US2584131A - Pyrrolidyl thiolesters - Google Patents

Pyrrolidyl thiolesters Download PDF

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US2584131A
US2584131A US97483A US9748349A US2584131A US 2584131 A US2584131 A US 2584131A US 97483 A US97483 A US 97483A US 9748349 A US9748349 A US 9748349A US 2584131 A US2584131 A US 2584131A
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pyrrolidyl
alpha
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degrees centigrade
ethyl
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James H Hunter
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Pharmacia and Upjohn Co
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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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • R is a member of the group consisting of aryl, aralkyl, cycloalkyl, and cycloalkenyl radicals
  • R. is a member of the group consisting of alkyl, aralkyl, aryl, cycloalkyl and cycloalkenyl radicals
  • R" is a member of the group consisting of pyrrolldyl-l and lower-alkyl-substituted pyrrolidyl-l radicals and wherein n is a member of the group consisting of the integers 2, 3, and 4.
  • the esters are usually oily liquids, readily soluble in most common organic solvents, but insoluble in water.
  • the acid addition salts such as the hydrochloride, sulfate, hydrobromide, nitrate, acetate, tartrate, succinate, and citrate are generally crystalline solids with well-defined melting points and are readily soluble in cold water, methanol, or ethanol; moderately soluble in ethyl acetate; and, insoluble in common aliphatic, cycloaliphatic and aromatic hydrocarbon solvents.
  • Atropine is considered to be a neurotropic agent, acting upon the smooth muscle tissue to overcome spasm originated by or produced through the autonomic nervous system.
  • Papaverine, an opium alkaloid is considered to be a musculotropic agent capable of acting on smooth muscle tissues to relieve spasm intrinsic in the muscle tissues themselves.
  • the free basic esters of the invention can be prepared readily by reacting an acid chloride having the formula:
  • the pyrrolidyl alkane thiols used in preparing the esters of the invention can be prepared from the corresponding alkanol according to the following reactions:
  • the intermediate pyrrolidylalkylisothiouro-, nium chloride hydrochlorides are stable crystalline compounds which can be isolated readily and crystallized from ethanol.
  • the hydrolysis of the isothiouronium chloride hydrochlorides is carried out an oxygen-free atmosphere, as the resulting pyrrolidylalkanthiols are oxidized to the disuhide by atmospheric oxygen. For this reason, it is preferred to use the solution formed by the hydrolysis of the isothiouronium salts for the preparation of its esters, rather than attempting to isolate and purify the unstable thiol.
  • pyrrolidyl alkanolseused in preparing the pyrrolidyl alkyithlols carfbe prepared in several ways.
  • a'haloalkanol can be reacted with p'yrrolidine or with an alkyl pyrrolidine and the desired pyrrolidyl alKanol obtainedi
  • an amino alcohol with succinic acid to form an N- hydroxyalkyl succinimide-or with a gamma keto 4
  • the salt Upon distilling the solvent, the salt remains as a residue, which can be recrystallized from alcohol, or other suitable organic liquid.
  • a mixture of ethyl alcohol and ethyl acetate is particularly suitable, in certain instances, for the recrystallization.
  • Salts with inorganic acids, especially with hydrochloric 'acid or with 'citric"acid have particularly well-defined crystalline structures. Certain of the polybasic acids, such as citric acid, combine with the amino esters in equimolecular proportions to form the monoamine salts.
  • pyrrolidyl alkanols may be prepared by condensing a pyrrolidine with formaldehyde and an aliphatic aldehyde to give an N-pyrrolidylaldehyde, which is readily reduced with aluminum isopropoxide in isopropyl alcohol to the desired pyrrolidyl or alkylpyrrolidyl alkanols.
  • N-pyrrolidylaldehyde which is readily reduced with aluminum isopropoxide in isopropyl alcohol to the desired pyrrolidyl or alkylpyrrolidyl alkanols.
  • Detailed preparations of pyrrolidyl and alkylpyrrolidyl alkanols by these methods are given here-v inafter.
  • reaction of an acidchlori-de and of a pyrrolidyl alkanthiol can be carried out conveniently by mixing the two substances together, preferably in the presence of an inert diluent, such as anhydrous xylene. Reaction usually occurs at ordinary temperatures and can be accelerated and carried substantially to completion by finally refluxing the mixture foraboutthirty minutes or longer.
  • an inert diluent such as anhydrous xylene.
  • Reaction usually occurs at ordinary temperatures and can be accelerated and carried substantially to completion by finally refluxing the mixture foraboutthirty minutes or longer.
  • thehydrochloride of'the basic ester Upon allowing the reaction mixture to cool, thehydrochloride of'the basic ester generally crystallizes and can be separated from any inert diluent by filtration.
  • g., ether to remove anythe esters of the invention can be an alkyl radi cal, and either-one or both of the two substituents can be aryl, aralkyl, cycloalkyl, or cycloalkenyl radicals.
