US2956062A - Esters of amino alcohols - Google Patents

Esters of amino alcohols Download PDF

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US2956062A
US2956062A US795598A US79559859A US2956062A US 2956062 A US2956062 A US 2956062A US 795598 A US795598 A US 795598A US 79559859 A US79559859 A US 79559859A US 2956062 A US2956062 A US 2956062A
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Carl D Lunsford
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms

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  • the present invention relates to esters of amino alcohols, more particularlycertain esters of N.- or l-substituted 3-pyrrolidinols. These novel compounds include the cycloalkyl-aryl-acetates and glycolates of 3-pyrrolidinols.
  • the concept constituting the present invention is illustrated by the following structural formula:
  • Quaternary ammonium salts such as alkyl salts, aralkyl salts, and the like, of the organic. bases illustrated in the general structural formula appearing above may be readily formed by treatment of the organic bases with the ap- 2,956,062 Patented Oct. 11, 1960,
  • the present invention is characterized by a particular, esterification of a secondaryalcohol attached directly to a ring carbon in the 3.,position of the pyrrolidine ring fraction.
  • the prior art into which the compounds of the present invention fall can be distinguished.
  • UnitedjStates Patent 2,695,301, Singhe teaches benzilates proceeding from the 2 position of the pyrrolidine ring but differs from the present invention in that the alcohol group is primary and extra-cyclic;
  • United States Patent 2,735,847, Magnoliae describes diphenyl acetates proceeding from the N or'l position in the pyrrolidine ring and involves extracyclic esterification.
  • intestinal quaternary salt forming substances, which in- 1 elude, for example, methyl chloride, methyl bromide, methyl iodide, methyl sulfate, methylbenzene-sulfonate, methyl p-toluenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-
  • propyl iodide isopropyl bromide, n-butyl chloride, n-butyl bromide, isobutyl bromide, sec.-butyl bromide, n-amyl bromide, n-hexyl chloride, benzyl chloride, benzyl bromide, and ethyl sulfate, yielding respectively the metrochloride, methobromide, methiodide, methyl methosulfate, fonate, ethochloride, ethobromide, ethiodide, n-propochloride, n-propobromide, n-propiodide, isopropobromide, n-butochloride, n-butobromide, isobutobromide, sec.-bu tobromide, n-amobromide, n hexochloride, benzochloride, benzo
  • a hydrocarbon radical such as alkyl, cycloalkyl, aralkyl and the like,fpreferably lower alkyl.
  • the preferred hydrocarbon radicals are alkyl, especially straight and branched chain lower alkyl radicals, cycloalkyl and aralkyl.
  • lower alkyl is defined toinclude straight and branched chain radicals of 1 -6 carbon atoms inclusive and includes such substituents as methyl, ethyl, isopropyl, tertiary butyl, isoamyl and the like.
  • c-ycloalkyL is defined to includepr-irnarily cyclic alkyl radicals contain: ing 5 to 8 carbon atoms inclusive and'encompass'es such substituents as cyclohexyl, cyclopentyl, methyl cyclohexyl, ethyl cyclopentyl, dimethyl-cyclohexyl, and cycloheptyl.
  • aralkyl are-such radicals as lower alkyl-substituted mono-carbocyclic aryl compounds such as benzyl, phenethyl, phenpropyl and the like.
  • R is a hydrocarbon radical containing less than 8 carbon atoms :and is selected from'the group consisting of lower alkyl,..cycloalkyl and aralkyl.
  • the cycloalkyl hydrocarbon radicals are defined as above; preferably, the cycloalkyl radical contains at least 5 and less than 8 carbon atoms.
  • R in the above structur'alformulaflfin column 1) R" is preferably an hydroxy radical.
  • R is preferably an hydroxy radical.
  • forreasons of activity the esters in the formof nontoxic, pharmaceutically acceptable acid addition and quaternary ammonium salt compounds; where a 3 in referring to the structural formula in column 1, R is lower alkyl, R is cyclopentyl and R" is hydroxy, are preferred.
  • the specifically preferred compounds are: a
  • alpha carbon of the acetate group preferably is further substituted by a hydroxy radical, i.e., wherein R" is a hydroxy radical.
  • R" is a hydroxy radical.
  • a highly preferred compound by reason of activity from these esters having a hydroxy radical on the alpha carbon of the acetate is the 1-rnethyl-3-pyrrolidyl alpha-cyclopentyl-mandelate methobrornide (1-methyl-3-(alpha-cyclopentylphenylhydroxyacetyloxy) pyrrolidine methobromide).
  • This compound was found to be active at a. dilution of about one part in 100,000,000 in counter-acting spasms induced by acetylcholine in isolated intestinal strips.
  • Other preferred compounds include l-methyl-3- pyrrolidyl alpha-cyclopentyl-mandelate hydrochloride and 1-ethyl-3-pyrrolidyl alpha-cyclopentyl-mandelate hydrochloride.
