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Pyrrolidines. IV. The Investigation of the Synthesis of 1-Methyl-2-pyrrolidineethanol - J. Org. Chem., 1961, 26 (5), pp 1531–1533 - DOI 10.1021/jo01064a054

Pyrrolidines. IV. The Investigation of the Synthesis of 1-Methyl-2-pyrrolidineethanol - J. Org. Chem., 1961, 26 (5), pp 1531–1533 - DOI 10.1021/jo01064a054

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Pyrrolidines. IV. The Investigation of the Synthesis of 1-Methyl-2-pyrrolidineethanol
Authors: YAO-HUA WU, JOHN R. CORRIGAN, R. F. FELDKAMP
J. Org. Chem., 1961, 26 (5), pp 1531–1533
Publication Date: May 1961 (Article)
DOI: 10.1021/jo01064a054
prodilidine 4-phenylpiperidines, phenylmorphans, arylmorphans, azaprocin, azabicyclo, azabicycloalkane, opioid, opiate, opioids, opiates, narcotic, analgesics, analgetics, central analgesics, opioid analgetics, semi-synthetic opiates, oxycodone, morphine, papaver somniferum, opium poppy, opium, drug, pharmacology, pharmacokinetics, pharmacodynamics, tramadol, tilidine, profadol, Spa, lefetamine, lephetamine, Santenol, 1,2-Diphenyl-1-dimethylaminoethane, (1R)-N,N-dimethyl-1,2-diphenylethanamine, levo-1,2-Diphenyl-1-dimethylaminoethane, Chemical Abstracts Registry CAS # 7262-75-1, PubChem CID 443970, ChemSpider 392017, C16H19N, salvinorin A B Salvia divinorum Neoclerodane Diterpenes, structure-activity relationship, SAR, medicinal chemistry, organic chemistry, chemistry, heroin, benzomorphans, morphinans, 4,5-epoxymorphinans, arylmorphans, phenylmorphans, methadone, diphenylpropylamines, mu opioid receptor, MOR, KOR, DOR, kappa opioid receptor, delta opioid receptor, buprenorphine, subutex, suboxone, drug synthesis, drug chemistry, drug manufacture, pethidine, demerol. Meperidine, prodine, promedol, piperidine, nitrogen chemistry, amine chemistry, 4-anilidopiperidines, 4-anilidopiperidines, piperazine, azaprocin, azabicycloalkanes, fentanyl, sufentanil, carfentanil, remifentanil, alfentanil, benzimidazoles, etonitazene, clonitazene, azabicylco, arylcyclohexylamines, arylcyclohexanes, daniel lednicer, central analgetics, opioid agonists, partial agonist-antagonists, dualists, partial agonists, mixed agonists, opioid addiction, heroin addiction, opioid dependence, opiate addiction, codeine, thebaine, etorphine, diprenorphine, dipipanone, phenadoxone, amidone, isomethadone, LAAM, methadyl acetate, herkinorin, alvimopan, P. somniferum, ohmefentanyl, TMF, 3MF, 3-methylfentanyl, mefentanyl, thiofentanil, tropane, chemical analogues, chemical analogs, chemical derivatives, fentanyl analogues, fentanyl analogs, dopamine, MPTP, MPPP, desmethylprodine, phenylethylamines, phenethylamines, amphetamines, methamphetamine, dextroamphetamine, stereochemistry, optical isomers, isomerism, enantiomers, enatiomeric, stereoisomerism, stereoisomers
Pyrrolidines. IV. The Investigation of the Synthesis of 1-Methyl-2-pyrrolidineethanol
Authors: YAO-HUA WU, JOHN R. CORRIGAN, R. F. FELDKAMP
J. Org. Chem., 1961, 26 (5), pp 1531–1533
Publication Date: May 1961 (Article)
DOI: 10.1021/jo01064a054
