United States Patent 0 1.

ice Patented May 31, 1966

3,254,124
1 2
peratures of 180 and 250° C. Preferably, I use a tem
. 3,254,124 perature of between 210 and 230° C. The starting ma
AMINOKETONES AND METHODS FOR terial is heated in a sealed vessel of some type, usually
THEIR PRODUCTION
Calvin L. Stevens, Detroit, Mich., assignor to Parke, Davis in a pressure bomb or in a sealed glass tube, for between
and Company, Detroit, Mich., a corporation of Michi 10 and ‘20 hours. Preferably, the reaction time .is limited
gan to 12 hours :2 hours. While the u-aminoketone pic
No Drawing. Filed June 29, 1962, Ser. No. 206,188 tured above can be rearranged when it is heated alone, I
. 12 Claims. (Cl. 260-5705) have also found that an amine of the formula
This application is a continuation-in-part of my earlier 10 R3NH2 '
?led United States application Serial Number 127,868, (the same amine that is present in the starting a-amino
, ?led July 31, 1961, for Process for the Preparation of ketone) can be used as a solvent for this pressure reac
Aminoketones, now abandoned. tion. Preferably, the u-aminoketone is heated alone.
This invention relates to novel aminoketones, to acid In carrying out the novel rearrangement of this inven
addition salts thereof, and to methods for producing the tion by heating a compound of the formula
same. More particularly, the invention relates to ca 0 R
aminoketones which in free base form have the formula /
0 R1
R.-_c|i-o
R—(|i—(|3——Rz \Rn
20 OH
NHR3
with an amine of the formula
wherein R, R1, and R3 are selected from among lower
alkyl groups containing 1 to 5 carbon atoms inclusive, R3NH2
lower aryl groups such as phenyl and substituted phenyl wherein R, R1, R2, and R3 are as de?ned earlier, I have
moieties, and groups wherein any one of R, R1, and R2 25 found that, although equivalent amounts of the a-hy
may be combined to form an alkylene bridge of from droxyketone and the amine will give the desired int-amino»
4 to 5 carbon atoms inclusive. ’ ketone, a 2 to 3-fold excess of-amine is to be preferred.
The free bases of the invention form acid addition salts At least one equivalent of the amine should be used. The
by reaction with any number of acids. Non-toxic, phar heating is carried out in a sealed vessel for between 10
maceutically acceptable acid addition salts are formed and 20 hours (preferably 12 hours :2 hours) at a tem
with acids such as a hydrochloric, hydrobromic, hydri perature of between 180 and 250° C. (preferably 210
odic, sulfuric, phosphoric, acetic, citric, tartaric, and p to 230° C.).
toluene sulfonic acids. These acid addition salts are con If desired, the intermediate oc-hydroxyimine from the
verted to the free bases by treatment with a base such as above reaction can be isolated. It has the formula
sodium hydroxide or sodium carbonate. 35
R3 R
Generally speaking, a-aminoketones are sparsely known
in the prior art. This is because of the di?iculties which
are encountered in attempting to prepare such com OH R2 ,
pounds. wherein R, R1, R2, and R3 are as de?ned earlier. The a
An object of this invention is to provide novel a-famino hydroxyimines can then be rearranged to the desired a
ketones. ' aminolcetones by heating in a solvent, prefenably Dec
Another object of this invention is to provide a method alin, at about 180‘ to 250° C. (prefemably185-200" (3.).
for producing u-aminoketones from a-hydroxyketones by It is also possible to prepare the above a-hydroxyimines
a rearrangement of the carbon skeleton of the hydroxy by reacting an amine of formula
ketone. ' 45
A further object of this invention is to provide a method
for rearranging more available a-aminoketones to get dif with a bromoketone of the formula
ferent more diiiicultly available a-aminoketones. 0 R
These and other objects which will appear hereinafter R1—(|3|—"C/
are realized by heating compounds of the general formula Br R2
wherein R, R1, R2, and R3 are as de?ned above. I
As mentioned earlier, the processes of this invention
involve a rearrangement of the carbon skeleton of the
55 starting material. In fact, a skeletal-rearrangement al
either alone or in the presence of at least one equivalent
ways takes place when the above-described processes are
of an amine of the formula carried out. This rearrangement can manifest itself in
a simple alkyl or aryl migration or it can result in either
ring expansion or ring contraction. In fact, if any two
wherein R, R1, R2, and R3 are as de?ned earlier and of R, R1, and R2 are combined to form a ring in the start
wherein Z represents —OH or -——NHR3. When Z is 60
ing material, the ?nal product will contain a ring of a
—OH, at least one equivalent of the amine, R3NH2, different size. The following examples will show the
should be used. various rearrangements which can take place:
In carrying out the process of this invention with a ’
compound of the formula, (1) Alkyl-aryl migration:
65

R1—C—C
‘l f‘
\ O C 2H5 O
R2
NHR:
Q-fi —C / —> C zHs-g —C /
70 IiII-I C 2H5 \C 2H5
where R, R1, R2, and R3 are as de?ned earlier, I have
found that the rearrangement proceeds between the tem- ' na NHC H3
 3,254,124
3
(2) Aryl-alkyl migration: ness a-anilino-ot-phenylcycloheptanone remains; M.P. 136T
138° C. An analytical sample is prepared by recrystalli
zation from ether-petroleum ether.
