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Патент USA US3093668

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United States Patent 0
1 r.‘
ICC
Patented June 11, 1963
1
ylethyl iodide or alpha-iodopropiophenone) , l-oxo-l-phem
‘
yl-Z-butyl sulfate (same as 1-ethyl~2-oxo-2-phenylethyl
3,093,652
ALKYL I-(Z-ARYL-Z-0XOALKYL)-4-PHENYLPIPER
sulfate), 2-oxo-2-phenylethyl methanesulfona-te, l-oxohl
IDINE-4-CARBOXYLATES AND THEIR PREPA
RATION
phenyl-Z-propyl benzenesulfonate, 2-oxo-2-pl1enylethyl
para-toluenesulfonate, or the like, with the bromides
being preferred. The reaction is carried out generally by
Bill Elpern, Walnut Creek, Calif, assignor to Sterling
I Drug Inc., New York, N.Y., a corporation of Dela
ware
heating, at a temperature between about 50° C. and
No Drawing. Filed Oct. 23, 1958, Ser. No. 769,059
6 Claims. (Cl. 260-2932)
with the 2~(monocarbocyclic-aryl)-2-oxo-(lower-alkyl)
150° C‘., the lower-alkyl 4-phenylpiperidine-4-carboxylate
10 halide, preferably the bromide, in the presence or ab
This invention relates to compositions of matter of the
class of substituted piperidines and to their preparation.
sence of a suitable solvent, but preferably in the presence
of a solvent such as a lower-alkanoL. Illustrative of the
reaction is the preparation of ethyl l-(2~oxo-2-phenyl
‘ The invention here resides in the concept of a com
. position having a molecular structure in which a 2~(mono
ethyl)~4-phenylpiperidine-4-carboxylate by heating ethyl
carbocyclic-aryl)-2-oxo~(lower-alkyl) radical is attached 15 4-phenylpiperidine-4-carboxylate .with 2-oxo-2-phenyl
to the nitrogen atom of the piperidine ring of lower-alkyl - ethyl bromide. This reaction is carried out preferably
in re?uxing n-butanol with stirring in the presence of an
alkaline agent such as sodium carbonate to neutralize the
4-phenylpiperidine-4~carboxylates and in a process for
physically embodying such concept.
hydrogen bromide formed by the reaction. The prod
The physical embodiments of the concept are useful as
intermediates in the preparation of compounds having 20 nets are isolated in free base form or in the form of
pharmacological activity, in particular, analgesic activity.
their acid-addition salts.
-
Speci?cally, they are useful in the preparation of the
My lower-alkyl 1-[2-(monocarbocycliciaryl)-2-oxo
corresponding lower-alkyl 1- [Z-(monocarbocyclic-aryl)-2
hydroxy-(lower-alkyl) ]-4-phenylpiperidine-4-carboxylates
(lower-alkyl)]-4-phenylpiperidine-4-carboxylates are use
gesic activity.
same invention.
ful in the free base'form or in the form of acid-addi
which have been tested by standard pharmacological eval 25 tion salts, and ‘both forms are within the purview of the
uation procedures in animals and found to possess anal
invention, and in fact, are considered to be one and the
in free base ‘form have the structural Formula I
Since my compounds are useful as in
termediates in the preparation of pharmacologically-ac
Among the compounds of my invention are thosewhich
tive compounds, the acids which can be used to prepare
30 the acid-addition salts arepreferably those which produce,
1 when combined with the freebase of the corresponding
1-‘[2-(monocarbocyclic-aryl)-2ehydroxy-(lower - alky1)]
compounds, pharmacologically acceptable salts, that is,
35
salts whose anions are relatively innocuous to the animal
organism in pharmacological doses of the salts, so that
. the bene?cial physiological properties inherent in the free
base are not vitiated by side effects ascribable to the
I
anions; in other words, the latter do not substantially
affect the pharmacological properties inherent in the cat
40 ions. In practicing my invention, I found it convenient
to employ the hydrochloride salts. However, other ap
where R represents hydrogen, methyl or ethyl and Ar is a
propriate pharmacologically acceptable salts within the
monocarbocyclic-aryl radical having six ring-carbon atoms.
