US2538794A - Alkamine esters of delta-cyclohexenylalkylacetic acids - Google Patents

Alkamine esters of delta-cyclohexenylalkylacetic acids Download PDF

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US2538794A
US2538794A US43543A US4354348A US2538794A US 2538794 A US2538794 A US 2538794A US 43543 A US43543 A US 43543A US 4354348 A US4354348 A US 4354348A US 2538794 A US2538794 A US 2538794A
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cyclohexenyl
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Moffett Robert Bruce
Hart Charlotte Anne
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GEORGE A BREON AND Co
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    • C—CHEMISTRY; METALLURGY
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    • 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
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Definitions

  • This invention relates to aminoalkyl esters of A -cyclohexenylalkylacetic acids and to therapeutically acceptable salts thereof which are useful as antispasmodic agents.
  • heterocyclic rings may be classed together as aliphatic tertiary-amino groups; the heterocyclic rings are distinctly non-aromatic in character and can be thought of as two alkyl groups joined together by a divalent bridge such as CHz-, -O- or S.
  • the acids which may be used to prepare the salts are those which produce, when combined with the basic esters, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that the beneficial physiological properties inherent in the basic esters are not vitiated by side-effects ascribable to the anions.
  • Appropriate acid addition salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, and sulfuric acid; and organic acids such as acetic acid, citric acid and tartaric acid.
  • the quaternary ammonium derivatives are obtained by the addition of alkyl or aralkyl esters of inorganic acids or organic suli'onic acids, such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, benzyl chloride, benzyl bromide, methyl sulfate, methyl benzenesulfonate, methyl-p-toluenesulfonate, etc.
  • alkyl or aralkyl esters of inorganic acids or organic suli'onic acids such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, benzyl chloride, benzyl bromide, methyl sulfate, methyl benzenesulfonate, methyl-p-toluenesulfonate, etc.
  • Synthetic antispasmodics usually have both a musculotropic (papaverine-like) action and neurotropic (atropine-like) action. It is desirable that new compounds be introduced which have high neurotropic activity but which lack the characteristic undesirable physiological side-effects of atropine.
  • the resulting AF-cyclohexeny w 1 malonic ester (CsH9)-CR-(COOC'2H5) 2, is hydrolyzed by heating with 30% alcoholic potassium hydroxide in a bomb at -150" 0., and decarboxylated at C. at atmospheric pressure, giving the desired A -cyclohexenylalkylacetic acid.
  • the malonic esters are diflicult to prepare because of the steric hindrance of the groups involved, an alternative procedure can be used. This is based on the method of Alexander and Cope [J. Am. Chem. Soc. 66, 886 (1944)]. which involves condensation 01' an aldehyde or ketone with ethyl cyanoacetate and reduction of the resulting ethylenic double bond, all carried out in one step.
  • the carbonyl compound used has a structure such that the group R in the resulting substituted cyanoacetic ester, R-CH(CN)-COOCzHs, has 4-6 carbon atoms.
  • condensation of ethyl cyanoacetate and methyl isopropyl ketone in the presence of ammonium acetate, acetic acid and alladium-on-charcoal in an atmoshere of hydrogen gives ethyl (1,2-dimethylpropyl) -cyanoacetate.
  • the malonic ester or cyanoacetic ester synthesis in a given case depends upon the nature of the alkyl group to be introduced. 11 the alkyl group to be introduced is of the straight chain type or is branched at the end, themalonic ester synthesis is preferred.
  • the alkyl group is branched, particularly near its point of juncture with the rest of the molecule, the cyanoacetic ester method is preferred.
  • a therapeutically acceptable acid such as hydrogen chloride in alcoholic solution.
  • the basic ester may be con-' to dissolve soluble salts and the organic layer is separated, washed with water and dried over (2) The A -cyclohexenylalkylacetic acid is re-.