Example 2
0 ' 0
I / o HaNHz II A sealed tube containing 1.83 g. (0.0089 mole) of 2
o H3—O —o —-> o—o —0 H! ethyl-2-methylaminobutyrophenone is placed in an auto
clave and surrounded with 15 ml. of toluene to counter
|\@
oH NRC... act any pressure which might develop in the tube. The
(3) Ring contraction: autoclave is heated at 250° C. for ten hours. The prod
10
uct, after ?ash distillation, is dissolved in dilute hydro
0
ll chloric acid and Washed with ether. The acid solution is
made basic and extracted with ether. The ether layer is
dried and the ether removed in vacuo. The residue is
0 H2 (|3\ o HaNHz
——> microdistilled to give a pale yellow liquid whose infrared
C 32 /C H2 0 H spectrum shows strong absorption at 1730 cm.—1. The
C Hz—C Hg crude 4-methyla-mino-4-phenyl-3-hexanone is isolated as
its hydrochloride. The precipitated hydrochloride is re
H / crystallized from ethanol and ether to give colorless crys
tals; M.P. 209—210° C. Recrystallization provided an
I CH2—CI‘I2 analytical sample; M.P. 210.5—211° C.
NHCHQ A portion of. the 4-methylamino-4-phenyl-3-hexanone
(4) Ring expansron: hydrochloride is converted to the free amine; B.P. 60—
0
65° C. (0.03 mm.), nD28-5 1.5135, d25 0.9972.
The conjugated a-aminoketone used as starting material
O
|| /
CHz-CHz
. CH2
"
0
/ \ /
0
<3 is prepared as follows: A steelautoclave containing 15.8
g. (0.08 mole) of 1,2-epoXy-2-ethyl-1-methoXy-1-phenyl
—C—O —-> | |\ butane and Y60 ml. of methylamine is heated at 140° C. for
\ CH2 CH2 NIICzI'I5
CHr-CH: / twelve hours. After excess methylamine is evaporated,
CH2 the residue is heated with 30 ml. of 3 N hydrochloric acid.
NHC2H5
The resulting solution is dried, the ether evaporated and
(5) Rmg expans1on: > , the residue distilled to give 2-ethyl-2-methylaminobutyro
01 phenone; B.P. 4—76° C.>(0.12 mm.), 111325 1.5227.
0
11 Example 3 '
Cl C
NOT-[3 CHHJH. / \ / 2-ethyl-2-hydroxybutyrophenone is placed in an auto
ll / Decalin CH; C
—C—C —-——-> | |\ clave with excess methylamine and heated at 240° C. for
\ 190u CH2 CH2 NHOH3 fourteen hours. From the reaction mixture 4-methyl
GE's-CH2 \ /
CH2 amino-4-phenyl-3-hexanone can be isolated as its hydro
OH
chloride; M.P. 208—210° C.
The a-‘aminoketones which can be prepared according
to the present invention are useful as chemical inter Example 4
mediates. For example, it is possible to reduce the ke A sealed tube containing 2.31 g. (0.0114 mole) of 1
tone group to a hydroxyl group via standard chemical methylaminocyclopentylphenylketone is heated at 220° C.
procedures to produce a-aminoalcohols.‘ Additionally, for ten hours. Using the previously described isolation
the a-aminoketones described herein have central nervous method of Example 2, Z-methylamino-Z-phenylcyclohex
system activity. Speci?cally, 3-methylamino-3-phenyl-2 anone is isolated as‘its hydrochloride; M.P. 256° C. .The
but-anone has analeptic activity and 4-methylamino-4 1-methylaminocyclopentylphenylketone used in the above
phenyl-3-hexanone has anti-convulsant activity. a-Meth A reaction is prepared as follows: Cyclopentylphenylketone
ylamino-u-methylcyclohexanone also has central nervous is brominated to give 1-bromocyclopentylphenylketone;
system activity. Further, 1-methylaminocyclohexylphen M.P. 29—30° C. Treatment of the bromoketone with dry
ylketone can be converted via standard chemical proce sodium methoxide gives 96% of 2-methoxy-2-phenyl-1
dures well known in the art to its oxime (M.P. 145-146° oxaspiro [2.4] heptane; B.P. 62—64° C. (0.05 mm.),
C.) which has central nervous system activity. 113325 1.5136. The epoxyether is treated with. excess
Of particular importance to this invention because of , methylamine at 130° C. for ten hours in an autoclave to
their cataleptoid activity are those compounds of the give 57% of 1-methylaminocyclopentylphenylketone;
formula B.P. 74~76° C. (0.03 mm.), 121329 1.5441.
? v X Example 5
A sealed tube containing 5.0 g. (0.026 mole) of 2
0 £2C \C /Q 60 methyl-Z-methylaminobutyrophenone is heated at 185° C.