  • Alkyl radicals which can be present as one of the substituents on the alpha carbon atom can have either a straight or branched carbon chain and include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary-butyl, hexyl, dodecyl, 'et cetera.
  • alkyl radical containing not more than 12 carbon atoms is preferred, although the compounds. of the-present invention are not to be limited in this respect.
  • Other substituent radicals, which can be present on the alpha carbon atom of the acid component include, among many others, phenyl, orthotolyl, para-tolyl, xylyl, benzyl, methyl-benzyl, diphenylmethyl, naphthyl, cyclohexyl, methylcyclohexyl, propylcyclohexyl, cyclohexenyl,
  • the pyrrolidyl alkanthiols used in preparing esters of the invention can bea pyrrolidyl-ethanthiol, a pyrrolidyl-propanthiol or a pyrrolidyl-butanthiol.
  • the carbon chain of the alkylene group -CnH2n-, can be either straight or branched.
  • the pyrrolidine ring can be either unsubstituted or it may containone or more lower-alkyl substituents, such as methyl, ethyl, propyl, isopropyl, butyl, secondarybutyl, tertiary-butyl, pentyl, isopentyl, et cetera. It is to be understood that Irdo notintend to limit myself to pyrrolidyl rings containing only one loweralkyl substituent on a ringcarbon atom of the pyrrolidyl ring, butintendtQ include, all loweralkyl substituted pyrrolidyl rings.
  • loweralkyl as used in this specification and the appended claims is intended any alkyl group. having from one to. five carbonatoms.
  • the pyrrolidine ring is attached to the alkylene group through the nitrogen atom.
  • esters of this invention may be named in at least two ways.
  • the ester For example, the ester:
  • Chill may be designated as l-[2-methyl-2 (2'-methyltate.
  • aqueous layer waswashed with ether, made, strongly alkaline with cold aqueous sodium hydroxide,and extracted four times with 200-milliliter portions of ether.
  • the ether extracts were combined, the solvent removed and the residue distilledunder a reduced pressure .of about 12 millimeters of mercury absolute. There was thus obtained 156.7 grams (91.5 percent of the theoretical yield) of ethyl alpha-(pyrrolidyl-l) -propio'nate, boiling at 84 degrees centigrade at a pressure of 12 millimeters of mercury absolute.
  • pyrrolidyl-alkyl-isothiouronium chloride hydrochlorides can be prepared from the pyrrolidyl allr'yl chloride hydrochlorides obtained from the alcohols 01 the previous preparations.
  • pyrrolidylalkanthiols and alkylpyrrolidylalkanthiols can be prepared by hydrolysis of thecorresponding isothiouronium chloride hydrochloride:
  • the reaction mixture which rapidly separated into two layers, was heated under reflux for two hours, poured into a mixture of dilute aqueous hydrochloric acid and the layers separated.
  • the organic layer was extracted with water, the aqueous solutions combined and extracted once with ether.
  • the aqueous solution was made basic with sodium'hydroxide, and the 2 (2 methylpyrrolidyl 1) ethyl alpha phenyl alpha (A cyclopentenyD- thiol acetate extracted with ether.
  • the ether extract was washed with water and dried.
  • esters and their salts were prepared:
  • esters of various pyrrolidylalkanthiols and alkylpyrrolidyl alkanthiols can be prepared as well as acid addition salts thereof.
  • esters having the formula:
  • R is a member oi the group consisting of alkyl, aryl aralkyl, cycloalkyl and cyc'loalkenyl radicals
  • R is a member oi the group consisting of alkyl, aryl aralkyl, cycloaulkyl
  • R is a memherof the group consisting of pyrrolidyl-l and lower-.alkylesubstituted pyrrdlidyl-i radicals and n is a, member of the group consisting of the integers 2, 3, and 4,:and 6b) acid addition salts thereof.
  • .R is and, .R is cycloalkenyl, R" is a lower-alkyl-substituted pyrrolidyl-l radical, and
  • esters having the formula:
  • R and R are aryl, R" is pyrrolidyl-l', and n is the integer 2.
  • R is aryl, R is alkyl, 'R" is pyrrolidyl-l n is the integer 3.
  • R is aryl, R" is cycloalkyl, R is pyrrolidyl-l and n is the integer 4.

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Description

Patented Feb. 5, 1952 UNITED STATES PATENT OFFICE PYRROLIDYL THIOLESTERS James H. Hunter, Kalamazoo, Mich., assignor to. The Upjohn Company, Kalamazoo, Mich., a
corporation of Michigan No Drawing. Application June 6, 1949 Serial No. 97,483
l1 Claims. (Cl. 260-313) wherein R is a member of the group consisting of aryl, aralkyl, cycloalkyl, and cycloalkenyl radicals, R. is a member of the group consisting of alkyl, aralkyl, aryl, cycloalkyl and cycloalkenyl radicals, R" is a member of the group consisting of pyrrolldyl-l and lower-alkyl-substituted pyrrolidyl-l radicals and wherein n is a member of the group consisting of the integers 2, 3, and 4.