  • N or 1. lower alkyl substituted compounds indicated greater activity and generally the alphacycloalkyl-mandelates were preferred.
  • esters of the present invention may be prepared by reaction of a l-hydrocarbon substituted-3-pyrrolidinol of the formulawherein R is as above with an alpha. aryl acetic acid compound of the formula:
  • R and R are as above and B isv hydroxy, halogen or lower alkoxy.
  • the transesterification reaction is conducted in the presence of a sodium metal catalyst until the theoretical amount of lower alkanol separates.
  • the reaction conditions are similar for all variants of starting compounds, i.e., the reactants, used in approximately equimolar amounts, are heated at reflux temperatures for periods of at least about one hour and usually from one to two. hours, preferably using a hydrocarbon solvent as the reaction medium.
  • Theresulting reaction product is extracted with dilute mineral acid,,e.g.
  • hydrochloric acid and the resulting extract basified (e.g. with aqueous sodium hydroxide) to yield the free base upon extraction with the appropriate solvent.
  • the acid addition salts and quaternary salts are produced from the base by reaction in solvent of the base and the appropriate acid or quaternizing reagent.
  • All compounds may be prepared by the alternative modifications of the procedure using either the acid or acid chloride, or the lower-alkyl ester of the acid, e.g., the methyl ester.
  • the hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride and crystallized from butanone; melting point l53.5154.5 C.
  • the methiodide quaternary precipitated from an ethereal solution was the base and excess methyl iodide after standing for several hours. It was crystallized from butanone; melting point 169.5-170.5 C.
  • the hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride and crystallized from butanone; melting point 107.5l09.5 C.
  • the methobrornide quaternary was precipitated from an ethereal solution of the base and excess methyl bro mide after standing for thirty-six hours. it was crystallized first from an ethyl acetate-ether mixture and then from butanone; melting point 104-106 C.
  • the hydrochloride was precipitated from an ethereal splution of: the base with ethereal hydrogen chloride and crystallized from butanone; melting point 142-143.5 C.
  • the hydrochloride was precipitated as an oil from an ethereal solution of the base with ethereal hydrogen chloride. This was crystallized from a methonol-ethyl acetate mixture and melted at 114-l15 C.
  • methyl bromide quaternary was precipitated from an ethereal solution of the base and excess methyl bromide after standing for seventy-two hours. It was purified by recrystallization from butanone and melted at 166.5- 168 C. r
  • EXAMPLE 5 -1-n-BUTYL-3-PYRROLIDYL ALPHA- CYCLOPENTYLMANDELATE
  • the hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride as an oil. It was crystallized from butanone and melted at 129-130 C.
  • hydrochloride salt was precipitated as an oil from an ethereal solution of the base with ethereal hydrogen "chloridei It' was crystallized from butanone; melting EXAMPLE 7.--1-ETHYL-3-PYRROLIDYL ALPHA- CYCLOPENTYLMANDELATE HYDROCHLORIDE
  • This compound was prepared according to the method outlined for the methyl derivative above (see Example 6).
  • the base boiled at 162-165 C./0.25 mm. After recrystallization from butanone :the salt melted 160- 161.5 C.
  • This compound was prepared according to the method outlined for the methyl derivative above as in Example 6.
  • the base boiled at 193-195 C./0.038 mm. After recrystallization from butanone and absolute ethanol the salt melted 2l2213.5 C.
  • EXAMPLE 9.lMETHYL-3-PYRROLIDYL ALPHA- CYCLOHEXYLMANDELATE A mixture of 10 grams (0.0403 mole) of methyl alphacyclohexylmandelate and 5 grams (0.0493 mole) of N- rnethyl-3-pyrrolidin0l' in ml. of n-heptane was refluxed for five hours under a Dean and Stark moisture trap. At approximately equal intervals starting at zero time three approximately 0.1 gram pieces of sodium metal were added to the reaction. At completion of the reflux time the heptane solution was extracted wtih icecold 3 N hydrochloric acid. The acid extract was basi-.
  • the hydrochloride salt was precipitated as a crystalline solid from an ethereal solution of the base with ethereal hydrogen chloride. It was crystallized from a butane methanol mixture; M.'P. 206-207 C. a I
  • the methyl bromide quaternary was prepared-by saturating a solution of the free base in dry'- ethyl etherfwith methyl bromide and allowing the solution to stand 15
  • the product precipitated as white crystals' 'and hours. was recrystallized from butanone; M.P. 253-255 C (d).
  • This decomposition range varies with the rate at which the sample is heated.
  • This material was converted to the hydrochloride salt by precipitation as a crystalline solid from an ethereal solution of the base with ethereal hydrogen chloride. This material was fractionally crystallized from methyl ethyl ketone and from an ethyl acetate methanol mixture. High and low melting isomers were obtained:
  • the low melting isomer is designated the alpha (0:) form and the high melting isomer is referred to as the beta (13) form in Table I.