l l\ for ten hours and‘worked up using the procedure followed
CH2 CH2 NHY
in Example 2. From the reaction is isolated crude 2—
CH2 methylamino-2-phenyl-3-pentanone; B.P. 59—60° C. (0.1
wherein X is selected from among hydrogen, halogen, mm.). The aminoketone is converted to the hydrochlo
hydroxy, methyl and methoxy and Y represents ‘a lower ride .and crystallized from ethanol-ether to give white crys
alkyl group containing 1 to 5 carbon atoms inclusive; tals; M.P. 192~193° C. The 2-methyl-2-methylamino
Those compounds wherein Y is methyl or ethyl are excep butyrophenone used in the above reaction is prepared as
tionally good and a-methylamino-a-phenylcyclohexanone follows: a-bromo-e-methylbutyrophenone is converted in
and a-ethylamino-a-phenylcyclohexanone are particularly 97% yield to 1,2-epoxy-l-methoxy-2-methyl-1-phenylbu
good cataleptoid agents. tane using sodium methoxide in methanol. The epoxy
Example 1 ether has B.P. 49° C. (0.1 mm.), nD26 1.4890. The
epoxyether is converted to 2~methyl-2-methylaminobutyr
a-Hydroxyphenylcyclohexylketone (10.0 g.) is heated ophenone in 66% yield using excess methylamine in a
at 200° C. in a steel bomb with excess aniline for 15 steel bomb at 150° C. for ten hours. The aminoketone .
hours. Upon evaporation of the reaction mixture to dry has B.P. 94° C. (0.45 mm.), 111326 1.5212.
 3,254,124
5 6
Example 6 clave at 200° C. for ten hours. Using the procedure of
A sealed tube containing 1.22 g. (0.0069 mole) of 2 Example 2, 3-methylamino-3-phenyl-2-bu.tanone is ob
methyl-Z-methyl-aminopropiophenone is heated at 240° C. tained as the hydrochloride; M.P. 2l1~212° C. Recrys
for ten hours. Isolation of the basic fraction by the pro tallization from ethanol-ether gives an analytical sample;
cedure of Example 2 gives aminoketone. An infrared 5 M.P. 213.5° C. '
spectrum of this product shows absorption at 1685 cm.-1 Example 11
and 1725 cm.‘1 of approximately equal intensity, indicat~ When 2-hydroxy-2-phenylcycloheptanone is heated in a
ing a possible mixture of conjugated and unconjugated steel bomb at 200° C. with excess methylamine for 15
aminoketones. Repeated crystallization of the hydro hours, a~methylaminophenylcyclohexylketone is isolated;
chloride of this mixture raises the melting point to 198 10 B.P. 104—l06° C. (0.09 mm.), 111327 1.5438; M.P. of hy
201° C. and an infrared spectrum of this product indicates drochloride 225-226° C.
chie?y unconjugated carbonyl. Further crystallization Example 12
gives pure 3-methylamino-3-phenyl-2-butanone hydro
chloride; M.P. 2l3.5° C. The 2-methyl-2-methylamino a-Ethylaminophenylcyclopentylketone (10.0 g.) is
propiophenone used in the above reaction is prepared as heated at 230° C. for twenty hours in the presence of ex~
follows: Treatment with excess methylamineat 1504° C. cess ethylamine. From the reaction mixture, 2-ethyl
for twenty-four hours in a sealed tube converts 1,2-epoxy amino-2-phenylcyclohexanone is isolated; 'B.P. 108~109°
1-methoxy-2~methyl-l-phenylpropane in 58% yield into 2— C. (0.5 mm.), nD25 1.5373.
methyl-2-methylaminopropiophenone; B.P. 70—71° C. u-Ethylaminocyclophentylphenylketone used in the
(0.3 mm.), 111325 1.5246. above reaction is prepared as follows: 2-methoxy-2-phen
yl-1-oxaspiro[2.4] -heptane (10.0 g.) is treated with excess
Example 7 ethylamine at 130° C. for ten hours in an autoclave to '
Six-tenths of a gram (0.0027 mole) of 1,1-diphenyl-1 give a-ethylaminocyclopentylphenylketone; B.P. 94° C.
hydroxy-2-propanone and 5 ml. of methylamine are sealed (0.1 mm.), 111325 1.5325; M.P. of hydrochloride, 183° C.
in a Pyrex tube and placed in an autoclave with 50 ml. of
toluene to counteract any pressure which develops in the
Example 13
sealed tube. The autoclave is heated at 200° C. for ten 1- hydroxycyclopentylphenylketone N - methylimine
hours and 2-methylamino-2-phenylpropiophenone is iso (2.95 g.) is rearranged 'by re?uxing in 30 ml. of Decalin for
lated as the hydrochloride; M.P. 215.5—216°. An infra 30 2 hours. Addition of an isopropanolic hydrochloric acid
red spectrum of the aminoketone shows only conjugated solution to the reaction mixture gives crude 2-methyl
carbonyl group absorption. amino-2-phenylcyclohexanone hydrochloride. Recrystal
lization from ethanol-ether gives pure Z-methylamino-Z
Example 8 phenylcyclohexanone hydrochloride, M.P. 255—257°.
In a bomb is placed 24.31 g. of freshly distilled a-meth 2-methylamino-2-phenylcyclohexanol is prepared by so
ylaminocyclopentylmethylketone. This is heated at 215° dium borohydride reduction of the parent aminoketone.
C. for ten hours, cooled, taken up in ether and extracted The aminoalcohol hydrochloride has M.P. 232° C.
with dilute acid. The acid layer is made basic and ex 1-hydroxycyclopentylphenylketone N-methylimine used
tracted with ether and methylene chloride. The solution in the above reaction is prepared as follows: l-bromo
is dried and the residue fractionally distilled to give 12 40 cyclopentylphenylketone (12.0 g.) is treated with 30 ml.
tmethylamino-2-methylcyclohexanone; B.P. 55—57° C. (2 of liquid methylamine and the reaction allowed to come
mm.), nD25 1.4710. The free a-aminoketone is then con to ‘room temperature over a one hour period. Ether (50
verted to 2-methylamino-2-methylcyclohexanone hydro ml.) is added to the reaction mixture,'the methylamine hy
chloride; M.P. 188-190° C. An analytical sample isvprel drobromide is removed, and the ether evaporated to leave
pared by recrystallization from ace-tone; M.P. 191.4~ 1-hydroxycyclopentylphenylketone N-methylimine, M.P.
