Note: Descriptions are shown in the official language in which they were submitted.
AHR-366
113349Ci
Cis and Trans-3-ARYLOXY-4-HYDROXYPYRROLIDINES
AND DERIVATIVES THEREOF
BACKGROUND OF THE INVENTION
1. FIELD OF INVENTION
The present invention relates to certain novel
cis and trans isomers of 3-aryloxy-4-hydroxypyrrolidines
and derivatives thereof which are useful in treating
depression, hypertension or heart arrythmias in animals,
with compositions prepared therefrom.
2. DESCRIPTION OF THE PRIOR ART
Compounds of the present invention have not been
available prior to the present invention. German Offen-
legungsschrift 2,738,477 has disclosed certain trans-3-
aryloxy-4-hydroxypyrrolidines and piperidines which have
pertinence to the present invention but which disclosure
is subsequent to the present invention. None of the
compounds disclosed in that reference are cis isomers.
15 Certain of the compounds of the present invention also
differ in having substitution of alkyl, phenylalkyl and
cycloalkyl on pyrrolidinyl nitrogen.
SUMMARY OF INVENTIO~
The present invention provides novel cis and trans
isomers of 3-aryloxy-4-hydroxypyrrolidines and derivatives
thereof which have important pharmacological activity.
The compounds of the invention are represented by the
following structure formula:
RlO O-Ar
~ Formula I
I (cis and trans isomers)
s~
113349S
wherein;
Rl represents hydrogen, loweralkyl, benzoyloxycarbonyl,
and N-loweralkylcarbamoyl,
R2 represents hydrogen, loweralkyl, cycloalkyl,
== 5 phenylalkyl, benzyloxycarbonyl, carbamoyl, ~-loweralkyl-
carbamoyl, N-di-loweralkylcarbamoyl and parafluorobenzoyl-
loweralkyl,
Ar = phenyl, substituted phenyl, l-naphthyl, 2-
naphthyl, l-indenyl and 2-indenyl, and the pharmaceutically
acceptable acid addition and quaternary salts thereof. The
compounds have cis or trans configuration.
The compounds of the present invention have anti-
depressant,hypotensive and cardiovascular activity in
animals.
Antidepressant activity was shown to be present by the
procedure given by Englehardt, E. L. et al., J. Med. Chem.
11 (2): 325 (1968) wherein the novel compounds of the
present invention were administered to mice intraperiton-
eally and the effectiveness of the compounds in blocking
the depressant effects which are induced in mice by intra-
venous administration of 2-oxo-3-isobutyl-9,10, dimethoxy-
1,2,3,4,6,7-hexahydro-llbh-b~nzo[a]quinolizine (tetrabenazine)
was determined.
Compounds of the invention for which pronounced anti-
depressant activity was observed have the formula:
HO 0-Ar
~ Formula Ia
I
R2
wherein R2 is hydrogen, lower-alkyl or phenylalkyl, and
Ar is phenyl or substituted phenyl.
Compounds preferred for their antidepressant activity
have the formula:
366
1133495
~ ( 0-2 )
I Formula Ib
alkyl
Illustrative of the antidepressant activity of compounds
of Formula Ia are the effective dosages determined by the
foregoing anti-tetrabenazine test.
Compound Antitetrabenazine (Mice)
Example ED~ (mq/kq)
3 3.7
46 3-5
49 4.8
48 2.8
The action of certain compounds disclosed in the
present invention in counteracting cardiac arrhythmia is
demonstrated by the following procedure. ~he procedure
is carried out under barbiturate anesthesia using adult
mongrel dogs of either sex weighing from 8 to 14 kg. A
Grass Model 7 polygraph was used for recording femoral
arterial blood pressure (Statham P23AC Transducer) and
the electrocardiogram (Grass 7P4 Preamplifier). Ouabian
25 was given intravenously in an initial dose of 40y/kg in a
second dose of 20y/kgJ given 30 minutes after the first
dose, and in subsequent doses of 10~/kg which were repeated
at 15 minute intervals as required for producing cardiac
arrhythmias that persisted for at least 15 minutes. When
30 the arrhythmias were established, the test compounds were
administered by infusion (Harvard Model 942 Infusion Pump)
into a femoral vein at a rate of 1 mg/kg/min. Concen-
trations of compounds were adjusted according to the weight
of the dog to allow a volume infusion of 1 ml/min.
Compounds that are considered to be active as antiarrhythmic
agents cause reversion to sinus rhythm which is maintained
for at least 60 minutes.
Compounds of the invention for which pronounced
antiarrhythmic activity was observed have the formula:
366
1133495
HO I OAr
I Formula Ic
R2
wherein R2 is hydrogen and lower alkyl, and Ar is 1 and
2-naphthyl and 4 and 5-indenyl.
The compound of Example 55 represents a preferred
compound exhibiting exceptional antharrhythmic activity at
a minimum effective dose of 10.7 mg/kg using the foregoing
procedure.
It is accordingly an object of the present invention
to provide cis and trans-3-aryloxy-4-hydroxypyrrolidines
and derivatives thereof and methods of making same, which
have a high degree of antidepressant activity.
Another object is to provide cis and trans-3-aryloxy-
4-hydroxypyrrolidines and derivatives thereof which have
antiarrhythmic and anti-hypertensive activities in animals.
A still further object is to provide methods of using
the cis and trans-3-aryloxy-4-hydroxypyrrolidines as anti-
depressants, hypotensive agents and antiarrythmic agents
in the treatment of living animals, especially mammalian
subjects in need of treatment. Additional objects will
be apparent to one skilled in the art and still other
objects will become apparent hereinafter.
113349S 366
DETAILED DESCRIPTIO~ O~ THE INVE~TIO~
The present invention encompasses the novel cis and
trans isomers of 3-aryloxy-4-hydroxypyrrolidines and
derivatives thereof as set forth hereinabove in Formula I
and the definitions therewith as composition of matter and
the utilization of these novel compounds in living animals
for their pharmacological effect as set forth hereinabove
and below.
The term "loweralkyl" as used in the specification
and claims includes straight and branched chain radicals of
up to eight carbon atoms inclusive and is exemplified by
such groups as methyl, ethyl, propyl, isopropyl, butyl
isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl,
octyl and the like.
The term "substituted phenyl" as used in the specifi-
cation and claims includes phenyl substituted in one to 3
positions by one or more radicals selected from halogen,
O-loweralkyl,~NHC(O)CH3, CF3, -C(O)CH3, -CH2CH=CH2, alkyl,
hydroxy, -OCH2phenyl, and -C(O)NH2.
By "cycloalkyl" is meant cycloalkyl radicals having
l to 9 carbon atoms and incl~des such radicals as cyclo-
propyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Representative of phenylalkyl radicals are benzyl
(phenylmethyl), ~-methylbenzyl, phenylethyl, phenylpropyl,
phenylbutyl and the like.
The starting materials used in preparing the novel
trans isomer compounds of Formula I are l-phenylalkyl-3,4-
epoxypyrrolidines such as l-benzyl-3,4-epoxypyrrolidine;
l-alkyl-3,4-epoxypyrrolidines such as l-ethyl-~,4-epoxy-
pyrrolidine, and l-cycloalkyl-7,4-epoxypyrrolidines such
as l-cyclohexyl-3,4-epoxypyrrolidine.
Preparation of these l-substituted epoxypyrrolidines
is represented by the following equation:
HO C~ Aqueous or
~5 ~ ~ ~ ¦ alcoholic base
I HH2CO ~ ¦ solution ~ ~ N J
R lV R J R II
III
~, 3~
1133~'15
wherein R is loweralkyl, phenylalkyl or cycloalkyl. Generally,
the chlorination step is accomplished in 2-6 hrs and the
intermediate III need not be isolated. Crude epoxypyrroli-
dines are obtained by solvent extraction and converted to
crystalline salt such as oxalates. Pure free base of the
epoxypyrrolidines may be obtained from the oxalate salt by
partitioning between 5% aqueous sodium carbonate and
methylene chloride and thereafter drying over anhydrous
sodium sulfate and evaporating the methylene chloride. The
pyrrolines used in these starting preparations are prepared
according to the procedure of U. S. Patent 3,691,198 and
the procedure for the preparation of l-cyclohexyl- ~ -
pyrroline is given in Preparation 1.
Preparation of the epoxypyrrolidines used to prepare
the trans isomers of Formula I are given in Preparations 2-4.
The starting materials used in preparing the cis isomers
of compounds of Formula I was cis-benzyl-3,4-pyrrolidine-
diol as given in Preparation 5. Cis-3,4-pyrrolidinediols
were first prepared by A. J. Hill et al., J. Amer. Chem.
Soc. ~, 3548 (1954).
\
366
1133495
Preparation 1
l-Cyclohexvl-~ -pyrroline.
A solution of 5.19 kg (52.3 moles) of cyclohexylamine
in 4.0 liters of benzene was heated to mild reflux (92c.)
and then the heating discontinued. To the solution was
added, dropwise, 1,635 g (13.1 moles) of 1,4-dichlorobutene
at a rate sufficient to maintain gentle reflux, 3 hours
time being required. Heating was continued and the reactants
were heated at reflux temperature for 18 hours. The mixture
was cooled to about 50C. and filtered to remove the hydro-
chloride salt. carbon dioxide was bubbled into the filtrate
to precipitate excess amine carbonate salt which was removed
by filtration. Solvent was removed from the filtrate by
distillation under reduced pressure and the reddish fluid
residue slightly contaminated with benzene weighed 1,506 g.
(76~ yield).
Preparation 2
l-Benzyl-3,4-epoxypyrrolidine Oxalate.