prodilidine 4-phenylpiperidines, phenylmorphans, arylmorphans, azaprocin, azabicyclo, azabicycloalkane, opioid, opiate, opioids, opiates, narcotic, analgesics, analgetics, central analgesics, opioid analgetics, semi-synthetic opiates, oxycodone, morphine, papaver somniferum, opium poppy, opium, drug, pharmacology, pharmacokinetics, pharmacodynamics, tramadol, tilidine, profadol, Spa, lefetamine, lephetamine, Santenol, 1,2-Diphenyl-1-dimethylaminoethane, (1R)-N,N-dimethyl-1,2-diphenylethanamine, levo-1,2-Diphenyl-1-dimethylaminoethane, Chemical Abstracts Registry CAS # 7262-75-1, PubChem CID 443970, ChemSpider 392017, C16H19N, salvinorin A B Salvia divinorum Neoclerodane Diterpenes, structure-activity relationship, SAR, medicinal chemistry, organic chemistry, chemistry, heroin, benzomorphans, morphinans, 4,5-epoxymorphinans, arylmorphans, phenylmorphans, methadone, diphenylpropylamines, mu opioid receptor, MOR, KOR, DOR, kappa opioid receptor, delta opioid receptor, buprenorphine, subutex, suboxone, drug synthesis, drug chemistry, drug manufacture, pethidine, demerol. Meperidine, prodine, promedol, piperidine, nitrogen chemistry, amine chemistry, 4-anilidopiperidines, 4-anilidopiperidines, piperazine, azaprocin, azabicycloalkanes, fentanyl, sufentanil, carfentanil, remifentanil, alfentanil, benzimidazoles, etonitazene, clonitazene, azabicylco, arylcyclohexylamines, arylcyclohexanes, daniel lednicer, central analgetics, opioid agonists, partial agonist-antagonists, dualists, partial agonists, mixed agonists, opioid addiction, heroin addiction, opioid dependence, opiate addiction, codeine, thebaine, etorphine, diprenorphine, dipipanone, phenadoxone, amidone, isomethadone, LAAM, methadyl acetate, herkinorin, alvimopan, P. somniferum, ohmefentanyl, TMF, 3MF, 3-methylfentanyl, mefentanyl, thiofentanil, tropane, chemical analogues, chemical analogs, chemical derivatives, fentanyl analogues, fentanyl analogs, dopamine, MPTP, MPPP, desmethylprodine, phenylethylamines, phenethylamines, amphetamines, methamphetamine, dextroamphetamine, stereochemistry, optical isomers, isomerism, enantiomers, enatiomeric, stereoisomerism, stereoisomers

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PYRROLIDINES.
IV
1531
MAY
1961
[CONTRIBUTION FROM THE
DEPARTMENT
OF SYNTHETIC OHGANIC CHEMISTRY, RESEARCH
DIVISION,
MEAD
JO~INSON
AND
CO.]
Pyrrolidines.
IV.
The
Investigation
of
the
Synthesis
of
1-Methyl-2-pyrrolidineethanol
Y.40-HUA WU, JOHN R. CORRIGAN,
AND
It.
F.
FELDKAMP
Received
June
13,
1960
I-Methyl-2-pyrrolidineethanol
was synthesized by four methods. Lithium aluminum hydride reduction
of
ethyl ccgoninate(obtained by the action
of
methylamine on diethyl p-hydromuconate) was the preferred procedure. The amino alcohol wastransformed into its benzilate ester for antispasmodic screening. The corrcsponding chloride reacted with phenothiazine togive 10-[2-(
l-methyl-2-pyrrolidinyl)ethyl]phenothiazinc
for antihistaminic testing.
In the course of some work in these laboratories,it became desirable to prepare 1-methyl-2-pyrroli
-
dineethanol
(I)
and certain derivatives for phar-macological comparison with similar derivativesof
1-methyl-3-pyrrolidinemethanol.
PCHZCHzOH
I
CH3
I
A
search of the literature revealed only onereportzP3 on the synthesis
of
this amino alcohol.The published procedure involved the reactionof N-pyrrylmagnesium bromide with ethylene oxideto form 2-pyrroleethanol (11) which was catalyti-cally reduced to 2-pyrrolidineethanol
(111)
andsubsequently N-methylated. The preparative route(Method
1)
was
repeated. &cause the reportedmethod gave poor yields and was impractical
for
large scale preparation, other synthetic approacheswere studied.