  • a metallic salt of a A -cyclohexenylalkyl- I acetic acid is heated or simply mixed with a tertiary-aminoalkyl halide. In this case the free basic ester is formed directly.
  • Quaternary ammonium salts are prepared by mixing the free basic ester with a lower alkyl or aralkyl ester of a strong inorganic acid or organic sulfonic acid, preferably in an inert organic solvent such as benzene or ether, with or Without gentle heating.
  • the salt either crystallizes immediately or can be obtained by concentration of the solvent.
  • EXAMPLE 1 Diethyl M-cyclohexenZ/Zmalomzte.-To a solution of 184 g. (8 m.) of sodium in 2.8 liters of absolute ethanol is added 641 g. (4 m.) of diethyl malonate and then 968 g. (4 m.) of 1,2-dibromocyclohexane is slowly run in. After refluxing for six hours the mixture is practically neutral. Most of the alcohol is then removed by distillation and the residue is diluted with 1 liter of water. The layers are separated and the organic layer is washed with water, dried over anhydrous sodium sulfate and distilled from a Claisen flask.
  • a cyclohexenyZ-isoamylacetic acid --A mixture of 40 g. of diethyl A -cyclohexenyl-isoamylmalonate with a solution of 40 g. of potassium hydroxide in 100 cc. of 95% ethanol is heated on a bomb in an oil bath at -160 C. for three hours. After cooling, the contents are diluted with water, extracted with ether and acidified with hydrochloric acid. The product is extracted with ether, and the ether solutions then washed thoroughly with water and dried over anhydrous sodium sulfate. After removing the solvent, the product is heated to C.
  • Beta-diethylaminoethyl A -cyclohexemllisoamylacetate and its hydrochZoride.A-cyclohexenyl-isoamylacetic acid (21.8 g., 0.104 m.) is neutralized to phenolphthalein with alcoholic sodium ethoxide, and 14.1 g. (0.014 m.) of betadiethylaminoethyl chloride in 40 cc. of isopropyl alcohol is then added. After standing for several days (or refluxing for several hours), the sodium chloride is removed by filtration, and the volatile solvents are distilled off. The basic ester is dissolved in ether, washed with water and extracted with cold dilute hydrochloric acid.
  • the hydrochloride of beta-diethylaminoethyl A -cyclohexenyl-isoamylacetate is prepared by passing dry hydrogen chloride gas into a solution of 16.1 g. of the free basic ester in absolute ether. A colloidal precipitate forms which crystallizes upon stirring. After filtering, washing with ether and drying, the hydrochloride is obtained; weight 10.8 g. (60%). Upon recrystallization from methyl isobutyl ketone it has the M. P. l01-105 C.
  • Beta-dimethylaminoethyl A -cyclohezcenylisoamylacetate and its hydroohlorida-Beta-dimethylaminoethanol (7.8 g., 0.088 m.) is dissolved in 70 cc. of dry pyridine and 20 g. (0.088 m.) of A -cyclohexenyl-isoamylacetyl chloride is added, and the mixture is' allowed to stand for a few minutes and finally heated on a steam bath for four hours. After cooling the mixture, it is shaken with a solution of 8 g. of sodium carbonate monohydrate in 150cc. of water and the water layer is separated and extracted with ether.
  • the hydrochloride is prepared in the manner described in Example 1, part d by passing dry hydrogen chloride gas through a solution of the basic ester in anhydrous ether.
  • the hydrochloride is obtained in about 46% yield and has the M. P. 114-115 C.
  • the hydrochloride of beta-(N-piperidyl) -ethyl A -cyclohexenyl-isoamylacetate is prepared in the usual manner from the free basic ester and hydrogen chloride gas in ether solution. It is obtained in about 76% yield and has the M. P.