  • Aqueous solutions of all materials were employed in these studies. Essentially, the method consisted of initially standardizing submaximal contractions of the isolated ileum to acetylchlorine chloride, histamine phosphate, serotonin creatinine sulfate and barium chloride. The test material was then introduced into the bath and two minutes later the ileum was again challenged with the various spasmogens. Tests were made at various concentrations of the compounds in the bath until it was possible to differentiate their relative activity as antagonists of the spasmogens.
  • the results of the pharmacological testing indicate that the compounds are predominantly acetylcholine antagonists and are eflective in inhibiting gastrointestinal motility in vivo and in vitro. In general, the compounds compared favorably in potency with Methantheline bromide under the conditions of these tests.
  • R is a cycloalkyl hydrocarbon radical containing five to eight carbon atoms inclusive and having five to seven carbon atoms inclusive in the ring, and
  • R" is a radical selected from the group consisting of hydrogen and hydroxyl; and nontoxic acid addition and lower-alkyl and benzyl quaternary ammonium salts thereof.
  • cycloalkyl lL wer-alkyl wherein the cycloalkyl radical contains five to eight carbon atoms, inclusive, and has five to seven carbon atoms, inclusive, in the ring.

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Description

Unit S wsPa U ESTERS F AlVIINO ALCOHOLS Carl D. Lnnsford, Richmond, Va., assignor to A. H. Robins Company, Inc., Richmond, Va., a corporation of Virginia No Drawing. Filed Feb. 26, 1959, Ser. No. 795,598
12 Claims. ((31. 260-3263) The present invention relates to esters of amino alcohols, more particularlycertain esters of N.- or l-substituted 3-pyrrolidinols. These novel compounds include the cycloalkyl-aryl-acetates and glycolates of 3-pyrrolidinols. The concept constituting the present invention is illustrated by the following structural formula:
shown above may be readily prepared as illustrated in the examples. below and include salts formed with such' inorganic and organic acids as hydrochloric, hydrobromic, hydriodic, sulfuric, sulfamic, phosphoric, acetic, glycolic, succinic, maleic, malic, citric, tartaric, ascorbic, benzoic,
cinnamic, mandelic, benzilic, diphenylacetic and the like.
Quaternary ammonium salts such as alkyl salts, aralkyl salts, and the like, of the organic. bases illustrated in the general structural formula appearing above may be readily formed by treatment of the organic bases with the ap- 2,956,062 Patented Oct. 11, 1960,
2 acid and separating by fractional crystallization the dandl-forms.,, V
Evaluations of the compounds of the above concept by standard pharmacological tests have indicated the utility thereof as inhibitors of gastrointestinal motility, comparing favorably in potency with 'Methantheline bromide; The compounds are predominantly antagonists ofacetylcholine.
This application isa continuation-in-part of Serial No. 666,250, Lunsford, filed June 17, 1957, entitled Esters of Amino Alcohols, now abandoned.
The present invention is characterized by a particular, esterification of a secondaryalcohol attached directly to a ring carbon in the 3.,position of the pyrrolidine ring fraction. The prior art into which the compounds of the present invention fall can be distinguished. United States Patent 2,655,511, Woodruif, describes N or 1 pyrrolidyl esters where the alkanol group is extra-cyclic to the pyrrolidine ring (where there is a methylene bridge attached to the heterocyclic nitrogen); UnitedjStates Patent 2,695,301, Blicke, teaches benzilates proceeding from the 2 position of the pyrrolidine ring but differs from the present invention in that the alcohol group is primary and extra-cyclic; United States Patent 2,735,847, Blicke, describes diphenyl acetates proceeding from the N or'l position in the pyrrolidine ring and involves extracyclic esterification.
propriate quaternary salt, forming substances, which in- 1 elude, for example, methyl chloride, methyl bromide, methyl iodide, methyl sulfate, methylbenzene-sulfonate, methyl p-toluenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-
propyl iodide, isopropyl bromide, n-butyl chloride, n-butyl bromide, isobutyl bromide, sec.-butyl bromide, n-amyl bromide, n-hexyl chloride, benzyl chloride, benzyl bromide, and ethyl sulfate, yielding respectively the methochloride, methobromide, methiodide, methyl methosulfate, fonate, ethochloride, ethobromide, ethiodide, n-propochloride, n-propobromide, n-propiodide, isopropobromide, n-butochloride, n-butobromide, isobutobromide, sec.-bu tobromide, n-amobromide, n hexochloride, benzochloride, benzobromide, ethosulfate, etc.-
.In the structural formula given above, the asterisks 'serve to point out the asymmetric carbon atoms present in many of the compounds of the present invention. When two asymmetric centers are present, pairs of diastereoisomers are possible. 'with their optically active forms are included within the scope of the present invention.