A mixture of 31.8 g. (0.20 mole) of N-benzyl- ~-
pyrroline, 25 1. of concentrated hydrochloric acid and
300 ml. of water was treated with a stream of chlorine gas
for 2 hr. The solution was filtered and the filtrate was
made basic with 20~ sodium hydroxide. The basic solution
was extracted with three 150 ml. portions of methylene
chloride. The combined methylene chloride extracts were
dried over magnesium sulfate and evaporated to give 48.5 g.
of crude chlorohydrin as a dark oil. This oil was stirred
with 200 ml. of 20~ sodium hydroxide 0.5 hr., 700 1. of
water was added, and the base was extracted with four 100-ml
portions of methylene chloride. The combined methylene
chloride extracts were dried over magnesium sulfate and
concentrated to yield 34.9 g. (99O of crude epoxide as a
dark oil. The oxalate salt was prepared in 81% yield.
Recrystallization from 95% ethanol gave the salt as off-white
needles, m.p. 148-49/d.
Analysis: Calculated for Cl9Hl5NO5: C,58.86; H,5.70; N,5.28
Found : C,58.55; H,5.68; N,5.25
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1133495
Preparation ~
l-Ethy1-3,4-epoxy-Pyrrolidine oxalate.
A mixture of 61 g. (o.63 mole) of l-ethylpyrroline,
50 ml. of concentrated aqueous hydrochloric acid and
600 ml. of water was treated with chlorine gas for 2.5 hr.
_= .
The mixture was filtered through cotton and the filtrate
was washed with two 100-ml. portions of methylene chloride.
The aqueous layer was made basic with 20% sodium hydroxide,
heated on a steam bath for 0.5 hr. and extracted with three
100-ml. portions of methylene chloride. The combined
extracts were dried over anhydrous sodium sulfate and
concentrated and the residue vacuum distilled to give 39.4 g.
(56O of the epoxide as a clear oil (b.p. 75-90 ~ 28 mm).
The epoxide was converted to the oxalate and the salt was
recrystallized from absolute ethanol to give white needles,
15 m.p. 142-4d.
Analysis: Calculated for CBHl3~Os: C,47.29; H,6.45; N,6.89
Found : C,47.12; H,6.42; ~,6.82
Preparation 4
l-Cyclohexyl-~,4-epoxYpyrrolidine Oxalate.
A solution of 151.3 g. (1.0 mole) of ~-cyclohexyl- ~ -
pyrroline, 100 ml of concentrated hydrochloric acid and 1.8
liters of water was treated with a stream of chlorine gas
until uptake ceased (~ 6 hrs). The solution was washed with
methylene chloride and the acidic solution was left standing
overnight. The solution was then made basic with 50% sodium
hydroxide and extracted with methylene chloride. The
combined extracts were concentrated to give 185 g of chloro-
hydrin as residue. The residue was slowly poured into an
ethanol solution containing 20% sodium hydroxide. The
mixture was stirred for 0.5 hr and then 3.5 liters of water
was added. The mixture was extracted with methylene chloride
and the combined extracts were dried over anhydrous sodium
sulfate and concentrated to give 154 g. (92%) of amine
epoxide~ An NMR analysis indicates this residue is 86%
epoxide and 14% 3,4-dichloro-N-cyclohexylpyrrolidine. The
residue was vacuum distilled to give the epoxide as a water-
366
1133~
white liquid, b.p. 71c at o.6 mm. A portion of the liquid
was converted to the oxalate to give a white solid, m.p.
155-6d when recrystallized from ethanol.
Analysis: Calculated for Cl2Hls~Os: C,56-02; H~7-44; ~5-44
Found : C,56.05; H,7-50; N,5-34
Preparation 5
l-Phenylmethyl-3,4-pyrrolidinediol MonohYdrochloride
cis Isomer.
A mixture of 80 g. (0.32 mole) of meso-1,4-dibromo-
2,3-dihydroxybutane, 34 g. (0.32 mole~ of benzylamine, 3 g.
of potassium iodide and 140 g. (1.0 mole) of potassium
carbonate in 250 ml of 95 ethanol was heated at reflux for
18 hr., then cooled and filtered. The filtrate was concen-
trated and the residue was washed with several portions of
boiling ethyl acetate. The extracts were combined, washed
with a small amount of water, dried over anhydrous sodium
sulfate and concentrated to give 30 g residue representing
a 48~ yield of 1-phenylmethyl-3,4-pyrrolidinediol cis isomer.
A portion was converted to the hydrochloride salt with
hydrogen chloride in isopropyl alcohol and recrystallized
from isopropyl alcohol as off-white granules, m.p. 115.0-
l 16 . 5.
Analysis: calculated for CllHl6C1~02: C,57.52; H,7-02;
N , 6 . lO
Found : C,57.16; H,6.91;
~,6.01
365
~1334~35
Synthesis of trans-isomer compounds of Formula I which
are part of the present invention and which also serve as
reactants for the preparation of other compounds of the
invention was started by reacting aryloxy compounds with
appropriately 1-substituted-3,4-epoxypyrrolidines as
exemplified by the following equation:
Trans Isomers
HO OAr
~ + ArOH heat ~J
N ¦ trans isomers
R2 R2
wherein ~ is phenylalkyl, alkyl and cycloalkyl, and Ar is
as defined hereinabove.
Synthesis of cis isomers which are part of the present
invention and which serve as reactants for other compounds
of the invention was started by reacting l-benzyl-~,4-
pyrrolidinediol cis isomer with Ar-F compounds according to
the following formula:
Cis Isomers
HO OAr
H~, I OH ~aH I l
~ NJ + ArF DME ~ ~INC ~ cis isomers
CH2CsHs C~H5
wherein Ar is as defined hereinabove.
3o
366
11334~
In preparing compounds having further variation under
Formula I, the following methods may be used for preparation
of either trans or cis isomers.
5 ( 1) R2 = Hydrogen, Rl = H or alkyl
~J H2 ,~
CcH~2H5 Pd/C H
(2) R2 = alkyl
R1 ~ OAr R1 ~ OAr
N + CH3I --~ N ~+
CH3 CH2C6Hs
CH2
C~H5 2) H2, Pd/C R O OAr
CH3
( 3) Rl = alkyl
2 5 HO ~ ~aH~
CH2 CH3I ICH2
C~Hs C~H5
~0
366
1133495
( 4) Rz = (CHz )2 - C ~F
RC~O-Ar + (CH3)zN-CHz-CH2-C~F
N
H
ROrJO-Ar
CHzCH2-C~F
(5)
HO OAr HO r~_OAr
r + Benzylchloro ~ N
N ~ formate
CH2 O = C-O-CH2 C 6H5
C6H5
C 6H5 CHz O- CO I I OA r
~NJ
O = C-O-CHz C 6H5
(6) Ar = phenyl substituted with halide;
2 5 R2 = H
C6H5CH2O-C-O~ O ~ (halo) 1-2
0 = C-OCH2 C 6H5 \~HBr
~J (halo~_a
366
1133495
7 ) R2 = -C-NHz
HO o--Ar HO~OAr
~ + ~itrourea ~ N
I C=O
H ~H2
(8) R2 = -~C~-N(CH3)2
HO ~OAr dimethyl HO rJOAr
H + carbamyl C= O
N-( CH3)2
O H
20 ( 9) R2 = -C-N-alkyl
OA r HO OA r
HO~ + isoYyanate 0C 3 ~J
H F=
2 5 ~H
CH3
366
11~
14
O O
( 10) Rl = CH3NHC-(), R2 = -C-N(CH3)2
O
HO I I OAr CH3NHC-O I I OAr
N J methyl ambient~ ~ N J
C= O + isocyanate temp. C= O
~(CH3)2 N(CH3)2
( 11) Rl = H, Ar = C~H5 starting from Ar = C~H4-halo
~Cl Ne ~J
CH2
C~H5
To obtain the free base of a compound prepared as a
salt, the salt is partitioned between methylene chloride
and 5% sodium hydroxide. The methylene chloride layer is
dried over sodium sulfate and concentrated to give the
base as residue.
The novel compounds of the present invention and the
methods for their preparation are exemplified more fully
by the following illustrative examples, the scope of the
invention is, however, not limited thereto. As will be
readily identifiable from a consideration of the examples
and the foregoing outline, many of the compounds under the
scope of Formula I may be also considered as intermediates
in the synthesis of other compounds of Formula I.
366
1~3349S
Example 1
Trans-4-phenoxy-1-Phenvlmethyl-3-pyrrolidinol.
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine,
13.2 g. of phenol and 3 drops of water was heated at 120 C.
under nitrogen gas for 20 hr. The mixture was cooled and
dissolved in 100 ml. ethyl ether. The ethereal solution was
extracted with 2 x 50 ml. of 5% sodium hydroxide and then
washed with water. After being dried with anhydrous sodium
sulfate, the solvent was evaporated and the residue weighed
14.3 g. Two crystallizations from cyclohexane gave analyti-
cally pure product melting at 101-104C. The yield was
24~ of theory.
Analysis: Calculated for Cl7Hl9NO2: C,75.81; H,7.11; N,5.20
Found : C,75.71; H,7.10; H,5.38
Example 2
Trans-3-hvdroxy-1-methyl-4-phenoxy-1-phenylmethyl-
pyrrolidinium Iodide.
A solution of 8.o g. (56 mmol) of methyl iodide in
30 ml. of dry ethyl ether was added dropwise to a stirred
solution of 7.0 g. (26 mmol) of trans-4-phenoxy-1-phenyl-
methyl-3-pyrrolidinol in 70 ml. of dry diethyl ether. The
mixture was stirred for two days and then concentrated
under reduced pressure. The 10.7 g. of crystalline residue
was washed with tetrahydrofuran and dried, and gave 10.4 g.
