Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
3 2 0
SPECIFICATION
Title of the Invention
SU~STITUTED ACETAMIDE COMPOUND
Field of the Invention
This invention relates to a novel substituted acetamide
compound and a pharmaceutically acceptable salt thereof.
More particularly, it relates to a novel substituted-
acetamide compound and a pharmaceutically acceptable salt thereof
which have anticholinergic activity, and are useful for the
treatment of dysuria such as pollakiuria, urinary incontinence or
the like in case of nervous pollakiuria, neurogenic bladder
dysfuction, nocturia, unstable bladder, cystospasm, chronic
cystitis, chronic prostatitis or the like; and for the treatment
of convulsion and/or hypanakinesis in case of gastric ulcer,
duodenal ulcer, gastro~ynsis, esophagospasm, gastritis, enteri-
tis, irritable colon syndrome, enteralgia, cholecystitis, cholan-
gitis, pylorospasm, pancreatitis, pai.n in case of pancreatitis,
biliary dyskinesia, aftereffect after cholecystectomy, urinary
calculus cystitis, dysmenorrhea, hidrosis, convulsion of urinary
tract; and which are expected to be useful for the treatment of
asthma, Parkinson disease, angina pectris or the like.
2~320
Prior ~rt
One object of this invention is to provide a novel sub-
stituted acetamide compound and a pharmaceutically acceptable
salt thereof which are useful for the treatment of aforesaid
diseases.
Another object of this invention is to provide a pharma-
ceutical preparation comprising, as an active ingredient, said
substituted acetamide compound or a pharmaceutically acceptable
salt thereof, which is useful as an agent for the treatment of
aforesaid diseases.
Disclosure of the Invention
The object substituted acetamide compound of this inven-
tion is novel and can be represented by the following formula
(I):
R'
R 2 - C - ( A' ) m - C O N H - (A 2 ) n - R~ (I)
Rs
wherein R1 and R2 are each aryl which may have suitable sub-
stituent,
R3 is hydrogen, hydro~y or lower alkyl,
R4 is a group represented by the following formula
(i), (ii), (iii) and (iv):
2lss3~a
.
~ N - R 5 ( i )
wherein R5 is hydrogen, methyl, ethyl, propyl, isopropyl or
imino protective group,
~ (i')
~ N - R 5
wherein R6 is lower alkyl,
N (iii)
~ N - R 7 ~iv)
wherein R7 is hydrogen, lower alkyl or imino protective group,
A1 and A2 are each lower alkylene, and
m and n are each O or 1,
provided that
(a) R5 is not ethyl when R1 and R2 are both phenyl,
R3 is hydro~y, A2 is methylene, m is O and n is 1,
~ ~15 ~ 3 2 ~
(b) R7 is not methyl when R1 and R2 are both phenyl, R3 is
hydro~y, and m and n are both 0.
The object compound (I) may have (an) asymmetric carbon
atom(s) and the stereo isomer caused by asymmetry is also includ-
ed in the scope of the present invention.
For the preparation of the object compound (I), a start-
ing compound which may be prepared according to the "Preparation"
e~emplarily illustrated later may be reacted according to the
"E~ample" also e~emplarily illustrated later.
Suitable pharmaceutically acceptable salts of the object
compound (I) are conventional non-to~ic mono or di salts and
include an organic acid addition salt [e.g., formate, acetate,
trifluoroacetate, maleate, tartrate, methanesulfonate, benzene-
sulfonate, toluenesulfonate, etc.], an inorganic acid addition
salt [e.g., hydrochloride, hydrobromide, hydroiodide, sulfate,
nitrate, phosphate, etc.], a salt with an amino acid [e.g.,
arginine salt, aspartic acid salt, glutamic acid salt, etc.],
metal salt such as alkali metal salt [e.g., sodium salt, potassi-
um salt, etc.], alkaline earth metal salt [e.g., calcium salt,
magnesium salt, etc.], ammonium salt, a salt with an organic base
[e.g., trimcthyl amine salt, triethyl amine salt, pyridine salt,
picoline salt, dicyclohexylamine salt, N,N'-dibenzyl ethylenedia-
mine salt, etc.], and the like.
In the above and subsequent descriptions of this specifi-
cation, suitable of the various definitions are explained in
~ 21~2~
detail as follows:
The term "lower" is intended to mean 1 to 6 carbon
atom(s), preferably to 1 to 4 carbon atom(s).
Suitable "aryl" in "aryl which may have suitable substit-
uent" may include phenyl, naphthyl, pentalenyl, anthracenyl and
the like.
"Suitable substituent" which may be substituted with the
above "aryl" may include halogen (e.g., fluorine, chlorine,
bromine, iodine), lower alkyl (e.g., methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, pentyl, he~yl, etc.), lower alkoxy
(e.g., metho~y, etho~y, propo~y, isopropo~y, buto~y, t-buto~y,
pentylo~y, he~ylo~y, etc.), and the like. A number of substituent
substituted to aryl may be one or more than one, preferably one
to three.
Accordingly, suitable "aryl which may have suitable
substituent" may include phenyl which has one suitable substitu-
ent selected from the group consisting of halogen, lower alkyl
and lower alko~y, in which the preferred one may be phenyl which
has halogen, phenyl which has (C1-C4)alkyl or phenyl which has
(C1-C4)alkoxy, and the more preferred onc may be phenyl which has
chlorine, phenyl which has fluorine, phenyl which has methyl or
phenyl which has metho~y.
Suitable "lower alkyl" may include the straight and
branched ones such as methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, pentyl, he~yl or the like, in which the preferred one
may be (C1-C4)alkyl, and the more preferred one may be methyl,
ethyl, propyl, isopropyl, butyl or t-butyl. 21 ~32~
Suitable "imino-protective group" may include the conven-
tional protective group such as substituted or unsubstituted ar
(lower)alkyl (e.g., trityl, benzhydryl, benzyl, 4-metho~ybenzyl,
etc.), dinitrophenyl, lower alko~y carbonyl(lower)alkenyl (e.g.,
1-metho~ycarbonyl-1-propene-2-yl, etc.), aroyl(lower)alkenyl
(e.g., 1-benzoyl-1-propene-2-yl, etc.), hydro~y ar(lower)alkyli-
dine (e.g., 2-hydro~ybenzylidene, etc.), silyl compound such as
tri(lower)alkylsilyl (e.g., trimethyl silyl, etc.), acyl as
e~emplified as follows, and the like.
Suitable "acyl" may include aliphatic acyl group, aromat-
ic acyl group, heterocyclic acyl group, and aliphatic acyl group
wherein the aliphatic chain is substituted with aromatic group or
heterocyclic group.
Suitable "aliphatic acyl group" may include saturated or
unsaturated, acyclic or cyclic acyl such as carbamoyl, lower
alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl,
varelyl, isovarelyl, pivaloyl, hexanoyl, etc.), lower alkane
sulfonyl (e.g., mesyl, ethane sulfonyl, propane sulfonyl, etc.),
lower alko~y carbonyl (e.g., metho~y carbonyl, etho~y carbonyl,
propo~y carbonyl, buto~y carbonyl, tert-butoxy carbonyl, etc.),
lower alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.),
(C3-C7)cycloalkane carbonyl (e.g., cyclohexane carbonyl, etc.),
amidino, protected carbo~y carbonyl such as lower alko~alyl
(e.g., metho~alyl, etho~alyl, tert-buto~alyl, etc.), and the
like.
~1~5320
Suitable "aromatic acyl group" may include aroyl (e.g.,
benzoyl, toluoyl, ~yloyl, etc.), arene sulfonyl (e.g., benzene
sulfonyl, tosyl, etc.), and the like.
Suitable "heterocyclic acyl group" may include heterocy-
clic carbonyl (e.g., furoyl, thenoyl, nicotinoyl isonicotinoyl,
thiazolyl carbonyl, thiadiazolyl carbonyl, tetrazolyl carbonyl,
morpholino carbonyl, etc.), and the like.
Suitable "aliphatic acyl group wherein the aliphatic
chain is substituted with aromatic group" may include ar
(lower)alkanoyl such as phenyl(lower)alkanoyl (e.g., phenyl
acetyl, phenyl propionyl, phenyl hexanoyl, etc.), ar
(lower)alko~y carbonyl such as phenyl(lower)alkoxy carbonyl
(e.g., benzyloxycarbonyl, phenetylo~y carbonyl, etc.), phenoxy
(lower)alkanoyl (e.g., pheno~yacetyl, pheno~ypropionyl, etc.),
and the like.
Suitable "aliphatic acyl group wherein the aliphatic
chain substituted with heterocyclic group" may include thienyl
acetyl, imidazolyl acetyl, furyl acetyl, tetrazolyl acetyl, thia-
zolyl acetyl, thiadiazolyl acetyl, thienyl propionyl, thiadiazo-
lyl propionyl, and the like.
Above e~emplified acyl may be rurther substituted with
carbo~y, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl,
butyl, tert-butyl, pentyl, he~yl, etc.), halogen (e.g., chlorine,
bromine, iodine, fluorine), carbamoyl, lower alkanoyl (e.g.,
formyl, acetyl, propionyl, etc.), ar(lower)alkyl (e.g., benzyl,
etc.), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl,
2 ~
butyl, tert-butyl, etc.), lower alkoxycarbonYl (e.g., methoxycar-
bonyl, etho~ycarbonyl, tert-buto~ycarbonyl, etc.),
ar(lower)alkylo~ycarbonyl (e.g., benzylo~ycarbonYl, etc.), ary-
lo~ycarbonyl (e.g., phenyloxycarbonyl, etc.), carbo~y(lower)alkyl
(e.g., carbo~ymethyl, carbo~yethyl, etc.), protected
carbo~y(lower)alkyl (e.g., tert-buto~ycarbonylmethyl, etc.), or
the like.