The twopairs of diastereoisomers are separated and resolution of the diastereoisomers into their optically active forms may be accomplished by combining the methobenzenesulfonate, metho-p-toluenesul- These diastereoisomers, together Therefore, it is an object of this invention to provide novelcycloalkyl-aryl-acetic acid esters of 3-py1'rolidinols. It is a further object of the present invention to provide such esters wherein the alpha carbon of the acetate group may be substituted by an additional radical such as hy-. droxyl and wherein the 3-pyrrolidine portion of the molecule is substituted in the N ortl position; I It is, an additional object of the present invention to provide novel acetylcholine antagonists having satisfactory activity when compared with known compounds currently in use as inhibitors of gastrointestinal motility.
Other objects. of the invention-will become apparent to those skilled in the art to which this invention pertains. Members of the new group of compounds. include the alpha-cycloalkyl-aryl.aceticand glycolicacid esters of 3- pyrrolidinols where the N or 1 position of the pyrrolidine ring substituted by a hydrocarbon radical such as alkyl, cycloalkyl, aralkyl and the like,fpreferably lower alkyl. Referring to'R' in the'above structuralformula, the preferred hydrocarbon radicals are alkyl, especially straight and branched chain lower alkyl radicals, cycloalkyl and aralkyl.
The term lower alkyl is defined toinclude straight and branched chain radicals of 1 -6 carbon atoms inclusive and includes such substituents as methyl, ethyl, isopropyl, tertiary butyl, isoamyl and the like. The term c-ycloalkyLis defined to includepr-irnarily cyclic alkyl radicals contain: ing 5 to 8 carbon atoms inclusive and'encompass'es such substituents as cyclohexyl, cyclopentyl, methyl cyclohexyl, ethyl cyclopentyl, dimethyl-cyclohexyl, and cycloheptyl. Included in the term aralkyl are-such radicals as lower alkyl-substituted mono-carbocyclic aryl compounds such as benzyl, phenethyl, phenpropyl and the like. Preferably, R is a hydrocarbon radical containing less than 8 carbon atoms :and is selected from'the group consisting of lower alkyl,..cycloalkyl and aralkyl. Q
Referringto R in the above structural formula the cycloalkyl hydrocarbon radicals are defined as above; preferably, the cycloalkyl radical contains at least 5 and less than 8 carbon atoms.
.Referring to R in the above structur'alformulaflfin column 1), R" is preferably an hydroxy radical. ,Gener'ally, forreasons of activity the esters in the formof nontoxic, pharmaceutically acceptable acid addition and quaternary ammonium salt compounds; where a 3 in referring to the structural formula in column 1, R is lower alkyl, R is cyclopentyl and R" is hydroxy, are preferred. Among the specifically preferred compounds are: a
1 ethyl 3 pyrrolidyl alpha-cyclopentylpheuylacetate methobrornide.
1 -'methyl 3 pyrrolidyl alpha-cyclopentyl-mandelate hydrochloride 1 methyl 3 pyrrolidyl alpha-cyclopentyl-mandelate methobrornide l-ethyl-S-pyrrolidyl alpha-cyclohexylphenylacetate hydrochloride l-methyl 3 pyrrolidyl alpha-cyclohexylphenylacetate methiodide 1 ethyl 3 -pyrrolidyl alpha-cyclohexylphenylacetate methiodide 1 benzyl 3 pyrrolidyl alpha-cyclohexylphenylacetate methobrornide The alpha carbon of the acetate group preferably is further substituted by a hydroxy radical, i.e., wherein R" is a hydroxy radical. Such compounds may be alternatively viewed as substituted glycolates or mandelates.
A highly preferred compound by reason of activity from these esters having a hydroxy radical on the alpha carbon of the acetate is the 1-rnethyl-3-pyrrolidyl alpha-cyclopentyl-mandelate methobrornide (1-methyl-3-(alpha-cyclopentylphenylhydroxyacetyloxy) pyrrolidine methobromide). This compound was found to be active at a. dilution of about one part in 100,000,000 in counter-acting spasms induced by acetylcholine in isolated intestinal strips. Other preferred compounds include l-methyl-3- pyrrolidyl alpha-cyclopentyl-mandelate hydrochloride and 1-ethyl-3-pyrrolidyl alpha-cyclopentyl-mandelate hydrochloride.
Generally, the N or 1. lower alkyl substituted compounds indicated greater activity and generally the alphacycloalkyl-mandelates were preferred.
The esters of the present invention may be prepared by reaction of a l-hydrocarbon substituted-3-pyrrolidinol of the formulawherein R is as above with an alpha. aryl acetic acid compound of the formula:
wherein R and R are as above and B isv hydroxy, halogen or lower alkoxy.
When B is lower alkoxy, the transesterification reaction is conducted in the presence of a sodium metal catalyst until the theoretical amount of lower alkanol separates. With this exception, the reaction conditions are similar for all variants of starting compounds, i.e., the reactants, used in approximately equimolar amounts, are heated at reflux temperatures for periods of at least about one hour and usually from one to two. hours, preferably using a hydrocarbon solvent as the reaction medium. Theresulting reaction product is extracted with dilute mineral acid,,e.g.
hydrochloric acid, and the resulting extract basified (e.g. with aqueous sodium hydroxide) to yield the free base upon extraction with the appropriate solvent. The acid addition salts and quaternary salts are produced from the base by reaction in solvent of the base and the appropriate acid or quaternizing reagent.