(97O of white powderJ m.p. 122-27C.
Analysis: Calculated for Cl~H22IN02: C,52.57; H,5-39; N~3-41
Found : C,52.78; H,5.45; ~,3.55
Example 3
Trans-l-methYl-4-phenoxy-3-pyrrolidinol.
A solution of 9.3 g. (22.6 mmol) of trans-3-hydroxy-1-
methyl-4-phenoxy-1-phenylmethylpyrrolidinium iodide in 200 ml.
of absolute ethanol and 100 ml. of 190 ethanol was stirred at
ambient temperature for 0.5 hr. with 2.6 g. (11.3 mmol) of
silver oxide. After 0.2 g. more silver oxide was added, the
mixture was warmed to 45C. and stirred for an additional
15 min. The mixture was separated by filtration through
366
1133495
16
,7~ s ~
Celite, and the volume of the filtrate was reduced to 200 ml.
This solution was treated with ca. 0.5 g. of 10% Pd/C
catalyst and was shaken with H2 in the Parr reduction
apparatus for 3 hr. The suspension was filtered through
Celite~and the filtrate was concentrated to give 4.3 g.
of crystalline solid. This material, when recrystallized
from cyclohexane, gave 3.66 g. (84%) of off-white crystals,
m.p. 89.0-90.0C.
Analysis: Calculated for CllHl5NO2: C,68.37; H,7-82: ~7-25
Found : C,68.11; H,7.83, N,7.22
ExamPle 4
Trans-3-methoxY-4-phenoxy-1-phenylmethylpyrrolidine
Oxalate.
8.1 g. (0.03 mole) of trans-4-phenoxy-1-phenylmethyl-
3-pyrrolidinol was mixed with 0.72 g (0.03 mole) of sodium
hydride (1.3 g of 55% in oil, washed with 3 x 10 ml diethyl
ether) in 50 ml. of dimethylformamide and stirred until
hydrogen evolution ceased. 4.3 g (0.03 mole) of methyl
iodide was added and the mixture was stirred for 18 hr.
The reaction was worked up by pouring into 400 ml of water
and extracting with 3 x 100 ml of diethyl ether. The
diethyl ether was evaporated, leaving 7.9 g of residue.
Addition of petroleum ether caused precipitation of starting
material, which was removed by filtration. The residue
after evaporation of the mother liquor was chromatographed
on silica gel eluting the product with 10% acetone in benzene.
The yield of pure product my ~MR was 5.0 g. (59%). A small
amount was converted to the oxalate in iso-PrOH and
recrystallized from i-PrOH; m.p. 122-25 C.
Analysis: calculated for C20H23~O~: C,64.33; H,6.21; N,3.75
Found : C,63~93; H,6.21; N,3.69
Example ~
Trans-3-methoxY-4-phenoxypYrrolidine Fumarate.
A solution of 4.2 g. (0.015 mole) of 3-methoxy-4-
phenoxy-l-phenylmethylpyrrolidine in 70 ml. of ethanol
was treated with ca 0.2 g of Pd/C catalyst and shaken under
hydrogen at 60OC. in the Parr apparatus for 3 hr. After
- ~fa~e ~ ~ ~ k
~o
11~ .
17
cooling, the mixture was filtered and the solvent was
evaporated. The 2.9 g (100%) of crude product (good purity
by NMR) was converted to the fumarate in isopropyl alcohol.
The pale yellow precipitate melted at 134-136 C.
Analysis: Calculated for Cl5Hlg~oe: C,58.25; H,6.19; N,4.53
Found : C,58.15; H,6.27; N,4.46
Example 6
Trans-4-phenoxv-3-pyrrolidinol Fumarate.
A solution of 14.8 g. of 1-benzyl-4-phenoxy-3-
pyrrolidinol in 200 ml. of ethanol was treated with ca.
3 g. of 10% palladium-on-charcoal catalyst and was shaken
with hydrogen at 60C. in the Parr reduction apparatus for
5 hr. The suspension was cooled, filtered and the solvent
evaporated at reduced pressure. The residue was converted
to the fumarate using isopropyl alcohol. The yield of
product, m.p. 158-62C. was 14.1 g (87%).
Analysis: Calculated for Cl4Hl7~0e: C,56-95; H~5-80; N~4-74
Found : C,56.91; H,5.97; ~,4.78
2 Example 7
Trans-1-(4-fluorophenyl)-3-(3-hYdroxy-4-phenoxy-1-
pyrrolidinyl)-l-propanone.
A mixture of 3.6 g. (0.02 mole) of 4-phenoxy-3-
pyrrolidinol, 5 g. (0.0215 mole) of ~-dimethylamino-p-
fluoropropiophenone hydrochloride, 10 g. of potassium
carbonate and 50 ml. of dimethylformamide was heated with
stirring at 70C. for 6 hr. while nitrogen gas was bubbled
through the reaction mixture. The mixture was poured into
water and extracted twice with benzene. The combined
extracts were dried over anhydrous sodium sulfate and
concentrated to give 6.1 g. of an oil as residue. The oil
was chromatographed on 130 g. of silica gel. The desired
compound was eluted with 20% acetone in benzene and 2.6 g.
(39O of an oil which gradually crystallized upon standing
was obtained. This solid was recrystallized from petroleum
ether diethylether to yield a white solid, m.p. 77-80C.
Analysis: Calculated for Cl~H20FN03: C,69.28; H,6.12; ~,4.25
Found : C,69.43, H,6.23; N,4.18
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1133495
18
ExamPle 8
Trans-4-(4-chlorophenoxy)-1-phenYlmethyl-3-Pyrrolidinol.
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine,
18.0 g. of p-chlorophenol and 3 drops of water was heated
at 120C. under nitrogen gas for 20 hr. The mixture was
cooled and dissolved in 100 ml. diethyl ether. The ethereal
solution was extracted with 2 x 50 ml. 5~ sodium hydroxide
and then washed with water. After being dried with anhydrous
sodium sulfate, the solvent was evaporated and the residue
weighed 14.3 g. Two crystallizations from cyclohexane gave
4.7 g. (290 of analytically pure product which melted at
101-104C .
Analysis: calculated for Cl7Hl8C1~02: C,67.21; H,5.97; ~,4.61
Found : C,67.35; H,6.10; ~,4.69
Example 9
Trans-3-(4-chlorophenoxy-4-lphenylmethyl[carbonylbis
(oxy)l~-l-pYrrolidine carboxylic acid phenylmethyl ester.
A solution of 14.0 g. (o.o46 mole) of trans-4-(4-
chlorophenoxy)-l-phenylmethyl-3-pyrrolidinol and 5 g. (0.05
mole) of triethylamine in 200 ml. of benzene was added
dropwise to a cold (15C.) solution of 30.0 g. (0.175 mole)
of benzylchloroformate in 100 ml. of benzene. The mixture
was allowed to warm to room temperature and stirred over
night. The precipitate was removed by filtration and
discarded and the filtrate was concentrated and the residue
heated under high vacuum to remove excess reactants and by-
products. The resulting gum was chromatographed on silica
gel, eluting the desired product with 20~ acetone in benzene.
5 g. of product was obtained after evaporation.
Example 10
Trans-4-(4-chloroPhenoxY)-~-pyrrolidinol HYdrobromide.
A solution of 5 g. of 3-(4-chlorophenoxy)-4-{phenyl-
methyl[carbonylbis(oxy)]}-l-pyrrolidinecarboxylic acid
phenylmethyl ester trans isomer in 30 ml. of ethanol and
50 ml. of 48~ hydrogen bromide was heated at 115C. for
16 hr. and then cooled and diluted with 100 ml. water. The
solution was extracted with 2 x 50 ml. of methylene chloride
366
1133~
19
and the aqueous layer was evaporated to dryness. The
powder that remained was the product in 82% yield with a
melting point of 190-92C.
Analysis: calculated for ClOHl3N02BrCl: C,40.77; H,4.45;
N,4.76
Found : C,41.01; H,4.46,
N,4.85
Example 11
Trans-3-(4-chlorophenoxY)-4-hydroxy-1-pyrrolidine-
carboxamide.
A solution of 4.4 g. of 4-(chlorophenoxy)-3-
pyrrolidinol and 2.8 g. of nitrourea in 100 ml. of 90
ethanol was heated at 50C. for 20 hr. Some of the
solvent was removed under vacuum and the remaining slurry
was diluted with 50 ml. water. The precipitate was
filtered, triturated with acetone, filtered and dried.
Yield 1.8 g., m.p. 223-225C.
Analysis: Calculated for CllHl3N203Cl- C,51-47; H~5-11;
N,10.91
Found : C,51.18, H,5.02;
N,10.88
Example 12
Trans-3-(4-chlorophenoxY)-4-hydroxY-N,N-dimethyl-l-
pyrrolidinecarboxamide.
A solution of 3.5 g. of 4-(4-chlorophenoxy)-3-
pyrrolidinol, 1.8 g. of dimethylcarbamyl chloride and 1.7 g.
f triethylamine in 300 ml of methylene chloride was
stirred for 60 hr. The solvent was removed under vacuum,
300 ml of benzene was added and the mixture was refluxed
for 2 hr., then filtered. After solvent evaporation, the
residue was dissolved in cyclohexane-benzene and charcoaled.
The product was then crystallized, collected by filtration
and recrystallized from cyclohexane-benzene; m.p. 137-142 C.
Analysis: calculated for Cl9Hl7N203Cl: C,54.84; H,6.02;
N,9.84
Found : C,54.64; H,6.01;
N,9.77
' 365
1133495
ExamPle 1~5
Trans-3-(4-chloroPhenoxy)-4-hydroxy-~-methY1-1-
pyrrolidinecarboxamide HemihYdrate.