Suitable "lower alkylene" may include the straight and
branced ones such as methylene, ethylene, trimethylene, tetra-
methylene, 1,1-dimethylethylene, pentamethylene, he~amethylene,
or the like, in which the preferred one may be (C1-C4)alkylene,
and the more preferred one may be methylene and ethylene. In the
object compound (I), direct chemical bond is formed without a
lower alkylene when m and/or n is 0.
Each definition of the present invention is as described
above with representatives thereof. The object compound (I) is
constructed under the optimum assortment of each difinition e~-
cepting the specific under-mentioned assortment.
(a) an assortment that both R1 and R2 are phenyl, R3 is
hydro~y, A2 is methylene, m is 0, n is 1, and R5 is ethyl
(b) an assortment that both of R1 and R2 are respectively
phenyl, R3 is hydro~y, m and n are respectively O and R7 is
methyl
Most preferred difinition of the present invention in-
cludes the following assortment, i.e., R1 and R2 are respectively
phenyl or phenyl which has fluorine, R3 is hydrogen, hydro~y or
21~2~
.
methyl, m is 0 or 1, A1 is methylene, n is 0 or 1, A2 is methyl-
ene or ethylene, R5 is hydrogen, methyl, ethyl, isopropyl,
imino-protective group, R~ is ethyl, R7 is hygrogen, methyl,
ethyl, isopropyl or imino-protective group.
Effect of the Invention
The object compound (I) and a pharmaceutically acceptable
salt thereof of this invention have anticholinergic activity and
are useful for the treatment of dysuria or other diseases as
mentioned before in human being and animals.
In the object compound (I) and a pharmaceutically accept-
able salt thereof, side effect such as mydriasis or the llke is
alleviated.
In order to illustrate the usefulness of the object
compound (I), the pharmacological test data of the representative
compound Or this invention is shown in the following.
Test 1
Test on Inhibltion of Urinary Bladder Contractions
Induced by Water Filing in Rats
[11 Test Method ----
Male Sprague-Dawly rats, weighing 240-450 g, were anes-
thetized with urethane 1.0 g/kg s.c. The bladder was e~posed
through a midline incision in the abdomen for the recording of
pressure within the bladder as follows; a balloon attached to one
21~532~
e~d of a stainless steel tube (O.D., 1.2 mm, 5 cm in length) was
inserted into the bladder through a small incision in the bladder
dome. The other end of the tube was connected to a pressure-
transducer. The ureters were ligated and cut, and the prozimal
cut end was cannulated with polyethylene tubing and the urine was
led outside.
Ilyperactive urinary bladder (hyperactive contractions of
the detrusor muscle) was induced by water filling of the bladder.
Therefore, the balloon in the bladder was filled with water of a
volume which caused a resting pressure Or about 10 mmllg. Systemic
blood pressure and heart rate were monitored from the common
carotid artery.
When the contractile responses to water filling became
constant, test compounds were administered intravenously.
[II] Test Compound
The Compound (I): N-(1,2,3,6-tetrahydropyridin-4-
yl)methyl-2-hydro~y-2,2-diphenylacetamide
[III] Test Result
The ED30 value (mg/kg) was as follows.
ED30 = 0.005 (mg/kg)
The pharmaceutical composition of this invention (an
agent for the prevention and/or the treatment of dysuria) can be
used in the form of a pharmaceutical preparation, for ezample, in
21~532~
solid, semisolid or liquid form, which contains the object com-
pound (I) or a pharmaceutically acceptable salt thereof, as an
active ingredient in admi~ture with an organic or inorganic
carrier or excipient suitable for rectal, pulmonary (nasal or
buccal inhalation), nasal, ocular, e~ternal (topical), oral or
parenteral (including subcutaneous, intravenous and intramuscu-
lar) administrations or insufflation or intravesica administra-
tion. The active ingredient may be compounded, for e~ample, with
the usual non-to~ic, pharmaceutically acceptable carrier for
tablets, pellets, troches, capsules, suppositories, creams,
ointments, aerosole, powders for insufflation, solutions, emul-
sions, suspensions, and any other form suitable for use. ~nd, if
necessary, in addition, au~iliary, stabilizing, thickening and
coloring age~ts and perfumes may be used. The object compound (I)
or a pharmaceutical acceptable salt thereof is/are included in
the pharmaceutical composition in an amount sufficient to prod`uce
the desired effect upon the process or condition of diseases.
For applying the composition to human being or animal, it
is preferable to apply it by intravenous, intramuscular, pulmo-
nary, or oral administration, or insufflation. While the dosage
of therapeutically effective amount of the object compound (I)
varies from and also depend~s upon the age and condition of each
individual patient to be treated, in the case of intravenous
administration, a daily dose of 0.01 - 20 mg of the object com-
pound (I) per kg weight of human being or animal, in the case of
intramuscular administration, a daily dose of 0.1 - 20 mg of the
=----
~ 5 3~ D
object compound (I) per kg weight of human being or animal, in
case of oral administration, a daily dose of 0.5 - 50 mg of the
object compound (I) per kg weight of human being or animal is
generally given for treating or preventing the aforesaid dis-
eases.
The following Preparations and Examples are given for the
purpose of illustrating this invention in more detail.
Preparation 1
Penzilic acid (5.00 g) and phosphorus pentachloride
(9.4 g) were stirred at 100 C for 3.5 hours. ~fter cooling, the
reaction mi~ture was partitioned between ice-water (50 ml) and
diethyl ether (100 ml). The organic layer was separated, washed
with brine, dried over magnesium sul~ate, and evaporated to give
crude 2-chloro-2,2-diphenylacetyl chloride (6.16 g). A solution
of 4-(aminomethyl)pyridine (1.97 g) in dry toluene (5 ml) was
added dropwise to a solution of crude 2-chloro-2,2-diphenylacetyl
chloride (6.16 g) in dry toluene (50 ml) at room temperature The
reaction mi~ture was stirred at room temperature for 1 hour,
diluted witll ethyl acetate (50 ml) and lN sodium hydro~ide solu-
tion (50 ml). The organic layer was separated, washed with lN-
sodium hydroxide solution (50 ml ~ 3), and evaporated to give
crude N-(pyridine-4-yl)methyl-2-chloro-2,2-diphenylacetamide
(9.06 g). ~ solution of the crude N-(pyridine-4-yl)methyl-2-
chloro-2,2-diphenylacetamide (9.06 g) in lN hydrochloric acid
12
2155~2~
(50 ml) was stirred at 70C for 2 hours. A~ter cooling, the solu-
tion was washed with diethyl ether (50 ml) and was made alkaline
wlth 6N sodium hydro~ide solution. The precipitated powder was
collected by filtration to give N-(pyridine-4-yl)methyl-2-hy-
droxy-2,2-diphenylacetamide (6.37 g) as a colorless powder.
mp:148-151 ~
IR(Nujol) :3330, 1650, 1600, 760, 740, 690cm~'
NMR(DMSO-d6,~) :4.33(2H, d, J=6.3Hz), 6.85(lH, s),
7.15-7.18(2H, m), 7.25-7.40(lOH, m), 8.42-8.45(2H, m),
8.84(1H, t, J=6.3Hz)
MASS(m/z) :183, 105
Preparation 2
A solution of N-(p~ridine-4-yl)methyl-2-hydroxy-2,2-dipheny-
lacetamide (80 g) and 4-metho~ybenzyl chloride (47.2 g) in N,N-
dimethylformamide (120 ml) was stirred at 65 C for 1 hour. After
cooling, the reaction mi~ture was diluted with acetone (500 ml)
and diethyl ether (100 ml) and stirred under ice cooling for 20
minutes. The precipitated powder was collected by filtration to
give 4-[(2-hydro~y-2,2-diphenylacetylamino)methyl]-1-(4-metho~y-
benzyl)pyridinium chloride (107.57 g) as a colorless powder.
mp:205-208~
IR(Nujol) :3250, 3050, 1650, 1610, 750, 700cm~'
NMR(DMSO-d~,~) :3.76(3H, s), 4.55(2H, d, J=5.9HZ),
5.72(2H, s), 6.99(2H, d, J=6.7Hz), 7.00(lH, s).
21553~
7.25-7.40(lOH, m), 7.53(ZH, d, J=6.7Hz),
7.87(ZH, d, J=6.7Hz), 9.13(2H, d, J=6.7Hz),
9.11(lH, t, J=5.9Hz)
MASS(m/z) :183. 93
Preparation 3 ~ ~
A solution of 4-acetylaminomethylpyridine (7.00 g) and
4-metho~ybenzyl chloride (6.8 ml) in acetone (100 ml) was stirred
for 4 hours under reflu~ and then for 30 minutes under ice cool-
ing. The precipitated powder was collected by filtration and
washed with acetone to give hygroscopic
4-acetylamino-methyl-1-(4-metho~ybenzyl)pyridinium chloride
(10.88 g) which was used for next step reaction (Preparation 4)
witllout further purification.
Preparation 4
To a solution of 4-acetylaminomethyl-1-(4-
methoxybenzyl)pyridinium chloride (10.88 g) in methanol (200 ml)
was added portionwise sodium borohydride (5.37 g) under ice
cooling and the resulting solution was stirred at room tempera-
ture for 13 hours. Water (10 ml) was added to the reaction solu-
tion, and the solvent was distilled of r. Ethyl acetate and water
were added to the residue, and the organic layer was separated,
washed with brine, dried over magnesium sulfate, and the solvent
was evaporated. The residue was subjected to column chlomatogra-
phy on silicagel with an eluent of a mi~ture of methylene chlo-
14
2 1 ~ ~ 3 ~ ~
ride and methanol (15:1) to give 4-acetylaminomethyl-1-(4-met-
hoxybenzyl)-1,2,3,6-tetrahydropyridine (7.27 g) as a pale yellow
oil.