The term “lower-alkylff asused herein, means alkyl
scope of the invention are those derived from mineral
acids such as hydrobromic acid, hydriodic acid, nitric
radicals having from one to six carbon atoms, inclusive, 45 acid, phosphoric acid, and sulfuric acid; and organic acids
,and is illustrated by methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, 2-butyl, n-amyl, n~hexyl, and the like.
The term “monocarbocyclic-aryl,” as used herein, means
,aryl radicals having six ring-carbon atoms or, in other
such as acetic acid, citric acid, tartaric acid, lactic acid,
methanesultonic acid, ethanesulfonic acid, quinic acid, and
the like, giving the hydrobromide, hydriodide, nitrate,
phosphate, sulfate, acetate, citrate, tartrate, lactate, meth
words, aryl radicals of the benzene series, and is illustrated 50 anesulfonate, ethanesulfonate and quinate, respectively.
by the unsubstituted phenyl radical and phenyl radicals >
The acid-addition salts are prepared either by dissolving
bearing low-molecular Weight substituents, preferably one
the free base in aqueous solution containing the appro
to three, illustrated bynitro, amino, (lower-alkyl) amino,
‘(lower-alkanoyl) amino, lower-alkyl, lower-alkoxy, benz
priate acid and isolating the salt by evaporating the solu
yloxy, lower-alkylmercapto, ‘lower-alkylsulfonyl, halo,
55 solvent, in which case the salt separates directly or can
‘and the like. Furthermore, these substituents can be in
be obtained by concentration of the solution.
Although pharmacologically acceptable salts are pre
ferred, all acid-addition salts are within the scope of my
‘any of the available positions of the phenyl nucleus, and
"where more than one substituen-t, they can be the same
or different and they can be in any of the various posi
tion, or by reacting the free base and acid in an organic
invention.
All acid-addition salts are useful as sources
tion combinations relative to each other. The (lower 60 of the free base form even if the particular salt per se
,alkyDamino,‘ (lower-alkanoyl)amino; lower-alkyl, lower- . is not desired as the ?nal product, as for example when
,alkoxy, lower-alkylmercapto and lower~alkylsulfonyl sub
the salt is formed only for purposes of puri?cation or
.stituents each has preferably from one to six carbon atoms
identi?cation.
‘which can be arranged as straight or branched chains.‘ '
The compounds of my invention are used either in free
The lower-alkyl l-[v(monocarbocyclic-aryl) -'2-oxo 65 base form or in the form of their acid-addition salts, pref
(lower-alkyl)]~4-phenylpiperidine-4-carboxylates are pre
erably the former,‘ when converted into the correspond
pared by ‘reacting a lower-alkyl _4-phenylpiperidine»'4~
“carboxylate with a 2-(monocarbocyclic-aryl)72-oxo-(low
ing lower-alkyl 1- [2-(monocarbocyclic-aryl)-2-hydroxy
(lower-alkyD] - 4-phenylpiperidine-4-carboxylates.
The
-er-alky1) ester of a strong inorganicgor an organic sul
‘conversion is carried out by reacting my compounds with
fonic acid. Suitable esters are illustrated by 2-oxo-V2 70 a reducing agent effective to reduce keto groups to hy
iphenylethyl bromide, .2-oxo-2-phehylethyl chloride, l-oxo r droxy groups. The reduction can be carried out both
by chemical methods and by catalytic hydrogenation.
1-phenyl-2~propyl iodide (same as 1-methyl-2-oxo42-phen
3,093,652
3
4
.
Suitable chemical reducing agents include lithium alumi
num hydride, lithium borohydride, sodium and ethanol,
aluminum isopropoxide, etc. Catalysts suitable when
.