A solution of 0.9 g. of 4-(4-chlorophenoxy)-3-
__ pyrrolidinol in 50 ml. of methylene chloride was cooled
--- 5 to 0C. and o.24 g. of methyl isocyanate in 5 ml. of
methylene chloride was added dropwise over the period of
10 min. Cooling was discontinued and stirring was
continued for 1 hr. Solvent was then removed and the
residue was crystallized from dimethylsulfoxide-water;
m.p. 95.0-98-5C-
Analysis: Calculated for Cl2Hl5~2O3Cl: C,51-53: H,5-77
N,10.02
Found : C,51.64; H,5.79;
~,10.09
Example 14
Trans-3-{~(methylamino)carbonyl~oxy~-4-(4-chloro-
phenoxy)-~,N-dimethyl-l-pyrrolidinecarboxamide.
A solution of 1.0 g. (0.003 mole) of trans-3-(4-
chlorophenoxy)-4-hydroxy-N,~-dimethyl-l-pyrrolidine
20 carboxamide and 1.0 g. (0.02 mole) of methylisocyanate in
20 ml. of methylene chloride was let stand at ambient
temperature for 48 hr. The solution was concentrated to
give an oil which crystallized upon standing. The solid
was recrystallized from benzene-cyclohexane to yield o.6 g.
25 (50%) of white solid, m.p. 132-134 C.
Analysis: Calculated for ClsH2oCl~3O4: C,52.71; H~5 90;
Found : C,53-09; H,5 9268
3o Example 1~
Trans-4-(2,6-dichlorophenoxY)-l-PhenYlmethyl-3-
pyrrolidinol.
A mixture of 35.0 g. of 1-benzyl-3,4-epoxypyrrolidine
and 32.6 g. of 2,6-dichlorophenol was heated at 125C. for
3 hr. The mixture was cooled, dissolved in methylene
chloride and extracted with dilute sodium hydroxide. The
residue after the solvent was evaporated was purified by
356
1133495
column chromatography. The product was eluted with 30~0
ethyl acetate in benzene and crystallized from cyclohexane.
Yield was 43 g (64O , m.p. 78-80C.
Analysis: Calculated for Cl7Hl7N02C12: C,60.37, H,5.07; N,4.14
Found : C,60.42; H,5.o6; N,4.12
Example 16
Trans-3-(2,6-dichloroPhenoxy)-4-~phenylmethyl r carbonyl
bis(oxy)11-1-pyrrolidinecarboxylic Acid Phenylmethyl Ester.
To a solution of 3.4 g. of trans-1-benzyl-4(2,6-
dichlorophenoxy)-3-pyrrolidinol and 1.05 g. of triethylamine
in 25 ml. of benzene was added dropwise a solution of 4.0 g.
of benzylchloroformate in 20 ml. of benzene. The mixture
was stirred for 30 min. after addition was complete; then
filtered and the solvent was evaporated under reduced
pressure. The residue was dissolved in 50 ml. methylene
chloride and 6.o g. of benzylchloroformate was added. The
mixture was stirred overnight; then the solvent was evaporated
and the residue chromatographed on silica gel. The product
was eluted with 20% ethyl acetate in benzene and then stirred
with petroleum ether until it crystallized. The white
crystals weighed 4.7 g. (90O and melted at 93-95 C.
Analysis: Calculated for C25H23~05Cl2: C,60.48; H,4.49;
~,2.71
Found : C,60.61, H,4.55
N,2.76
ExamPle 17
Trans-4-(2.6-dichloroPhenoxv)-~-Pyrrolidinol Hvdro-
bromide.
A solution of 12.2 g. 3-(2,6-dichlorophenoxy)-4-
[phenylmethyl(carbonylbis(oxy))]-l-pyrrolidinecarboxylic
acid phenylmethyl ester trans isomer in 120 ml. of ethanol
30 and 140 ml. of 48~ hydrogen bromide was stirred at 125C.
for 16 hr. and then cooled and diluted with 300 ml. water.
The solution was then extracted with 2 x 100 ml. methylene
chloride and the aqueous layer was evaporated to dryness.
Trituration with 30% diethylether in isopropyl alcohol gave
7.4 g. (95%) of white crystalline hydrobromide; m-p-
366
1133495
22
192-5C.
Analysis: Calculated for ClOEIl2~O2BrCl2: C,36.51; H,3.68,
~,4.26
Found : C,36.49; H,3.72;
N,4.36
ExamPle 18
Trans-4-(2,3-dichlorophenoxv)-1-phenylmethyl-3-
~rrolidinol HYdrochloride.
A mixture of 21.5 g. (0.12 mole) of 1-benzyl-3,4-
epoxypyrrolidine, 27.8 g. (0.17 mole) of 2,3-dichlorophenol
10 and 2 drops of concentrated hydrochloric acid was heated at
120C. overnight. The dark mixture was dissolved in
methylene chloride and washed with four 100-ml portions of
5% sodium hydroxide and once with water. The methylene
chloride layer was dried over anhydrous sodium sulfate-
15 potassium hydroxide and concentrated to give 35.8 g of dark
gum as residue. This gum was chromatographed on 800 g. of
silica gel and the product was eluted with an acetone-
benzene solution. The appropriate fractions were concen-
trated to give 25 g. (60%) of an oil. A portion of this
20 oil was converted to the hydrochloride to yield white
solid, m.p. 219-22 C.
Analysis: calculated for Cl7Hl8Cl3N02: C,54.50; H,4.84;N,3.74
i Found : C,54.53; H,4.82;N,3-53
Example 19
Trans-4-(2,3-dichlorophenoxy)-1-~(phenylmethoxy)
carbonyll-3-pyrrolidinol.
A mixture of 8.5 g (0.023 mole) of trans-4-(2,3-di-
chlorophenoxy)-l-phenylmethyl-3-pyrrolidinol hydrochloride
and 100 liters of methyl chloride was cooled and treated
30 dropwise with a solution of 23 g (0.125 mole) of benzyl-
chloroformate in 100 ml of methylene chloride. The mixture
was stirred at ambient temperature for 48 hr and then washed
successively with water, 2~ hydrochloric acid, 5% sodium
hydroxide and water. The methylene chloride layer was dried
35 over anhydrous sodium sulfate and then subjected to vacuum
distillation at 100/1.0 mm. to remove the methylene
366
11334195
chloride, excess benzylchloroformate and benzyl chloride.
An NMR analysis of the pot residue indicated only the
oxygen was substituted. An additional 25 ml. of benzyl-
chloroformate and 100 ml. of methylene chloride was added
5 to the residue and the solution stirred at ambient tempera-
ture for 48 hr. The mixture was purified as above to give
14.6 g. of residue which was chromatographed on 300 g. of
silica gel. The chromatography gave 5.6 g. of the di-
substituted compound (See Example 20) and 1.0 g. of the
10 titled compound as a white solid, m.p. 130-2C. (recrystal-
lized from benzene).
Analysis: Calculated for Cl~sHl7Cl2NO4: C,56.56; H,4.48,
~,3.67
Found : C,56.80; H,4.48,
N,3.67
Example 20
Trans-3-(2,3-dichlorophenoxy)-4-~phenylmethylrcarbonylbis
(oxy)~ pyrrolidine carboxylic acid phenylmethylester.
This disubstituted compound resulted from chromatography
separation in amount of 5-6 g. in Example 19.
Example 21
Trans-4-(2,3-dichlorophenoxy)-3-pvrrolidinol Hvdro-
bromide,
A mixture of 5.6 g. (0.011 mole) of 3-(2,3-dichloro-
phenoxy)-4-{phenylmethyl[carbonylbis(oxy)~}-1-pyrrolidine
25 carboxylic acid phenylmethylester trans isomer, 60 ml. of
ethanol and 70 ml. of 48% aqueous hydrogen bromide was
heated at 125C. overnight. The mixture was poured into
150 ml. of water and extracted three times with methylene
chloride. The aqueous solution was concentrated to give an
30 oily residue which crystallized upon standing. The solid
was washed with isopropyl alcohol-diethylether, collected
by filtration and recrystallized from isopropyl alcohol-
diethylether to yield 1.5 g. (45%) of a pinX solid, m.p.
134 8C
35 Analysis: Calculated for ClOHl29rCl2N02: C,36.51; H,3 68,
Found : C,36.54; H,3.69
N,4.32
366
3 3
24
Example 22
Trans-l-benzYl-4-(~-methylphenoxv)-3-PYrrolidinol
HYdrochloride.
A mixture of 17.5 g. of 1-benzyl-3,4-epoxypyrrolidine
and 20 g. of m-cresol was heated at 115C. for 18 hr. under
nitrogen gas. After cooling, the mixture was dissolved in
benzene and washed with 5% sodium hydroxide to remove
; excess cresol. Stirring with 50 g. of silica gel removed
much of the colored material. The solution was reduced in
volume and some of the residue was converted to the hydro-
chloride. This salt was recrystallized from isopropyl
alcohol-diethyl ether and melted at 163-165C.
Analysis: calculated for Cl8H22NO2C1: C,67.60; H,6 93;
Found : C,67.39; H,6.97;
~,4.43
Example 23
Trans-4-(3-methylphenoxy)-3-pyrrolidinol Oxalate.
A solution of 8.2 g. of 1-benzyl-4-(3-methylphenoxy)-
3-pyrrolidinol in 150 ml. of ethanol was treated with ca.
0.5 g. of 10~ palladium-on-charcoal catalyst and was shaken
with hydrogen at 60C. in the Parr apparatus for 2 hr. The
suspension was cooled, filtered and the solvent evaporated
under vacuum. The base was converted to the oxalate in
isopropyl alcohol, filtered and dried. The salt was
obtained in 86~ yield and melted at 150-155C.