IR(film) : 3300, 1650, 1610, 760cm~l
NMR(CDCl 9, ~ ) 1. 98(s, 3H), 2.10(br s, 2H),
2.56(t, J=5.7Hz, 2H), 2.95(br s, 2H), 3.52(s, 2H),
3.76(s, 2H), 3.80(s, 3H), 5.53(t, J=1.5Hz, lH),
5.95(br s, lH), 6.80-6.90(m, 2H), 7.20-7.30(m, 2H)
MASS(m/z) : 274(M~), 215, 121
Preparation 5 .
4-Acetylaminomethyl-1-propylpyridinium iodide was ob-
tained by reacting 4-acetylmethylpyridine as a raw material, in a
similar manner to that o~ Preparation 3.
mp: 135-137 ~ (washed with acetone)
IR(Nujol) : 3250, 1670, 1640, 760, 750 cm~'
NMR(DMS0-d6, ~) : 0.87(t. J=7.3Hz, 3H), 1.65-2.00(m, 2H),
1.97(s, 3H), 4.45-4.55(m, 4H), 7.96(d, J=6.8Hz, 2H)
8.67(t, J=5.8Hz, lH), 8.98(d, J=6.8Hz, 2H)
MASS(m/z) : 193(MI), 149, 107
Preparation 6
4-~cetylaminomethyl-1-propyl-1,2,3,6-tetrahydropyridine
w~s obtained by reacting the compound obtained in Preparation 5
as a raw material, in a similar manner to that Or Preparation 4.
~15~2~
IR(film) : 3300, 3050, 1650,750cm~'
NMR(CDClJ, ~) : O.91(t, J=7.3Hz, 3H),
1.58(t, quartet, J=7.3Hz, J=5.7Hz, 2H), l.99(s, 3H),
2.23(br s, 2H), 2.30-2.40(m, 2H), 2.56(t, J=5.7Hz, 2H)
2.95(d, J=1.6Hz, 2H), 3.79(d, J=5.4Hz, 2H),
5.54-5.57(m, lH), 5.66(br s, lH)
MASS(m/z) : 196(MI), 167, 96
Preparation 7
3-Acetylamino-1-ethyl-1,2,3,6-tetrahydropyridine was ob-
tained as an oil by reacting 3-acetylaminomethyl-1-ethylpyridini-
um iodide as a raw material, in a similar manner to that of
Preparation 4.
bp 150 ~ /0.08mmHg (kugelrohr)
IR(film) : 3270, 1640, 1540cm~'
NMR(CDClJ, ~) : 1.15(3H, t, J=7Hz, CHa),
1.99(3H, s, COCHs), 2.19(2H, m, NCH2CH2CH=),
2.49(2H, quartet, J=7Hz, NCHzCH9),
2.52(2H, t, J=611z, CH2CHzN),
Z.72(2H, d, J=2.5Hz, NCH2C=),
3.78(2H, d, J=5.5Hz, CHzN), 5.65(lH, m, HC=),
5.8(1H, m, NH)
MASS(m/z) : 182(MI), 123, llO(b~se), 108
Preparation 8
4-Acetylaminomethyl-1-benzyl-1,2,3,6-tetrahydropyridine
16
~1~532~
.
was obtained via 4-acetylaminomethyl-l-benzyl-pyridinium bromide
by reacting ~-acetylamino-methYlpYridine and benzyl bromide as
raw materials, in a similar manner to those of rreparations 3 and
4.
IR(Film):3250, 1650, 740, 700cm~'
NMR(CDC13,~) :1.98(s, 3H), 2.00-2.15(m, 2H),
2.15-2.35(m, 2H), 2.97(br s, 2H), 3.45(s, 2H),
3.95-4.00(m, 2H), 5.53(br s, lH), 5.84(br s, lH),
7.20-7.40(m, 5H)
MASS(m/z) :244(M+), 185, 172
Preparation 9
A solution of 4-acetylaminomethyl-l-(4-metho~ybenzyl)-
l,2,3,6-tetrahydropyridine (5.00 g) and 6N aqueous solution of
sodium hydro~ide (16 ml) in methanol (32 ml) was refluxed for 23
hours, and then the solvent was evaporated. Ethyl acetate and lN
sodium hydro~ide aqueous solution were added to the residue. The
organic layer was separated, washed with brine, dried over magne-
sium sulfate, and the solvent was evaporated. The residue was
subjected to column chromatographY on silicagel with an eluent of
a mixture of methylene chloride and methanol (lO:l - 2:1) to give
4-aminomethyl-l-(4-metho~ybenzyl)-l,2,3,6-tetrahydropyridine
(2.31 g) as an oil.
IR(film):3370, 1610, 760, 730cm~
~532~
NMR(CDCl 3, ~ ) 1. 84(br s, 2H), 2.13(br s, 2H),
2.57(t, J=5.8Hz, 2H), 2.99(br s, 2H), 3.20(br s, 2H),
3.53(s, 2H),3.80(s, 3H), 5.53-5.57(m, lH),
6.80-6.90(m, 2H), 7.20-7.30(m, 2H)
MASS(m/z) : 232(M~), 202, 121
Preparation 10
4-Aminomethyl-1-propyl-1,2,3,6-tetrahydropyridine was
obtained by reacting 4-acetylaminomethyl-1-propyl-1,2,3,6-
tetrahydropyridine as a raw material, in a similar manner to that
of Preparation 9.
bp: 140-150 C/lOmmHg (Kugelrohr)
IR(Film) : 3270, 1600cm~'
NMR(CDCl~, ~) : 0.92(t, J=7.3Hz, 3H), 1.10-1.70(br s, 2H),
1.55(t, quartet, J=7.3Hz, J=5.7Hz, 2H),
2.14(d, J=1.6Hz, 2H), 2.30-2.40(m, 2H),
2.57(t, J=5.7Hz, 2H), 2.96-3.00(m, 2H), 3.10(s, 2H),
5.53-5.57(m, lH)
MASS(m/z) : 154(M'), 125, 96
Preparation 11
4-Aminomethyl-1-benzyl-1,2,3,6-tetrahydropyridine was
obtained by reacting 4-acetylaminomcthyl-1-benzyl-1,2,3,6-
tetrahydropyridine as a raw material, in a similar manner to that
of Preparation 9.
IR(Film) : 3370, 3270, 1600, 740, 700cm~'
1~
~ 21~5320
NMR(CDC13, ~) : 1.61(s, 211), 2.13(br s, 2H),
2.58(t, J=5.8Hz, 2H), 2.95-3.05(m, 2H), 3.20(br s, 2H)
3.59(s, 2H), 5.50-5.55(m, lH), 7.20-7.37(m, 5H)
MASS(m/z) : 202 (Mf), 172, 97
I'reparation 12
3-Aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine was
obtained by reacting 3-acetylaminomethyl-1-ethyl-1,2,3,6-tetrahy-
dropyridine as a raw material, in a similar manner to that of
Preparation 9.
bp: 100-105 ~ /8.5mmHg (Kugelrohr)
IR(Nujol) : 3450, 3370, 3280, 3200cm~'
NMR(CDCl~ 1.14(3H, t, J=7Hz, CH3),
1.61(2H, s, NH2), 2.21(2H, m, CH2CH2CH=),
2.47(2H, quartet, J=7Hz, NCH2CH~),
2.49(2H, t, J=6Hz, NCH2CH2CH=), 2.93(2H, m, CH2N),
3.20(2H, m, CHzN), 5.62(1H, m, CH=)
MS(m/z) : 140(M~), 123(base), 110, 108
Preparation 13
Acetic anhydride (17.5 ml) was added to a stirred solu-
tion of 3-aminomethylpyridine (10.0 g) in acetic acid (30 ml) at
room temperature. The resulting mi~ture was stirred at room
temperature for 30 minutes and concentrated in vacuo to afford
3-acetylaminomethylpyridine as a crude oil, which was converted
19
21~32~
to 3-acetylaminomcthyl-1-ethylpyridinium iodide by reacting with
ethyl iodide in a similar manner to that of Preparation 3, and
then crystallized from a mi~ture o~ n-he~ane and ethyl acetate to
g~ve pale yellow crystals.
mp: 110-111 C
IR(Nujol) : 34Z0, 3260, 1640cm~'
NMR(DMS0-d~ 1.54(3H, t, J=7.5Hz, CH3),
1.93(3H, s, COCH3), 4.44(2H, d, J=6Hz, CH2NCO),
4.64(2H, quartet, J=7.5Hz, NCH2CH~),
8.12(1H, t, J=7.5Hz, pyridinium H),
8.43(lH, d, J=7.5Hz, pyridinium H),
8.59(lH, t, J=6Hz, NH), 9.0(2H, m, pyridinium H)
MASS(m/z) : 135, 107
Preparation 14
A mi~ture of ethyl 3,3-diphenyl-2-propenoate (4.28 g) in
3N-sodium hydroxide aqueous solution (28 ml) and ethanol (50 ml)
was allowed to stand overnight at room temperature and stirred at
50Cfor 2 hours. Ethyl acetate and brine were added to the mi~-
ture and the resulting solution was acidified with concentratcd
hydrochloric acid. The organic layer was separated, dried over
magnesium sulfate, and the solvent was evaporated in vacuo to
give 3,3-diphenyl-2-propenoic acid.
mp: 158-161 C (washed with ethyl acetate)
2~ ~32~
.
