US2648666A - Quaternary ammonium salts derived - Google Patents

Quaternary ammonium salts derived Download PDF

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US2648666A
US2648666A US2648666DA US2648666A US 2648666 A US2648666 A US 2648666A US 2648666D A US2648666D A US 2648666DA US 2648666 A US2648666 A US 2648666A
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tropate
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Definitions

  • the present invention relates to new therapeutically active quaternary ammonium compounds and more particularly to esters of tropic acid containing a heterocyclic quaternary nitrogen atom, and the production thereof.
  • the compounds which comprise m invention have the following general structural formula CHzOH CH3 wherein n is an integer no greater than 4 and m is either 2 or 3, X being an equivalent of an anion.
  • tropic acid esters which are included in this invention are those of the 1,2,5- trimethyl-N- (hydroxyalkyl) -pyrrolidinium and N-methyl N -(hydrxyalkyl) 2,6 lupetidinium salts, the hydroxyalkyl group being a hydroxyethyl, hydroxypropyl or hydroxybutyl group.
  • the compounds of this invention show unusual and valuable properties, especially in their blocking action on autonomic nervous functions.
  • These blocking agents difier from the usual sympathicolytics and parasympathicolyti'cs in that their principal point of attack is not the neuromuscular junction, but the ganglion. By a direct action on the ganglia, both sympathetic and parasympathetic impulses are blocked.
  • N-haloalkyl-2,5-dimethylpyrrolidines are prepared from the N-hydroxyalkyl-Z,5-dimethylpyrroles by hydrogenation and treatment of the resulting pyrrolidines with thionyl chloride.
  • the methods in the literature for the preparation of such N-hydroxyalkyl-Z,S-dimethylpyrroles from pyrrole derivatives are quite unsatisfactory. I have discovered a new method for preparing hydroxyalkyl-dimethylpyrroles in which 2,5- hexanedione is condensed with an alkanolamine, preferably by boiling under nitrogen, which permits the use of readily available starting mate-' rials and gives excellent yields.
  • EXAMPLE 4 1- (delta-hydroxbutyl) 2,5-dimethylpyrrole
  • EXAMPLE 5 ZI'ropate of I-(deZta-hydroarbutyl) -2,5-dz'methylpyrrolidine 9.7 g. of l-(delta-chlorobutyl) -2,5-dimethyl -;pyrrolidine are dissolved in isopropanol and treated with got tropic acid and boiled. under .refiux for 3 hours- The solvent is then removed 1 under vacuum and the residual syrup washed with g-ether.
  • EXAMPLE 7 Tropate of l-(beta-hydroxyethyl)-2,6-Zupetidine 27 g. of l-(beta-chloroethyl)-2,6-lupetidine, 2'7 g. of tropic acid and ml. of isopropanol are heated to reflux temperature for 4 hours, then cooled to 0, filtered and washed with ethyl methyl ketone. 28 g. of white crystals, melting at -126 are obtained, consisting of the hydrochloride of the desired ester. One then distil's the original filtrate in vacuum to remove the solvent, adds water, makes the solution alkaline with potassium carbonate, extracts with ether and evaporates. Thus 18 g. of the oily free base are obtained.
  • Beta-(2,6-lupetz'dz'no)-ethyl tropate methobromz'de 20 g. of beta-(2,6-lupetidino) -ethyl ester of tropic acid are dissolved in ml. of ethyl methyl ketone in a citrate bottle, 7 g. of methyl bromide are added and the charge heated to 70-80" for 15 hours. The crystalline product is filtered and washed with ethyl methyl ketone to yield 18 g. of thick prisms, melting at 166-167". On standing overnight, the original ethyl methyl ketone filtrate yields an additional amount of crystals. Upon recrystallization from isopropanol, a melting point of 169-170 is obtained.
  • the citrate may be prepared from the bromide by dissolving three mols of the latter in methanol and adding one mol of silver citrate and two mols of citric acid.
  • EXAMPLE 9 Tropate of l-(delta-hyprorybutyl) -2,6-lu.petidine 20 g. of l-(delta-chlorobutyl)-2,6-lupetidine are heated with 17.5 g. of tropic acid and 100 ml. of isopropanol to reflux temperature for 5 hours, then cooled with ice. The precipitate is filtered and washed with ethyl methyl ketone. One dissolves the resultant hydrochloride in water, adds potassium carbonate to make the solution alkaline, extracts with ether and evaporates to obtain the oily free base.
  • EXAMPLE 10 Tropate of N-(deZta-hydrorybutyl) -N- methyl-2,6-Zupctid'z'nium bromide
  • a citrate bottle 26 g. of the tropate of 1- (delta-hydroxybutyl) -2,6-lupetidine, prepared as in Example 9, are dissolved in 200 .ml. of ethyl methyl ketone, 8.5 g. of methyl bromide are added and the charge heated for 24 hours.
  • n is an integer from 2 to 4 inclusive and m is an integer greater than 1 and less than 4, and wherein X is an equivalent of an anion.
  • n is an integer from 2 to 4 inclusive and X is an anion.
  • X is an anion
  • n is an integer frdn'i- 2 to 4 inclusive.
  • Beta-(2,6-1upetidino) ,-ethy1- tropate metho q i .n