25 Analysis: Calculated for Cl3Hl7NO5: C,55.12; H,6.o5; NJ4.94
Found : C,54.75; H,6.o7; N,5.o6
Example 24
Trans-4-(2 ~-dimethylphenoxy)-l-phenvlmethyl-~-
pyrrolidinol.
A mixture of 17.5 g. (0.10 mole) of 1-benzyl-3,4-
epoxypyrrolidine, 18.3 g. (0.15 mole) of 2,3-dimethylphenol
and 2 drops of concentrated hydrochloric acid was heated at
120C under a nitrogen atmosphere overnight. The reaction
mixture was dissolved in methylene chloride and washed with
four 100-ml portions of 5~ sodium hydroxide and once with
water. The methylene chloride layer was dried over
~66
11334~35
anhydrous sodium sulfate-potassium hydroxide and concen-
trated to give 28.6 g. of dark oil as residue. This oil was
chromatographed on 600 g. of silica gel and the product was
eluted with an acetone-benzene solution. The appropriate
fractions were concentrated to give an oil which crystal-
lized upon standing. This solid was recrystallized from
ligroin to give 9.1 g. (31%) of white solid, m.p. 100-4 C.
Analysis: Calculated for ClgHz~N02: C,76.74; H,7.80; N,4.71
Found : C,76.92; H,7.86; N,4.80
Example 2~
Trans-4-(2,3-dimethylphenoxy)-~-pyrrolidinol HYdro-
bromide.
A solution of 9.1 g. (0.031 mole) of trans-4-(2,3-
dimethylphenoxy)-l-phenylmethyl-3-pyrrolidinol in 100 liters
of ethanol was hydrogenated over 10~ palladium-on-charcoal
at 50 psi and 60C. until hydrogen uptake ceased. The
~~~i mixture was filtered through Celite~and the filtrate was
concentrated to give an oil as residue which solidified upon
standing. The solid was converted to the hydrobromide and
this salt was recrystallized from isopropyl alcohol-ethyl-
acetate-diethylether to yield 4.9 g (55%) of tan needles,
m.p. 152-3C.
Analysis: calculated for Cl2Hl8~rNO2: C,50.01; H,6.30; N,4.86
Found : C,50.29; H,6.42; N,4.85
Example 26
Trans-4-(2-methoxyphenoxY~-l-phenylmethyl-3-pyrrolidinol.
A mixture of 40 g. of crude 1-benzyl-3,4-epoxypyrroli-
dine and 70 g. of guaiacol was heated at 120C. for 20 hr.
Aspirator vacuum was then used to distill off the excess
guaiacol. The residue was dissolved in methylene chloride
and extracted with dilute sodium hydroxide. The methylene
chloride solution was dried over anhydrous sodium sulfate
and the solvent was evaporated. The residue weighed 54 g.,
was chromatographed on 1 kg. of silica gel. The product was
eluted with 50% ethyl acetate in benzene and crystallized
from cyclohexane. The m.p. was 115-117C. and the yield
was 27%.
Tf~/e ~r k
366
26
Analysis: Calculated for ClaH2lN09: C,72.22; H,7.07; N,4.68
Found : C,72.30; H,7.o4; N,4.70
Example 27
Trans-4-(2-methoxvphenoxv)-3-Pvrrolidinol Fumarate.
_:- 5 A solution of 11.5 g. of 1-benzyl-4-(o-methoxyphenoxy)-
3-pyrrolidinol in 200 ml. of ethanol was treated with ca.
2 g. of 10% palladium-on-charcoal catalyst and was shaken
with hydrogen at 60 C. in the Parr reduction apparatus for
5 hr. The suspension was then cooled, filtered, and the
solvent evaporated at reduced pressure. The base was
converted to the fumarate which melted at 158-160C.
Yield was 9.8 g. (78%).
Analysis: Calculated for C15HlgN~7: C,55.38; H,5.89; N,4.31
Found : C,55.38; H,5.89; N,4.13
Example 28
Trans-4-(4-methoxvphenoxv)-1-phenvlmethvl-3-pvrrolidinol.
A mixture of 17.5 g. (0.10 mole) of 1-benzyl-3,4-
epoxypyrrolidine, 13.4 g. (0.11 mole) of p-methoxyphenol,
and 3 drops of water was heated on a steam bath overnight.
The dark residue was dissolved in methylene chloride and
~he solution was washed with two 50-ml. portions of 5~
sodium hydroxide. The ~ethylene chloride layer was dried
over anhydrous sodium sulfate and concentrated to give 23.7 g.
of viscous dark oil. This oil was chromatographed on 480 g.
of silica gel 60 and the product was eluted with a 1:1
benzene:ether solution. The appropriate fractions were
concentrated to give 10.0 g. of a yellow oil which crystal-
lized upon scratching. The solid was recrystallized from
cyclohexane to yield 7.2 g. (24%) tan solid, m.p. 84-5 C.
30 Analysis: Calculated for Cl8H2lN0~: C,72.22; H,7.07; N,4.68
Found : C,72.20; H,7.15; N,4.61
Example 29
Trans-4-(4-methoxyDhenoxv~-~-pvrrolidinol oxalate
(3:4)
A solution of 4.0 g. (0.0134 mole) of trans-4-(4-
methoxyphenoxy)-l-phenylmethyl-3-pyrrolidinol in 75 liters
366
~133~'95
of ethanol was hydrogenated over 0.4 g. of 10% Pd/C at
60C. overnight. The reaction mixture was cooled, filtered
through Celite~ and the filtrate concentrated to give the
base as a white solid. This solid was converted to the
oxalate and recrystallized from methanol to yield white
flakes, m.p. 173-175C.d.
Analysis: Calculated for C41H53N3O25: CJ52-40; H,5-68; ~J4-47
Found : C,52.17; H,5.62; N,4.66
Example 30
Trans-4-(2-ethoxvphenoxv)-1-phenylmethyl-3-pyrrolidinol.
A mixture of 45.5 g. (o.26 mole) of 1-benzyl-3,4-
epoxypyrrolidine (60 g. of 76~ epoxide), 48 g. (0.35 mole) of
o-ethoxyphenol and 8 drops of concentrated hydrochloric acid
was heated at 145C. for 16 hr. The mixture was cooled,
dissolved in methylene chloride and washed with dilute
sodium hydroxide solution. The methylene chloride layer was
dried over anhydrous sodium sulfate and the solvent was
removed under reduced pressure. The residue was chroma-
tographed on 1 kg. of silica gel using 20% acetone in benzene
as the eluent. Two recrystallizations from cyclohexane gave
8.o g. (10%) of tan needles, m.p. 88.5-go.oc.
Analysis: Calculated for ClgH23NO3: C,72.82; H,7.40; ~,4.47
Found : C,72.64; H,7.39; ~,4.56
Example ~1
Trans-4-(2-ethoxYPhenoxy)-~-pYrrolidinol Fumarate.
A solution of 7.4 g. (24 m~oles) of trans-4-(2-ethoxy-
phenoxy)-l-phenylmethyl-3-pyrrolidinol in 150 ml. of absolute
ethanol was treated with about 0.5 g. of 10% Pd/C catalyst
and was shaken with hydrogen in the Parr reduction apparatus
at 60C. for 1.5 hr. The mixture was cooled and filtered and
the filtrate was concentrated. The residue (5.3 g., 100%)
was converted to the fumarate in isopropyl alcohol to give a
white powder; m.p. 173.0-174.5C.
Analysis: Calculated for Cl~H2 1~7: C,56.63; H,6.24; ~,4.13
F~und : C,56.60; H,6.27; N,4.12
T~ r k
366
1133~95
28
Example 32
Trans-4-[4-(phenylmethoxy~phenoxy~-l-phenylmethyl-3
pyrrolidinol.
A mixture of 40 g. of 1-benzyl-3,4-epoxypyrrolidine
and 42 g. of 4-benzoxyphenol was heated at 130C. for 8 hr.
On cooling, the mixture crystallized. Three crystal-
lizations from petroleum ether-cyclohexane gave fluffy
white crystals melting at 98.0-100.0C. The yield was
6.o g. (8O .
Analysis: Calculated for Cz4H25NO3: C,76.78; H,6.71; N,3.73
Found : C,76,83; H,6.82; NJ3.57
Example 33
Trans-4-(4-hvdroxyphenoxv)-3-pvrrolidinol Hemioxalate.
Six grams of l-benzyl-4-(4-benzoxyphenoxy)-3-pyrrolidinol
in 150 ml. of ethanol was treated with ca. 1 g. of palladium-
on-charcoal and shaken under hydrogen at 60C. in the Parr
apparatus for 3 hr. The mixture was then cooled, filtered
and the ethanol removed. The oxalate was made in
isopropyl alcohol acetone and recrystallized from 90~ ethanol.
The salt decomposed at 235C.
0 Analysis: calculated for CllHl4NO5: C,55.00; H,5.87; N,5.83
~ound : C,54.54; H,5.83; N,5.65
Example 34
Trans-4-(3-trifluoromethYlphenoxy)-l-phenvlmethyl-~-
: ~,~
A mixture of 24.0 g. of 1-benzyl-3,4-epoxypyrrolidine
and 22.2 g. of 3-trifluoromethylphenol was heated at 130C.
for 3 hr. The mixture was cooled, dissolved in methylene
chloride and extracted with dilute sodium hydroxide-
The residue after the solvent was evaporated was purified
by column chromatography. The product, which was eluted
using 30% ethyl acetate in benzene weighed 17.7 g. (38%).
A small portion when converted to the oxalate melted
at 139-141C.