The esters are usually oily liquids, readily soluble in most common organic solvents, but insoluble in water. The acid addition salts, such as the hydrochloride, sulfate, hydrobromide, nitrate, acetate, tartrate, succinate, and citrate are generally crystalline solids with well-defined melting points and are readily soluble in cold water, methanol, or ethanol; moderately soluble in ethyl acetate; and, insoluble in common aliphatic, cycloaliphatic and aromatic hydrocarbon solvents.
Members of this new group of compounds have been prepared and found to have value as antispasmodics and as intermediates for the preparation of more complex organic molecules. These compounds have exhibited most desirable antispasmodic properties, having the combined effect of papaverine and atropine. Atropine is considered to be a neurotropic agent, acting upon the smooth muscle tissue to overcome spasm originated by or produced through the autonomic nervous system. Papaverine, an opium alkaloid, is considered to be a musculotropic agent capable of acting on smooth muscle tissues to relieve spasm intrinsic in the muscle tissues themselves.
In clinical practice it is not always possible to determine which type of spasm is present. Furthermore, both types may be present simultaneously. presenting a situation in which an antispasmodic efiective against only a single type is, obviously, of limited utility. The compounds with which the present invention is concerned possess musculotropic and neurotropic activity and upon administration, exhibit a dual antispasmodic effectiveness of suflicient degree to render them useful in treating either of the previously mentioned types of spasm, or both simultaneously, if both should be present.
The free basic esters of the invention can be prepared readily by reacting an acid chloride having the formula:
with a pyrrolidyl alkanthiol having the formula:
' R.CnH2nSI-I wherein R, R, R' and n have the values given previously. It is to be here noted that it is possible to have thio-esters having the sulfur in two possible places. Those esters having the formula are called thion esters and those having the formula -(ll-SR" of thionyl chloride is usually employed and the excess subsequently removed by distillation under a reduced pressure, leaving the acid chloride as a residue, which is generally sufilciently pure for use without further purification, but which can be fractionally distilled, if further purity is desired. Acid bromides can be prepared in a similar manner using thionyl. bromide.
. The pyrrolidyl alkane thiols used in preparing the esters of the invention can be prepared from the corresponding alkanol according to the following reactions:
01: R"-o..H,..-s-o=NH-2Hc1 n"-c.m..sn
IQ'Hr v wherein R" has the value given.
The intermediate pyrrolidylalkylisothiouro-, nium chloride hydrochlorides are stable crystalline compounds which can be isolated readily and crystallized from ethanol. The hydrolysis of the isothiouronium chloride hydrochlorides is carried out an oxygen-free atmosphere, as the resulting pyrrolidylalkanthiols are oxidized to the disuhide by atmospheric oxygen. For this reason, it is preferred to use the solution formed by the hydrolysis of the isothiouronium salts for the preparation of its esters, rather than attempting to isolate and purify the unstable thiol. The pyrrolidyl alkyl chlorides', some of them-described and claimed in copending application Serial 773,521, filed September 11, 1947, now abandoned, are readily preparedby the reaction of thionyl chloride on pyrrolidylalkanol hydrochlorides.
The pyrrolidyl alkanolseused in preparing the pyrrolidyl alkyithlols carfbe prepared in several ways. Thus,- a'haloalkanol can be reacted with p'yrrolidine or with an alkyl pyrrolidine and the desired pyrrolidyl alKanol obtainedi In certain instances, it is advantageous to first condense pyrrolioine or an alkyl pyrrolidine with a haloketone, an ester of a saturated halo-aliphatic acid, or an ester of an alpha-beta unsaturated aliphatic acid to form an ester of a pyrrolidyl aliphatic acid or a pyrrolidyl ketone. In other instances, it may be advantageous to condense an amino alcohol with succinic acid to form an N- hydroxyalkyl succinimide-or with a gamma keto 4 Upon distilling the solvent, the salt remains as a residue, which can be recrystallized from alcohol, or other suitable organic liquid. A mixture of ethyl alcohol and ethyl acetate is particularly suitable, in certain instances, for the recrystallization. Salts with inorganic acids, especially with hydrochloric 'acid or with 'citric"acid, have particularly well-defined crystalline structures. Certain of the polybasic acids, such as citric acid, combine with the amino esters in equimolecular proportions to form the monoamine salts.
Only one of the two substituents on the alpha carbon atom of the aliphatic acid component of aliphatic acid 'to form an N hydroxyalkylpyrrolidone. The carbonyl groups of these compounds may then be easily reduced with lithium aluminum hydride in absolute ether to the desired pyrrolidyl and alkylpyrrolidyl alkanols. Other pyrrolidyl alkanols 'may be prepared by condensing a pyrrolidine with formaldehyde and an aliphatic aldehyde to give an N-pyrrolidylaldehyde, which is readily reduced with aluminum isopropoxide in isopropyl alcohol to the desired pyrrolidyl or alkylpyrrolidyl alkanols. Detailed preparations of pyrrolidyl and alkylpyrrolidyl alkanols by these methods are given here-v inafter.
