CA1133495A - Cis and trans-3-aryloxy-4- hydroxypyrrolidines and derivatives thereof - Google Patents

Abstract

ABSTRACT OF THE INVENTION
Cis and trans-3-aryloxy-4-hydroxypyrrolidines and derivatives thereof having the formula:

Description

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~

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

wherein R2 is hydrogen, lower-alkyl or phenylalkyl, and Ar is phenyl or substituted phenyl.
Compounds preferred for their antidepressant activity have the formula:

~ ( 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 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:

HO I OAr I Formula Ic 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.

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).
\

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 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-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 ~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 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 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 C~H5 2) H2, Pd/C R O OAr ( 3) Rl = alkyl 2 5 HO ~ ~aH~

C~Hs C~H5 ~0 ( 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 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

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

11~

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

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.

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 ,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~ .

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 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 1133~

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 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 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-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 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.

35 Analysis: Calculated for ClOHl29rCl2N02: C,36.51; H,3 68, Found : C,36.54; H,3.69 N,4.32 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 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 ~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 1133~95 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 1133~,~5 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 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 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 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 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 11 3.~95 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 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 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 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 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 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.

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 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.

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 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.

Claims (41)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing compounds having the formula I:
cis and trans isomers wherein;
R1 is selected from the group consisting of hydrogen, lower alkyl, benzyloxycarbonyl and N-loweralkylcarbamoyl, R2 is selected from hydrogen, lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-diloweralkylcarbamoyl and parafluorobenzoyl-loweralkyl, Ar is selected from phenyl, substituted phenyl, l-naphthyl, 2-naphthyl, 1-indenyl and 2-indenyl, and the pharmaceutically acceptable addition and quaternary salts thereof, which process comprises (a) to form a trans isomer, reacting a 3,4-epoxypyrrolidine of formula or a salt thereof, with a compound of formula ArOH, wherein Ar is as defined above and R2 represents alkyl, cycloalkyl or phenylalkyl, to obtain the trans isomer of a compound of formula and, if required, converting this compound to another trans-compound of formula I and, if required, converting the trans-compound of formula I into a pharmaceutically acceptable acid addition or quaternary ammonium salt, or (b) to form a cis isomer, reacting a 3,4-pyrrolidinediol of formula or a salt thereof, with a compound of formula ArF, wherein Ar is as defined above and R2 represents benzyl, to obtain the cis isomer of a compound of formula and, if required, converting this compound to another cis-compound of formula I and, if required, converting the cis-compound of formula I into a pharma-ceutically acceptable acid addition or quaternary ammonium salt.

2. A process according to claim 1 wherein process (a) is used and the 3,4-epoxypyrrolidine and compound of formula ArOH are heated together.

3. A process according to claim 1 wherein process (a) is used and the 3,4-epoxypyrrolidine is substituted in the 1-position by an alkyl group.

4. A process according to claim 1 wherein process (a) is used and the 3,4-epoxypyrrolidine is substituted in the 1-position by a benzyl group.

5. A process according to claim 1 wherein process (b) is used and the reaction is carried out in the presence of sodium hydride and dimethyl form-amide as solvent.

6. A process according to claim 1 wherein process (b) is used and a compound of formula ArF is used in which Ar represents phenyl or halophenyl.

7. A process according to claim 1, wherein the product in which R2 represents benzyl is converted by hydrogenolysis to a compound of formula I
in which R2 represents a hydrogen atom.

8. A process according to claim 1, 5 or 6 wherein the 1-benzyl compound of formula I is reacted with a lower alkyl iodide to form a quaternary ammonium iodide salt followed by treatment with silver oxide and then hydro-genation to obtain a compound of formula I in which R2 is the lower alkyl group of the alkyl iodide.

9. A process according to claim 1, 5 or 6, wherein the 1-benzyl com-pound of formula I is reacted with a lower alkyl halide in the presence of sodium hydride to obtain a compound of formula I in which R1 is the lower alkyl group derived from the alkyl halide.