EXAMPLE 2
Ethyl 1 - (1-Ox0-1-Phenyl-2-Pr0pyl)-4-Phenylpiperidine
4-Carboxylate
catalytic hydrogenation is employed include Raney nickel,
platinum oxide, copper-chromium oxide, and other cata
lysts generally effective to catalyze hydrogenation of keto
A mixture containing 27.0 g. of ethyl 4-phenylpiperidine
4-carboxy1ate hydrochloride, 21.3 g. of l-oxo-l-phenyl-Z
groups to hydroxy groups. The preferred reductive pro
propyl bromide (alpha-bromopropiophenone), 150 cc. of
dry n-butanol and 210 g. of anhydrous sodium carbonate
cedure in practicing my invention comprised the catalytic
was re?uxed with stirring for about twenty-three hours.
hydrogenation of my intermediate keto compounds in
lower-alkanol, e.g., n-butanol, solution using Raney nickel 10 To the hot reaction mixture was added about 100 cc. of
methanol and the mixture was ?ltered while hot to re
as the catalyst. Illustrative of this procedure is the re
move the sodium bromide formed by the reaction. The
action of ethyl 1-[l~(3,4~dibenzyloxyphenyl)-l-oxo-2
?ltrate was allowed to cool and the crystalline product
that separated was collected and recrystallized several
the presence of Raney nickel to produce ethyl 1-[l-(3,4 15 times from absolute ethanol, several times from n-butanol
and once from 2-propanol. There was thus obtained
dihydroxyphenyl) - 1 - hydroxy-Z-butyl]~4-phenylpiperi
about 5 g. of ethyl 1-(l-oxo-l-phenyl-Z-propyl)-4-phenyl
dine-4-carboxylate, which can be isolated in free base
piperidine-4- carboxylate, M. P. 123.3—125.1° C. (corr.).
form or in the form of its acid-addition salt.
butyl]-4-phenylpiperidine-4-carboxylate with hydrogen
under pressure at a temperature about 50 to 100° C. in
Analysis.-—Calcd. for C23H27NO3I C, 75.59; H, 7.45;
The lower-alkyl 1 - [2~(monocarbocyclic-aryl)-2-hy
droxy - (lower-alkyl)]-4-phenylpiperidine-4-carboxylates 20
O, 13.13. Found: C, 75.76; H, 7.17; O, 12.95.
addition salts, as discussed hereinabove for the correspond
4-carboxylate is ‘obtained as its hydrochloric acid-addition
salt by treating its solution in ether with gaseous hydrogen
are useful in the free base form or in the form of acid
ing intermediate lower-alkyl 1-[2- (monocarbocyclic-aryl)
2-oxo- (lower-alkyl) ]-4-phenylpiperidine-4-carboxylates.
Ethyl 1-( l-oxo~l-phenyl-2-propyl) ~4-phenylpiperidine
chloride and collecting the precipitated hydrochloride.
Other representative lower-alkyl 1-[2-(monocarbocy
Another aspect of my invention resides in ethyl 1-[1 25
clic-aryl) - 2-oxo-(lower-alkyl) ]-4-phenylpiperidine-4-car
(3,4 - dihydroxyphenyl) - 1-hydroxy-2-butyl]-4-phenylpl
boxylates that can be prepared according to the procedure
peridine-4-carboxylate and its acid-addition salts, said
described in Example 1 using the corresponding lower
salts embracing those disclosed hereinabove for my inter
alkyl 4-phenylpiperidine-4-carboxylate and appropriate 1
mediate lower-alkyl 1-[2-(monocarbocyclic-aryl)~2-oxo
(lower-alkyl) ]-4-phenylpiperidine-4-carboxylates.
The molecular structures of the compounds of my in
vention are established by their mode of synthesis and
corroborated by the correspondence of calculated and
[2-(monocarbocyclic-aryl)-2-oxo-(lower-alkyl)] ester of
30 a strong inorganic acid or an organic sulfonic acid are
the following compounds of Examples 3-15. These com
pounds can be isolated in their free base form or in the
form of their acid-addition salts, preferably their hydro
found values for the elementary analyses for representa
chlorides.
tive examples.