- The reaction of an acidchlori-de and of a pyrrolidyl alkanthiol can be carried out conveniently by mixing the two substances together, preferably in the presence of an inert diluent, such as anhydrous xylene. Reaction usually occurs at ordinary temperatures and can be accelerated and carried substantially to completion by finally refluxing the mixture foraboutthirty minutes or longer.- Upon allowing the reaction mixture to cool, thehydrochloride of'the basic ester generally crystallizes and can be separated from any inert diluent by filtration. The free estercan be recovered and purified by dissolving the crude hydrochloride in water, extracting the solution with a suitable solvent;e. g., ether, to remove anythe esters of the invention can be an alkyl radi cal, and either-one or both of the two substituents can be aryl, aralkyl, cycloalkyl, or cycloalkenyl radicals. Alkyl radicals which can be present as one of the substituents on the alpha carbon atom can have either a straight or branched carbon chain and include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary-butyl, hexyl, dodecyl, 'et cetera. Generally speaking, an alkyl radical containing not more than 12 carbon atoms is preferred, although the compounds. of the-present invention are not to be limited in this respect. Other substituent radicals, which can be present on the alpha carbon atom of the acid component include, among many others, phenyl, orthotolyl, para-tolyl, xylyl, benzyl, methyl-benzyl, diphenylmethyl, naphthyl, cyclohexyl, methylcyclohexyl, propylcyclohexyl, cyclohexenyl,
methylcyclohexenyl, cyclopentyl, and cyclopentenyl radicals. The pyrrolidyl alkanthiols used in preparing esters of the invention can bea pyrrolidyl-ethanthiol, a pyrrolidyl-propanthiol or a pyrrolidyl-butanthiol. The carbon chain of the alkylene group -CnH2n-,, can be either straight or branched. The pyrrolidine ring can be either unsubstituted or it may containone or more lower-alkyl substituents, such as methyl, ethyl, propyl, isopropyl, butyl, secondarybutyl, tertiary-butyl, pentyl, isopentyl, et cetera. It is to be understood that Irdo notintend to limit myself to pyrrolidyl rings containing only one loweralkyl substituent on a ringcarbon atom of the pyrrolidyl ring, butintendtQ include, all loweralkyl substituted pyrrolidyl rings. By loweralkyl as used in this specification and the appended claims is intended any alkyl group. having from one to. five carbonatoms. The pyrrolidine ring is attached to the alkylene group through the nitrogen atom. w
The esters of this invention may be named in at least two ways. For example, the ester:
Chill may be designated as l-[2-methyl-2 (2'-methyltate. The second systemvis used throughout this specification and the appended claims.
Certain procedures by which the compounds of the present invention may be prepared are apparent from the following examples which are given by way of illustration and are not to be,
construed as limiting.
PREPARATION OF PYRROLIDYL ALKANOLS Preparation 1..-EthyZ-alpha- (pyrrolidyl-1) -propionate.
To a stirred solutionv of 181 grams of'ethylalpha-bromopropionate' in 200 milliliters of ben- 1 zene, 148 grams of pyrrolidine was added at a substantially uniform rate over. a period of one hour. The reaction was quite vigorous causing the solvent to boil. When all of the pyrrolidine had been added, the solution was boiled under reflux for an additional hour, cooled, poured into about 300 milliliters of ice-water, acidified with dilute aqueous hydrochloric acid to a pH of about 2, and the resulting two layers separated. The aqueous layer waswashed with ether, made, strongly alkaline with cold aqueous sodium hydroxide,and extracted four times with 200-milliliter portions of ether. The ether extracts were combined, the solvent removed and the residue distilledunder a reduced pressure .of about 12 millimeters of mercury absolute. There was thus obtained 156.7 grams (91.5 percent of the theoretical yield) of ethyl alpha-(pyrrolidyl-l) -propio'nate, boiling at 84 degrees centigrade at a pressure of 12 millimeters of mercury absolute.
Preparation 2.-2 (pyrrolidyld) -propanol-1 A mixture of 7.6 grams of lithium aluminum hydride and 250 milliliters of dry ether was prepared and 61.7 grams of ethyl alpha-(pyrrolidyll)-propionate added to the mixture slowly enough to cause gentle refluxing of theether. The mixture was then allowed to stand for a few minutes without cooling and 20 milliliters of water added dropwise. The mixture was then cooled by adding ice and the mixture acidified with hydrochloric acid to a pH of about 2. The aqueous layer was separated, washed with ether and then rendered strongly basic with solid sodium hydroxide. The basic solution was then extracted repeatedly with ether, the ethereal extracts combined and dried with anhydrous potassium carbonate. The ether was then removed by evaporation and the residual oil fractionally distilled. There was thus obtained 38.1 grams of 2-(pyrrolidyl-1) -propanol-1 boiling at 80 degrees centigrade at a pressure of 11 millimeters of mercury absolute, and having-an index of refraction, n of 1.4758. I
Preparation 3 2 Following substantially the procedure given in Preparations 1 and 2, the following alcohols were prepared:
1. 2-methyl-3-(pyrrolidyl-1) -propanol-1, boiling at 91 degrees centigrade at a pressure of 12 millimeters of mercury absolute; 11. of 1.4620.