IR(Nujol) :1690, 1660, 1610, 720,700cm~'
NMR(CDC1~ 6.32(s, lH), 7.10-7.40(m, 10H)
MASS (m/z) : 224(M~), 179, 165
Examlllc 1
To a solution of 4-[(2-hydro~y-2,2-
diphenylacetylamino)methyl]-l-(4-methoxybenzyl)pyridinium chlo-
ride (lOO g) in methanol (800 ml) was added portionwise sodium
borohydride (32.7 g) at lO - 20 C in a nitrogen atomosphere. The
resulting solution was stirred at room temperature for l hour,
and then the mixture was evaporated. Ethyl acetate (l Q ) and
water (500 ml) were added to the residue, and the organic layer
was separated, washed with water (500 ml), brine (500 ml), dried
over magnesium sulfate, and evaporated to give N-[l-(4-
metho~ybenzyl)-l,2,3,6-tetrahydropyridin-4-yl]methyl-2-hydro~y-
2,2-diphenylacetamide as crude oil. A mi~ture of the crude oil
and l-chloroethyl chloroformate (25 ml) in methylene chloride
(700 ml) was refluxed for l hour. Methanol (350 ml) was added to
the mi~ture. The solution was reflu~ed for 30 minutes, and the
solvent was evaporated. The residue was treated with 4N-hydrogen
chloride in ethyl acetate, crystallized and recrystallized from
cthanol to give N-(l,2,3,6-tctrahydropyridin-4-Yl)-mcthyl-2-
hydroxy-2,2-diphenylacetamide hydrochloride as colorless crystals
(4l.64).
mp:222-224 ~
IR(Nujol) :3350, 1650, 750, 730, 690cm~'
21~320
NMR(DMS0-d6, ~) : 2.15(2H, br s), 3.10(2H, t, J=5.9Hz),
3.34(2H, br s), 3.70(2H, d, J=5.5Hz), 5.41(lH, br s),
6.82(1H, s), 7.20-7.45(10H, m), 8.34(1H, t, J=5.5Hz),
9.15(2H, br s)
MASS(m/z) : 322(M~), 183, 95
Example 2
2-Hydroxy-2,2-diphenyl-N-[(1,2,3,6-tetrahydro-4-
pyridyl)methyl]acetamide (1.00 g) was hydrogenated over 10 %
palladium on carbon in methanol. After the catalyst was removed
by filtration, the filtrate was evaporated in vacuo and recrys-
tallized from ethanol to give 2-hydro~y-2,2-diphenyl-N-[(piperi-
dine-4-yl)methyl]acetamide hydrochloride
(0.35 g)-
mp: 251-253 ~
IR(Nujol) : 3360, 2470, 1650, 1600, 750, 730, 700cm~'
NMR(DMS0-d6, ~) : 1.10-1.40(m, 2H), 1.50-1.80(m, 3H),
2.65-2.90(m, 2H), 2.90-3.10(m, 2H), 3.10-3.30(m, 2H),
6.75(s, lH), 7.20-7.45(m, lOH), 8.28(br s, lH),
8.69(br s, 2H)
MASS(m/z) : 324(M~), 183, 105
Elemental analysis: C20H24N202-HCl
Calculated value: C 66.56, H 6.98, N 7.76
Actual value: C 67.04, H 7.09, N 7.76
Example 3
21~320
.
2-llydro~y-N~ methylpipcridinc-4-yl)mcthyll-2,2-diphe-
nylacetamide hydrochloride was obtained by reacting
N-[(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)methyll-2-hydroxy-
2,2-diphenylacetamide as a raw material, in a similar manner to
that of Example 2.
mp:237-239 ~
IR(Nujol) :3430, 3150, 1670, 790, 770, 710, 700cm~'
NMR(DMS0-d6,~) :1.20-1.50(m, lH), 1.60-1.80(m, 2H),
2.20-3.20 (m, 8H), 2.68(s, 3H), 6.73(s, lH),
7.20-7.35 (m, lOH), 8.30(br s, lH), 9.70-9.90(br s, lH)
MASS(m/z) :338(M+), 183, lO~
Elemental analysis: C2lH26N202 HCl
Calculated value: C 67.28, H 7.26, N 7.47
Actual value: C 67.64, H 7.56, N 7.53
E~ample 4
A solution of 2,2-diphenyl-2-hydro~y-N-[[1-(4-
metho~ybenzyl)-1,2,3,6-tetraphydropyridine-4-yl]methyl]acetamide
(1.03 g) and benzyl chloroformate (0.437 g) in 1,2-dichloro-
ethane (lO ml) was stirred at room temperature for 4 hours,
diLuted with water, and cxtractcd wlth mcthylcnc chloride. Thc
extract was dried over magnesium sulfate, evaporated in vacuo,
and chromatographed over silica gel usin~ methylene chloride-
methanol as an eluent to afford N-[(1-benzylo~ycarbonyl-1,2,3,6-
tetrahydropyridine-4-yl)methyl]-2,2-diphenyl-2-llydro:~y-acetamide
2~ 5~ 32 ~
.
(0.797 g) as an oil.
IR(film) : 3390, 1690, 1670cm~'
NMR(CDCl~, ~) : 1.99(2H, br s, =CCH2CH2N),
3.52(2H, t, J=5.5Hz,CH2CH2NCOO), 3.76(lH, s, OH),
3.90(4H, m, =CHCH2NCOO and CONCHz), 5.13(2H, s, OCH2),
5.37(lH, br s, =CH), 6.49(lH, m, CONH),
7.3-7.5(15H, m, aromatic H)
MASS(m/z) : 183, 105, 91, 77
Example 5
A mi~ture of N-[[1-(4-metho~ybenzyl)-1,2,3,6-tetrahydro-
pyridine-4-yl]methyl]-2,2-diphenyl-2-hydroxy acetamide (2.77 g) and
1-chloroethyl chloroformate (0.75 ml) in 1,2-dichloroethane
(55 ml) was reflu~ed for 30 minutes. Methanol (50 ml) was added
to the mixture, and the solutlon was refluxed for 1 hour and
evaporated. The residue was purified by column chromatography on
silica gel with a mi~ture Or dichloromethane and methanol (10:1),
methanol, and then a mi~ture of methanol and 28 % ammonia water
(10:1), successively, as an eluent. The eluate was evaporated.
Thc residue was treated with 4N-hydrogen chloride in ethyl ace-
tate, crystallized, and recrystallized from methanol and ethyl
acetate to give N-[Ll,2,3,~-tetrahYdropYridine-4-yl]methyl]-2~2-
diphenyl-2-1lydroxy acetamide hydrochloride as colorless crystals
(1.33 g).
mp:223-224 ~
IR(Nujol) :3350, 1650, 750, 730, 690cm~'
24
2 1 5 !~
NMR(DMSO-d6, ~) : Z.15(br s, 21I), 3.10(t, J=5.91~z, 2H),
3.34(br s, 2H), 3.70(d, J=5.5Hz, 2H), 5.41(br s, lH),
6.82(s, lH), 7.20-7.45(m, lOH), 8.34(t, J=5.5HZ, lH),
9.15(br s, 2H)
MASS(m/z) 322(M~), 183, 95
Example 6
A solution of N-[ll-benzyloxycarbonyl-1,2,3,6-tetrahy-
dropyridine-4-yl]methyl]-2,2-diphenyl-2-llydroxyacetamide (186 mg)
in 25 % hydrogen bromide-acetic acid solution (1.86 ml) was
stirred for 30 minutes under ice cooling and for 3 hours at room
temperature, and then evaporated in vacuo. The residue was
partitioned between diisopropyl ether and water. The aqueous
layer was separated, basified with lN sodium hydro~ide solution,
and e~tracted with methylene chloride. The methylene chloride
layer was washed with brine, dried over magnesium sul~ate, evapo-
rated in vacuo. The residue was purified by column chromatography
on silica gel using methylene chloride-methanol as an eluent to
afford 2,2-diphenyl-2-hydro~y-N-[(1,2,3,6-tetrahydropyridine-4-
yl)methyl]acetamide (85 mg) as a colorless powder, which was
recrystallized with ethanol.
mp: 151-153 C
Elemental analysis:
Calculated value: C 74.51, H 6.88, N 8.69
Actual value: C 74.59, H 7.08, N 8.74
IR(Nujol) : 3380, 3300, 1670cm~'
21~5320
NMR(CDCls, ~) : 1.95(2H, m, =CCH2CHzNII),
2.85(2H, t, J=5.5Hz, CH2CH2NH),
3.23(2H, br s, =CHCH2NH), 3.35(2H, br, =NH and OH),
3.84(2H, d, J=5.5Hz, CONHCH2), 5.44(lH, br s, =CH),
6.70(lH, t, J=5.5Hz, CONH),
7.25-7.5(10H, m, aromatic H)
MASS(m/z) : 322(M~), 183(base), 105(base), 96(base)
Example 7
To a solution of N-[(1,2,3,6-tetrahydropyridin-4-
yl)methyl~-2,2-diphenyl-2-hydro~y acetamide (6.00 g) in methanol
(60 ml) was added a solution of methanol (20 ml) at room tempera-
ture. The resulting solution was evaporated in vacuo and the
residue was crystallized and recrystallized from ethanol to give
N-1(1,2,3,6-tetrahydropyridine-4-yl)methyl]-2,2-diphenyl-2-
hydro~yacetamide methanesulfonate as colorless crystals (6.66 g).
mp: 195-197 ~
IR(Nujol) : 3400, 1670, 1590, 780, 750, 740, 700cm~'
NMR(DMSO-d6, ~) : 2.14(br s, 2H), 2.31(s, 3H),
3.14(t, J=6.lHz, 2H), 3.51(br s, 2H),
3.71(d, J=6.lHz, 2H), 5.40(br s, lH), 6.81(s, lH),
7.20-7.41(m, lOH), 8.36(t, J=6.lHz, lH),
8.65(br s, 2H)
MASS(m/z) : 323(M~l)
Elemental analysis: C20H22N202-CH~SOlH
26
21~32~
.