  • Beta-diethylaminoethyl A -cyclohexenylsec-butylacetate and its hydrochlorida-This is prepared from the substituted acetic acid using sodium ethoxide and beta-diethylaminoethyl chloride according to the method shown in Example 1, part d- Nine and six-tenths grams of acid results in about 8.6 g. (60%) of beta-diethylaminoethyl A cyclohexenyl sec butylacetate, B. P. 109 C. (0.04 mm.) n 1.4701;
  • the hydrochloride is prepared in the usual manner from the basic-ester and dry hydrogen chloride gas in ether solution. When recrystallized from methyl isobutyl ketone, the hydrochloride melts at 105-110 C.
  • Y is an alkylene bridge of 2-5 carbon atoms and R and R" are lower alkyl groups and acid 1.
  • R is an alkyl group of 4-6 carbon atoms and Y is an alkylene bridge of 2-5 carbon atoms; and acid addition and quaternary ammonium salts thereof.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

Patented Jan. 23, 1951 NITED STATES PATENT OFFICE 2,538,794 E ESTEES F A CYCLOIIEXENYL- AIKYLAGETIO ACIDS Robert Bruce Moflett, Kalamazoo, Mich., and
Charlotte Anne Hart, Kansas City, Mo., assignors to George A. Breon and Company,
City, Mo., a corporation of wssouri No Drawing. Application August 10, 1948, Serial No. 43,543
, 1 This invention relates to aminoalkyl esters of A -cyclohexenylalkylacetic acids and to therapeutically acceptable salts thereof which are useful as antispasmodic agents. This is a continuationin-part of our copending application, S. N. 642,427, filed January 19, 1946,
These esters have the formula where R is an alkyl group of 4-6 carbon atoms, Y is an allrylene bridge having at least two carbon atoms separating the oxygen and nitrogen atoms, and -N=B is a tertiary-amino group wherein B represents two alkyl groups or the atoms neces sary to complete a heterocyclic ring. More specifically Y may be a divalent hydrocarbon radical such as ethylene, propylene, butylene, l-methyl-= ethylene, Z-methylethylene or l-methylbutylene; and -N=B includes such structures as dimethylamino, ethylmethylamino, diethylamino, dipropylamino, dibutylamino, butylpropylamino, piperidyl, z-methylpiperidyl, morpholinyl, thiomorpholinyl, beta-hydroxyethylethylamino, etc. These may be classed together as aliphatic tertiary-amino groups; the heterocyclic rings are distinctly non-aromatic in character and can be thought of as two alkyl groups joined together by a divalent bridge such as CHz-, -O- or S.
These compounds are generally used in the form of water-soluble acid-addition salts or quaternary ammonium derivatives. The acids which may be used to prepare the salts are those which produce, when combined with the basic esters, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that the beneficial physiological properties inherent in the basic esters are not vitiated by side-effects ascribable to the anions. Appropriate acid addition salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, and sulfuric acid; and organic acids such as acetic acid, citric acid and tartaric acid. The quaternary ammonium derivatives are obtained by the addition of alkyl or aralkyl esters of inorganic acids or organic suli'onic acids, such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, benzyl chloride, benzyl bromide, methyl sulfate, methyl benzenesulfonate, methyl-p-toluenesulfonate, etc.
Synthetic antispasmodics usually have both a musculotropic (papaverine-like) action and neurotropic (atropine-like) action. It is desirable that new compounds be introduced which have high neurotropic activity but which lack the characteristic undesirable physiological side-effects of atropine.
Our compounds are distinguished by h h neurotroplc activity, and, in addition, several mem= bers of the series show antihistaminic action.
Our compounds are conveniently prepared by esterification of the corresponding substituted acetic acid, (Col-I9) --CHR-COOH. The acids themselves are prepared in the following manner. The sodio derivative of diethyl n -cyclohexenylmalonate, (Cal-Is) -CH-(C0OC2H5) r, is alkylated with RX, where R is an alkyl group of 4-6 carbons and X is a halogen atom, i. e., chlorine, bromine or iodine. The resulting AF-cyclohexeny w 1 malonic ester, (CsH9)-CR-(COOC'2H5) 2, is hydrolyzed by heating with 30% alcoholic potassium hydroxide in a bomb at -150" 0., and decarboxylated at C. at atmospheric pressure, giving the desired A -cyclohexenylalkylacetic acid.