10. A process according to claim 7, wherein the product of formula I in which R2 is hydrogen is reacted with .beta.-diloweralkyl amino-p-fluoropropiophenone, or a salt thereof, to obtain a compound in which R2 is a p-fluorobenzoylethyl group.

11. A process according to claim 1, 5 or 6, wherein the 1-benzyl com-pound of formula I is reacted with benzylchloroformate, to obtain a compound of formula I in which R2 is a benzyloxycarbonyl group or both R1 and R2 are benzyloxycarbonyl groups.

12. A process according to claim 1 which includes the step of reacting a compound in which Ar represents halophenyl and R2 is a benzyloxycarbonyl group with hydrogen bromide to obtain a compound in which Ar represents halo-phenyl and R2 is hydrogen.

13. A process according to claim 7, wherein a product of formula I in which R2 is hydrogen is reacted with nitrourea to convert R2 to a carbamoyl group.

14. A process according to claim 7 wherein a product of formula I in which R2 is hydrogen is reacted with a diloweralkyl carbamyl chloride to con-vert R2 into an N,N-diloweralkyl carbamoyl group.

15. A process according to claim 7 wherein a product of formula I in which R2 is hydrogen is reacted with a lower alkyl isocyanate to convert R2 to an N-loweralkyl carbamoyl group.

16. A compound of formula I as defined in claim 1 when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

17. A process according to claim 1 wherein the reactants are selected to obtain a trans isomer in which Rl and R2 are both hydrogen and Ar is a 2,6-dichlorophenyl group.

18. A process for preparing trans-4-(2,6-dichlorophenoxy)-3-pyrrolidinol and its hydrobromide salt which comprises reacting 3-(2,6-dichlorophenoxy) 4-[phenylmethyl(carbonylbis(oxy))]-1-pyrrolidinecarboxylic acid phenylmethyl ester trans isomer with hydrogen bromide to obtain trans-4-(2,6-dichlorophen-oxy)-3-pyrrolidinol hydrobromide salt and, if required, converting the salt to the free base.

19. A process according to claim 18 wherein the 3-(2,6-dichlorophenoxy)-4-[phenylmethyl(carbonylbis(oxy))]-1-pyrrolidinecarboxylic acid phenylmethyl ester trans isomer is obtained by reaction between trans-1-benzyl-4-(2,6-dichlorophenoxy)-3-pyrrolidinol and benzylchloroformate.

20. A process according to claim 19 wherein the trans-1-benzyl-4-(2,6-dichlorophenoxy)-3-pyrrolidinol is obtained by reacting 1-benzyl-3,4-epoxy-pyrrolidine with 2,6-dichlorophenol.

21. Trans-4-(2,6-dichlorophenoxy)-3-pyrrolidinol and its hydrobromide salt when made by a process according to claim 18, 19 or 20 or an obvious chemical equivalent thereof.

22. A process according to claim 1 wherein the reactants are selected to obtain a trans isomer in which R1 is hydrogen,R2 is an ethyl group and Ar is a phenyl group.

23. A process for preparing trans-1-ethyl-4-phenoxy-3-pyrrolidinol and its oxalate salt which comprises reacting 1-ethyl-3,4-epoxypyrrolidine and phenol and, if the oxalate salt is required, reacting the product with oxalic acid.

24. Trans-1-ethyl-4-phenoxy-3-pyrrolidinol and its oxalate salt when made by a process according to claim 23 or an obvious chemical equivalent thereof.

25. A process according to claim 1 wherein the reactants are selected to obtain a trans isomer in which R1 is hydrogen, R2 is a methyl group and Ar is a phenyl group.

26. A process for preparing trans-1-methyl-4-phenoxy-3-pyrrolidinol which comprises treating trans-3-hydroxy-1-methyl-4-phenoxy-1-phenylmethyl-pyrrolidinium iodide with silver oxide, followed by hydrogenation.