2. 3-(pyrrolidyl-1) -butanol-1, boiling at 114 degrees centigrade at a pressure of 21 millimeters of mercury absolute; n of 1.4742.
3. 3 -(pyrrolidyl-1) -butanol-2, boiling at 79degrees centigrade at a pressure of 13 millimeters of mercury absolute; n of 1.4610.
4. 4-(pyrrolidyl-1) -butanol-2, boiling at 87 degrees centigrade at a pressure of 13 millimeters of mercury absolute; n of 1.4611.
Preparation 4.3- (pyrrolidyZ-I) -pr0zJanoZ-1 A mixture wasprepared consisting of 50.7 grams of sodium hydroxide, 45.7 grams of water and 60.5 grams of pyrrolidine. The mixture was stirred vigorously and 100 grams of 3-chloropropanol-lwas added to the mixture at a substantially uniform rate over a period of one-half hour. The temperature rose gradually and was maintained between about 75 and 100 degrees centigrade during the addition. The mixture was then stirred for an additional thirty minutes and fiinally allowed to stand for several hours. Solid sodium hydroxide was then added until the mixture was saturated and the oily layer 'which formed was separated. The aqueous layer was of mercury absolute, index of refraction, n of;
Preparation 5 Following substantially the procedure given in.
Preparation 4,4-(pyrrolidyl-1) -butanol-21, boiling at 113 degrees centigrade at a pressure of 12 millimeters of mercury, n of 1.4705, was prepared from pyrrolidine and 4-chlorobutanol-1.
Preparation 6.2-methyl-2-(pyrrolidyl-l propanoZ-l A mixture of 44.6 grams of 2-amino-2-methylpropanol-l, 108 grams of tetramethylene dibromide and 200 milliliters of toluene was boiled under reflux for three hours, 84 grams of sodium bicarbonate added and the refluxing continued for an additional fifteen hours. The mixture was then cooled, 80 milliliters of 50 percent aqueous sodium hydroxide added, the organic layer removed, sufiicient water added to dissolve the salt and the aqueous solution extracted continuously for nine hours. The organic extracts were combined, dried over anhydrous potassium carbonate and distilled. The distillate, melting at 27.5 degrees centigrade, was dissolved in dilute acid and treated with sodium nitrite to remove any secondary amine. After extracting with ether, the aqueous solution Was made basic with sodium hydroxide and extracted three times with 100- milliliter portions of ether. The ether solutions were combined, dried, the ether removed and the residue distilled under a reduced pressure of about 12 millimeters of mercury absolute. There was thus obtained 54 grams (75.5 percent of the theoretical yield) of 2-methyl-2-(pyrrolidyl-D'- propanol-l, boiling at 87 degrees centigrade at a pressure of 12 millimeters of mercury absolute, indexof refraction, a of 1.4720, freezing point 30 degrees centigrade.
Preparation 7 .1 (Z-hydroxyethyl) -5- methylpyrrolidone-Z A suspension of 0.2 gram of platinum oxide catalyst in 25 milliliters of absolute ethanol was reduced to platinum and-then a solution of 34.8 grams of levulinic acid and 37.8 grams of ethanolamine in 75 milliliters of absolute alcohol added. The mixture hydrogenated at about 50 pounds pressure and room temperature for four hours, at which time the theoretical amount of hydrogen had been consumed. After the catalyst and solvent had been removed, the residue was,
fractionally distilled. There was thus obtained 7 Preparation 8.2-(2-methylpyrrolidyl) 1 -ethanol By a procedure similar to that described in Preparation 2, fifty-one grams of 1-(2-hydroxyethyl)-5-methylpyrrolidone-2 was reduced with 18 grams of lithium aluminum hydride in 400 milliliters of ether. Fractional-distillation yielded 35 grams (76 percent of the theoretical yield) of -2-(2-methy1pyrrolidyl-1)-ethanol, boiling at- 7 81 degrees centigrade at a pressure of 16 millimeters of mercury absolute, index of refraction, n 'of1.4680. Preparation 9 By a procedure similar to that described in Preparations 7 and 8, the following compounds were prepared:
1. 2- (2,3-dimethylpyrro1idyl-1) -ethanol, boiling at 86 degrees centigrade at a pressure of 13 milliliters of mercury absolute, 11- of 1.4661.
2. 3-(2-methylpyrrolidyl-l) -propanol-1, boiling at. 100 degrees Centigrade at a pressure of 18 millimeters of mercury absolute, 11. of 1.4672.