Description

Patented Aug. 11 1953 QUATERNARY AMMONIUM SALTS DERIVED FROM HETEROCYCLYLALKYL ES-TERS OF TROPIC ACID Richard A. Robinson, Morton Grove, 11]., assignor to G. D. Searle & 00., Chicago, III., a corporation of Illinois No Drawing. Application March 1, 1950,
Serial No. 147,149
8 Claims. (01. 260-2943) The present invention relates to new therapeutically active quaternary ammonium compounds and more particularly to esters of tropic acid containing a heterocyclic quaternary nitrogen atom, and the production thereof.
The compounds which comprise m invention have the following general structural formula CHzOH CH3 wherein n is an integer no greater than 4 and m is either 2 or 3, X being an equivalent of an anion.
Among the tropic acid esters which are included in this invention are those of the 1,2,5- trimethyl-N- (hydroxyalkyl) -pyrrolidinium and N-methyl N -(hydrxyalkyl) 2,6 lupetidinium salts, the hydroxyalkyl group being a hydroxyethyl, hydroxypropyl or hydroxybutyl group.
The compounds of this invention show unusual and valuable properties, especially in their blocking action on autonomic nervous functions. These blocking agents difier from the usual sympathicolytics and parasympathicolyti'cs in that their principal point of attack is not the neuromuscular junction, but the ganglion. By a direct action on the ganglia, both sympathetic and parasympathetic impulses are blocked.
In the preparation of these compounds I prefer to heat the N-haloalkyl derivative of the di-, methyl pyrrolidine or lupetidine with tropic acid in an organic solvent such as a lower alkanol or alkanone to replace the halogen by a tropyl group. The resulting ester hydrochloride is converted into the free base and the latter suitably dissolved in an organic solvent such as an aliphatic ketone and treated with a methylating agent, preferably one which is not sterically hindered.
The N-haloalkyl-2,5-dimethylpyrrolidines are prepared from the N-hydroxyalkyl-Z,5-dimethylpyrroles by hydrogenation and treatment of the resulting pyrrolidines with thionyl chloride. The methods in the literature for the preparation of such N-hydroxyalkyl-Z,S-dimethylpyrroles from pyrrole derivatives are quite unsatisfactory. I have discovered a new method for preparing hydroxyalkyl-dimethylpyrroles in which 2,5- hexanedione is condensed with an alkanolamine, preferably by boiling under nitrogen, which permits the use of readily available starting mate-' rials and gives excellent yields. 1 My'invention will be described more fully in (CHQWX 2 g conjunction with the following examples. It should be understood, however, that these examples are given by way of illustration only and that the invention is not to be construed as limited in spirt or in scope by the details set forth. It will be clear to those skilled in the art that many modifications in materials and methods may be made Without departing from the invention. In each of these examples, temperatures are given in degrees centi'grade, parts by weight are given in grams (g.) and parts by volume are in milliliters (ml). Pressures during vacuum distillation are measured in millimeters of mercury (mm.).
- EXAMPLE 1 1- (beta-hydrox yethyl) -2,5-dimethyl-pyrrole 112 g. of acetonyl-acetone are added to g. of ethanolamine under nitrogen at such a rate that the temperature does not exceed 100. The mixture is then stirred and heated at about 90 under reflux for 1.5 hours. One vacuum distils at 20 mm. in a nitrogen atmosphere. 78 g. of water and unused reagents are distilled at 85-116". The residue, weighing about g., principally composed of the l-(beta-hydroxyethyl) -2,5-dimethyl-pyrrole, is filtered through charcoal and may be hydrogenated without further purification. It may also be advantageously purified by distillation at 137 at 18 mm. pressure.