Analysis: Calculated for C20H20NO~F3: C,56.21; H,4 72;
Found : C,56.48; H,4.77;
~,3.44
365
1133~,~5
29
Example ~5
Trans-4-(~-trifluoromethylphenoxy~-~-pvrrolidinol
Hydrochloride.
A solution of 12.6 g. of trans-1-benzyl-4-(3-trifluoro-
methylphenoxy)-3-pyrrolidinol in 200 ml. of ethanol was
5 treated with ca. 2 g. of 10% palladium-on-charcoal catalyst
and was shaken with hydrogen at 60C. in the Parr reduction
apparatus for 16 hr. The suspension was cooled, filtered
and the solvent evaporated at reduced pressure. The residue
was dissolved in ether and converted to the hydrochloride.
lO The yield of product melting at 145-8C. was 9.8 g.
(9~0 -
Analysis: Calculated for CllHl3N02ClF3: C,46.58: H,4.62;
~,4.94
Found : C,46.42; H,4.68;
~,5-07
ExamPle ~6
Trans-4-[(4-hydroxy-1-phenylmethyl-pyrrolidin-3-yl)oxy~
benzamide.
A mixture of 28 g. of l-benzyl-3,4-epoxypyrrolidine and
20.6 g. of 4-hydroxybenzamide was heated at 130C. for 8 hrs.
20 The cooled mixture was columned on silica gel using 5%
methanol in ethyl acetate to elute the product, which was
then crystallized from chloroform-benzene-methanol. The
yield was 19~ of product melting at 133.0-6.0 C.
Analysis: Calculated for Cl~H20~203: C,69.21; H~6-45; ~,8-97
Found : C,69.11; H,6.46, ~1,8.82
Example 37
Trans-4-r(4-hydroxy-3-pyrrolidinyl)oxy~benzamide.
-
Eight grams of 4-[(4-benzamide)oxy]-1-benzyl-3-
30 pyrrolidinol was treated with ca. l g. of lO,~ palladium-on-
charcoal and dissolved in lO0 ml. of ethanol and shaken with
hydrogen at 60C. for 4 hr. The suspension was then cooled
and filtered. The precipitate was washed with hot methanol
and the washings combined with the mother liguor. The
35 solvent was evaporated to 150 ml. and cooled overnight. The
366
3o
product was filtered and dried and melted at 199-204C. with
decomposition. The yield was 80%.
Analysis: Calculated for CllHl~203: C,59-45; H~6-35; ~12-61
Found : C,59.47; H,6.45; N,12.57
ExamPle 38
Trans-N-l4-~(4-hydroxy-1-phenylmethyl-~-pyrrolidinly)
oxy~phenyl~acetamide.
A mixture of 35.0 g. of 1-benzyl-3,4-epoxypyrrolidine,
30.2 g. of p-acetamidophenol and two drops of water was
~0 heated at 125C. for 3 hr. The mixture was then cooled,
dissolved in 50% ethyl acetate in benzene and washed with
dilute sodium hydroxide. When the solvent was removed, the
residue weighed 56 g. It was chromatographed using 370 g.
of silica gel and the product was eluted with ethyl acetate.
After crystallization from 50% ethyl acetate in benzene, the
product melted at 130-32C. and weighed 26.1 g. (40%).
Analysis: calculated for ClgH22N2O3: C,69.92; H,6.79; ,8 58;
Found : C,69.61; H,6.69; ~,8.44
Example 39
Trans-~-r4-r(4-hydroxy-3-pyrrolidinyl)oxylphenyl~
acetamide Hemifumarate.
A solution of 12.4 g. of 1-benzyl-4-(4-acetamido-
phenoxy)-3-pyrrolidinol in 200 ml. of ethanol was treated
with ca. 2 g. of 10% palladium-on-charcoal catalyst and was
shaken with hydrogen at 60C. in the Parr reduction apparatus
for 16 hr. The suspension was then cooled, filtered and the
solvent evaporated at reduced pressure. The residue weighed
9 g. and was converted to the fumarate and crystallized
from isopropyl alcohol. The yield of salt was 10.2 g. (90%)
which melted at 200-05 C.
Analysis: Calculated for Cl4HlaN205: C,57.14; H,6.17; N,9.52
Found : C,56.90; H,6.22; N,9.29
365
1133~j;
Example 40
Trans-4-(1-naPhthalenvloxv~-1-phenylmethyl-3-
rrolidinol Oxalate.
~Y
A mixture of 17.5 g. (0.10 mole~ of crude 1-benzyl-3,4-
epoxypyrrolidine, 15.0 g. (0.11 mole) of l-naphthol and
1 drop of concentrated hydrochloric acid was heated on a
steam bath overnight. The dark mixture was dissolved in
methylene chloride and the solution was extracted with
three 50 ml. portions of 5% sodium hydroxide. The methylene
chloride layer was dried over anhydrous sodium sulfate and
concentrated to give 25.5 g. (80O of black gum as residue.
This residue was chromatographed on 500 g. of silica gel
and the product was eluted with 1:1 ethyl ether;benzene
to give 9.9 g. (31~) of white solid, m.p. 106-8C. when
recrystallized from cyclohexane.
Analysis: Calculated for C2lH21NOz: C,78.97; H,6-63; N~4-39
~ound : C,79.08; H,6.67; ~,4.45
The oxalate was prepared as a white solid, m.p. 190-2 C.
when recrystallized from nitromethane.
Analysis: Calculated for C23H23NO~: C,67.47; H,5.66; ~,3.42
Found : C,67.00; H,5.68; N,3.57
Example 41
Trans-4-(1-naphthalenyloxv)-3-pYrrolidinol.
Eighteen grams of l-benzyl-4-(1-naphthoxy)-3-pyrrolidinol
in 200 ml. of ethanol was treated with ca. 2 g. of 10~
palladium-on-charcoal under hydrogen at 60 C. for 20 hr.
The mixture was cooled, filtered and ethanol removed. The
residue was crystallized from benzene and had a melting
point of 112-115 C.
Analysis: Calculated for Cl4Hl5~O2: C,73.34; H,6.59; N,6.11
Found : C,73.39; H,6.64; ~,5.90
366
1133495
32
Example 42
Trans-4-~lH-2,3-dihydroinden-4-yl)oxy~-1-phenylmethyl-
3-pyrrolidinol.
A mixture of 28 g. of 1-benzyl-3,4-epoxypyrrolidine
and 20.1 g. of 4-indanol was heated at 130C. for 8 hr. The
~ 5 residue was chromatographed on silica gel using ethyl acetate
to elute the product. The yield of product after crystal-
lization from cyclohexane was 6%, melting at 98-101C.
Analysis: calculated for C20H23~02: C,77.64; H,7-49; N~4-53
Found : C,77.41, H,7.52, ~,4.37
Example 43
Trans-4-[lH-2,3-dihydroinden-4-yl)oxy]-3-pyrrolidinol
Hydrochloride.
l-Benzyl-4-(4-indanoxy)-3-pyrrolidinol (2.7 g.) in
100 ml. of ethanol treated with ca. 0.5 g. lO~o palladium-on-
charcoal and was shaken with hydrogen at 60C. in the Parr
apparatus for 5 hr. The suspension was then cooled, filtered
and the solvent removed. The residue was converted to the
hydrochloride in ether and dried for 18 hr. at 40C.
under vacuum. The yield of product melting at 174-180C.
was 91%.
Analysis: calculated for Cl3Hl6NO2Cl: C,61.06; H,7.09; ~,5.48
Found : C,60.80; H,7.16, ~,5.46
Example 44
Trans-4-[(1,2-dihydroinden-5-yl)oxyl-1-phenylmethyl-
3-pyrrolidinol HYdrochloride.
A mixture of 35 g. of 1-benzyl-3,4-epoxypyrrolidine
and 28 g. of 5-indanol was heated at 130C. for 3 hr. The
mixture was then cooled, dissolved in methylene chloride
and extracted with dilute sodium hydroxide. After solvent
evaporation the residue was columned on silica gel, and the
product was eluted with 50% ethyl acetate in benzene. The
hydrochloride salt was formed in ether and was recrystallized
from ethanol-acetone. The yield of salt melting at 153-5C.
was 12.3 g. (18%).
Analysis: Calculated for C20H24NO2Cl: C,69.45, H,6.99; N,4.o5
Found : C,69.13; H,6.93; N,3.99
366
1133~5
Example 4~
Trans-4[(2,3-dihydro-lH-inden-5-yl)oxy~-3-pyrrolidinol
Oxalate.
A solution of 6.0 g. of 1-benzyl-4-(5-indanoxy-3-
pyrrolidinol in 100 ml. of ethanol was treated with ca.
0.5 g. 10~ palladium-on-charcoal and was shaken with
hydrogen at 60C. in the Parr apparatus for 3 hr. The
suspension was then cooled, filtered, and the solvent
removed. The oxalate was prepared in isopropyl
alcohol and melted at 179.0-181.0C.
Analysis: Calculated for C15HlgNO~: C,58.25; H,6.19; N,4.53
Found : C,58.13; H,6.14; ~,4.58
Example 46
Trans-l-ethyl-4-phenoxy-3-pYrrolidinol Oxalate
Hydrate (4:1)-
A mixture of 22.6 g. of 1-ethyl-3,4-epoxypyrrolidine
and 18.6 g. of phenol was heated at 150C. for 0.5 hr.,
and then distilled. The product boiled at 120/0.025 mm.
The yield of pure product was 25.0 g. (60O . A portion of
the base was converted to the oxalate which melted
at 134-7C. after it was recrystallized from isopropyl
alcohol.