Preparation 1 0.N- (Z-hydroxyethyl) -alphamethylsuccinimide A mixture of 66 grams of alpha-'nethylsuccinic acid and 73.4 grams of monoethanolamine was heated by means of an oil bath, the temperature gradually rising to 260 degrees centigrade until distillation stopped. The residue was distilled under a reduced pressure of less than one milimeter of mercury absolute, to obtain a viscous oil which upon fractional distillation yielded 67.8 grams (86.4 percent of the theoretical yield) of N-(2-hydroxyethyl) alpha methylsuccinimide, boiling at 102 degrees centigrade at a pressure of 0.01 millimeter of mercury absolute, refractive index of 1.4970.
Preparation 11.-2- (Ii-methylpg'yrrolidyZ-I) ethanol By a procedure similar to that described i1.
Preparation 2, 62.8 grams of N-(2-hydroxyethyl) aLlpha-methylsuccinimide was reduced with 30 grams of lithium aluminum hydride. Upon fractional distillation there was obtained 35 grams (68.1 percent of the theoretical yield) of 2-(3- methylpyrrolidyl-l)-ethanol, boiling at 105 degrees centigrade at a pressure of 45 millimeters of mercury absolute, refractive index, n of 1.4640.
Preparation 12 By a procedure. similar to that described in Preparations and 11, the following alcohols were prepared:
1. 2-(3,3-dimethylpyrrolidyl-1) -ethanol, boiling at 81 degrees centigrade at a pressure of 13 millimeters of mercury absolute; a of 1.4580.
2. 2-(3,4-dimethylpyrrolidyl-1) -ethanol, boiling at 86 degrees centigrade at a pressure of 12 millimeters of mercury absolute; n of 1.4594.
3. 2-(2,4,4-trimethylpyrrolidyl-1) -ethancl, boiling at 84 degrees centigrade at a pressure of 14 millimeters of mercury absolute; n of 1.4535.
PREPARATION OF PYRROLIDY L ALKYL HALIDES Preparation 13.2-(Z-methylpyrrolidyl-l) ethyl chloride hydrochioride iii) Preparation, 1 4
' Following substantiallythe procedure given in.
Preparation 13, the following pyrrolidyl-alkyl chloride hydrochlorides" were prepared:
1'. 2-(pyrro1idyl-D-propy1 chloride hydrochloride,..mel ting at 150-163 degrees centigrade.
2: 4-(pyrro1idyl-1) -n'-buty1 chloride hydrochloride, melting at.111-113 degrees centigrade.
3'. 2=methyl-3-(pyrrolidyl-1)-n-propyl chloride hydrochloride, melting at 1645-1655 degrees centigrade. I
In a like manner, other pyrrolidyl alkyl' chloride hydrochlorides. can be prepared from the alcohols described in the preceding preparations as well as those described in J. Am. Chem. Soc.
70, 3101 (1948), and a copending application.
Serial 773,521, filed September 11, 1947.
PREPARATION OF ISOTHIOURONIUM CHLORIDES Preparation 1 5 .-2- (methylpyrroiz'dylr 1') -ethyl isothiouroniam chloride hydrochloride A solution of 46 grams'of Z-(Z-methylpyrrolidyl-l) -ethyl chloride hydrochloride and 19 grams of thioureain 50 milliliters of ethanol was boiled under reflux for twenty hours on a steam bath..
Upon cooling, crystals separated which were filtered, washed. with. ethanol and acetone, recrystallized from 250 milliliters of ethanol and. dried- There was: thus obtained. 43.3. grams percent of the theoretical yield) of 2=-(2-methylpyrroli-- dyl-1)-ethy1 isot-hiouronium chloride; hydrochloride, melting at 216-218 degrees centigrade.
Preparation 16 Following substantially the procedure given. in Preparation 15, the following pyrrolidyl-alkyl-isothiouronium chloride hydrochlorides were prepared:
1. 2-(pyrrolidyl-1)-ethyl-isothiouronium chloride hydrochloride, melting at 174-175 degrees centigrade. a v
2. 2 (pyrrolidyl 1) propyl isothiouronium chloride hydrochloride, melting at 184.5-186 degrees centigrade.
- 3. 4- (pyrrolidyl 1) n butyl-isothiouronium chloride hydrochloride; melting at 168-1695 .de
grees centigrade.
4. 2-methy1-3- (pyrrolidyl-l) -n-propyl-isothiouronium chloride hydrochloride, melting at 215-- 2165 degrees centigrade.
'In a like manner, other pyrrolidyl-alkyl-isothiouronium chloride hydrochlorides can be prepared from the pyrrolidyl allr'yl chloride hydrochlorides obtained from the alcohols 01 the previous preparations.
PREPARATION OF THIO ALCOHOLS Preparation 1 7.--2-(Z-methylpyrrolidyZ-1)- ethanthiol A solution of 16.9 grams of 2-(2-methylpyrrolidy1-l)-ethyl isothiouronium chloride hydrochloride in 30 milliliters of water and asolution of 5.3 grams of sodiumv hydroxide in 20 milliliters of water were mixed in a container at room temperature. The flask was attached to an apparatus adapted for continuous extraction with ether, the air displaced with nitrogen and 'the mixture then extracted with. peroxide-free ether for six hours.