35
EXAMPLE 3
The following examples will further illustrate the in
vention without, however, limiting it thereto.
Ethyl 1-(2-oxo-2-phenylethyl)-4-phenylpiperidine-4_car
boxylate is obtained following the procedure described in
EXAMPLE 1
Example 1 using ethyl 4-phenylpiperidine-4-carboxylate
Lower-A lkyl 1- [2—(M0nocarb0cyclic-Aryl) -2-0x0- (Low
and 2-oxo-2-phenylethyl bromide (alpha-bromoacetophe
er-Alkyl)1-4-Phenylpiperidine-4-Carb0xylates
40
none).
The preparation of these compounds is illustrated by
EXAMPLE 4
the following preparation of ethyl 1-[1-(3,4-dibenzyloxy
Methyl 1 ~ (2-oxo-2-phenylethyl)-4-phenylpiperidine-4
phenyl) - l-oxo-2-butyl] -4-phenylpip eridine-4-carb oxylate.
A mixture containing 11.6 g. of ethyl 4-phenylpiperi 45 carboxylate is obtained following the procedure described
in Example 1 using methyl 4-phenylpiperidine-4-carboxyl
dine-4-carboxylate, 22 g. of l-(3,4-dibenzyloxyphenyl)-1
ate and 2-oxo-2-phenylethyl chloride (alpha-chloroaceto
oxo-2-butyl bromide (alpha-bromo-3,4-dibenzyloxybutyr
phenone).
ophenone), 100 cc. of dry n-butanol and 10 g. of anhy
EXAMPLE 5
drous sodium carbonate was re?uxed with stirring for
about twenty-four hours. The reaction mixture was al 50
n-Propyl 1 - [1 - (4-ethoxypheny1)-l-oxo-2-propyl1-4
lowed to cool to room temperature and the precipitated
phenylpiperidine-4-carboxylate is obtained following the
sodium bromide was ?ltered off. The ?ltrate was distilled
in vacuo to remove the solvent, thereby leaving a solid
material which was crystallized from acetone-absolute
procedure described in Example 1 using n-propyl 4-phenyl
ethanol to yield 24.3 g. of the product, ethyl Lil-(3,4 55
piperidine-4~carboxylate and 1-(4-ethoxyphenyl)-l-oxo-2
propyl bromide ( alpha-bromo-4-ethoxypropiophenone).
EXAMPLE 6
dibenzyloxyphenyl) - 1-oxo-2-butyl]-4-phenylpiperidine
4-carboxylate, M.P. 118.1-120.1° C. (corr.).
n-Butyl 1-[ 1-(3,4-dimethoxyphenyl)-1-oxo-2=butyl]-4
Analysisr-Cakd. for C38H41NO5: C, 77.12; H, 6.99;
O, 13.52. Found: C, 76.82; H, 6.77; O, 13.68.
Ethyl 1 - [1-(3,4-dibenzyloxyphenyl)-1-oxo-2-butyl]-4
60
phenylpiperidine-4‘carboxylate is obtained following the
procedure described in Example 1 using n-butyl 4-phenyl
piperidine-4Jcarboxylate and 1-(3,4-dimethoxyphenyl)-1
phenylpiperidine-4-carboxylate is obtained as its hydro
oxo-2-butyl bromide (alpha-bromo-3,4-dimethoxybutyro
chloric acid-addition salt by treating its solution in ether
phenone).
with gaseous hydrogen chloride and collecting the pre
EXAMPLE 7
cipitated salt. Similarly, use of hydrobromic acid, sul
famic acid or ethanesulfonic acid in place of hydrochloric 65
n-Hexyl 1-[2-(4-isopropylphenyD-Z-oxoethyl]-4-phenyl
acid results in the formation of the corresponding hydro
piperidine-4-carboxylate is obtained following the proce
bromide, sulfamate or ethanesulfonate salt, respectively.
dure described in Example 1 using n-‘hexyl 4-phenylpiper
Any other acid-addition salt can be prepared in a similar
idine-4-carboxylate and 2-(4-isopropylphenyl)-2-oxoethyl
manner using the desired acid.
bromide.