191.8, pKa (50% CH3OH)=8.40. 72-74". .

The starting u-methylaminocyclopentylmethylketone Example 14

used in the above reaction is prepared as follows: Cyclo 1-hydroxycycl-ophentylphenylketone (10.0 g.) is dis
pentylmethylketone is brominated with N-bromosuccin solved in an excess of liquid methylamine and the solu—
imide to give 77% of 2-bromocyclophenylmethylketone; 50 tion is heated in an autoclave at 200° for 5 hours. Ether
B.P. 75—77° C. (8 mm.), r1325 1.4900, Which, when treated (50 ml.) is then added and the ether solution is extracted
with excess methylamine in benzene solution for four days three times with three 50 ml. portions of 6 N hydrochloric
at room temperature, gives 76% of 2-methylaminocyclo acid. Evaporation of the acid solution leaves 2-methyl
pentylmethylketone; B.P. 49‘—50° C. (1.5 mm.), nD25 amino-Z-phenylcyclohexanone as its hydrochloride, M.P.
1.4642. The hydrochloride melts at 117~119° C. 255—256°, after crystallization from ethanol-ether.
Example 9 The free-base, Z-methylamino-2-phenylcyclohexanone,
can be isolated by neutralizing its hydrochloride salt with
A sealed tube containing 2.7 g. 4-hydroxy-4-p-henyl-3d dilute sodium hydroxide, extracting with ether and re
hexanone is heated with excess methylamine at 200° C. moving the ether. '
for ten hours. From this reaction mixture 4-methyl 60 Addition of su?icient sulfuric acid to neutralize 2-meth
amino-4-phenyl-3-hexanone is isolated as the hydrochlo~ ylamino-2-phenylcyclohexanone gives 2~methylamino-2
ride; M.P. 211-212‘’ C. phenylcyclohexanone sulfate. '
The 4-hydroxy-4-phenyl-3-hexanone used as starting If citric acid is used in place of sulfuric acid, the prod
material in the above reaction can be prepared as ‘follows: uct is 2-methylamino-2-phenylcyclohexanone citrate.
2-ethyl-2-hydroxybutyrophenone is dissolved in anhydrous 65 If acetic acid is used in place of sulfuric acid, the
ether, a 5 to 6-fold excess of ?nely pulverized anhydrous product is Z-methylamino- -phenylcyclohexanone acetate.
potassium hydroxide is added, the mixture is stirred for If p-toluene sulfonic acid is used in place of sulfuric
1 to 2 hours, and then poured over ice. The ether layer is acid, the product is 2-methylamino-Z-phenylcyclohexa
separated, dried over anhydrous sodium sulfate, evap none p-toluene sulfonate.
orated to dryness, and the 4-hydroxy-4-phenyl-3-hexanone 70
distilled; BJP. 67° C. (0.22 mm.). Example 15
Example 10 l-hydroxycyclopentyl-(o-chlorophenyl) ~ketone N-meth
ylimine (2.0 g.) is dissolved in 15 ml. of Decalin and
Five grams (0.030 mole) of 3-hydroxy-3-phenyl-2-buta re?uxed for two and one-half hours. After evaporation
none and 25 ml. of methylamine are heated in an auto 75 of the Decalin under reduced pressure, the residue is ex- '
 3,254,124.
8
tracted with dilute hydrochloric acid, the solution treated of the bromoketone with dry sodium methoxidegives the
with decolorizing charcoal, and the resulting acidic solu epoxyether, Z-methoxy-Z-(p-methylphenyl) - 1 - oxaspiro
tion is made basic. The liberated product, Z-methyl [2.4] heptane, B.P. 64° (0.1 mm.). The epoxyether is
amino-2-(o-chlorophenyl)-cyclohexanone, after crystal— treated with excess ethylamine in an autoclave at 130°,
lization from pentane-ether, has M.P. 92-93° C. The for 10 hours to give l-ethylaminocyclopentyl-(p-methyl
hydrochloride of this compound has M.P'. 262-—263°. phenyl)-ketone,- B.P. 96° (0.07 mm.). This ketone is
The l-hydroxycyclopentyl-t(o-chlorophenyl)-ketone N converted to its hydrochloride, M.P. l96-19'7°, in the
methylimine used in the above reaction is prepared as usual manner.
follows: To the Grignard reagent prepared from 119.0 If the epoxyether described in paragraph two of this
g. of cyclopentylbromide and 19.4 g. of magnesium is 10 example is treated with excess propylamine instead of I
added 55 .2‘ g. of o-chlorobenzonitrile. The reaction mix ethylamine, the resulting product is l-propylaminocyclo
ture is stirred for three days and thereafter hydrolyzed pentyl-(p-methylphenyl)-ketone. This product can then
in the usual manner. From the hydrolysis there is ob 1 be rearranged as described in the ‘?rst paragraph of this
tained o-chlorophenylcyclopentylketone, B.P. 96-97° example to give 2-propylamino-2-(p-methylphenyl)-cyclo
(0.3 mm.), nD25 1.5452. To 21.0 g. of the ketone is 15 hexanone. '

added 10.0 g. of :bromine in 80 ml. of carbon tetrachlo
ride. l-bromocyclopentyl-(o-chlorophenyl)-ketone, B.P.