EXAMPLE 2 Tropate of I-(beta-hydromyethyl)-2,5dim thyZ- pyrrolidine 28 g. of l-(beta -hydroxyethyl) -2,5-dimethylpyrrole are hydrogenated using 1.5 g, of platinum oxide in ml. of acetic acid. The calculated amount of hydrogen is abSQrbed in about one hour. After filtration of- -the catalyst the acetic acid is removed at 20mm. pressure, the residue dissolved in water and treated with excess strong alkali, and the free base isolated by ether extraction. At 18 mm. pressure most of the material distils at 86-91. The hydrochlori-de of the 1- (beta-hydroxyethyl) 2,5- dimethyl pyrrolidine, recrystallized from ethyl methyl ketone, melts at 167-168". L
100 g. of the base are dissolved in 300 ml. of
' chloroform and treated at 5-20 with dry HCl gas until the hydrochloride is formed. '75 m1. of thionyl'chloride are added and the solution boiled With reflux for 1 .5 hoursflThe solvent is then removed as far as practical under vacuum. The
"- residue is washed with anhydrous ether and ethyl odium comes white on recrystallization from ethyl methyl ketone.
35 g. of the 1- (betal-chloroethyl) -2,5-dimethylpyrrolidine hydrochloride are dissolved in water, precipitated by excess sodium carbonate, ex tracted with ether, dried over potassium hydroxide, filtered with charcoal and evaporated under vacuum. 26 g. of this clear base are dissolved in isopropanol. treated with 32 g. of tropic acid and boiled with reflux for 160 minutes. The solvent is than removed under vacuum and the syrupy residue washed with ether. After standing for several hours the product crystallizes. By filtration, washing with ether and drying at '70-80, 40 g. of white crystals of the hydrochloride are obtained which melt at 90. Recrystallization from ethyl methyl ketone gives white crystals, melting at 106-108".
EXAMPLE 3 Beta- (2,5-dimethylpyrrolidino) ethyl tropate methobromz'de 48.5 g. of oily tropic acid ester of l-(betahydroxyethyl)-2,5 -dimethyl pyrrolidine, prepared as in Example 2, are dissolved in 150 ml. of ethyl methyl ketone and treated with methyl bromide until 18 g. are absorbed. After standing for 18 hours there is separation of some methobromide crystals. One heats for 40 hours to 70-80% filters and washes with ethyl methyl ketone to obtain 60 g. of white crystals, which melt at 185-186.
(3113 CHzOH CH-CH:
om m om cm In order to prepare the citrate one dissolves three mols of the bromide in methanol and adds one mol of silver citrate and two citric acid.
EXAMPLE 4 1- (delta-hydroxbutyl) 2,5-dimethylpyrrole EXAMPLE 5 :ZI'ropate of I-(deZta-hydroarbutyl) -2,5-dz'methylpyrrolidine 9.7 g. of l-(delta-chlorobutyl) -2,5-dimethyl -;pyrrolidine are dissolved in isopropanol and treated with got tropic acid and boiled. under .refiux for 3 hours- The solvent is then removed 1 under vacuum and the residual syrup washed with g-ether. fAiter standing overnight crystals appealrs Onafiltera-washes the crystals with ether sand dries-at 80 to-contain 13 g. of white crys- "tals of theirhydrochloride. One dissolves these seat solution alkaline by adding carbonate. Qextracts with ether and evap- '4 EXAMPLE 6 Tropate of l-(delta hydroxbutyl) 1,2,5 in methyl-pyrrolidinium sulfate 12. g. of the tropate of 1 (delta-hydroxybutyD-Z, 5-dimethyl-pyrrolidine, prepared as in Example 4, are dissolved in 50 ml. of ethyl methyl ketone and treated with 2.9 of dimethyl sulfate. One heats for several hours at 75, filters and washes with ethyl methyl ketone to obtain the white crystals of the tropate of the l-(deltahydroxybutyl) -1 ,2,S-trimethyl-pyrrolidinium sulfate.