Calculated value: C 60.27, H 6.26, N 6.69, S 7.66
Actual value: C 60.32, H 6.32, N 6.62 , S 7.86
Example 8
~ mixture Or N~ etho~ycarbonylpiperidine-4-yl)-2,2-
diphenylacetamide (4.00 g) and potassium hydro~lde (2.0 g) in
methyl cellosolve (30 ml) was refluxed for 3.5 hours. Ethyl
acetate (100 ml) and water (300 ml) were added to the mi~ture and
resulting solution was separated. The aqueous layer was e~tracted
wlth ethyl acetate (100 ml x 3). The combined organic layers were
evaporated in vacuo and treated with 4N hydrogen chloride in
ethyl acetate to give N-(piperidine-4-yl)-2.2,-diphenylacetamide
hydrochloride.
mp: 233-235 ~ (washed with ethyl acetate)
IR(Nujol) : 3500, 3300, 1630, 740, 720cm~'
NMR(DMS0-d6, ~) : 1.45 1.75(m, 2H), 1.75-2.00(m, 2H),
2.80-3.10(m, 2H), 3.10-3.25(m, 2H), 3.70-3.95(m, lH)
4.97(s, lH), 7.10-7.40(m, lOH), 8.59(d, J=7.4Hz, lH),
8.86(br s, 2H)
MASS(m/z) : 294(M+), 229, 167, 127
Elemental analysis: C,DH22NzO HCl
Calculated value: C 65.41, H 7.22, N 8.03
Actual value: C 65.67, H 7.32, N 8.12
Example 9
27
21~i~3,?0
.
2-llydroxy-N-(pipcridinc-4-yl)-2~2-diphenylacetamidc hydro-
chloride was obtained by reacting
N-(l-etho~ycarbonylpiperidin-4-yl)-2-hydroxY-2~2-diphenylacetamide
as a raw material, in a similar manner to that of E~ample 8.
mp: 193-195 C (washed with acetone)
IR(Nujol) : 3300, 2700, 2600, 2470, 1660, 770, 750, 730, 700
cm-'
NMR(DMS0-d6, ~) : 1.60~2.00(m, 4H), 2.75-3.05(m, 2H),
3.05-3.30(m, 2H), 3.75-4.00(m, lH), 6.77(s, lH),
7.20-7.95(m, lOH), 8.15(d, J=7.7Hz, lH),
8.94(br s, lH), 9.10(br s, lH)
MASS(m/z) : (no M~) , 183, 105
~lemental analysis: C ,9H22N202~HCl
Calculated value: C 64.67, H 6.76, N 7.94, Cl 10.05
Actual value: C 64.79, H 6.93, N 7.92, Cl 9.98
E~ample 10
A solution of N-(pyridine-4-yl)methyl-2-hydro~y-2~2-dipheny-
lacetamide (2.00 g) and methyl iodide (1.6 ml) in acetone
(100 ml) was refluxed for 3 hours and evaporated to give 1-meth-
yl-4-L(2-hydro~y-2,2-dipllenylacc~ylamino)-mctllyl]pyridinium
iodide as a crude oil. The oil was dissolved in methanol (50 ml),
and sodium borohydride (0.95 g) was added to the solution. The
resulting mi~ture was stirred for 1 hour at room temperature, and
then evaporated. The residue was partitioned between ethyl ace-
215~3,~
.
tate and lN sodiu~ llydro~ide solution. The organic layer wasFeparated, washed with water, brine, dried over magnesium sul-
rate, and evaporated. The residue was treated with 4N-hydrogen
chloride in ethyl acetate, crystallized and recrystallized from
2-propanol and methanol to give N-(1-methyl-1,2,3,6-tetrahydrop-
yridine-4-yl)methyl-2-hydro~y-2,2-diphenylacetamide (0.41 g).
mp: 173-174 C
IR(Nujol) : 3340, 3200, 2550, 1660, 770, 750, 720, 700cm~'
NMR(DMSO-dfi, ~) : 2.00-2.50(2H, m), 2.80-3.90(4H, m),
2.73(3H, s), 3.72(2H, d, J=6.lHz), 5.38(1H, s),
6.82(1H, s), 7.20-7.40(10H, m), 8.37(1H, t, J=6.lHz)
10.77(lH, br s)
MASS(m/z) : 336(M~), 183, 109
E~ample 11
N-(1-ethylpyridinio-4-yl)methyl-2-hydroxy-2,2-diphenyla-
cetamide iodide was obtained by reacting
N-(pyridine-4-yl)methyl-2-hydroxy-2,2-diphenylacetamide and
methyl iodide as raw materials, in a similar manner to that Or
Example 10.
mp: 123-124 ~
IR(Nujol) : 3350, 1650, 780, 740, 720, 700cm~'
NMR(DMSO-dfi, ~) : 1.52(t, J=7.2Hz, 3H), 4.57(q, J=7.2Nz, 2H)
4.60(d, J=6.OHz, 2H), 7.00(s, lH), 7.20-7.50(m, lOH),
7.85(d, J=6.6Hz, 2H), 9.01(d, J=6.6Hz, 2H),
29
~1~532~
.
9.13(t, J=6.OHz, lH)
MASS(m/z) : (no M~) , 183, 105
Example 12
A mixture of 2-hydro~y-2,2-diphenyl-N-[(1,2,3,6-
tetrahydropyridine-4-yl)methyl]acetamide hydrochloride (0.70 g)
and sodium cyanoborohydride (0.18 g) in dry methanol (15 ml) and
dry acetone (5 ml) was stirred for 4 days at room temperature,
and therl the mixture was evaporated in vacuo. Ethyl acetate and
lN sodium hydroxidc solution were added to the residue. The
organic layer was separated, washed with brine, dried over magne-
sium sulfate, and evaporated in vacuo. The residue was treated
with 4N-hydrogenchloride in 1,4-dio~ane, and crystallized to give
2-hydroxy-N-[(1-isopropyl-1,2,3,6-tetrahydropyridine-
4-yl)methyl]-2,Z-diphenylacetamide hydrochloride (0.58 g).
mp: 126-127 C (washed with 1,4-dioxane)
IR(Nujol) : 3250, 1660, 760, 700cm~'
NMR(DMSO-d6, ~) : 1.26(d, J=6.6Hz, 6H), 2.05-2.25(m, lH),
2.30-2.60(m, lH), 2.75-3.10(m, lH), 3.25-3.50(m, 2H),
3.58(br s, 2H), 3.73(d, J=6.OHz, 2H), 5.42(s, lH),
6.83(br s, lH), 7.15-7.60(m, lOH), 8.36(t, J=6.OHz,lH)
10.30(br s, lH)
Elemental analysis: C23H2~N202 HCl l/2H20
Calculated value: C 67.39, H 7.38, N 6.83, Cl 8.65
21~320
Actual value: C 67.40, H 7.84, N 6.58, Cl 8.35
E~ample 13 --
N-(1-ethylpiperidine-4-yl)-2-hydroxy-2,2-diphenylaceta-
m.ltle ful~aratc was obtalncd by rcacting N-(pipcridille-4-yl)-2-11y-
dro~y-2,2-diphenylacetamide as a raw material, in a similar
manner to that of Example 12.
mp: 197-199 ~ (recrystallization from isopropyl alcohol)
IR(Nujol) : 3420, 2350, 1670, 750, 700, 670cm~'
NMR(DMSO-d6, ~) : 1.05(t, J=7.2Hz, 3H), 1.45-1.65(m, 4H),
2.15-2.40(m, 2H), 2.54(q, J=7.2Hz, 2H),
Z.85-3.05(m, 2H), 3.55-3.75(m, lH), 6.50(s, lH),
7.20-7.40(m, llH), 7.96(d, J=8.OHz, lH)
Elemental analysis: C2,Hz6N20 1/2C~H~04 1/2}{zO
Calculated value: C 68.13, H 7.21, N 6.91
Actual value: C 67.97. H 7.41, N 6.67
Example 14
N-(1-isopropylpiperidine-4-yl)-2,2-diphenylacetamide
rumarate was obta~ned by reacting N-(piperidine-4-yl)-2,2-diphe-
nyl-acetamide hydrochloride as a raw material, in a similar
manner to that of E~ample 12.
mp: 175-177 ~ (washed with acetone)
IR(Nujol) : 3200, 2650, 2500, 1660, 790, 770, 740, 700cm~'
NMR(DMSO-d6. ~) : 1.13(d, J=6.6Hz. 6H), 1.45-1.75(m, 2H),
31
~ 21~5320
1.75-2.00(m, 2H), 2.65-2.90(m. 2H), 3.00-3.25(m, 3H),
3.65-3.90(m, lH), 4.93(s, lH), 6.54(s, 3H),
7.10-7.35(m, lOH), 8.43(d, J=7.3Hz, lH)
MASS(m/z) : 336(M+), 321, 167
Elemental analysis: C22H2~N20-3/2(CqH~0~)
Calculated value: C 65.87, H 6.71, N 5.49
Actual value: C 65.60, H 6.84, N 5.57
E~ample 15
N~ ethylpiperidine-4-yl)-2,2-diphenylacetamide fumarate
was obtained by reacting N-(piperidine-4-yl)-2,2-diphenylaceta-
mide hydrochloride as a raw material, in a similar manner to that
o Examle 12.
mp: 179-181 ~ (washed with acetone)
IR(Nujol) : 3250, 1690, 1760, 790, 760, 740cm~'
NMR(DMS0-d6, ~) : 1 05(t, J=7.2Hz, 3H), 1.30-1.60(m, 2H),
1.70-1.85(m, 2H), 2.25-2.40(m, 2H),
2.55(q, J=7.2Hz, 2H), 2.90-3.10(m, 2H),
3.40-3.55(m, lH), 4.91(s, lH), 6.55(s, 2H),
7.20-7.30(m, lOH), 8.34(d, J=7.4Hz, lH)
MASS(m/z) : 322(M+), 307, 167, 111
Elemental analysis: C2,H26N20 C~H~0~ 1/2HzO
Calculated value: C 67.10, H 6.98, N 6.26
Actual value: C 66.78, H 6.97, N 6.05
215~32~
, ,.