Ill-114° (0.1 mm.) is isolated in the usual manner.
Since it is unstable, it must be used immediately. The
bromoketone (29.0 g.) is dissolved in 50* ml. of liquid 20 example to give- 2-’butylamino-2-(p-methylphenyl)-cyclo
methylamine. After one hour, the excess liquid methyl
amine is allowed to evaporate. The organic residue is
dissolved in pentane, and upon evaporation of the solvent,
l-hydroxycyclopentyl-(o-chlorophenyl) - ketone N-meth
ylimine, M.P. 62°, is isolated.
If instead of rearranging l-hydroxycyclopentyl-(o
chlorophenyl)-ketone N-methylimine one heats l-hy
droxycyclopentyl - (p-chlorophenyl) ,- ketone N - methyl
imine in Decalin, the product which results is 2-methyl
amino-2-(p-chloropheny1) -cyclohexanone. The hydro
chloride of this aminoketone has M.P. 221-222.” C.
The l-hydroxycyclopentyl-(p~chlorophenyl)-ketone N
methylimine used as starting material in the preparation
of 2-methylamino-2-(p-chlorophenyl)-cyclohexanone is
prepared in the same manner as l-hydroxycyclopentyl
(o-chlorophenyl)-ketone N-methylimine. Cyclopentyl
(p-chlorophenyl)-ketone ‘is brominated to give l-bromo
cyclopentyl-(p-chlorophenyD-ketone, M.P. 57-58". The
bromoketone, upon treatment with liquid methylamine,
gives 2-hydroxycyclopentyl-(p-chlorophenyl)-ketone N
methylirnine, M.P. 64—65 °'.
If one rearranges l-hydroxycyclopentyl-(m-chloro
phenyl)-ketone N-methylimine instead of l-hydroxycyclo
pentyl-(o-chlorophenyl)-ketone N-methylimine, the prod
uct of the rearrangement is 2-methylamino-2-(m-chloro
phenyl ) -cyclohexanone. . -
The hydroxycyclopentyl-(m-chlorophenyl)-ketone N
methylimine used as starting material is prepared in a
manner similar to that described above for l-hydroxy
cyclopentyl-(o-chlorophenyl)-ketone N-methylimine and
l-hydroxycyclopentyl (p-chlorophenyl) -ketone N-methyl
imine. Cyclopentyl-(m-chlorophenyl)-ketone is bromi~
nated to give l-brornocyclopentyl-(rn-chlorophenyl)
ketone. The bromoketone, upon treatment with liquid
methylamine, gives 2-hydroxycyclopentyl - (m - chloro
phenyl)—k‘etone N-methylim-ine.
Example 16
1-ethylaminocyclopentyl-(p-methylphenyl)ketone ( 10.0
g.) is heated at 230° for eight hours in an autoclave in 60 in paragraph 1 of this example to give' 2—‘b~utylar_nino-2
the presence of excess ethylamine. The product, after
?ash distillation, is dissolved in dilute hydrochloric acid
and washed with ether. The acid solution is made basic
with dilute sodium hydroxide and extracted with ether.
The ether layer is dried over sodium sulfate, the sodium 65 methylphenyl)-ketone instead of l-ethyla-minocyclopen
sulfate removed, and the ether evaporated in vacuo. The
residue is then distilled to give Z-ethylamino-Z-(p-methyl
phenyl)-cyclohexan0ne. The free base is dissolved in
ether and precipitated as its hydrochloride, M.P. 234
235° C.
The 1-ethylaminocyclopentyl-(p-methylphenyl)-ketone
used in the above reaction is prepared as follows: Cyclo
pentyl-(p-methylphenyl)~ketone is brominated in the usual
manner to give l-bromocyclopentyl-(p-methylphenyl)~
ketone, B.P. 114° (0.01 mm.), "D25 1.5724. Treatment
If the epoxyether is treated with excess butylamine'in
stead of ethylarnine', the resulting product is l-b-utylamino
cyclopentyl-(p-methylphenyl)~ketone. This product can
be rearranged as described in the ?rst paragraph of this
hexanone.
If the epoxyether is treated with excess pentylamine in
stead of ethylamine, the resulting product is l-pentyl
aminocyclopentyh(p-methylphenyl)=ketone. This prod
25 uct can then 'be rearranged as described in the ?rst para
graph of this example to give 2-pentylamino-2-(p-methyl- '
phenyl)-cyclohexanone.
If one rearranges 1-methylaminocyclopentyl-(o-meth
ylphenyl)-ketone instead of l-ethylaminocyclopentyl
30 (p-methylphenyl)'-ketone, the resulting product is Z-meth
ylamino-2—(o-methylphenyl)-cyclohexanone. This com
pound easily forms a hydrochloride, M.P. 263-264".