The above-described preparation of ethyl 1-[l-(3,4-di 70
EXAMPLE 8'
benzyloxyphenyl) - 1 - oxo-2-butyl]-4-phenylpiperidine
4-carboxylate also can be carried out by using in place
of 1-(3,4-dibenzyloxyphenyl)-1-oxo-2-butyl bromide oth
er esters such as 1-(3,4-dibenzyloxyphenyl)-1-oxo-2-butyl
chloride or 1-(3,4-dibenzyloxyphenyl)-1-oxo-2-butyl para
toluenesulfonate.
Ethyl 1 - [1 - (4-nitrophenyl)-1-oxo-2-propyl]-4-phenyl
piperidine-4-carboxylate is obtained following the proce
dure described in Example 1 using ethyl 4-phenylpiperi
dine-4-carboxylate and 1-(4-nitrophenyl)-1-oxo-2~propyl
75 bromide.
3,093,652
5
EXAMPLE 9'
. ,
collected, washed with ether and dissolved in a minimum
;
quantity of Z-propanol (about 3Q cc.). To this solution
Ethyl 1-[ 1'-(4-aminophenyl)ll-oxo-i-propyll -4-phenyl
was added about 300 cc. of ethyl acetate and the resulting
solutionwas treated gradually with ether until a perma
piperidine-4-oarboxylate is obtained following the proce
dure described in Example 1 using ethyl 4~phenylpiperi
dine-4—carboxylate and 1-(4aamin'ophenyl)-l-oxo-Z-propyl
bromide. Alternatively, this compound is obtained by re
nently cloudy solution resulted. The precipitate which
separated was collected, triturated with dry ether and col
lected by ?ltering. There was thus obtained 5.5g. of
acting the corresponding nitrophenyl compound of Exam
ple 8 with a reducing agent effective to reduce nitro groups
to amino groups, e.g., iron and hydrochloric acid.‘ - ‘i >
EXAMPLE 10
.
ethyl 1-[1-(3,4 - dihydroxyp'henyD-1-hydroxy-2-butyl]-4
phenylpiperidine-4-carboxylate in the form of its hydro
10 chloride, M.P. 103-1165” C. (corn) with decomposition.
Analysis.—Calcd. for C24H31NO5J-ICI: C, 63.04; H,
‘
7.17;‘ Cl, 7.88. Found: C, 63.73; H, 7.31; CI, 7.97. .
Isopropyl 1-[2 .- (3-n-butylaminbphenyD-Zaoxoethyl]-4—
Following the above procedure using hydrobromic acid,
phenylpiperidine-4~carboxy1ate is obtained following the
sulfamic acid or ethanesulfonic acid in place of hydrogen
proceduredescribed in ‘Example 1 using isopropyl 4-phen
ylpiperidine-4dc-arboxylate and 2-(3-n-butylaminophenyl) 15 chloride results in the formation of the corresponding
hydrobromide, sulfamate- or ethanesulfonate, respectively.
2Joxoethyl bromide.
Pharmacological evaluation of ethyl l-[1-(3,4-dihy
EXAMPLE 11
droxyphenyD-l-hydroxy - 2 -1butyl] -4-phenylpiperidine-4
Ethyl 1-[1-(4-acetylaminopheny1)-1 - oxo - 2-propyl]-4a
carboxylate hydrochloride in (aqueous solution adminis
phenylpiperidine-4dcarboxylate is obtained following the 20 tered intraperitoneally by the Rat Thermal Stimulus Meth
procedure described in Example 1 using ethyl 4-phenyl
od of Bass and Vander Brook [1. Am. Pharm. Assoc, Sci.
piperidine-4carboxylate and l-(4~acetylaminophenyl)-1
Ed., 41, 569-570 (1952)] has shown that this compound
oxo-2-propyl bromide. Alternatively, this product is ob
is approximately one-third as active an analgesic as meper
tained by reacting the corresponding aminophenyl com
idine hydrochloride.
pound of Example 9 with an 'acetylating agent, e.g., acetic 25 Following the above procedure described in Example
anhydride.