27. A process according to claim 26 wherein the trans-3-hydroxy-1-methyl-4-phenoxy-1-phenylmethyl-pyrrolidinium iodide is obtained by reacting trans-4-phenoxy-1-phenylmethyl-3-pyrrolidinol with methyl iodide.

28. A process according to claim 27 wherein the trans-4-phenoxy-1-phenylmethyl-3-pyrrolidinol is obtained by reacting 1-benzyl-3,4-epoxypyrro-lidine with phenol.

29. Trans-1-methyl-4-phenoxy-3-pyrrolidinol when prepared by a process according to claim 26, 27 or 28 or an obvious chemical equivalent thereof.

30. A process according to claim 1 wherein the reactants are selected to obtain a trans isomer in which R1 is hydrogen, R2 is an ethyl group and Ar is a 2,6-dichlorophenyl group.

31. A process for preparing trans-4-(2,6-dichlorophenoxy)-1-ethyl-3-pyrrolidinol and its hydrochloride salt which comprises reacting 1-ethyl-3,4-epoxypyrrolidine with 2,6-dichlorophenol and, if the hydrochloride salt is required, reacting the product with hydrogen chloride.

32. Trans-4-(2,6-dichlorophenoxy)-1-ethyl-3-pyrrolidinol when prepared by a process accordlng to claim 31 or an obvious chemical equivalent thereof.

33. A process according to claim 1 wherein the reactants are selected to obtain a trans isomer in which R1 is hydrogen, R2 is hydrogen and Ar is a 2,3-dichlorophenyl group.

34. A process for preparing trans-4-(2,3-dichlorophenoxy)-3-pyrrolidinol and its hydrobromide salt which comprises reacting 3-(2,3-dichlorophenoxy)-4-{phenylmethyl[carbonylbis(oxy)]}-1-pyrrolidine carboxylic acid phenylmethyl ester trans isomer with hydrogen bromide to obtain the hydrobromide salt and, if required, converting the salt to the free base.

35. A process according to claim 34 wherein the 3-(2,3-dichlorophenoxy)-4-{phenylmethyl[carbonylbis(oxy)]}-1-pyrrolidine carboxylic acid phenylmethyl ester trans isomer is obtained by reacting trans-4-(2,3-dichlorophenoxy)-1-phenylmethyl-3-pyrrolidinol hydrochloride with benzyl chloroformate.

36. A process according to claim 35 wherein the trans-4-(2,3-dichloro-phenoxy)-1-phenylmethyl-3-pyrrolidinol hydrochloride is obtained by reacting 1-benzyl-3,4-epoxypyrrolidine with 2,3-dichlorophenol, followed by reaction with hydrogen chloride.

37. Trans-4-(2,3-dichlorophenoxy)-3-pyrrolidinol and its hydrobromide salt when prepared by a process according to claim 34, 35 or 36 or an obvious chemical equivalent thereof.

38. A process according to claim 1 wherein the reactants are selected to obtain a compound in which R1 is hydrogen, R2 is hydrogen or a lower alkyl group and Ar is a 1-naphthyl, 2-naphthyl, 4-indenyl or 5-indenyl group.

39. A process according to claim 1 wherein the reactants are selected to obtain a trans isomer in which R1 is hydrogen, R2 is an ethyl group and Ar is a 1-naphthyl group.

40. A process for preparing trans-1-ethyl-4-(1-naphthalenyloxy)-3-pyrrolidinol and its hydrochloride salt which comprises reacting 3,4-epoxy-1-ethylpyrrolidine and 1-naphthol and, if the hydrochloride salt is required, reacting the product with hydrogen chloride.

41. Trans-1-ethyl-4-(1-naphthalenyloxy)-3-pyrrolidinol and its hydro-chloride salt when prepared by a process according to claim 40 or an obvious chemical equivalent thereof.