The l-methylaminocyclopentyl - (o-methylphenyl)-ke—
tone ‘used as starting material is prepared as follows: 0
Methylphenylcyclopentylketone is brominated to give 1
lbromocyclopentyl - (oanethylphenyD-ketone. Although
unstable, this bromoketone can be evaporatively distilled
at 0.005 rnm., bath temperature 90-95", to give an
analytically pure sample. Treatment of the bromoketone
40 with dry sodium methoxide gives 2-methoxy-2-(o-methyl
phenyl)-1-oxaspiro[2.4]heptane. Treatment of the epoxy
ether with excess methylamine in an autoclave at 130°
for 10 hours gives 1-methylaminocyclopentyl-(o~methyl
phenyl)-ketone. The hydrochloride of this compound is
prepared in ‘the usual manner and has M.P. 161—162° C.
If one rearranges 1-isopropylaminocyclopentylphenyl
ketone instead of l-ethylaminocyclopentyl - (p-methyl
phenyl)-ketone, the resulting product is 2-isopropylamino
Z-phenylcyclohexanone. The hydrochloride of 2-isopro
pylamino-2-phenylcyclohexanone is formed in the usual
manner.
The 1-isopropylaminocyclopentylphenylketone used as
starting material is prepared .by treating 2-methoxy-2
phenyl-1-oxaspiro[2.4]heptane (10.0 g.) with excess iso
propylamnie in an autoclave at 130° for 20 hours.
\If 2-methoxy-2-phenyl-l-oxaspiro[2.4]heptane is re‘
acted with n-butylamine in an autoclave at 130° for '15
' hours, 1~b-utylaminocyclopentylphenylketone is obtained.
This aminoketone is rearranged ‘by the procedure given
' phenylcyclohexanone. The hydrochloride of 2-butyl
amino~2-phenylcyclohexanone is ‘formed in the usual man
ner.
If one rearranges 1-isopropylaminocyclopentyl- (m
-tyl~(p-met-hylphenyl)-ketone, the product obtained is l
isopropylamino-Z- (m-me thylphenyl) ~cyclohexanone.
The 1-isoproplylaminocyclopentyl - (m-methylphenyD
ketone used as starting material in the above reaction is
70 prepared as follows: m-Methylphenylcyclopentylketone
is .brominated to give 1-bromocyclopentyl->(m-methylphen
yl)—ketone. Treatment of the bromoketone with dry
sodium methoxide gives 2-methoxy-l2-(m-methylphenyl)
1-oxaspiro[2.4]hep.tane. The epoxyether is treated with
excess isopropylamine in an autoclave at 130° for 20
 3,254,124
10
hours to give 1-isopropylaminocyclopentyl-(m-methyl (o-methoxyphenyl)-ketone N-methylimine, M.P. 78
phenyl)~ketone. I 79° C., is isolated.
If one rearranges 1-methylaminocyclopentyl-(p-meth If one rearranges l-hydroxycyclopentyl-(m-methoxy
OXyphenyD-ketone instead of l-ethylaminocyclopentyl -phenyI)-ketone N-methylimine instead of l-hydroxycyclo
(p~methylphenyl)-ketone, the product obtained is 2-meth pentyl-(p-lmet-hoxyphenyl)-ketone N-methylimine, the
ylamino-Z-(p-methoxyphenyl)-cyclohexanone, whose -hy product obtained is 2-methylarnino-2-(m-methoxyphen
drochloride has M.P. 216-218" C. This aminoketone . yl)-cyclohexanone.
can subsequently be reduced to .2—methylamino~2-(p-meth The starting l-hydr-oxycyclopentyl-(m-methoxyphen
Ioxyphenyl)-cyclohexanol, M.P. 107-1117“. yl)-ketone N-methylimine is \prepared as follows: m
The lunethylaminocyclopentyl - (p-rnethoxyphenyl) 10 Methoxyphenylcyclopentylketone is brominated to give
ketone used as starting material in the above reaction is 1 - *bromocyclopentyl-(mamethoxyphenyl)-l<etone. The
prepared as follows: p-Methoxyphenylcyclopentylketone bromoketone is then treated, as described above, with an
i-s brominated to give 1-bromocyclopentyl-(p-methoxy excess of methylamine to give l-hydroxycyclopentyl-(m
_ phenyl)-ketone, M.P. 36—36.5° C. ‘It is also possible to methoxyphenyl)-ketone N-methylirnine.
chlorinate p-methoxyphenylcyclopentylketone in a similar 15 If 1-hydroxycyclopenty1-(o-methylphenyl)-ketone N
manner to get 1-chlorocyclopentyld(p-methoxyphenyl) methylimine is rearranged instead of lahydroxycyclope-n
ketone, M.P. 37—38° C. Treatment of either the bromo tyl-(p-methoxyphenyl)-ketone N-methylirnine, the prod
ketone or chloroketone with dry sodium methoxide gives uct isolated is Z-methylamino-Z-(o-methylphenyl)-cyclo
2 - methoxy-2— (p-methoxphenyl ) -1-oxaspiro [2.4] heptane, hexanone, whose ‘hydrochloride has M.P. 263-264° C.
B.P. 90-91" C. (0.1 mm), nD25 1.5237, M.P. 45-48° C. 20’ The starting iminoalco'h-ol is prepared as follows: 0
Treatment of the epoxyether with excess methylamine in Methylp-henylcyclopentylketone is brominated to give 1
an autoclave at 130° ‘for 10 hours gives l-methylamino bromocyclopentyl-(o-methylphenyl)-ketone. Treatment
cyclopentyl - (p-methoxyphenyl) - ketone, BsP. 115-116" of the brom'oketone with excess methylamine, as described
(0.1 mm.), nD25 1.5565. The hydrochloride of this above, gives 1-hydroxycyclopentyl-(o-methylphenyl)~ke
aminoketone has M.P. 167-168" C. 25 tone N-methylimine.