MgBr
H
I1
H
I11
One of the first methods considered
was
the N-methylation of 2-pyrrolidineethanol
(111)
preparedaccording to the general scheme of Baker
et
aL4
This synthetic route (Method
2)
comprised thereaction of methyl ethyl @-ketoadipate with
(1)
Y.
H.
Wu
and R. F. Feldltamp,
J.
Org.
Chem.,
to
be
published.(1915).
(2)
K.
Hess,
F.
hlerck, and C. Uibrig,
Ber.,
48,
1886(3) Since the completion of our work another report hasappeared
[F.
P.
Doyle,
M.
D.
Mehta,
G.
S.
Sach, and
J.
L. Pearson,
J.
Chem.
SOC.,
4458 (1958)] on the preparationof 2-(
1-methyl-2-pyrrolidy1)ethanol
by the reduction
of
ethyl
a-(
1-methyl-2-pyrryl) acetate.(4) B. R. Baker, R.
E.
Schaub, and
J.
H.
Williitms,
J.
Org.
Chem.,
17,
116 (1952).
beiizylamine to produce ethyl l-benzyl-5-oxo-2-pyrroline-2-acetate (IV) which was reduced withlithium aluminum hydride to 1-benzyl-2-pyrroli-dineethanol (V)
.
Hydrogenolysis over palladiumgave 2-pyrrolidineethanol
(111).
N-Methylat,ionby the method
of
Clarke
et
produced the de-sired
l-methyl-2-pyrrolidineethanol
which wasidentical with the product prepared by Method
1.
H3COOCCH~CH2COCHzC00C2H5
~CH2COOC,H5
L% 
mCHzCH20H
v
R R
IV.
R
=
CBH~CHZ
VI.
R=CHs
I.
R=CH,
V.
R
=
C6HsCHz
A
third scheme investigated (Method
3)
similarto the above, involved the reaction between methyl-amine and methyl ethyl @-ketoadipate by Ruggliarid Maeder’s methods to produce e&yl l-methyld-
oxo-2-pyrroline-2-acetate
(VI)
,
which, with excesslithium aluminum hydride, was reduced to thepyrrolidineethanol. The latter reduction was never
100%
complete for infrared spectra’ of differentsamples showed the presence of a few per cent ofdouble bond contaminant. The slightly higherindices of refraction also reflected the presence ofan unsaturated impurity.Reduction
of
ethyl ecgoninate (VIII) withlithium aluminum hydride was the last methodstudied (Method
4).
The required ethyl ecgoninate
was
obtained by the action of methylamine ondiethyl p-hydromuconate (VII)
.
The reaction is
C2H50VCH2CH=CHCH2COOCzHs
3
0
VI1
CH3
VI11
(5)
H.
T.
Clarke, H.
€3.
Gillespie, and
S.
Z.
Weisshaus,
(6)
P.
Ruggli and A. Maeder,
Helv.
Chim. Acta,
25,
936(7) We we indebted
to
Mr.
John G. Schmidt
for
infrared
J.
Am.
Chem.
SOC.,
55,
4571 (1933).(1942).spectra.
 
1532
WU,
CORRIGAN,
AND FELDKAMP
VOL.
26
similar to the synthesis of ecgoninic acid employedby Evans,
et
aL8
A
comparison
of
the availabilities of startingmaterials, the percentage yields, the purities ofthe final products
as
indicated by their infraredspectra, and the amounts
of
work and time re-quired for these four preparative routes showed thatMethod
4
was the most favorable. Therefore, itwas chosen
for
the synthesis
of
a
larger amount of
1-methyl-2-pyrrolidineethanol.
This amino alcohol was converted to its benailateester by transesterification with methyl benailatein n-heptane according to Feldkamp.@The esterwas tested in comparison with the benzilates of1-substituted 3-pyrrolidinemethanols.
lo
Reaction
of
the amino alcohol with thionylchloride produced the chloride which was condensedwith phenothiazine to give
10-
[2-(
l-methyl-2-
pyrrolidinyl)ethyl]phenothiaaine.
