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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". .
added 10.0 g. of :bromine in 80 ml. of carbon tetrachlo If the epoxyether is treated with excess butylamine'in
ride. l-bromocyclopentyl-(o-chlorophenyl)-ketone, B.P. stead of ethylarnine', the resulting product is l-b-utylamino
Ill-114° (0.1 mm.) is isolated in the usual manner. cyclopentyl-(p-methylphenyl)~ketone. This product can
Since it is unstable, it must be used immediately. The be rearranged as described in the ?rst paragraph of this
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 hexanone.
amine is allowed to evaporate. The organic residue is If the epoxyether is treated with excess pentylamine in
dissolved in pentane, and upon evaporation of the solvent, stead of ethylamine, the resulting product is l-pentyl
l-hydroxycyclopentyl-(o-chlorophenyl) - ketone N-meth aminocyclopentyh(p-methylphenyl)=ketone. This prod
ylimine, M.P. 62°, is isolated. 25 uct can then 'be rearranged as described in the ?rst para
If instead of rearranging l-hydroxycyclopentyl-(o graph of this example to give 2-pentylamino-2-(p-methyl- '
chlorophenyl)-ketone N-methylimine one heats l-hy phenyl)-cyclohexanone.
droxycyclopentyl - (p-chlorophenyl) ,- ketone N - methyl If one rearranges 1-methylaminocyclopentyl-(o-meth
imine in Decalin, the product which results is 2-methyl ylphenyl)-ketone instead of l-ethylaminocyclopentyl
amino-2-(p-chloropheny1) -cyclohexanone. The hydro 30 (p-methylphenyl)'-ketone, the resulting product is Z-meth
chloride of this aminoketone has M.P. 221-222.” C. ylamino-2—(o-methylphenyl)-cyclohexanone. This com
The l-hydroxycyclopentyl-(p~chlorophenyl)-ketone N pound easily forms a hydrochloride, M.P. 263-264".
methylimine used as starting material in the preparation The l-methylaminocyclopentyl - (o-methylphenyl)-ke—
of 2-methylamino-2-(p-chlorophenyl)-cyclohexanone is tone ‘used as starting material is prepared as follows: 0
prepared in the same manner as l-hydroxycyclopentyl Methylphenylcyclopentylketone is brominated to give 1
(o-chlorophenyl)-ketone N-methylimine. Cyclopentyl lbromocyclopentyl - (oanethylphenyD-ketone. Although
(p-chlorophenyl)-ketone ‘is brominated to give l-bromo unstable, this bromoketone can be evaporatively distilled
cyclopentyl-(p-chlorophenyD-ketone, M.P. 57-58". The at 0.005 rnm., bath temperature 90-95", to give an
bromoketone, upon treatment with liquid methylamine, analytically pure sample. Treatment of the bromoketone
gives 2-hydroxycyclopentyl-(p-chlorophenyl)-ketone N 40 with dry sodium methoxide gives 2-methoxy-2-(o-methyl
methylirnine, M.P. 64—65 °'. phenyl)-1-oxaspiro[2.4]heptane. Treatment of the epoxy
If one rearranges l-hydroxycyclopentyl-(m-chloro ether with excess methylamine in an autoclave at 130°
phenyl)-ketone N-methylimine instead of l-hydroxycyclo for 10 hours gives 1-methylaminocyclopentyl-(o~methyl
pentyl-(o-chlorophenyl)-ketone N-methylimine, the prod phenyl)-ketone. The hydrochloride of this compound is
uct of the rearrangement is 2-methylamino-2-(m-chloro prepared in ‘the usual manner and has M.P. 161—162° C.
phenyl ) -cyclohexanone. . - If one rearranges 1-isopropylaminocyclopentylphenyl
The hydroxycyclopentyl-(m-chlorophenyl)-ketone N ketone instead of l-ethylaminocyclopentyl - (p-methyl
methylimine used as starting material is prepared in a phenyl)-ketone, the resulting product is 2-isopropylamino
manner similar to that described above for l-hydroxy Z-phenylcyclohexanone. The hydrochloride of 2-isopro
cyclopentyl-(o-chlorophenyl)-ketone N-methylimine and pylamino-2-phenylcyclohexanone is formed in the usual
l-hydroxycyclopentyl (p-chlorophenyl) -ketone N-methyl manner.
imine. Cyclopentyl-(m-chlorophenyl)-ketone is bromi~ The 1-isopropylaminocyclopentylphenylketone used as
nated to give l-brornocyclopentyl-(rn-chlorophenyl) starting material is prepared .by treating 2-methoxy-2
ketone. The bromoketone, upon treatment with liquid phenyl-1-oxaspiro[2.4]heptane (10.0 g.) with excess iso
methylamine, gives 2-hydroxycyclopentyl - (m - chloro propylamnie in an autoclave at 130° for 20 hours.
phenyl)—k‘etone N-methylim-ine. \If 2-methoxy-2-phenyl-l-oxaspiro[2.4]heptane is re‘
acted with n-butylamine in an autoclave at 130° for '15
Example 16 ' hours, 1~b-utylaminocyclopentylphenylketone is obtained.
1-ethylaminocyclopentyl-(p-methylphenyl)ketone ( 10.0 This aminoketone is rearranged ‘by the procedure given
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 ' phenylcyclohexanone. The hydrochloride of 2-butyl
?ash distillation, is dissolved in dilute hydrochloric acid amino~2-phenylcyclohexanone is ‘formed in the usual man
and washed with ether. The acid solution is made basic ner.
with dilute sodium hydroxide and extracted with ether. If one rearranges 1-isopropylaminocyclopentyl- (m
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 -tyl~(p-met-hylphenyl)-ketone, the product obtained is l
residue is then distilled to give Z-ethylamino-Z-(p-methyl isopropylamino-Z- (m-me thylphenyl) ~cyclohexanone.
phenyl)-cyclohexan0ne. The free base is dissolved in The 1-isoproplylaminocyclopentyl - (m-methylphenyD
ether and precipitated as its hydrochloride, M.P. 234 ketone used as starting material in the above reaction is
235° C. 70 prepared as follows: m-Methylphenylcyclopentylketone
The 1-ethylaminocyclopentyl-(p-methylphenyl)-ketone is .brominated to give 1-bromocyclopentyl->(m-methylphen
used in the above reaction is prepared as follows: Cyclo yl)—ketone. Treatment of the bromoketone with dry
pentyl-(p-methylphenyl)~ketone is brominated in the usual sodium methoxide gives 2-methoxy-l2-(m-methylphenyl)
manner to give l-bromocyclopentyl-(p-methylphenyl)~ 1-oxaspiro[2.4]hep.tane. The epoxyether is treated with
ketone, B.P. 114° (0.01 mm.), "D25 1.5724. Treatment 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.