If 1-methylaminocyclopentyl- (p-chlorophenyl ) ~ketone Example 18
is rearranged instead of liethylaminocyclopentyl-(p-rneth 2 - methylamino-Z-(0-benzyloxyphenyl)-cyclohexanone
ylphenyl)-ketone, the product obtained is Z-methyla-mino (1.0 g.) is re?uxed for three hours with 16 ml. of 4 N
_ 2-(p-chlorophenyl)-cyclohexanone whose hydrochloride hydrochloric acid solution. ‘Evaporation of the solvent
has M.P. 221-222° C. 30
followed by neutralization with 6 N sodium hydroxide
1 - methyl-aminocyclopentyl - (p-chlorophenyl)~ketone
and extraction with ether gives an etheral solution of 2
used as starting material in the above reaction is pre met-hylam-ino-Z-(oahydroxyphenyl)-cyclohexanone. Re
pared as follows: p-chlorophenylcyclopentylketone is .b-ro moval of the ether gives the pure cyclohexanone. This
minated to give 1-bromocyclopentyl-(p-chlorophenyl)~ke compound can exist lboth in the -keto form and as the
tone, M.P. 57-58° C. Treatment of the bromoketone closed hemiacetal compound.
with dry sodium met-hoxide gives Z-methoxy-Z-(p-chloro The Z-r'nethylamino-Z-(0-benzy1oxyphenyl)~cyc1ohex
phenyl)-1-oxaspiro[2.4]heptane, B.P. 82° (0.2 mm), anone used as starting material in this reaction is pre
nD25 1.5623. Treatment of the epoxyether withexcess pared as vfollows: o-Benzyloxyphenylcyclopentylketone is
methylamine in an autoclave :at 130° for 10 hours gives brominated to give l-lbromocyclopentyl-(o-benzyloxy
1 - methylaminocyclopentyl - (p-chlorophenyl)-ketone,
p-henyl)-ketone. Treatment of the bromoketone with ex
whose ‘hydrochloride has M.P. 153-155". cess liquid methylamine followed by isolation as de
Example 17 scribed in Example 17 affords 1-hydroxycyclopenty1-(o
l - hydroxycyclopentyl-(p-met-hoxyphenyl)-ketone N
benzyloxyphenyl)-ketone 'N-methylimine. Re?uxing this
met-hylimine (10.0 g.) is ‘rearranged by re?uxing in 30 iminoalcohol (10.0 g.) in 50 ml. of Decalin for two hours
45 followed by evaporation of the Decalin under reduced
:ml. of Decalin for 2 hours. _Addition of isopropanolic pressure, extraction of the residue wit-h dilute hydro
\hydrogen chloride to the reaction mixture gives crude 2 chloric acid, ‘treating the hydrochloric acid with decoloriz
methylamino-2-(p-methoxyphenyl)-cyclohexanone hydro ing carbon and then making the resulting acidic solution
chloride, M.P. 2l6-218° C. This aminoketone can easily basic with sodium hydroxide liberates 2-methyIa-mino-2
be reduced to the corresponding 2-methylamino-2—(p— 50
meth'oxyphenyl)-cyclohexanol, M.P. 107-117° C. using (o-benzyloxyiphenyl)-cyclohexanone, whose hydrochlo
an alcoholic solution of sodium borohydride. ride has M.P. 227-228° C.
If 2 - methylamino-Z-(m-benzyloxy/phehyl) - cyclohex
The starting material, namely v1-hydroxycyclopentyl-(p
anone (1.0 g.) is re?uxed for 3 hours with 16 ml. of 4
met-hoxyphenyl)-ketone N-methylimine, is prepared as
follows: p-methoxyphenylcyclopentylketone is bromi 55 N hydrochloric acid solution and the reaction is worked
up as described in paragraph 1 of this example, the result
nated to give 1-bromocyclopentyl-(p-methoxyphenyl)-ke ing product is 2-met-hylamino-2—(m-hydroxyphenyl)-cy—
tone, M.P. 36-365” C. Treatment of the bromoketone
(12.0 g.) with 30 ml. of liquid methylamine for one clohexauone.
The 2 - methylamine-2-(m-benzyloxyphenyl)-cyclohex
hour, followed by evaporation of the liquid methylamine, anone used as starting material in this reaction is prepared
solution of the organic res-idue in pentane, and subsequent 60 as follows: m-Benzyloxyphenylcyclopentylketone is bro
evaporation of the solvent gives l-hydroxycyclopentyl-(p minated to give 11-‘bromocyc1opentyl-(m-benzyloxyphen
methoxyphenyl)-ketone N-methylimine, M.P._ 38-39” C. y1)-ketone. Treatment of the bromoketone with excess
- When 1-hydroxycyclopentyl-(o-methoxyphenyl)sketone
N-methylimine is rearranged in place of l-hydroxycyclo liquid methylamine gives l-hydroxycyclopentyl-(m-ben
pentyl-(.p~methoxyphenyl)-ketone N-methylimine, the re
zyloxyphenyD-ketone N --methylimine. Rearrangement
65 of this im-inoalcohol as described in paragraph two of
sulting product is Zamethylamino-Z-(o-methoxyphenyl) this example gives Z-methylamino-‘Z-(m-benzyloxyphen
cyclohexanone, Whose hydrochloride has M.P. 211
y1)-cyclohexanone. .