Pharmacologicalcomparison between this derivative and the cor-responding 3-pyrrolidinylmethyl" compound wasalso carried out.
EXPERIMENTAL
l2
Method
1:
l-Methyl-b-pyTrolidineelhanol.
The proceduresof Iiess
el
a1
,*
were repeated. The yields and physical con-stants of the intermediates and the product are listed in thefollowing table.Yield,Compound
%
nY
B.P., mm.%Pyrroleethanol(II) 6-7 1.5321 101-103 (0.35)2-Pyrrolidineethqnol61
.9
1.4820 63-69 (0.21)1-Methyl-2-pyrroli- 41.1 1.4685114-116 (28)(111)dineethanol (I)
Anal.
Calcd. for C7HlsNO:
N,
10.84. Found: N, 10.62.
Method
&:
~-~arbomethoxypropiony~chloride.
The aridchloride was prepared according to Ruggli and Maedersin
88%
yield from the starting succinic anhydride, b.p.98-99" (27 mm.). Casonls has described a similar synthesis.
Diethyl
3-carhomethoxypropion~~lm~~onate.
The procedure
of
Baker,
et
~l.~'
was followed. The yield of the product
was
GG%,
b.p. 128-134' (0.5 mm.),
n","
1.4500.
Methyl
ethyl P-ketoadipate.
The above ma1on:ttc ester washydrolyzed and decarboxylated according to Raker,
el
ul.,'
to
give
a
52% yield of product, b.p.
86-88'
(0.2 mm
),
ny
1.4398.
A
simplified procedure
for
the preparation
of
a similar
cstrr,
dimethyl p-ketoadipate, in
38%
overall yield hasrcccntly been published.14
Ethyl
I-benryl-5-ozo-~-pyr~o~ine-%-ace~ate
(IV)
.
The con-
(8)
G.
L.
Evans,
I€.
W.
Gray, and H.
W.
Jacohson,
(9)
R.
F.
Fcldkamp,
J.
Am. Chem.
Soc.,
74,
3834 (1952).
(
10)
Y.
13.
Wu,
R.
F.
Feldkamp,
J.
R.
Corrigan, and
I*.
J.
Rhodes,
J.
078.
Chem.,
26,
1519 (1961).
(
11)
Y.
H.
M'u
and R.
F.
Feldkamp,
J.
Org.
Chem.,
26,
1529 (1961).(12) Melting points and boiling points are uncorrected.Microanalyses by Clark Microanalytical Laboratory,Urbana, Ill.(13)
J.
Cason,
Org.
Syntheses,
Coll. Vol.
111,
169 (1955).(14)
J.
Korman,
J.
org.
Chem.,
22,
848 (1957).
.I.
Am. Chem. Soc.,
72,
2727 (1950).densation of methyl ethyl P-ketixrdipate with bemylaminefollowed by cyclization
ufi
dcsc:ril)cd by Baker,,
et
ul.,'
gavethe desired produrt in
900/o
crude
yictld,
m.p.
G3-70'.
I-B~nzyl-~-pyrroZidineelha7Lol
(V)
.
Tlic
lithium aluminumhydride rcduction
of
ethyl
1-l)cnzgI-5-oxo-2-pyrrolinc-2-
acetate (IV) produrcd
:L
50% yield of the pyrrolidinecthanol,b.p. 117-123' (0.55 nim.),
n::
1.5343.
Anal.
Calcd. for ClaHluNO:C, 6.82. Found: N, 6.65.
I
-Meth~l-b-pyrrolidineethanol
(I). 1-Benzyl-2-pyrrolidinc-ethanol (V) (5.5
g.,
0.027 mole) waa debenzylated in 75 ml.
of
acetic acid over 1.5
8.
of 10% palladium-on-charcoal withliydrogcn at 3 atm. The crude 2-pyrrolidineethanol
(111)
(2.8 g., 90%) was N-methylated hy refluxing with
2.8
g.
(0.06
mole) of
90%
formic acid and 2.3
g.