The preparation of the starting N-substituted-3-pyrrolidinols used in the present invention has been previously described in United States Patents 2,830,997 and 2,838,- 521, Lunsford.
The following examples illustrate the preparation of the compounds of the present invention:
All compounds may be prepared by the alternative modifications of the procedure using either the acid or acid chloride, or the lower-alkyl ester of the acid, e.g., the methyl ester.
EXAMPLE l.-1-METHYL-3 -PYRROLIDYL ALPHA- CYCLOHEXYLPHENYLACETATE To a solution of 71 grams (0.3 mole) of alpha-cyclohexylphenylacetyl chloride in toluene were added 35.5 grams (0.35 mole) of l-methyl-3-pyrrolidinol at a dropwise rate with stirring. After complete addition the mixture was refluxed for four hours, cooled and extracted with 3 N hydrochloric acid. The acid extract was basified with aqueous sodium hydroxide and extracted with chloroform. The chloroform layer was washed, dried over sodium sulfate and concentrated. The residue was distilled at reduced pressure. Yield 50 grams (55 percent); boiling point l44-l47 C. at 0.5 mm.
The hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride and crystallized from butanone; melting point l53.5154.5 C.
The methiodide quaternary precipitated from an ethereal solution was the base and excess methyl iodide after standing for several hours. It was crystallized from butanone; melting point 169.5-170.5 C.
EXAMPLE 2.--l-n-BUTYL-3-PYRROLIDYL ALPHA- CYCLOPENTYLPHENYLACETATE To a solutionof 89 grams (0.4 mole) of alpha-cyclm pentylphenylacetyl chloride in benzene were added 71.5 grams (0.50 mole) of l-n-butyl-3-pyrrolidinol at a dropwise rate with stirring. After complete addition the mixture was refluxed for two hours, cooled and extracted with 3 N hydrochloric acid. The acid extract was basified with aqueous sodium hydroxide and extracted with ether. The layer was washed, dried over sodium sulfate, and concentrated. The residue was distilled at reduced pressure. Yield grams (67 percent); boiling point -155 C. at 0.1 mm.
The hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride and crystallized from butanone; melting point 107.5l09.5 C.
The methobrornide quaternary was precipitated from an ethereal solution of the base and excess methyl bro mide after standing for thirty-six hours. it was crystallized first from an ethyl acetate-ether mixture and then from butanone; melting point 104-106 C.
EXAMPLE 3 .l-BENZYL-3-PYRROLIDYL ALPHA- CYCLOHEXYLPHENYL-ACETATE To a solution of 71 grams (0.3 mole) of alpha-cyclohexylphenylacetyl chloride in toluene were added 62 grams (0.35 mole) of 1-benzyl-3-pyrrolidinol, at a dropwise rate with stirring. After complete addition the mixture was refluxed for four hours, cooled and extracted with 3 N hydrochloric acid. The acid extract was basified with aqueous sodium hydroxide and extracted with chloroform.
70 The chloroform layer was washed, dried over sodium sulfate and concentrated. The residue was distilled at reduced pressure. Yield 45.5 grams (40 percent); boiling point l8718'9 C. at 0.01 mm.
The hydrochloride was precipitated from an ethereal splution of: the base with ethereal hydrogen chloride and crystallized from butanone; melting point 142-143.5 C.
The methyl bromide quaternary precipitated from an ethereal solution of the base and excess methyl bromide, after standing for twenty-four hours, as an oil. This was crystallized from an ethyl acetate-ethermethanol mixture; melting point 183-185 C.
EXAMPLE 4.1-METHYL-3 -PYRROLIDYL ALPHA- CYCLOPENTYLPHENYLACETATE To a solution of 52 grams (0.244 mole) of alpha-cyclopentylphenylacetyl chloride in benzene were added 25 grams (0.248 mole) of 1-methyl-3-pyrrolidinol, at a dropwise rate, with stirring. After complete addition the mixture was refluxed for two hours, cooled and extracted with 3 N hydrochloric acid. The acid extract was basified with aqueous sodium hydroxide and extracted with ether. The ether layer was washed, dried over sodium sulfate, and concentrated. Theresidue was distilled at reduced pressure. Yield 40 grams (63 percent); boiling point 144-147? C. at 0.2 mm. s
The hydrochloride was precipitated as an oil from an ethereal solution of the base with ethereal hydrogen chloride. This was crystallized from a methonol-ethyl acetate mixture and melted at 114-l15 C.