Analysis: Calculated for C5~H78~4O25: C,55.72; H,6.51; ~,4.64
Found : C,55.83; H,6.38; ~,4-63
Example 47
Trans-l-ethvl-4-PhenoxY-3-PYrrolidinolmethylcarbamate
Ester.
A solution of 6.5 g. of 1-ethyl-4-phenoxy-3-pyrrolidinol
and 1.9 g. of methyl isocyanate in 80 ml. of benzene was
allowed to stand under nitrogen gas for 5 days. The crystal-
line solid remaining on evaporation of the benzene was
recrystallized from cyclohexane. The yield of product
melting at 88-94C. was 6.5 g. (79O .
Analysis: Calculated for Cl4H20N2O3: C,63.62; H,7.63; N,10.60
Found : C,63,61; H,7.60; ~,10.62
366
11 3.~95
34
Example 48
Trans-4-(2-chlorophenoxv)-1-ethyl-3-Pyrrolidinol
HYdrochloride .
A mixture of 17.0 g. (0.15 mole) of 1-ethyl-3,4-epoxy-
pyrrolidine, 20.5 g. (0.16 mole) of o-chlorophenol and 3
drops concentrated hydrochloric acid was heated on a steam
both overnight. The oil was dissolved in methylene
chloride and washed with three 50-ml. portions of 5% sodium
hydroxide and one 50-ml. portion of water. The methylene
chloride solution was dried over anhydrous sodium sulfate,
concentrated and chromatographed on silica gel to give
8.9 g. (25%) of an oil as residue. The oil was converted
to the hydrochloride and recrystallized from ethyl acetate-
acetonitrile to yield white powder, m.p. 108-110C.
Analysis: Calculated for Cl2Hl7Cl2N02: C,51.81; H,6.16;
N,5.o4
Found : C,51.65; H,6.17;
~,5.09
Example 49
Trans-4-(2,6-dichlorophenoxy~-1-ethyl-3-pyrrolidinol
Hydrochloride.
A mixture of 11.3 g. (0.10 mole) of 1-ethyl-3,4-
epoxypyrrolidine, 18.0 g. (0.11 mole) of 2,6-dichlorophenol
and 2 drops concentrated hydrochloric acid was heated on a
steam bath overnight. The oil was dissolved in methylene
chloride and washed with three 50-ml. portions of 5%
sodium hydroxide and one 50-ml. portion of water. The
methylene chloride solution was dried over anhydrous sodium
sulfate, concentrated and chromatographed on silica gel to
give 12.9 g. (47%) of an oil residue. The oil was converted
to the hydrochloride and recrystallized from isopropyl
3o alcohol-diethyl ether to yield 12.3 g. (39%), m.p. 160-162 C.
Analysis: calculated for Cl2Hl~Cl3~02: C,46.10; H,5 16;
Found ~,4 48
356
1133~$
Example ~0
Trans-l-ethyl-4-(3-methylphenoxy~-3-pyrrolidinol
o~alate Hemihydrate.
A mixture of 17 g. of 1-ethyl-3,4-epoxypyrrolidine
and 16.2 g. of m-cresol was heated at 125C. for 45 min.
and then vacuum distilled. The yield of product boiling
at 135C./.02 mm was 37%. This was converted to the
oxalate which melted at 116-119C.
Analysis: Calculated for C3OH44~2013: C,56-24; H, 6 92,
Found : C,56.66; H,6 68;
N,4.15
ExamPle ~1
Trans-4-(2-ethoxyphenoxy)-1-ethyl-3-pyrrolidinol.
A mixture of 17.0 g. (0.15 mole) of 1-ethyl-3,4-
epoxypyrrolidine, 22.1 g. (0.16 mole) of o-ethoxyphenol
and 3 drops of concentrated hydrochloric acid was heated
on a steam bath overnight. The oil was dissolved in
methylene chloride and washed with three 50-ml. portions
of 5~ sodium hydroxide and one 50-ml. portion of water.
The methylene chloride solution was dried over anhydrous
sodium sulfate, concentrated and chromatographed on
silica gel to give 8.1 g. (21%) of an oil which crystal-
lized on standing. The solid was recrystallized from
cyclohexane to yield a tan solid, m.p. 73-75 C.
Analysis: Calculated for Cl4H2lN0~: C,66.90; H,8.42; ~,5.57;
Found : C,66.49; H,8.43; N,5.48
ExamPle 52
Trans-1-{4-[(1-ethyl-4-hydroxy-3-pyrrolidinyl)oxy]-
3-methoxyphenyl}ethanone Sesquioxalate.
A mixture of 17.0 g. (0.15 mole) of acetovanillone and
1-ethyl-3,4-epoxypyrrolidine and 3 drops of water was
heated on a steam bath overnight. The mixture was dissolved
in 250 ml. of methylene chloride and extracted with three
150-ml. portions of 5% sodium hydroxide and one 100-ml.
portion of water. The methylene chlorid~ layer was dried
over anhydrous sodium sulfate and concentrated to give 19.0 g.
~6
1133495
36
crude oil. This oil was chromatographed on 400 g. of silica
gel. The desired product was eluted with acetone. The
fractions were concentrated to give 14.0 g. of oil which was
treated with oxalic acid in isopropyl alcohol. The
resulting white solid was recrystallized twice from isopropyl
alcohol to yield 13.4 g. (24%) of sesquioxalate, m.p.
121-3C.
Analysis: Calculated for ClgH24~Olo: C,52-17; H~5-84; ~3-38
Found : C,52.45; H,5.90; N,3.60
lô ExamPle ~3
Trans-l-ethyl-4-r2-(2-Propenvl)phenoxyl-3-pyrrolidinol
Oxalate.
A mixture of 17.0 g. of 1-ethyl-3,4-epoxypyrrolidine
and 20.0 g. of 2-allylphenol was heated at 130C. for 1.5 hr.
then cooled and chromatographed on silica gel, using 20%
methanol in ethyl acetate to elute the product. A portion
of the total yield, 18.5 g. (50O was converted to the
oxalate which melted at 142-5C.
Analysis: Calculated for Cl~H23NOB: C,60.52; HJ6.87; ~,4.15
Found : CJ60~30; HJ6.79; ~J3.98
Example ~4
Trans-l-ethyl-4-r2-(2-propenyl)phenoxyl-3-pyrrolidinol
ethylcarbamate (ester).
A mixture of 7.3 g. of trans 4-(2-allylphenoxy)-1-
ethyl-3-pyrrolidinol and 2.5 g. of ethylisocyanate in 30 ml.
of benzene was stirred for 48 hr. The benzene was replaced
by petroleum ether and the solution chilled. The yield of
precipitate melting at 53-6C. was 78%.
Analysis: Calculated for ClBH2~2O3: C,67.90; H,8.23; N,8.80
Found : C,67.91; H,8.o8; ~,8.79
Example ~
Trans-l-ethYl-4-(1-naPhthalenvloxY)-3-pyrrolidinol
HYdrochloride.
A mixture of 22.6 g. of 3,4-epoxy-1-ethylpyrrolidine
and 28.8 g. of l-naphthol was heated to 130C. for 1 hr.
The mixture was cooled, dissolved in benzene and extracted
366
37
with dilute sodium hydroxide. The benzene wa~ evaporated
and the residue was chromatographed on silica gel, eluting
the product with 40% methanol in ethyl acetate. The hydro-
chloride of the product was made and recrystallized
from ethanol-acetone. The yield of salt melting at 206-7C.
was 17.5 g. (30O -
Analysis: calculated for ClBH20~02Cl: C,65.41; H,6.86; ~,4.77
Found : C,65.29; H,6.93; N,4.70
Example 56
Trans-l-ethyl-4-[(lH-2,3-dihydroinden-4-yl)oxy]-3-
pyrrolidinol.
A mixture of 17 g. of 1-ethyl-3,4-epoxypyrrolidine and
20 g. of 4-indanol was heated at 125C. for 1 hr. then
cooled and dissolved in ethyl acetate and chromatographed on
silica gel, using 25% methanol in ethyl acetate to elute
the product. The yield of product melting at 87-goC. after
recrystallization from cyclohexane was 15 g. (40%).
Analysis: Calculated for C15H2lN02: C,72.84; H,8.56; N,5.66
Found : C,72.92; H,8.52; N,5.48
Example 57
Trans-l-ethyl-4-t(lH-2,~-dihydroinden-5-yl)Oxy]-3-
pyrrolidinol Maleate.
A mixture of 15.0 g. (0.132 mole) of 1-ethyl-3,4-
epoxypyrrolidine, 20 g. (0.15 mole) of 5-indanol and 1 drop
of water was heated on a steam bath overnight. The oil was
dissolved in methylene chloride and washed with three 50-ml.
portions of 5% sodium hydroxide and one 50-ml. portion of
water. The methylene chloride was dried over anhydrous
sodium sulfate and concentrated to give 28.5 g. of a dark
residue. This residue was chromatographed on 500 g. of
silica gel and the product was eluted with methanol. This
oil was converted to the maleate to yield 16.6 g. (35%) of
cream colored needles, m.p. 147-8C.
Analysis: calculated for ClgH2 5~0B: C,62.80; H,6.93; ~,3.85
35 Found : C,62.74; H,6.88; ~,3.83
366
1133495
38
ExamPle 58
Trans-l-cvclohexyl-4-phenOxv-3-pyrrolidinol Compound
with Cvclohexane-sulfamic Acid.