EXAMPLE 7 Tropate of l-(beta-hydroxyethyl)-2,6-Zupetidine 27 g. of l-(beta-chloroethyl)-2,6-lupetidine, 2'7 g. of tropic acid and ml. of isopropanol are heated to reflux temperature for 4 hours, then cooled to 0, filtered and washed with ethyl methyl ketone. 28 g. of white crystals, melting at -126 are obtained, consisting of the hydrochloride of the desired ester. One then distil's the original filtrate in vacuum to remove the solvent, adds water, makes the solution alkaline with potassium carbonate, extracts with ether and evaporates. Thus 18 g. of the oily free base are obtained.
EXAMPLE 8 Beta-(2,6-lupetz'dz'no)-ethyl tropate methobromz'de 20 g. of beta-(2,6-lupetidino) -ethyl ester of tropic acid are dissolved in ml. of ethyl methyl ketone in a citrate bottle, 7 g. of methyl bromide are added and the charge heated to 70-80" for 15 hours. The crystalline product is filtered and washed with ethyl methyl ketone to yield 18 g. of thick prisms, melting at 166-167". On standing overnight, the original ethyl methyl ketone filtrate yields an additional amount of crystals. Upon recrystallization from isopropanol, a melting point of 169-170 is obtained.
The citrate may be prepared from the bromide by dissolving three mols of the latter in methanol and adding one mol of silver citrate and two mols of citric acid.
EXAMPLE 9 Tropate of l-(delta-hyprorybutyl) -2,6-lu.petidine 20 g. of l-(delta-chlorobutyl)-2,6-lupetidine are heated with 17.5 g. of tropic acid and 100 ml. of isopropanol to reflux temperature for 5 hours, then cooled with ice. The precipitate is filtered and washed with ethyl methyl ketone. One dissolves the resultant hydrochloride in water, adds potassium carbonate to make the solution alkaline, extracts with ether and evaporates to obtain the oily free base.
EXAMPLE 10 Tropate of N-(deZta-hydrorybutyl) -N- methyl-2,6-Zupctid'z'nium bromide In a citrate bottle 26 g. of the tropate of 1- (delta-hydroxybutyl) -2,6-lupetidine, prepared as in Example 9, are dissolved in 200 .ml. of ethyl methyl ketone, 8.5 g. of methyl bromide are added and the charge heated for 24 hours. After standing for one day the crystalline product is filtered and washed with ethyl methyl ketone to obtain white crystals of the tropate of N (delta-hydroxybutyl) N methyl 2,6 lupetidinium bromide, which may be further purified by recrystallization from isopropanol. 5
fcl'ai mz' g 1. Compounds of the general formula CHzOH CH: Q H
COOC,.Hz,.N oHz)...'X
OH: CH
wherein n is an integer from 2 to 4 inclusive and m is an integer greater than 1 and less than 4, and wherein X is an equivalent of an anion.
2. Compounds of the following structural formula wherein n is an integer from 2 to 4 inclusive and X is an anion.
3. Salts of beta (1,2,5 trimethyl 1 pyrro1idinim)-ethy1 tropate having the formula in which X is an anion.
4. Halides of beta 1,2,5 trimethyl 1 pyrro1idinium)-ethy1 tropate.
5. salts of an N-methyl-2.6-1upetidinium-alkyl tropate having the formula onion CH:
6, in which X is an anion, and n is an integer frdn'i- 2 to 4 inclusive.
6. Halides of beta-(N-methy1-2,6-1upetidinium) -ethy1 tropate.
7. Beta-(2,6-1upetidino) ,-ethy1- tropate metho= q i .n
8.- Beta (2.5 dimethyipyrrdiidinh) ethyl tropate methobromid'e.-
RIGHARD A, ROBINSON References Cited in the file of patent UNITED STATES PATENTS OTHER REFERENCES Braun et aL, Chem. Abstr., v01. 16 (1922), pp. 3473-3474.
Reid et 2.1., Jour. Amer. Chem. Sec v01. (1948), pp. 3100-3102,