212° C. Example 19
The starting l-hydroxycyclopentyl-(oJmethoxyphenyD
ketone N-methylimine used in the above reaction is pre 70 Z-methylamino - 2 - (p-methoxyphenyl)-cyclohexan0ne
pared as follows: o-Methoxyphenylcy-clopentylketone is (5.0 g.) is re?uxed in v1‘5 ml. of an acetic acid solution
brominated to give l-br-omocyclopentyl-(o-methoxyphen saturated with gaseous hydrobromic acid for 12 hours.
yl)-keto-ne, M.P. 26-27” C. The bromoketone is then The solvent is removed and the residue is put on a
treated with excess liquid methylamine as described in strongly basic quaternary ammonium hydroxide ion ex
paragraph two of this example ‘and l-hydroxycyclopentyl 75 change column. Elution with methanol removes all of
 3,254,124.
11 l2
the starting material. Subsequent elution ‘with a meth sisting of lower alkyl groups containing 1 to 5 carbon
anolic solution containing 1% hydrochloric acid gives atoms inclusive and phenyl groups of the formula:
2-methylamino - 2 - (p - hydroxyphenyl)~cyclohexanone,
M.P. 157-158° C. (decomposition), whose hydrochloride
‘has M.P. 213-214° C. ~ Preparation of the starting mate
rial, namely 2-methylamino-2-'(p-methoxyphenyl)-cycl0
hexanone is described in Examples 16 and 17. wherein X is selected ‘from the group consisting of hydro
I claim: gen, chloro, bromo, lower ‘alkyl containing 1 to 5 carbon
1. A member of the class consisting of a free base and atoms, hydroxy, alkoxy containing 1 to 5 carbon atoms
pharmaoeutically acceptable acid- addition salts thereof, 10 and 'benzyloxy groups and groups wherein any two of
said free ‘base having the formula: R, R1, and R2 may be combined to form an alkylene
bridge of vfrom 4Kto 5 carbon atoms inclusive and wherein
R3 is a lower alkyl group.
8. A process for the preparation of 2-ethylamino-2
15 phenylcyclohexanone which comprises heating 2-ethyl
H20 OH: NHY aminophenylcyclopentylketone in a sealed vessel at a
CH2
temperature of between 180 and 250° C. for between 10
and 20 hours.
wherein X is selected from the group consisting of hydro 9. A process for the preparation of 4-methylamino-4
gen, chloro, bromo, methyl, methoxy and hydroxy and Y 20' phenyl-ES-hexanone which comprises heating 2~ethyl-2
represents a lower alkyl radical containing 1 to 2 carbon methylaminobutyrophenone in a sealed vessel at a tem
atoms inclusive. perature of between 180 and 250° C. for ‘between 10 and
2. 2 - methylamino-2-(o-chlorophenyl)-cyclohexanone 20 hours.
hydrochloride. 10. A process for the preparation of Z-methylamino-Z
3. 2 - methylamino - 2 - (o-hydroxyphenyl)-cyclohex 25 methcylcyclohexanone which comprises heating a-meth
anone hydrochloride. ylaminocyclopentylmethylketone in a sealed vessel at a.
4. 2 - methylamino - 2 - (m-hydroxy-phenyl)-cyclohex
temperature of between 180°.and 250° C. for 10 to 20
anone hydrochloride. hours.
5. 2 - methylamino - 2 - phenylcyclohexanone hydro 11. A process for the production of lit-methylamino
chloride. phenylcyclohexylketone which comprises heating 2-hy
6. 2-ethylamino-2-phenylcyclohexanone hydrochloride. droxy ~2-pheny1cycloheptanone with at least one equiva
7. A process for the production of a compound of the lent of methylamine in a sealed vessel at a temperature
formula: ' of between 180 and 250° C. for between 10 and 20 hours.
0 B1 12. A process'for the production of 2-methylamino
II / 35 2-phenylpropiophenone which comprises heating 1,1-di
.
R—-C-—(|J—R
NHR,
phenyl-l-hydroxy-Z-propanone with at least one equiva
lent of methyl'amine in a sealed vessel at a temperature
which comprises heating ‘in a sealed vessel at a tempera of between 180 and 250° C. for between 10 and 20 hours.
ture between 180° and 250° C. for between 10 and 20
hours a member of the group consisting of 40 References Cited by the Examiner
(A) A compound of the formula: UNITED STATES PATENTS
3,068,236 12/1962 Krapcho _____'____ 260-566 X
R1—(IJI—C£RQ FOREIGN PATENTS
N113, 45
853,775 11/1960 Great Britain.
and
OTHER REFERENCES
(B) The combination of a compound of the formula:
Julian et al., “Jour. American Chemical Soc.,” vol. 67,
(2.)
50 pages 1203-11 (-1945).
R1—(II|"—C£R2 Stevens et al., “Jour. Amer. Chem. Soc.,” vol. 84, pages
(‘>11 2272-74 (1962).
Takahashi et al., “Chemical Abstracts,” vol. 52, pages
and at least one equivalent of a compound of the
formula: -
10909-14 (1958).
(b) R3NH2 CHARLES B. PARKER, Primary Examiner.
wherein R, R1 and R2 are selected from the group con ROB'ERT V. HINES, Assistant Examiner.