16 using in place of ethyl 1-[1-(3,4-dibenzyloxyphenyl)-1
EXAMPLE 12
oxo-2dbutyl]-4-phenylpiperidine-4-carboxylate the 1-[2
(monocarbocyclic-aryl)-2-oxo-(lower-alkyl)] compounds
Ethyl 1- [ 1-(Z-methylmercaptophenyl)-1~oxo-2-butyl]-4
of Examples 3-15, the corresponding l-[2~(monocarbo
phenylpiperidine-4-carboxylate is obtained following the
procedure described in Example 1 using ethyl 4-phenyl 30 cyclicaaryl)-2-hydroxy-(lower~a1kyl)] compounds are ob
tained. For example, use of the products of Examples 2,
3, 5 and 9 results in the formation of ethyl l-(l-hydroxy-l
piperidine-4-oarboxylate and l-(2~methylmercaptophenyl)
l-oxo-Z-butyl bromide.
EXAMPLE 13>
Ethyl 1 [ 1-(4-n-butylsulfonylphenyD-l-oxo-2-propyl] -4 35
phenylpiperidine-4~carboxylate is obtained following the
procedure described in Example 1 using ethyl 4-phenyl
be isolated in their free ‘base form or in the form of their
l-oxo-Z-propyl bromide.
piperidine-4-carboxylate is obtained following the proce
dure described in Example 1 using ethyl 4-phenylpiperi
dine-4-carboxylate and 2-(3,4-diehlorophenyl)~2-oxoethyl
bromide.
40
clic~ary1) -2-hydroxy- (lower~alkyl) ]-4-phenylpiperidine~4
[formulation can be prepared using conventional excip
ients, and the powder can be compounded in capsule
form. These preparations can be administered orally or,
EXAMPLE 15
Ethyl 1-[1-(2-chloro-4-ethoxyphenyl)-l-oxo-Z-propyl]
in the case of aqueous preparations, intramuscularly or
4-phenylpiperidine-4Jcarboxylate is obtained following the
procedure described in Example 1 using ethyl 4-phenyl
intravenously.
I claim:
1. A composition of matter selected from the group
piperidine-4-carboxyl-ate and l-(2-chloro-4-ethoxyphenyl)
1-oxo-2—propyl bromide.
(Lower-Alkyl) ]~4-Phenylpiperidine-4-Carb0xylates
acid-addition salts, preferably the hydroehlorides.
The above-described l-owenalkyl I-[Z-(monocarbocy
earboxylates can be formulated in the same manner as
meperidine, e.g., in aqueous or aqueous-ethanol menstru
45 urn, or in solid form, e.ig., tablet or powder. The tablet
.
EXAMPLE 16
Lower-Alkyl 1 - [2- (Monocarbocyclic-A ryl ) -2-Hydroxy
(4~aminophenyl)-l-hydroxy-Z-propyl] - 4 - phenylpiperi
dine-4-carboxylate, respectively. These compounds can
piperidine-4acarboxylate and 1-(4-n-butylsulfonylphenyl)
EXAMPLE l4
Ethyl 1-[2-(3,4 - dichlorophenyl)-2-oxoethyl]-4-phenyl
phenyl-Z-propyl)-4-phenylpiperidine-4-carboxylate, ethyl
1-(2-hydroxy - 2 - phenylethyl)~4-phenylpiperidine-4-car
boxylate, n-propyl 1-[1-(4-ethoxyphenyl)-l-hydroxy-Z
propyl]~4-phenylpiperidine-4-carboxylate and ethyl 1-[1
consisting of lower-alkyl 1-[2-(monocarbocyc1ic-aryD-2
oxo- (lower-alkyl) ]-4-phenylpiperidine—4carboxyl-ates hav
55 ing the formula
The preparation of these compounds is illustrated by
the following preparation of ethyl 1-[1-(3,4-dihydroxy
p‘henyl)-l-hydroxy-Z-butyl]-4 - phenylpiperidine-4-carbox 60
ylate.