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2993054A (en) * 1954-03-22 1961-07-18 Upjohn Co Alpha-five carbon cyclic hydrocarbon mandelic acid esters of beta-pyrrolidino-ethanol

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE116335C (en) *
US1704660A (en) * 1925-01-15 1929-03-05 Winthrop Chem Co Alkaminesters of the ortho-aminobenzoic acids and process of making same
US1784903A (en) * 1927-03-30 1930-12-16 Samuel M Mcelvain Piperidine derivative and process of producing it
US1987546A (en) * 1932-03-22 1935-01-08 Hoffmann La Roche Process for the manufacture of basic esters of phenyl substituted fatty acids
US2079962A (en) * 1934-07-12 1937-05-11 Soc Of Chemical Ind Basic esters of polyarylacetic acids and process of making the same
US2265184A (en) * 1938-08-05 1941-12-09 Ciba Pharm Prod Inc Basic esters and process of preparing same
US2448998A (en) * 1945-06-30 1948-09-07 Samuel M Mcelvain 3-(2', 6'-dimethylpiperidino)-propyl salicylate and acid addition salts thereof
US2480224A (en) * 1947-03-31 1949-08-30 Searle & Co Fluorenyl esters and method
US2552502A (en) * 1947-09-11 1951-05-08 Upjohn Co Beta-(pyrrolidyl-1)-propanol-2

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE116335C (en) *
US1704660A (en) * 1925-01-15 1929-03-05 Winthrop Chem Co Alkaminesters of the ortho-aminobenzoic acids and process of making same
US1784903A (en) * 1927-03-30 1930-12-16 Samuel M Mcelvain Piperidine derivative and process of producing it
US1987546A (en) * 1932-03-22 1935-01-08 Hoffmann La Roche Process for the manufacture of basic esters of phenyl substituted fatty acids
US2079962A (en) * 1934-07-12 1937-05-11 Soc Of Chemical Ind Basic esters of polyarylacetic acids and process of making the same
US2265184A (en) * 1938-08-05 1941-12-09 Ciba Pharm Prod Inc Basic esters and process of preparing same
US2448998A (en) * 1945-06-30 1948-09-07 Samuel M Mcelvain 3-(2', 6'-dimethylpiperidino)-propyl salicylate and acid addition salts thereof
US2480224A (en) * 1947-03-31 1949-08-30 Searle & Co Fluorenyl esters and method
US2552502A (en) * 1947-09-11 1951-05-08 Upjohn Co Beta-(pyrrolidyl-1)-propanol-2

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2993054A (en) * 1954-03-22 1961-07-18 Upjohn Co Alpha-five carbon cyclic hydrocarbon mandelic acid esters of beta-pyrrolidino-ethanol

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