A mixture of 33.5 g. (0.2 mole) of N-cyclohexyl-3,4-
epoxypyrrolidine, 18.8 g. (0.02 mole) of phenol and 2 drops
=- 5 concentrated hydrochloric acid was heated on a steam bath
overnight. The reaction mixture was dissolved in methylene
chloride and washed with three 100-ml portions of 5%
sodium hydroxide and once with 100 ml. of water and dried
over potassium hydroxide-anhydrous sodium sulfate. The
methylene chloride solution was concentrated to give
36.4 g. of oil as residue. The oil partially crystallized
and the solid was washed with petroleum ether, collected
by filtration and recrystallized from cyclohexane to give
11.0 g. (21%) of a white solid. This solid was converted
to the hexamate to yield white needles, m.p. 163-5C.,
recrystallized from isopropyl alcohol.
Analysis: Calculated for C22H3BN205S: C,59.97; H,8-24
~,6.36
Found : C,59.99; H,8.29;
~6.30
Example ~9
Cis-4-Phenoxy-l-Phenvlmethvl-3-Pvrrolidinol.
A slurry of 2.4 g. (0.1 mole) of sodium hydride
(4.2 g. of 57% oil dispersion, washed with ether to remove
the oil) in 30 ml. of dimethylformamide was stirred while
a solution of 19.3 g. (0.1 mole) of 1-benzyl-3J4-dihydroxy-
pyrrolidine, cis isomer, (I) in 30 ml. of dimethylformamide
was added dropwise. The mixture was heated at 50C. for
1 hr., then a solution of 19.2 g. (0.2 mole) of fluoro-
benzene in 30 ml. of dimethylformamide was added in one
portion. The mixture was heated at 90C. for 18 hr., then
cooled and concentrated under vacuum. The residue was
dissolved in benzene and washed with water. The semicrystal-
line residue from the concentrated organic fraction was
dissolved in cyclohexane and the solution was decanted from
an insoluble oil (mostly I). The cyclohexane solution was
treated with charcoal to remove residual I and then
366
39
crystallized as fluffy, off-white needles (m.p. 88.5-90d.)
which weighed 1.2 g. (4.5%).
Analysis: Calculated for Cl7Hl9~02: C,75.ôl; H,7.11; ~,5.20
Found : C,75.88; H,7.27; ~,5.16
Example 60
Cis-4-(3-chlorophenoxy)-l-phenvlmethYl-3-pyrrolidinol.
A slurry of 1.2 g. (50 mmoles) of sodium hydride
(2.1 g. of 57% oil dispersion, washed with ether to remove
the oil) in 25 ml. of dimethyl sulfoxide was stirred while
9.6 g. (50 mmoles) of 1-benzyl-3,4-dihydroxypyrrolidine,
cis isomer, in 25 ml. of dimethyl sulfoxide was added.
The mixture was stirred at ambient temperature for one hr.,
then 50 ml. of dimethyl sulfoxide was added and the
temperature was raised to 95C. for 0.5 hr. Mechanical
stirring of the thick slurry was necessary while 13 g.
(100 mmoles) of m-chlorofluorobenzene was added. During
the heating period of 1 hr. at 95C., all precipitate
dissolved. The reaction mixture was concentrated by vacuum
distillation of the dimethyl sulfoxide and excess m-chloro-
fluorobenzene. The residue was poured into water and
extracted with hot cyclohexane. The organic extracts were
combined, dried over anhydrous sodium sulfate and concen-
trated to give 7.5 g. (49%) of off-white crystals, m.p.
86-87.5C.
Analysis: Calculated for Cl7HlBClN02: C,67.21; H,5.97; ~,4.61
Found : C,67.33; H,6.oo; ~,4.56
ExamPle 61
Cis-3-(3-chloroPhenoxY)-4-hYdroxv-l-methvl-l-phenvl-
methylpyrrolidinium Iodide.
A mixture of 15.2 g. (0.05 mole) of cis-4-(3-chloro-
phenoxy)-l-phenylmethyl-3-pyrrolidinol and 56 g. (0.4 mole)
of methyl iodide was heated at reflux for 60 hr. Excess
methyl iodide was removed under vacuum. The pasty residue
was washed with ether-acetone, leaving 13 g. (59%) of
granular tan powder, m.p. 118-25C.
366
Analysis: calculated for Cl8H2lClINO2: C,48.51; H,4.75;
~,3.14
Found : C,48.27; H,4.75;
~,3.19
ExamPle 62
Cis-l-methyl-4-Phenoxy-3-pyrrolidinol.
A solution of 12.5 g. (28 mmoles) of cis-3-(3-
chlorophenoxy)-4-hydroxy-1-methyl-1-phenylmethylpyrrolidinium
iodide in 400 ml. of ethanol was stirred at 45C. with
3.5 g. (15mmoles) of silver oxide for 1 hr. The solids
were removed by filtration and the filtrate was concen-
trated to 100 ml., treated with 0.5 g. of 10% palladium-on-
charcoal catalyst and was shaken under hydrogen at 60C.
for 3 hr. The mixture was cooled and the catalyst was
collected by filtration. The filtrate was concentrated and
the residue was treated with dilute sodium hydroxide and
extracted into methylene chloride. The solution was concen-
trated and redissolved in hot cyclohexane, treated with
charcoal, separated by filtration through Celite and
recrystallized from cyclohexane to give 4.6 g. (85%) of
white needles (m.p. 78-81C).
Analysis: Calculated for CllHl5~02: C,68.37; H,7.82; N,7.25
Found : C,68.42; H,7.87; ~,7.19
Example 63
Cis-4-Phenoxy-3-pvrrolidinol cis isomer Hydrochloride
HYdrate (4-1).
A solution of 16.0 g. (53 mmoles) of cis-4-(3-chloro-
phenoxy)-l-phenylmethyl-3-pyrrolidinol in 100 ml. of
absolute ethanol and 5 ml. concentrated hydrochloric acid
was treated with 0.5 g. of 10~ palladium-on-charcoal catalyst
and was shaken under hydrogen at 60C. for 16 hr. The
mixture was cooled and the catalyst was separated by
filtration through Celite. The filtrate was concentrated and
the white crystalline residue was triturated with ether-
acetone. Weight of white powder~ 9.8 g. (86%), m.p. 128-37C.
was obtained.
Analysis: Calculated for C4OH58Cl4~409: C,54.55; H,6.64; N,6.36
Found : C,54.26; H,6.41; ~,6.27
r k
366
1133495
41
Formulation and Administration
Effective quantities of any of the foregoing pharma-
cologically active compounds of Formula I may be adminis-
tered to a living animal body for therapeutic purposes
according to usual modes of administration and in usual
forms, such as orally in solutions, emulsions, suspensions,
pills, tablets and capsules in pharmaceutically acceptable
carriers and parenterally in the form of sterile solutions.
For the parenteral administration the carrier or
excipient may be a sterile, parenterally acceptable liquid;
e.g., water or a parenterally acceptable oil; e.g., arachis
oil contained in ampules.
Although very small quantities of the active materials
of the present invention are effective when minor therapy
is involved or in cases of administration to subjects having
a relatively low body weight, unit dosages are usually from
five milligrams or above and preferably 25, 50, or 100
milligrams or even higher, depending, of course, upon the
emergency of the situation and the particular result desired.
Five to 50 milligrams appears optimum per unit dose or usual
broader ranges appear to be 1 to 500 milligrams per unit dose.
Daily dosages should preferably range from 10 mg. to 100 mg.
The active ingredients of the invention may be combined with
other pharmacologically active agents as stated above. It is
only necessary that the active ingredient constitute an
effective amount, i.e., such that a suitable effective dosage
will be obtained consistent with the dosage form employed.
Obviously, several unit dosage forms may be administered at
about the same time. The exact individual dosages as well
as daily dosages will, of course, be determined according to
standard medical principles under the direction of a physician
or veterinarian.
The following formulations are representative for all
of the pharmacologically active compounds of this invention.
366
3495
42
FORMULATIO~S
1. Capsules
Capsules of 5 mg., 10 mg., 25 mg., and 50 mg. of
active ingredient per capsule are prepared. With the
higher amounts of active ingredient, reduction may be made
in the amount of lactose.
Tvpical blend for encapsulation Per capsule, mq.
L a c t o s e 2125 596
Magnesium stearate 4
Total 394
Additional capsule formulations preferably contain a
higher dosage of active ingredient and are as follows:
loo 250 500
mg. per mg. per mg. per
15 Ingredients CaPsule CaPsule CaPsule
Active ingredient, 100 250 500
as salt
Lactose 287 81 47
Magnesium stearate 4 6 8
20Total 399 500 650
In each case, uniformly blend the selected active
ingredient with lactose, starch, and magnesium stearate
and encapsulate the blend.
252. Tablets
A typical ormulation for a tablet containing 5.o mg.
of active ingredient per tablet follows. The formulation
may be used for other strengths of active ingredient by
adjustment of weight of dicalcium phosphate.
3 Per Tablet, mq.
1. Active ingredient 5.o
2 Corn starch 15.0
3 Corn starch (paste) 12.0
4 Lactose 35. o
5 Dicalcium phosphate 132.0
6. calcium stearate 2.0
Total202.0
, 366
1133~95
43
Uniformly blend l, 2, ~ and 5. Prepare 3 as a 10 per
cent paste in water. Granulate the blend with starch
paste and pass the wet mass through an 8 mesh screen. The
wet granulation is dried and sized through a 12 mesh screen.
The dried granules are blended with the calcium stearate
and compressed.
3. Injectable - 2~ sterile solution Per cc
Active ingredient mg. 20
Preservative, e.g.
chlorobutanol, wt./vol. percent 0.5
Water for injection q.s.
Prepare solution, clarify by filtration, fill into vials,
seal and autoclave.
Various modifications and equivalents will be apparent
to one skilled in the art and may be made in the compounds,
compositions and methods of the present invention without
departing from the spirit or scope thereof, and it is
therefore understood that the invention is to be limited
only by the scope of the appended claims.