In some cases where the malonic esters are diflicult to prepare because of the steric hindrance of the groups involved, an alternative procedure can be used. This is based on the method of Alexander and Cope [J. Am. Chem. Soc. 66, 886 (1944)]. which involves condensation 01' an aldehyde or ketone with ethyl cyanoacetate and reduction of the resulting ethylenic double bond, all carried out in one step. In preparing the compounds of the present invention the carbonyl compound used has a structure such that the group R in the resulting substituted cyanoacetic ester, R-CH(CN)-COOCzHs, has 4-6 carbon atoms. For example, condensation of ethyl cyanoacetate and methyl isopropyl ketone in the presence of ammonium acetate, acetic acid and alladium-on-charcoal in an atmoshere of hydrogen gives ethyl (1,2-dimethylpropyl) -cyanoacetate. The sodio-derivative of the mono-substituted cyanoacetic ester in then alkylatedwith a A -cyclohexenyl halide to give an ethyl A cyclohexenylalkylcyanoacetate,
(CeHo) CR(CN) COOC2H5 This is hydrolyzed and decarboxylated to the corresponding A -cyclohexenylalkylacetic acid, (CeH9)-CHRCOOH, although in lower yield than the hydrolysi and decarboxylation of the corresponding malonic ester. Substituted acetamides appear as byproducts and more drastic conditions of hydrolysis lead to decomposition.
Instead of alkylating malonic ester, 9. substituted malonic ester or substituted cyanoacetic ester with a A' cyclohexenyl halide, it is often preferable to use the more readily available 1,2- dibromocyclohexane. The simple alkylation product, a 2-bromocyclohexylmalonic or cyanoacetic ester, is not obtained. Under the conditions of the reaction, hydrogen bromide is lost giving rise to the desired 2-3 double bond.
The preferred method, the malonic ester or cyanoacetic ester synthesis, in a given case depends upon the nature of the alkyl group to be introduced. 11 the alkyl group to be introduced is of the straight chain type or is branched at the end, themalonic ester synthesis is preferred.
If the alkyl group is branched, particularly near its point of juncture with the rest of the molecule, the cyanoacetic ester method is preferred.
The esters of our invention, having the general formula CeH9CH(R)COOY-N=B as described above, and their acid addition salts, are prepared from the free acid by one of the following methods.
(1) An acid halide or anhydride of a A -cyclohexenylalkylacetic acid is reacted with a tertiaryaminoalkanol of the formula HO-Y-N=B, where Y is an alkylene-bridge of at least 2 carbon atoms and N=B is a tertiary-amino group. The reaction is effected by simple admixture of the two components although heating is generally used to accelerate the reaction; The free basic ester is obtained by addition of alkali to the reaction mixture. verted to an acid addition salt by the addition,
preferably in non-aqueous medium, of a therapeutically acceptable acid, such as hydrogen chloride in alcoholic solution.
The basic ester may be con-' to dissolve soluble salts and the organic layer is separated, washed with water and dried over (2) The A -cyclohexenylalkylacetic acid is re-.
(4) A metallic salt of a A -cyclohexenylalkyl- I acetic acid is heated or simply mixed with a tertiary-aminoalkyl halide. In this case the free basic ester is formed directly.
Quaternary ammonium salts are prepared by mixing the free basic ester with a lower alkyl or aralkyl ester of a strong inorganic acid or organic sulfonic acid, preferably in an inert organic solvent such as benzene or ether, with or Without gentle heating. The salt either crystallizes immediately or can be obtained by concentration of the solvent.