Examplc 16
A mi~ture of benzylic acid (2.21 g) and 1,1'-carbonyl-
diimidazole (1.73 g) in dry dichloromethane (45 ml) was stirred
ror 2.5 hours at room temperature. Then 4-aminomethyl-1-(4-
methoxybenzyl)-1,2,3,6-tetrahydropyridine (2.25 g) in dry dichlo-
romethane (20 ml) was added dropwise over 20 minutes. The mi~ture
was stirred for 45 minutes at room temperature and evaporated.
Ethyl acetate and lN sodium hydro~ide were added to the residue.
The organic layer was separated, washed twice with water, dried
over magnesium sulfate, and evaporated. The residue was purified
by column chromatography on silica gel with a mi~ture of dichlo-
romethane and methanol (10:1) as an eluent to give N-[[1-(4-
metho~ybenzyl)-1,2,3,6-tetrahydropyridine-4-yl]methyl]-
2,2-diphenyl-2-hydro~yacetamide (3.47 g) as a pale yellow oil.
IR(CHCl~) : 3370, 1660, 1610, 750, 730, 700cm~'
NMR(CDCl~, ~) : 2.02(br s, 2H), 2.52(t, J=5.8Hz, 2H),
2.91(br s, 21{), 3.50(s, 2H), 3.80(s, 3H),
4.10(br s, lH), 4.14(s, 2H), 5.39(br s, lH),
6.39(br s, lH), 6.85(d, J=12.7Hz, 2H),
7.20-7.50(m, 12H)
MASS(m/z) : 442(M+), 202, 121
E~ample 17
N-[(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-
2,2-diphenyl-2-hydro~yacetamide o~alate was obtained by reacting
benzylic acid and 1-methyl-4-aminomethYl-1,2,3,6-tetrahydropyri-
33
21~2~
dine as raw materials, in a similar manner to that of E~ample 16.
mp: 185-190 ~
IR(Nujol) : 1650, 1600, 770, 750, 730, 700cm~'
NMR(DMSO~da, ~) : 2.09(br s, 2}1), 2.50(s, 3}1),
2.81(t, J=5.9Hz, 21{), 3.19(br s, 2H),
3.68(d, J=6.OHz, 2H), 4.98(br, 2H), 5.37(s, lH),
7.20-7.45(m, llH), 8.26(t, J=6.OHz, lH)
MASS(m/z) : 336(M+), 215, 183, 109
E~ample 18
2-Hydro~y-2,2-diphenyl-N-l(1-propyl-1,2,3,6-tetrahydrop-
yridine-4-yl)methyl]acetamide hydrochloride was obtained by
reacting benzylic acid and 1-propyl-4-aminomethyl-1,2,3,6-tet-
rahydropyridine as raw materials, in a similar manner to that of
Example 16.
mp: 96-98 ~ (recrystallization from a mixture of
ethyl acetate-methanol-diisoPropyl ether)
IR(Nujol) : 3250, 1660, 770, 740, 700cm~'
NMR(DMSO-d6, ~) : 0.89(t, J=7.3Hz, 3H), 1.60-1.80(m, 2H),
2.00-2.55(m, 2H), 2.90-4.20(m, 8H), 5.89(br s, lH),
6.82(s, lH), 7.20-7.45(m, lOH), 8.37(t, J=6.lHz, lH),
10.50(br s, lH)
MASS(m/z) : 364(M~), 335, 183, 137
Elemental analysis: C28H28N202 HCl
Calculated value: C 66.80, H 7.41, N 6.77, Cl 8.57
34
21~2~
.
Actual value: C 66.77, H 7.76, N 6.44, Cl 8.57
I~ample l9 - ~~
N-[(l-benzyl-1,2,3,6-tetrahYdropyridine-4-yl)methyl]-2-
hydroxy-2,2,-diphenylacetamide hydrochloride was obtained by
reacting benzylic acid and l-benzyl-4-aminomethyl-l,2,3,6-tet-
rahydropyridine as raw materials, in a similar manner to that of
Example 16.
mp:139-141 C (recrystallization from a mixture of
methanol-ethyl acetate-diisopropyl ether)
IR(Nujol) :3450, 3200, 2570, 1660, 750, 710, 680cm~'
NMR(DMSO-d6,~) :2.00-2.50(m, 2H), 2.70-3.50(m, 2H),
3.50(br s, 2H), 3.72(d, J=6.OHz, 2H), 4.30(s, 2H),
5.38(s, lH), 6.81(s, lH), 7.25-7.63(m, 15H),
8.36(t, J=6.OHz, lH), 10.92(br s, lH)
Elemental analysis: C27Hz8N202 HCl
Calculated value: (as 0.8 H20 )
C 69.98, ~ 6.66, N 6.05, Cl 7.65
Actual value: C 69.94, H 6.67, N 5.94, C1 7.63
E~ample 20
N-[(1-ethyl-l,2,3,6,-tetrahydropyridine-3-yl)methyl]-2,2-
diphenyl-2-hydro~yacetamide l/2 ~umarate was obtained by reacting
benzylic acid and l-ethyl-3-aminomethYl-l,2,3,6-tetrahydropyri-
dine as raw materials, in a similar manner to that of Example 16.
mp:185-186 ~ (recrystallization from isopropyl alcohol)
2~5~3~a
.
IR(Nujol) : 3400, 2750-2600, 1675, 1590cm~'
NMR(DMSO-d6, ~) : 1.02(3H, t, J=7Hz, CH~),
2.09(2H, m, =CHCHzCHz), 2.45-2.65(4H, m, NCHz x 2),
2.92(2H, s, =CCHzN), 3.68(2H, m, CONCHz),
5.52(1H, br s, =CH), 6.51(2H, s, fumaric acid=CH),
7.25-7.4(10H, m, aromatic H), 8.21(lH, br s, CONH)
MASS(m/z) : 350(M~), 183, 124(base), 105
Elemental analysis: C2 zH26N202 1/2C~H~O~
Calculated value: C 70.57, H 6.91, N 6.86
Actual value: C 70.36, H 7.11, N 6.72
Example 21
To a mi~ture of 4,4'-difluorobenzophenone (2.0 g) and
zinc iodide (0.1 g) in dry dichloromethane (15 ml) was added
trimethylsilyl cyanide (1.35 ml) at room temperature. The result-
ing mi~ture was stirred for 40 hours at the same temperature, and
then the solvent was evaporated in vacuo. Concentrated hydro-
chloric acid (30 ml) was added to the residue and the mi~ture was
stirred at 90C for 14 hours. The mi~ture was partitioned between
ethylacetate and water. The organic layer was separated and
evaporated in vacuo. The residue was partitioned between diiso-
propylether and lN aqueous sodium hydro~ide. The organic layer
was washed with lN aqueous sodium hydro~ide three times. The
combined aqueous layers were acidified with concentrated
hydrochloric acld and extracted with ethyl acetate twice.
36
215532~
The combined organic layers were washed with ~ater and
brine, dried over magnesium sulfate and evaporated in vacuo to
give crude 4,4'-dirluorobenzilic acid (0.80 g). To a solution of
this crude 4,4'-difluorobenzilic acid (0.80 g) and N,N'-carbonyl-
diimidazole (0.60 g) in dry dichloromethane was added dropwise a
solution of 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine
(0.60 g) in dichloromethane at room temperature.
The resulting mi~ture was stirred at room temperature,
cvaporated in vacuo. The residue was partitioned between ethylac-
etate and lN aqueous sodium hydro~ide. The combined organic
layers were washed with water and brine, dried over magnesium
sulrate, and evaporated in vacuo. The residue was purified by
column chromatography on silica gel and then on alumina and
treated with 4N hydrogenchloride in ethylacetate to give 2,2-
bis(4-~luorophenyl)-2-hydro~y-N-[(1-ethyl-1,2,3,6-tetrahydropyri-
dine-4-yl)methyl]acetamide hydrochloride.
mp: 155-157 ~ (washed with diisopropyl ether)
IR(Nujol) : 3350, 3270, 2500, 1660, 1600, 820, 770cm~'
NMR(DMS0-d~, ~) : 1.24(t, J=7.2Hz, 3H), 2.00-2.45(m, 2H),
2.85-3.80(m, 6H), 3.09(quartet, J=7.2Hz, 2H),
5.39(s, lH), 6.96(s, lH), 7.10-7.20(m, 4H),
7.35-7.45(m, 4H), 8.46(br s, lH), 10.21(br s, lH)
MASS(m/z) : 386(M~), 371, 219, 123, 110
Elemental analysis: C2 zH2~NzOzF2 HCl 1/3HzO
Calculated value: C 61.61, H 6.03, N 6.53, Cl 8.27
Actual value: C 61.69, H 6.09, N 6.54, Cl 8.27
2~ ~32~
.