The methyl bromide quaternary was precipitated from an ethereal solution of the base and excess methyl bromide after standing for seventy-two hours. It was purified by recrystallization from butanone and melted at 166.5- 168 C. r
EXAMPLE 5.-1-n-BUTYL-3-PYRROLIDYL ALPHA- CYCLOPENTYLMANDELATE A mixture of 54 grams (0.216 mole) of methyl alphacyclopentylmandelate and 39 grams (0.272 mole) of l-n-butyl-Bpyrrolidinol in 500 ml. of heptane was refiuxed under a Dean and Stark moisture trap, with the addition of four 0.1 gram pieces of sodium at one hour intervals. After five hours refluxing the solution was concentrated at one half volume, diluted with ether and washed with water. The ether layer was dried over sodium sulfate and concentrated. Theresidue was fractionally distilled at reduced pressurel Yield 60 grams (80.5 percent); boiling point 160-165 C. at 0.04 mm.
The hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride as an oil. It was crystallized from butanone and melted at 129-130 C.
Analysis.Calcd for C H NO 1-HCl: or, 9.28.
Analysis.Calcd for C H NO -CH Br: Br, 18.15.
Found: Br, 17.98.
A mixture of 42.5 grams (0.17 mole) of methyl alphacyclopentyl mandelate and 18 grams (0.175 mole) of 1-methyl-3-pyrrolidinol in 500 ml. of heptane-was refiuxed under a Dean and Stark moisture trap, with the addition of four 0.1 gram pieces of sodium at one hour intervals. After five hours refluxing the solution was concentrated to one half volume, and extracted with cold 3 N HCl. The acid extract was made alkaline with aqueous sodium hydroxide and extracted with ether which was washed, dried over sodium sulfate, filtered and concentrated. The residue was fractionated at reduced pressure. Yield 33 grams (64%); boiling point 151154 C./0.2 mm. 11 1.5265.
The hydrochloride salt was precipitated as an oil from an ethereal solution of the base with ethereal hydrogen "chloridei It' was crystallized from butanone; melting EXAMPLE 7.--1-ETHYL-3-PYRROLIDYL ALPHA- CYCLOPENTYLMANDELATE HYDROCHLORIDE This compound was prepared according to the method outlined for the methyl derivative above (see Example 6). The base boiled at 162-165 C./0.25 mm. After recrystallization from butanone :the salt melted 160- 161.5 C.
Analysis.--Calcd for C H NO Cl, 10.02. Found: Cl-, 9.82.
EXAMPLE 8.1 CYCLOHEXYL-3-PYRROLIDYL ALPHA CYCLOPENTYLMANDELATE HYDRO- CHLORIDE.
This compound was prepared according to the method outlined for the methyl derivative above as in Example 6. The base boiled at 193-195 C./0.038 mm. After recrystallization from butanone and absolute ethanol the salt melted 2l2213.5 C.
Analysis.Calcd for C H NO -HC1: Cl", 8.69. Found: Cl, 8.81.
EXAMPLE 9.lMETHYL-3-PYRROLIDYL ALPHA- CYCLOHEXYLMANDELATE A mixture of 10 grams (0.0403 mole) of methyl alphacyclohexylmandelate and 5 grams (0.0493 mole) of N- rnethyl-3-pyrrolidin0l' in ml. of n-heptane was refluxed for five hours under a Dean and Stark moisture trap. At approximately equal intervals starting at zero time three approximately 0.1 gram pieces of sodium metal were added to the reaction. At completion of the reflux time the heptane solution was extracted wtih icecold 3 N hydrochloric acid. The acid extract was basi-. fied with saturated aqueous potassium carbonate and extracted with ether. The ether extract was washed, dried over magnesium sulfate and concentrated. The residual oil was distilled at -163 C./ 0.3 mm. giving an amber oil product. Yield 8.7 grams (68%).
The hydrochloride salt was precipitated as a crystalline solid from an ethereal solution of the base with ethereal hydrogen chloride. It was crystallized from a butane methanol mixture; M.'P. 206-207 C. a I
Analysis.-Calcd for C H NO -HCl: C-l"',- 10.02. Found: c1,10.00. I I
The methyl bromide quaternary was prepared-by saturating a solution of the free base in dry'- ethyl etherfwith methyl bromide and allowing the solution to stand 15 The product precipitated as white crystals' 'and hours. was recrystallized from butanone; M.P. 253-255 C (d).
This decomposition range varies with the rate at which the sample is heated.
Analysis.Calcd for C H NO -Br: Br 19.38. Found: Br", 19.27. i a As pointed out in column 1, those compounds which have two asymmetric centers are capable of existing in two diastereoisomeric forms. These two-forms can be separated by fractional crystallization as shown in the following exam l ture trap. At approximately equal intervals, starting at zero time, three approximately 0.1 gram pieces of sodium metal were added to the reaction. At completion of the reflux time the heptane solution was extracted with ice cold 3 N hydrochloric acid. The acid extract was basified with aqueous sodium carbonate and extracted with ether. The ether extract was washed, dried over sodium sulfate and concentrated. The residual oil was distilled at 1571-60 C./0.05- mm., giving an amber oil product. Yield 31.7 grams (56%). V
This material was converted to the hydrochloride salt by precipitation as a crystalline solid from an ethereal solution of the base with ethereal hydrogen chloride. This material was fractionally crystallized from methyl ethyl ketone and from an ethyl acetate methanol mixture. High and low melting isomers were obtained:
Other compounds within the scope of the invention are shown in Table I. In each instance the free base as well as the indicated acid addition or quaternary salt was prepared.