(0.026 mole) of35% formaldehyde according to Clarke,
et
al.6
A
yield
of
0.4
g.
f
11.5%) of
1-methyl-2-pyrrolidineethanol
(I) was
ob-
tained upon distillation of the crude product, b.p. 96" (14mm.),
ny
1.4680. The infrared spectrum agreed with that ofmaterial prepared by Method
1.
Method
3:
Ethyl l-methyld-oz~&pElrol~ne-~~ftute
(VI).This compound was prepared by a modification
of
the pro-cedure reported by Ruggli and Macder.8 Methyl cthyl
@-
ketoadipate (102
g.,
0.505 mole) was dissolved
in
300 ml
of
methanol and cooled in an ice bath. Methylamine gas
(33
g.,
1.06 moles) was introduced over approximately
1
hr. andthe resulting Rolution allowed
to
warm gradually (1.5
hr.)
to room temperature. The crystalline mass which separatedwas stored overnight at
0'
before collecting on a filter. Thesolid product was washed with
a
small volume of methanoland dried at 65'; yield, 44 g. (47.5%), m.p. 120-121".
A
second crop of product was obtained by concentrating themother liquor to onethird the original volume and storingat
0';
weight, after collecting and drying, 5 g. (5.5%); m.p.119-120°.
A
recrystallized Rample from another run had
a
meltingpoint
of
120-122'. The infrared spectrum sliowcd
a
strongband at 6.15
p
suggesting that the double bond had shiftcdinto conjugation with the carbonyl
group.
Anal.
Calcd. for CoH13N0,:N, 7.65. Found:
N,
7.70.
l-Meth?/l-b-p!/rrolidincelha.nol
(I).
A
solution of 13.2 g.(0.072 mole)
af
cthyl
l-mcthyl-boxo-2-pyrroIine-2-acctitte
(VI)
in 100 ml. of tetrahydrofuran
was
addcd dropwise in25 min. to
a
slurry
of
7
g.
(0.18 molc) of lithium aluminunihydride in
100
ml. of tetrahydrofur:m. The rcwtion mix-ture, after being stirred and refluxed
for
5 hr.,
was
cooledin an icc bath and treated carefully with 10 ml. of water.The mixture was filtered and the filtcr cskc extrwtcd with
300
ml. of ethanol. The filtrate and extracts wcre roml)inedand concentrated, leaving an oily residue whkh
was
frac-tionated under reduced pressurc to givc 5.43
g.
(GOYo)
of
the product,
h.p.
101-104° (21 mm.),
ng
1.47W.
Anal.
Calcd. for C7HlbNO: N, 10.84.
Fourid:
N,
10.7:s.
Method
4:
Diethyl P-hph"mate
(VII).
A
mixture of34.5 g. (0.24 molc) of @-hydromuconicacid prepared accord-ing
to
Evans,
et
al.,8
10 ml. of concd. sulfuric acid, and 250ml. of anhydrous ethanol was refluxed for 24 hr. The rcsiducohtained after removing the ethanol under redurcd pressurcwas dissolved in
100
ml. of chloroform. The resulting solu-tion was washed successively with
50
m].
of
saturated brineand 50 ml. of saturated sodium bicarbonate. Fractionaldistillation gave the diethyl p-hydromuconate (VII) (40.2
g.,
84.1%)
aa
a
colorless oil, b.p. 144-148" (23 mm.),
ny
I
.4410.
Ethyl ecyminate
.(VIII). Mcthylsminc gas
(6.8
g.,
0.22mole) waa introduced into
40
g.
(0.20 mole) of diethylp-hydromuconate (VII). The mixture was transferrcd
to
R
steel bomb and heated at 210-230"
for
2 hr. The contentswere fractionated under reduced pressure to give 23.4
g.
(63%) of ethyl ecgoninat,e (VIII)
as
a light colorcd oil,b.p. 164-184' (21 mm.),
ny
1.4646.
Anal.
Calcd.
for
COHlbNO~:C, 58.36;
11,
8.16.
Found:
C, 58.43;
H,
7.68.
I-Methyl-8-pyrsolidieet~nol
(I).
A
solution
of
18
g.
(0.1 mole)
of
ethyl ecgoninate (VIII) in 30 ml.
of
tetrahydro-

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