I~'xample 22
A solution of 3-amino-1-azabicyclo[2,2,2]octane in ben-
%ene (12 ml) was added dropwise to a stirred solution of
2-chloro-2,2-diphenylacetyl-chloride (6.30 g) in benzene
(17 ml)-n-he~ane (11 ml) at room temperature. The resulting
mixture was stirred for 3 hours and 30 minutes at room tempera-
ture and partitioned between toluene and water. The organic layer
was e~tracted twice with lN hydrochloric acid and the aqueous
layers were combined, washed with diethyl ether, stirred at 70c
for 1 hour, cooled with ice water, basified with 5 % sodium
hydroxide aqueous solution, and e~tracted twice with ethyl ace-
tate. The ethyl acetate layers were combined, washed with brine,
dried over sodium sulfate, and evaporated in vacuo. The residue
was washed with diisopropyl ether to afford a colorless powder
(2.90 g), which was converted to the hydrochloride in a usual
manner. The hydrochloride was recrystallized from ethanol to
afford N-(1-azabicyclo[2,2,2,]octan-3-yl)-2,2-diphenyl-2-hydro~-
yacetamide hydrochloride as a colorless powder.
mp:261-265 ~ (dec.)
IR(Nujol) :3300, 2800-2300, 1660cm~'
Il
NMR(DMSO-d6,~) :1.6-2.1(5H, m, ~ H ),
3.05-3.6(6H, m, N(CH2)~), 4.15(lH, m, CONHCE),
6.87(1H, S, OH), 7.25-7.45(10H, m, aromatic H),
38
2I ~532~
.
8.59(1H, d, J=7Hz, CONH), 10.36(1H, br s, HCl)
MASS(m/z) :336(M+), 183(base), 105
Elemental analysis: C2,Hz4N20z HCl
Calculated value: C 67.64, H 6.76, N 7.51
Actual value: C 67.67, H 7.10, N 7.31
Example 23
N~ etho~yearbonylpiperidine-4-yl)-2-hydroxy-2~2-diphe-
nyl acetamide was obtained by reaeting 4-amino-l-etho~yearbonyl-
piperidine and benzylic acid as raw materials, in
a similar manner to that of Example 16.
mp:128-131 ~ (washed with n-hexane)
IR(Nujol) :3300, 1650, 1620, 760, 740, 720cm~'
NMR(CDC1~,~) :1.00-1.41(m, 2H), 1.23(t, J=7.lHz, 3H),
1.70-2.00(m, 2H), 2.75-3.00(m, 2H), 3.90-4.20(m, 3H),
4.08(q, J=7.lHz, 2H), 6.67(d, J=8.OHz, lH),
6.93(s, lH), 7.20-7.50(m, lOH)
MASS(m/z) :382(M~), 370, 216, 183
Example 24 - ~
2,2-Diphenyl.2-hydroxy-N-[2-(l-methylpiperidine-4-yl)-
ethyl]acetamide fumarate was obtained by reacting 4-(2-aminoeth-
yl)-l-methylpiperidine and benzylic aeid as raw materials, in a
similar manner to that of E~ample 16. The residue was chromato-
graphed over siliea gel using ehloroform - methanol as an eluent
to afrord white powder.
39
~l~S320
.
mp: 151-152 ~
IR(Nujol) : 3360, 3250, 3200, 2740-2100, 1700, 1670cm~'
NMR(DMSO-d6, ~) : 1.15-1.45(5H, m, CH and CHz x 2),
1.7(2H, m, CH2), 2.35(2H, m, CH2), 2.45(3H, s, CH9),
3.0-3.2(4H, m, CH2x 2), 6.50(2H, s, HC=CH),
7.2-7.4(llH, m, aromatic H and OH),
8.15(1H, t, J=6Hz, NH)
MASS(m/z) : 352(M~), 337, 183(base)
Elemental analysis: C22H2#N20z C~H40~
Calculated value: C 66.65, H 6.88, N 5.98
Actual value: C 67.02, H 7.05, N 5.94
Example 25
N-[(1-ethylpiperidine-3-yl)methyl]-2,2-diphenyl-2-
hydroxyacetamide hydrochloride as a colorless crystallization was
obtained by reacting 3-aminomcthyl-1-ethylpiperidine and benzylic
acid as raw materials, in a similar manner to that of E~ample 16.
free base:
IR(Nujol) : 3310, 2800-2300, 1660cm~'
NMR(CDC13, ~) : 0.95(1H, m, piperidine H),
1.00(3H, t, J=7Hz, CH9), 1.5-1.95(6H, m, piperidine H)
2.30(2H, quartet, J=7Hz, NCHzCH3),
2.7(2H, m, piperidine H), 3.1-3.35(2H, m, CONCH2),
4.15(1H, br, OH), 6.86(1H, br t, NH),
7.25-7.53(1OH, m, aromatic H)
21~32~
MASS(m/z) : 352(M+), 337, 183, 105(base)
hydrochloride:
mp: 181-182 ~ (recrystallization from isopropyl alcohol)
IR(Nujol) : 3360, 3220, 2660, 2570, 1655cm~'
NMR(DMSO-d6, ~) : 1.05(lH, m, piperidine H),
1.16(3H, t, J=7Hz, CH3), 1.75(3H, m, piperidine H),
2.1(lH, m, piperidine H), 2.45(1H, m, piperidine H),
2.7(lH, m, piperidine H),
2.95-3.35(6H, m, NCH2CH3, piperidine H, and CONCH2),
6.79(lH, s, OH), 7.2-7.45(lOH, m, aromatic H),
8.40(1H, t, J=6Hz, NH), 10.2(1H, br, HCl)
MASS(m/z) : 352(MI), 337, 183, 105(base)
~lemental analysis: C22H2~N202 HCl
Calculated value: C 67.94, H 7.52, N 7.20
Actual value: C 67.76, H 7.68, N 7.15
Example 26 ..
2-llydroxy-N-[2-(1-methylpyrolidine-2-yl)ethyl]-2,2-
diphenylacetamide hydrochloride was obtained by reacting 2-(2-
aminoethyl)-1-methylpyrrolidine and benzylic acid as raw materi-
als, in a similar manner to that o~ Examplc 16
mp: 155-157 ~ (recrystallization from a mixture of
ethanol and ethyl acetate)
IR(Nujol) : 3400, 3180, 2620, 1660, 770cm~'
41
21~32~
.
NMR(DMS0-d~ 1.40-1.95(m, 4H), 1.95-2.25(m, 2H),
2.64(s, 3H), 2.75-3.10(m, 2H), 3.10-3.25(m, 2H),
3.35-3.55(m, lH), 6.76(s, lH), 7.20-7.50(m, lOH),
8.38(br s, lH), 10.36(br s, lH)
MASS(m/z) : 338(MI), 323, 183, 155, 84
Elemental analysis: C2,H30NzOz HCl
Calculated value: C 67.28, H 7.26, N 7.47, Cl 9.46
Actual value: C 67.29, H 7.53, N 7.46, Cl 9.44
Example Z7
N-(1-etho~ycarbonylpiperidine-4-yl)-2,2-diphenylacetamide
was obtained by reacting 4-amino-1-etho~ycarbonylpiperidine and
benzylic acid as raw materials, in a similar manner to that of
Example 16.
mp: 163-165 C (washed with n-hexane)
IR(Nujol) : 3300, 1650, 770, 750, 730, 700cm~'
NMR(CDcl~, ~) : 1.10-1.35(m, 5H), 1.80-2.00(m, 2H),
2.80-2.95(m, 2H), 3.90-4.15(m, 5H), 4.90(s, lH),
5.52(d, J=7.5Hz, lH), 7.20-7.40(m, lOH)
MASS(m/z) : 366(M~), 199
Example 28
N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-3,3-
di.phenylpropionamide oxalate was obtained by reacting 4-amino-
mcthyl-1-ethyl-1,2,3,6-tetrahydropyridine and diphenylpropion
acid as raw materials, in a similar manner to that of E~ample 16.
42
3 2 ~
p: 133-134 C (recrystallization from a mixture of
isopropyl alcohol and diisopropyl ether)
IR(Nujol) : 3330, 2600, 1720, 1640, 1600, 750, 710cm~'
NMR(DMS0-d~, ~) : 1.18(t, J=7.2Hz, 3H), 1.95(br s, 2H),
2.89(d, J=8.2Hz, 2H), 3.01(q, J=7.2Hz, 2H),
2.95-3.10(m, 2H), 3.39(br s, 2H), 3.54(br s, 2H),
4.47(t, J=8.2Hz, lH), 4.88(s, lH), 7.10-7.30(m, lOH),
8.13(br s, lH)
MASS(m/z) : 348(M+), 333, 167, lZ3
Elemental analysis: C2~H2~N20~C2H20~
Calculated value: C 68.47, H 6.90, N 6.39
Actual value: C 68.46, H 6.97, N 6.31
~xample 29 =- -
N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl~-3,3-
diphenyl acrylamide oxalate was obtained by reacting 4-aminometh-
yl-1-ethyl-1,2,3,6-tetrahydropyridine and 3,3-diphenylpropene
acid as raw materials, in a similar to that of E~ample 16.
mp: 163-164 ~ (recrystallization from a mixture of
isopropyl alcohol, ethyl acetate and methanol)
IR(Nujol) : 3330, 2720, 1720, 1640, 770, 700cm~'
NMR(DMS0-d6, ~) : 1.20(t, J=7.3Hz, 3H), 2.11(br s, 2H~,
3.08(q, J=7.3Hz, 2H), 3.00-3.20(m, 2H), 3.51(br s, 2H)
3.55-3.70(m, 2H), 4.40(br s, 2H), 5.22(s, lH),
6.50(s, lH), 7.10-7.40(m, lOH), 8.15-8.20(m, lH)
43
2155~2~
MASS(m/z) : 346(M+), 207, 123
Elemental analysis: C2aH26N20-C2H204
Calculated value: C 68.79 , H 6.47, N 6.42
Actual value: C 69.21 , H 6.53, N 6.40
l~xample 30
N-[(l-ethyl-1,2,3,6-te~rahydropyridine-4-yl)methyl]-
10,11-dihydro-5-hydroxy-5H-dibenzo[a,d]cycloheptene-5-carbo~amide
hydrochloride was obtained by reacting 4-aminomethyl-1-ethyl-
1,2,3,6-tetrahydropyridine and 5-hydro~y-511-10,11-
dihydrobenzo[a,d,]cycloheptene-5-carboxylic acid as raw materi-
als, in a similar manner to that of Example 16.
