .
4-(o-chlorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal hydroiodide;
4-(o-chlorophenyl)-4-dimethylaminocyclohexanone;
4-(m-anisyl)-4-dimethylaminocyclohexanone, ethylene
ketal free base;
4-(m-anisyl)-4-dimethylaminocyclohexanone, ethylene
ketal hydrochloride;
4-(m-anisyl)-4-dimethylaminocyclohexanone;
4-dimethylamino-4-(p-tolyl)cyclohexanonet ethylene
ketat free base;

-179-

llQ~516 328~


4-dimethylamino-4-(p-tolyl)cyclohexanone, ethylene
ketal hydrochlor~de;
4-d~methylamino-4-(p-tolyl)cyclohexanone;
4-dimethylamino-4-phenylcyclohexanone;
S 4-(p-bromophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal free base;
4-(p-bromophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal hydrochloride;
4-(p-bromophenyl)-4-dimethylaminocyclohexanone;
4-(2,4-dichlorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal free base;
4-(2,4-dichlorophenyl)-4-dimethylaminocyclohexanone,
ethylene ketal hydrochloride;
4-dimethylamino-4-(2-thienyl)cyclohexanone, ethylene
ketal;
4-(m-tolyl)-4-dimethylaminocyclohexanone free base;
4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-
l-one, ethylene ketal free base;
4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-
20 . l-one, ethylene ketal hydrochloride;
4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohex-
anone;
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone,
ethylene ketal;
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone;
4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone
ethylene ketal free base;
4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone
ethylene ketal.hydrochloride;
4-(p-hydroxyphenyt)-4-(n-butylmethylamino)cyclohexanone;

-180

32~6


4-(p-trifluoromethylphenyl)--4-d;methylaminocyclo-
hexanone, ethylene ketal free base;
4-(p-trifluoromethylphenyl)-4-dimethylaminocyclo-
hexanone, ethylene ketal hydrochloride,
4-(p-chlorophenyl)-cis-2-methyl-4-dimethylaminocyclo-
hexanone;
4-(p-chlorophenyl)-trans-2-methyl-4 dimethylamino-
cyclohexanone;
4-(m-hydroxyphenyl)-4-(n-propylmethylamino)cyclohex-
anone ethylene ketal free base;
4-(m-hydroxyphenyl)-4-(n-propylmethylamino)cyclo-
hexanone, ethylene ketal hydrochloride;
4-(m-hydroxyphenyl)-4-(methyl-N-pentylamino)cyclohex-
anone ethylene ketal free base;
4-(m-hydroxyphenyl)-4-(methyl-n-pentylamino)cyclo-
hexanone ethylene ketal hydrochloride;
4-(m-hydroxyphenyl)-4-(l-bu~ylmethylamino)cyclohex-
anone ethylene ketal free base;
4-(m-hydroxyphenyl)-4-(i-butylmethylamino)cyclohex-
anone ethylene ketal hydrochloride;
4-(m-acetoxyphenyl)-4-dimethylaminocyclohexan-1-one;
4-(m-acetoxyphenyl)-4-(methyl-n-butylamino)cyclohex-
anone;
4^(m-hydroxyphenyl)-4~(1-pyrrolidinyl)cyclohexanone;
. 4-(m-hydroxyphenyl)-4-(1-pyrrolidinyl)cyclohexanone,
ethylene ketal;
4-(m-acetoxyphenyl)-4-(1-pyrrolidinyl)cyclohexanone;
4-(m-hydroxyphenyl)~4-dimethylaminocyclohexanone tri-
methylene ketal;
4-(m-acetoxyphenyl)-4-(n-propylmethylamino)cyclohexanone;

. -181- - .

3286
~ 5 ~ 6

4-(m-acetoxyphenyl)-4-(isobutylmeth,ylanl~no)cyclo-
hexanone;
4-tm-acetoxyphenyl)-4-(n-pentylmethylamino)cyclohex-
anone;
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone
trimethylene ketal;
4-(m-acetoxyphenyl)-4-(n-butylmethylamino)cyclohex-
anone hydrochloride; and
4-(m-hydroxyphenyl)-4-(n-propylmethylaminojcyclohex-
anone for the 4-(methyl-n-butylam;no)-4-(m-hydroxyphenyl)-
cyclohexan-1-one ethylene ketal hydrochloride of the
examples.
Example 93
The compositions prepared in the preceding Examples
lS 85, 87, 89, 90 and 9l can be used for testing for narcotic
dependence by inducing withdrawal symptoms in drug addicts.
Also, they are useful for counteracting respiratory and
central nervous system depression induced by morphine or
related analgesics.
Although compounds of Formula VIII can induce
analgesia, their additional activ;ty of being at the same
time narcotic antagonists considerably diminishes the risk
of addiction to the particular drug. One can say that the
narcotic antagonist activity of the compounds of this inven-
tion acts as an internal safety device directed toward
moderating any inherent properties of physical dependence of
the medication caused by its narcotic-type analgetic action.
As a result, one can use the free bases or salts to obtain
narcotic type analgesia with minimal risk o~ physical
dependence.

-l~2-