The ethereal solution of 2-(2-methylpyrroli- .dyl-D-ethanthiol thus obtained was dried with anhydrous calcium sulfate and used directly in Ex ample; l.
. 9 In a like manner, the following pyrrolidylalkanthiols and alkylpyrrolidylalkanthiols can be prepared by hydrolysis of thecorresponding isothiouronium chloride hydrochloride:
' PREPARATION OF THIO-ESTERS Example 2.(2-methylpyrroZidyZ-1)-ethyl alphaphenyZ-alpha- (A -cyclopentenyb -thz'ol acetate The 'dry ethereal extract containing 2-(2- methylpyrrolidyl-l)-ethanthiol from Preparation' 17 was added to a solution of 13.3 grams of alpha phenyl --alpha (A cyc1opentenyl)- acetyl chloride contained in 50 milliliters of anhydrous benzene. The reaction mixture, which rapidly separated into two layers, was heated under reflux for two hours, poured into a mixture of dilute aqueous hydrochloric acid and the layers separated. The organic layer was extracted with water, the aqueous solutions combined and extracted once with ether. The aqueous solution was made basic with sodium'hydroxide, and the 2 (2 methylpyrrolidyl 1) ethyl alpha phenyl alpha (A cyclopentenyD- thiol acetate extracted with ether. The ether extract was washed with water and dried.
-2- (2-methyl-pyrrolidyl-1) -ethyl alpha-phenylalpha-(A -cyclopentenyl)-thiol acetate hydrochloride was prepared by passing dry hydrogen chloride into a portion of the above ethereal solution of the free base. The salt, after crystallization from ethyl acetate, melted at 111-115 degrees centigrade.
Analysis:
Calculated for CgoHzs'Cl-NOS N 3.83 S 8.76 019.69. Found: 3.61 8.83 9.64.
In a like manner the following esters and their salts were prepared:
1. 2 (pyrrolidyl-1) ethyl alpha,alpha diphenyl-thiolacetate hydrochloride, melting at 140-141 degrees centigrade.
Analysis:
Calculated for CQOHEIICINOS: N Found:
2. 2-(pyrrolidyl-1) -ethyl alpha-cyclopentyl alpha-n-propylthiolacetate, boiling at 107 degrees centigrade at a pressure of 0.025 millimeter of mercury absolute. Hydrochloride, melting at 146-148 degrees centigrade.
Analysis:
Calculated for CNH 'CINOS: S 10.02 ll-11.08. Found 9.89 11.09,
- 3. 2-.(pyrrolidy1-1) 1-propyl alpha-phenyl-al; pha-isobutylthiolacetate citrate, meltingat 1.58- 1585 degrees centigrade.
Analysis: I A I x Calculated for C H 2ClNOS: N356 S8.14"Cl,9.0 0.
Found: v 3.69, 8.14 0.13.
5. 2-methyl-3-(pyrrolidyl-1) l-propyl alpha.- phenyl alpha cyclopentylthiolacetate; boiling at 160-170 degreesscentigr'ade at a pressure-of 0.05 millimeter of mercury Jabsolute; Hydrochloride, melting at 121-124 degrees centigrade. 5
Analysis: I I f Calculated for 'CmH CINOS: N 3.67' s 8.39 "Cl 9.28.
Found: 3.77 8.36; 9.46.
6. 2- (2-methylpyrro1idy1 1) -ethyl' alpha f A cyclopentenyl alphaen propylthiolacetate tcitrate was prepared by adding a slight excess of, citric acid in ethanol to anethyl acetate solution of the free ester.. The citrate melted at -102 degrees centigrade. f
In a manner similar tothat ofv the above Exam ple, the following esters of various pyrrolidylalkanthiols and alkylpyrrolidyl alkanthiols can be prepared as well as acid addition salts thereof.