free base: colorless crystals
IR(Nujol) : 3460, 3390, Z740, 1640cm~l
NMR(DMSO-d6, ~) : 0.98(3H, t, J=7Hz, CH3),
1.86(2H, br s, CH2CHzN),
2.25-2.45(4H, m, CH2CH2NCH2CIls)~
2.75-2.9(4H, m, =CHCH2N and cycloheptene CH2),
3.3-3.45(2H, m, cycloheptene CH2),
3.54(2H, d, J=6Hz, CONCH2), 5.29(lH, s, =CH),
6.81(lH, s, OH), 7.05-7.25(6H, m, aromatic H),
7.46(1H, t, J=6Hz, NH), 7.75-7.85(2H, m, aromatic H)
MASS(m/z) :.376(M~), 209, 123(base), 1 io
hydrochloride: colorless crystals
mp: 158-159.5 ~ (ethyl acetate crystals)
44
_
3 2 ~
IR(Nujol) : 3420, 3330, 2730-2000, 1655cm~'
NMR(DMSO-d6, ~ ) : 1. 23(3H, t, J=7Hz, CH~),
1.95-2. 45(2H, m, CH2CH2N),
2.75-3. 15(5H, m, NCH2CH3, cycloheptene CH2, and
pyridine H), 3. 3-3. 45 (4H, m, pyridine Hx 2 and
cycloheptene CH2),
3. 35-3. 65(3H, m, CONCH2 and pyridine Hx 2),
5. 30(lH, br s, =CH), 6.89(lH, s, OH),
7. 05-7. 25(6H, m, aromatic H),
7. 75-7. 85(3H, m, NH and aromatic Hx 2),
10. 5(lH, br, HCl)
MASS(m/z) : 376(M+), 209 (base), 123, 110
Elemental analysis: C2~H29N202C1-3/2H20
Calculated value: C 65. 52, H 7. 27, N 6. 37, Cl 8. 06
Actual value: C 65. 68, H 7.27, N 6. 38, Cl 8. 06
E~ample 31
A solution of 2,2-diphenyl propionic acid (0.70 g)
i.n thionyl chloride (2.3 ml) was refluxed for 2 hours and evapo-
rated in vacuo. Toluene (10 ml) was added to the residue and
evaporated in vacuo. To a solution of the residue in dry dichlo-
romethane (10 ml) was added drop~ise a mixture of
4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (0.43 g) and
triethylamine (1.5 ml) in dry dichloromehthane (10 ml) at room
temperature. The resulting mixture was stirred for 3 hours at
room temperature. Dichloromethane and water were added to the
21s~32a
.
reaction mixture, and then the organic layer was separated,
washed successively with water three times. lN aqueous sodium
hydroxide solution, and brine, dried over magnesium sulfate, and
evaporated in vacuo. The residue was purified by column chloma-
tography on silica gcl with a mixture of dichloromethane and
methanol (20:1) as an eluent, treated with 4N hydrogen chloride
ln ethyl acetate, recrystallized from isopropyl alcohol and
isopropyl ether to give N-[(1-ethyl-1,2,3,6-tetrahydropyridine-
4-yl)m~hyl]-2,2-diphenyl propionamide hydrochloride.
mp: 93-94 C
IR(Nujol) : 3450, 3350, 2670, 2600, 1630, 760, 740cm~'
NMR(DMS0-~6, ~) : 1.24(t,J=7.2Hz, 3H), 1.89(s, 3H),
2.0~-3.70(m, 8H), 3.06(q, J=7.2Hz, 2H), 5.31(br s, lH)
7.10-7.40(m, lOH), 7.64(br s, lH), 10.08(br s, lH)
Elemental analysis: C2~H2~N20 HCl
Calculated value: C 68.56, H 7.75, N 6.95, Cl 8.80
Actual value: C 68.82, H 7.95, N 6.89, Cl 8.95
E~ample 32
N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl~-
2,2,-dipl~cnyl acetamidc hydrochloride was obtained by reacting
4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine and 2,2-diphenyl
acetyl chloride as raw materials, in a similar manner to that of
Example 31.
mp: 205-207 ~ (recrystallization from a mixture of
ethanol and diisopropyl ether)
46
215~32~
.
IR(Nujol) : 3270, 3070, 2670, 2550, 2470, 1640, 750, 700cm~'
NMR(DMS0-dG, ~) : 1.23(t, J=7.2Hz, 3H), 2.00-2.40(m, 2H),
2.80-3.00(m, 4H), 3.04(q, J=7.2Hz, 2H),
3.60-3.80(m, 2H), 5.06(s, lH), 5.39(s, lH),
7.10-7.35(m, lOH), 8.67(t, J=5.7Hz, lH),
10.43(br s, 111)
MASS(m/z) : 334(MI), 167, 123
Elemental analysis: C22H26N20 HCl
Calculated value: C 71.24, H 7.34, N 7.55, Cl 9.56
Actual value: C 71.30, H 7.62, N 7.52, Cl 9.73
Example 33
A mi~ture of 2-chloro-2,2-diphenyl acetyl chloride
(0.80 g) and 4-diethylaminomethylpiperidine (0.51 g) were stirred
for a while at room temperature and diluted with methylene chlo-
ridc (10 ml). The resulting mixture was stirred for 1 hour at the
same temperature, and partitioned between ethyl acetate and
water. The ethyl acetate layer was washed with sodium hydroxide
aqueous solution and water, dried over magnesium sulfate, and
~vaporated in vacuo. The residue was dissolved in dio~ane
(7.4 ml) and lN hydrochloric acid (3.7 ml). The solution was
fitirred at 90C for 1 hour and 30 minutes, evaporated in vacuo,
and e~tracted with ethyl acetate. The e~tract was washed with
sodium hydro~ide aqueous solution and water, dried over magnesium
sulfate, evaporated in vacuo, and chromatographed over silica gel
47
21~532~
u~ing chlorororm an~ methanol as an eluent to arford 1-(2,2-
(liphenyl-2-hydro~yacetyl)-4-diethylaminomethylpiperidine (0.33 g)
as an oil, which was con~erted to the hydrochloride (0.20 g) in a
usual manner.
free base:
NMR(CDC13, ~) : 0.93(6H, t, J=7Hz, CH~x 2),
0,95-1.95(5H, m, piperidine CH2CHCH2),
2.06(2H, d, J=6.5Hz, CHCH2N),
2.43(4H, quartet, J=7Hz, N(CH2CH3)z),
2.68(2H, m, CONCH x 2), 3.59(lH, m, CONCH),
4.74(lH, m, CONCH), 6.22(lH, s, OH),
7.4(10H, m, aromatic H)
MASS(m/z) : 380(M~), 183, 86(base)
hydrochloride:
mp: 175-176 C (recrYstallization from isopropyl alcohol)
IR(Nujol) : 3400, 3160, 2760-2300, 1610cm~'
NMR(DMSO-d6, ~) : 0.7(1H, m, piperidine CH),
1.05(1H, m, piperidine CH), 1.18(6H, t, J=7Hz, CH~x 2)
1.45(1H, m, piperidine CH), 1.9(2H, m, piperidine CH),
2.65(2H, m, CONCH x 2), 2.8(2H, m, CHCH2N),
3.05(4H, m, N(CH2CH3)2), 4.15(1H, m, CONCH),
4.4(lH, m, CONCH), 6.92(lH, s, OH),
7.3(lOH, m, aromatic H), 9.9(lH, br, HCl)
MASS(m/z) : 380(M~), 183, 86(base)
48
21~32~
Elemental analysis: C2~ 2N202 HCl l/2H20
Calculated value: C 67.67, H 8.04, N 6.58, Cl 8.32
Actual value: C 67.62, H 8.08, N 6.51, Cl 8.32
~ample 34
A solution of 4-bromo-2,2-diphenylbutanoic acid and
thionyl chloride (1.37 g) in dry chloroform (20 ml) was refluxed
for 4 hours and evaporated in vacuo to afford the corresponding
acid chloride.
To a mixture of 4-aminomethyl-1-ethyl-1,2,3,6-
tetrahydro-pyridine (0.73 g) and triethylamine (2.6 ml) in di-
chloromethane (15 ml) was added the obtained crude acid chloride
in dichloromethane (15 ml) at room temperature and the resulting
mixture was stirred overnight. The solvent was evaporated in
vacuo, and ethyl acetate and lN aqueous sodium hydro~ide were
added to the residue. The organic layer was separated, washed
with water (three times) and brine, dried over magnesium sulfate,
and evaporated in vacuo. The residue was purified by column
chlomatography on silica gel with a mi~ture Or dichloromethane
and methanol (15:1) as an eluent, further on alumina with a
mi~ture of n-he~ane and ethylacetate (20:1) as an eluent. The
obtained free base was treated with fumaric acid (229 mg) in a
usual manner to give 1-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-
yl)methyl]-3,3-diphenyl-2-pyrrolidinone fumarate (0.54 g).
49
2153 ~2 ~
.
mp: 90C ~ (resolution) (washed with n-hexane)
IR(Nujol) : 2500, 1680, 800, 770, 750, 700cm~'
NMR(DMSOd6, ~) : l.ll(t, J=7.2Hz, 3H), 2.17(br s, 2H),
2.73(q, J=7.2Hz, 2H), 2.80-2.90(m, 4H), 3.24(br s, 2H)
3.86(s, 2H), 4.11(t, J=6.4Hz, 2H), 5.53(s, lH),
6.52(s, 2H), 7.10-7.40(m, lOH)
MASS(m/z) : 360(Ml), 238, 165, 123