A mixture containing 11.3 g. of ethyl 1-[1-(3,4~di
||
0 $135 0—-0-(lower-alky1)
0\
(lléa CH:
OH:
H:
benzyloxyphenyl) - 1 - oxo-Z-buty-l]-4-phenylpiperidine-4
carboxylate, Raney nickel catalyst and enough dry n
butanol to bring the total volume to 90‘ cc. was hydro 65
genated under pressure. The reaction time was about
ninety minutes and the temperature was kept between 70
where R represents a member selected from the group
and 80° C., with the initial hydrogen pressure being about
consisting of hydrogen, methyl 1and ethyl, C6H5 represents
680 lbs/sq. inch and the ?nal pressure being about 580
1=bs./ sq. inch. “The reaction mixture was then ?ltered to 70 phenyl and Ar represents a monocarbocyclic-aryl radical
selected from the group consisting of unsubstituted-phenyl
remove the catalyst and the ?ltrate was concentrated in
and phenyl having from one to three substituents selected
vacuo to yield the viscous oily product, ethyl 1-[1-(3,4
dihydroxyphenyl) - 1 - oxo-2-butyl]-4-phenylpiperidine-4
from the group consisting of nitro, amino, (lower-IatlkyD
amino, (lowerdalleanoyDam-ino, lower<a1kyl, lowerdalkoxy,
carboxylate. This was dissolved in about 400 cc. of dry
ether and the resulting solution was treated with gaseous 75 benzyloxy, lower-alkylmercapto, lower~alkylsulfonyl and
halo; and acid-addition salts thereof.
hydrogen chloride. The precipitate which separated was
3,093,652
7
8
2. Ethyl 1- (l-oxo-l-phenyl-Z-propyl)-4-phenylpiperi
2,846,437
Elpern _______________ __ Aug. 5, 1958
dine-4-carboxylate.
3. Ethyl 1-[l-(3,4-dibenzyloxyphenyl)-l-oxo-2-butyl]
4-phenylpiperidine-4-oarboxy1ate.
2,858,316
Morren ______________ __ Oct. 28, 1958
2,962,501
Cutler at ‘al ___________ .._ Nov. 29, 1960
FOREIGN PATENTS
4. The process of preparing ethyl 1-[1-(3,4-dihydroxy-'
phenyD-l-hydroxy - 2 - butyl]- 4 -phenylpiperidine-4-car
boxylate which comprises catalytically hydrogenating
ethyl 1-[1-(3,4 -dibenzyloxyphenyl) - 1 - 0xo-2-butyl1-4
phenylpiperidine-4-carboxylate.
546,982
Belgium _____________ __ Apr. 30, 1956
OTHER REFERENCES
Braenden et 1211.: Bull. World Health Org., vol. 13, pp.
(1955).
5. Ethyl l-[1-(3,4-dihydroxyphenyl)-1-hydroxy-2-'bu- 10 956-962
Gaylor: Reduction With Complex Metal Hydrides, pp.
tyl] -4-phenylpiperidine-4-carb oxyl ate.
100-1 (1956).
‘6. Ethyl 1- [ 1-( 3,4-dihydroxyphenyl) -1-hydroxy-2-bu
Perrine et ‘21.: J. Org. Chem., vol. 21, pp. 125—126
tyl]-4-phenylpiperidine-4-carboxylate hydrochloride.
(1956).
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,776,293
Levy et a1. ____________ .... Ian. 1, 1957
Janssen et ral.: Acta Physiol. et Phlarmacol. Neerland
15 vol. 7, pages 373402 (1958).
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