2- (pyrrolidyl- 1) -ethyl alpha,alpha-diphenylthiolacetate 2- (2,3-dimethylpyrrolidyl-1 -.ethyl alpha,alphadiphenylthiolacetate 2- (3,4-dimethylpyrrolidyl-l) '-ethyl alpha,alphadiphenylthiolacetate f 2- (2,4,4-trimethy1pyrrolidy1-1 pha-diphenylthiolacetate' 1 V 2-(2-ethy1pyrrolidyl-1) -ethyl alpha, alpha diphenylthiolacetate 2 methyl 2 (pyrrolidyl --"1) 1 propyl alpha;alpha-diphenylthiolacetate' 2 methyl --3 (pyrrolidyl 1) alpha,alpha-diphenylthiolacetate 1 (2,5 dimethylpyrrolidyl 1) 2 propyl alpha,alpha diphenylthiolacetate 1 (pyrrolidyl 1) 3 butyl alpha,alphadiphenylthiolacetate 1 (pyrrolidyl 1) 4 pentyl alpha,alpha}- diphenylthiolac'etate" i f 2-(pyrrolidyl-1) -ethy1 alpha-phenyl alpha-A cyclopentenylthiolacetate v 2 (2,4,4 trimethylpyrrolidyl 1) ethyl alpha-phenyl alpha-A cyclopentylthiolacetate 2 (2 ethylpyrrolidyl 1) ethyl alpha phenyl alpha-A -cyclophentylthiolacetate 3-(pyrrolidyl-1) -1-propyl alpha-phenyl alpha- A -cyclohexenylthiolacetate 2-(pyrrolidyl-1)-ethyl alpha-phenyl alpha-cyclopentylthiolacetate 2 (2,4,4 trimethylpyrrolidyl 1) ethyl alphaphenyl alpha-cyclopentylthiolacetate :3-(pyrrolidyl-l)-1-propyl alpha-phenyl alphacyclopentylthiolacetate 2- (2-ethylpyrrolidyl-1) -1-propyl alpha phenyl alpha-cyclohexylthiolacetate 3-(pyrrolidyl-1) -2-butyl alpha-phenyl alphacyclohexylthiolacetate 2-(2 methylpyrrolidyl-l) -ethyl alpha phenylalpha-isobutylthiolacetate 3-(pyrrolidyl-1) -1butyl alpha-phenyl alpha-isobutylthiolacetate ethyl alpha,al-
1 propyl 3- (pyrrolidyl-ll-l-butyl alpha-N-cyclohexenyl 'alpha-A 1cyclopentenylthiolacetate 2-(2-ethy1pyrrolidy1-1) ethyl alpha. cyclopentenyl alphaQ-n-propylthiolacetate 2-t2-ethylpyrrolidyl-L) ethyl 'tenyl alpha-n-butylthiolacetate 'l-'(i,5- dimethylwrr lidylel)-2-propy1 alpha-icy- 1mm alpha nshutylthlolacetate 'Variousmodincations maybe made in the comhi the 'present invention without departhi'g from the spirit or scope thereof, and it "is to be understood that I limit myself only as defined in the appendedclaims.
l. A member of the group consisting of (a) esters having the formula:
"wherein-Rim amember oi' the group consisting of aryl, aralkyl, cycloalkyl and cyc'loalkenyl radicals, R is a member oi the group consisting of alkyl, aryl aralkyl, cycloaulkyl "and .cycloalkenyl radicals, R is a memherof the group consisting of pyrrolidyl-l and lower-.alkylesubstituted pyrrdlidyl-i radicals and n is a, member of the group consisting of the integers 2, 3, and 4,:and 6b) acid addition salts thereof.
2. Acid addition :salts of esters having the rormula:
rv herein .R is and, .R is cycloalkenyl, R" is a lower-alkyl-substituted pyrrolidyl-l radical, and
.n is lthe integerl ialpha-cyclopen- 12 r 3. Acid addition salts of esters having the formula:
. R HlSC,Hz--
where R and R are aryl, R" is pyrrolidyl-l', and n is the integer 2.
4. Acid addition salts of esters having the formula:
whereinR is aryl, R is alkyl, 'R" is pyrrolidyl-l n is the integer 3.
5. Acid addition salts of esters having the formula:
H..JIf. G fs..JC
wherein R is aryl, R is zcyclqalkenyl, R" .is pyrrolidyl-l and n is the integer 6. Acid addition salts of esters having the formula: I
wherein R is aryl, R" is cycloalkyl, R is pyrrolidyl-l and n is the integer 4.
7. '2 (2 methylpyrrolidyl -1) ethyl alphaphenyl alpha-(A eyclopenteny'l) thiolaceta'te hydrochloride.
8. 2 (pyrrolidyil "1) ethyl alpha, alphadiphenyl-thiolacetate hydrochloride.
'9. 2 pyrrolidy1- 1') l propyl alpha-phenylalpha-isobutylthiolacetate citrate.
10. 4 fpyrrolidyl 1) butyl alpha-phenylalpha-A -cyclohexenylthiolacetate hydrochloride.
1'1. 2 methyl 3 '(pyrrolidyl 1) 1 propyl alpha-phenyl-alpha-cyclopentylthiolacetate hydrochloride.
JAMES H. REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Number Name Date Allen Oct. 21, 1941

Claims (1)

1. A MEMBER OF THE GROUP CONSISTING OF (A) ESTERS HAVING THE FORMULA:
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3041351A (en) * 1955-11-04 1962-06-26 Hills Bros Coffee Heterocyclic mercaptan compounds

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US2259869A (en) * 1939-09-30 1941-10-21 Shell Dev Insecticide and repellent

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2259869A (en) * 1939-09-30 1941-10-21 Shell Dev Insecticide and repellent

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3041351A (en) * 1955-11-04 1962-06-26 Hills Bros Coffee Heterocyclic mercaptan compounds

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