Table I R C Hz-N-R C-C O O CH I A CH2CH7 R R A Salt Calculated f01'- Pegcient Found M.W M.P., C
CH3 Cy-CsHu H HCI CwHwNOrHCl 16. 49 10. 46 337. 88 153. 5-154. 5 C 115 cy-CsHu H 1101 CzoHzoN'Oz-HCl 10. 01 10. 14 351. 91 125 -127. 5 i-CsH'; CY-CaHn H HCI CzrHmNOz-HCI 9. 69 9. 67 365. 9.1 164 -167 D-C4Ha Cy-CaHu H H01 CwzHmNOz H01 9: 34 9. 28 379. 96 100 -151 i-C4Ho Cy-CsHn H H01 CHHKJNO: H01 9. 34 9. 27 379. 96 139. 5-1415 t-C4H9 (Dy-C 11 H I'ICI CzzHzgNOz H01 9. 34 9. 43 379. 96 141 -142 (By-0 11 1 cy-OuH H HCl C24H3 NO2 HCl 8. 73 8. 62 405. 98 226 -227. 5 CaHsCHz Cy-CeHrr H V HCl C25H31NO HC1 8. 57 8. 69 413. 93 142 -143. 5 CH3 CY-CgHq H H01 C15H25NO2 HCl 10. 95 10. 93 323. 85 114 -115. 5 C2115 CY-C5H9 H 1101 OmHzrNOz-HCI 10. 49 10. 31 337. 88 113 --114 11-C4H9 Cy-CsHa H H01 C2iH31NO2-HC1 9. 69 9. 67 365. 93 107. 5-109. 5 CY-CsHn (.y-C5Hq H H01 Cz3H33NOz-HC1 9. Q5 8. 90 391. 97 191 192. 5 C5H CH2 Cy-C5H9 H H01 CttHtONOz-HCl 8. 86 8. 70 399. 94 138 -139 CH3 Cy-CuHu H. CH3]: CZOHKUNO'g-I 28. 62 28. 67 443. 37 169. 5-176 5 CH3 cy-O5H H CHsBI' C aHaoNOa-Bl 26. 16 20. 2S 2116. 36 177. 5-179 C2115 Cy-CgH H CH3]: CmHazNOrI 27. 74 27. 70 457. 40 130 133 1-C4H9 Cy-CaHn H CHaBI CnHaeNOrBl 18. 23 17. 93 4'33. 168. 5-170 t-CtHe Cy-CuHn H CH3B1 CggHaaNOg- B1 18. 23 18. 12 438. 45 177 -178 CoH5CHz Cy-CaHn H CHaB! CznHuNOz-BI 16. 92 16. 62 472. 46 183 -185 H3 cy-O H H CHzBI CmHzgNOz-Br 20. 96 21. 13 382. 34 166. 5-163 CgH5 try-C514 H CHsBI CZUHanNOzBl 26. 16 26. 14 396. 37 152. 5-154 n-C Hq Cy-C H9 H CHaBI' CMHIHNOziBI 18. 83 18. 72 424. 42 167. 5-108. 5 cy-CgHn 0y-C5H9 H CHaBI HHMNOL'BT 17. 74 18. O1 448. 45 191. 5-193 CeH5CHz cy-C H H CHaBr Cz5H32NO2-Br 17. 51 17. 67 407. 43 175. 5-176. 5 H3 (By-C5119 OH H01 CrgH aNOa-HCI 10. 43 10. 30 509. 85 170 -171. 5 C2115 (fly-C 119 OH HCl CmHzlNOs-HCJ 16. 62 9. 82 .553. 88 160 -161. 5 H'CJHQ (By-C5119 OH 1101 CmHgzNOg-HCI 9. 2S 9. 17 381. 93 129 -13[) (fly-05H ey-C H OH H01 CuHsaNOrHCl 8. 69 8. 81. 467. 97 212 -213. 5 CH3 (III-C 11 OH CHzBI CnHrsNOa-BI 26. 66 19. 78 398. 3-1 193 494. 5 D'C-IHG (y-C5110 OH CHaBI' CzgHzqNOa-BI 18. 15 17. 98 140. 42 176 -177. 5 CBH5CH2 Cy-C H9 OH CHaBr C251'I32NO3BI' 16. 84 16. S3 474. 43 173 -175 cy-CuHn CY-C H9 OH CHaBr C24H35NO3'B1' 17. 13 16. 93 466. 4.5 193 196 CH3 C"-C6Hr1 OH HC1 CIQHQ'INOZ'HCl 10. 02 10. O0 353. S6 206 -2U7 CH3 (By-09H OH CHgBl CzuHeuNOz-Br 19. 38 19.27 412. 36 253 255 0211561401111) cyIhI-In OH H01 C1aH2gNO3-C1 9. 64 9. 68 367. 91 184 185 CgHaQi-fOlfll) (Dy-C51 1 OH IIC-l CzoHzqNOs- C1 9. 64 9. 65 367. 91 219 -220. 5 021-15 cy-C H OH CHaBl' CzrHtzNOyBt 18. 74 18. 59 426. 39 181 -182. 5
2.5 grams of material, M.P. 184185, and 13.8 grams of material melting 219-2205". A mixture of these two isomers melted at 178182 C.
Analysis of high melting is0mer.Calcd for C H NO -HCl: C, 65.29; H, 8.22. Found C, 65.55; H, 8.33.
Analysis of low melting is0mer.Calcd for c, H,,N0 -Hc1; C, 65.29; H, 8.22. Found: C, 65.45; H, 8.39.
The low melting isomer is designated the alpha (0:) form and the high melting isomer is referred to as the beta (13) form in Table I.
In the same manner as given in the preceding examples, by reacting the appropriate l-hydrocarbon substituted-3- pyrrolidinol with the appropriate esterifying agent, additional compounds within the scope of the general structural formula are prepared.
Representative products prepared from the chosen starting materials are as follows:
alpha-cyclopentylphenylacetate In evaluating the compounds of the present invention pharmacologically the following experimental testing procedure was utilized.
ISQLATED GUINEA PIG ILEUM STUDIES Guinea pigs were killed by a blow on the head. The ileum was removed and terminal segments were suspended in a ml. smooth muscle bath containing Tyrodes solution which was maintained at 37 C. The bath was aerated by bubling a continuous stream of oxygen through it. Intestinal activity was recorded by a balanced ink-writing lever yielding five-fold magnification on a Gorrell and Gorrell kymograph operated at speed P.
Aqueous solutions of all materials were employed in these studies. Essentially, the method consisted of initially standardizing submaximal contractions of the isolated ileum to acetylchlorine chloride, histamine phosphate, serotonin creatinine sulfate and barium chloride. The test material was then introduced into the bath and two minutes later the ileum was again challenged with the various spasmogens. Tests were made at various concentrations of the compounds in the bath until it was possible to differentiate their relative activity as antagonists of the spasmogens.
The results of the pharmacological testing indicate that the compounds are predominantly acetylcholine antagonists and are eflective in inhibiting gastrointestinal motility in vivo and in vitro. In general, the compounds compared favorably in potency with Methantheline bromide under the conditions of these tests.
Various modifications may be made in the compounds of the present invention without departing from the spirit and scope thereof, and it is to be understood that the invention is limited only by the scope of the appended claims.
I claim:
1. A compound selected from the group consisting of esters of B-pyrrolidinols having the structural formula wherein R is a hydrocarbon radical selected from the group consisting of lower alkyl, phenylalkyl containing up to nine carbon atoms inclusive, and cycloalkyl containing five to eight carbon atoms inclusive and having five to seven carbon atoms inclusive in the ring.
R is a cycloalkyl hydrocarbon radical containing five to eight carbon atoms inclusive and having five to seven carbon atoms inclusive in the ring, and
R" is a radical selected from the group consisting of hydrogen and hydroxyl; and nontoxic acid addition and lower-alkyl and benzyl quaternary ammonium salts thereof.
2. l-methyl- 3 -pyrrolidyl alpha-cyclopentylmandelate methobromide.
3. 1-methyl-3 -pyrrolidyl alpha-cyclopentylmandelate hydrochloride.
4. 1-ethyl-3-pyrrolidyl alpha-cyclopentylphenylacetate methobromide.
5. l-methyl 3 pyn'olidyl alpha cyclohexylphenylacetate methiodide.
6. l-methyl 3 pyrrolidyl alpha cyclohexylphenylacetate hydrochloride.
7. l-ethyl 3 py-rrolidyl alpha cyclohexylphenylacetate methiodide.
8. l-benzyl-3-pyrrolidyl alpha-cyclohexylphenylacetate methobromide.
9. 1-lower-alkyl-3 pyrrolidyl cycloalkylmandelate having the structural formula:
cycloalkyl lLwer-alkyl wherein the cycloalkyl radical contains five to eight carbon atoms, inclusive, and has five to seven carbon atoms, inclusive, in the ring.
10. Non-toxic acid addition salt of a compound of claim 9.
11. Non-toxic lower-alkyl quaternary ammonium salt of a compound of claim 9.
12. l-methyl 3-pyrrolidyl alpha-cyclopentylmandelate.
References Cited in the file of this patent Richters Organic Chemistry, vol. 3, pp. 3 to 4 (1923).

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1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF ESTERS OF 3-PYRROLIDINOLS HAVING THE STRUCTURAL FORMULA
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