EXAMPLE 1 (a) Diethyl M-cyclohexenZ/Zmalomzte.-To a solution of 184 g. (8 m.) of sodium in 2.8 liters of absolute ethanol is added 641 g. (4 m.) of diethyl malonate and then 968 g. (4 m.) of 1,2-dibromocyclohexane is slowly run in. After refluxing for six hours the mixture is practically neutral. Most of the alcohol is then removed by distillation and the residue is diluted with 1 liter of water. The layers are separated and the organic layer is washed with water, dried over anhydrous sodium sulfate and distilled from a Claisen flask. The fraction distilling at 88-130 (0.1 mm.) is redistilled through an efficient column, giving about 625 g. (65%) of diethyl A -cyclohexenylmalonate, B. P. 87; C. (0.11 mm.); np =l.4595; d4 =1.0443.
(b) Diethyl A -cycloheccenyl-isoamylmalonate. --To 17.3 g. (0.75 m.) of sodium melted under 150 cc. of dry toluene in a 1 liter flask is slowly added, with vigorous stirring, 180 g. (0.75 m.) of diethyl A -cyclohexenylmalonate. The mixture is refluxed until practically all of the sodium has reacted, and then 136 g. (0.9 m.) of isoamyl bromide is added. After refluxing for twelve hours the reaction mixture is cooled and neutralized with acetic acid. Enough water is added anhydrous sodium sulfate. After removal of low-boiling solvents, the product is distilled at reduced pressure, first from a modified Claisen flask and then through an efilcient column giving about 113 g. (48.5%) of diethyl A -cyclohexenyl-isoamylmalonate, B. P. 97 C. (0.02 mm.) n =1.4643; d4 =0.9993.
(c) A cyclohexenyZ-isoamylacetic acid.--A mixture of 40 g. of diethyl A -cyclohexenyl-isoamylmalonate with a solution of 40 g. of potassium hydroxide in 100 cc. of 95% ethanol is heated on a bomb in an oil bath at -160 C. for three hours. After cooling, the contents are diluted with water, extracted with ether and acidified with hydrochloric acid. The product is extracted with ether, and the ether solutions then washed thoroughly with water and dried over anhydrous sodium sulfate. After removing the solvent, the product is heated to C. until carbon dioxide ceases to be evolved, and then is distilled at reduced pressure from aClaisen flask, giving about 28 g. of A cyclohexenyl-isoamylacetic acid, B. P. 104 C. (0.07 mm.); n =1.4746; d4 =0.9669.
(d) Beta-diethylaminoethyl A -cyclohexemllisoamylacetate and its hydrochZoride.A-cyclohexenyl-isoamylacetic acid (21.8 g., 0.104 m.) is neutralized to phenolphthalein with alcoholic sodium ethoxide, and 14.1 g. (0.014 m.) of betadiethylaminoethyl chloride in 40 cc. of isopropyl alcohol is then added. After standing for several days (or refluxing for several hours), the sodium chloride is removed by filtration, and the volatile solvents are distilled off. The basic ester is dissolved in ether, washed with water and extracted with cold dilute hydrochloric acid. The acid solution is washed with ether and made basic with sodium carbonate. The liberated basic ester is extracted with ether and the ether solution is dried over anhydrous sodium sulfate. Distillation of the product at reduced pressure after removal of the ether gives about 17.4 g. (54%) of beta-diethylaminoethyl A -cyclohexenyl-isoamylacetate, B. P. 109 C. (0.029 mm.); n =1.466O; d4 =0.9285.
The hydrochloride of beta-diethylaminoethyl A -cyclohexenyl-isoamylacetate is prepared by passing dry hydrogen chloride gas into a solution of 16.1 g. of the free basic ester in absolute ether. A colloidal precipitate forms which crystallizes upon stirring. After filtering, washing with ether and drying, the hydrochloride is obtained; weight 10.8 g. (60%). Upon recrystallization from methyl isobutyl ketone it has the M. P. l01-105 C.
EXAMPLE 2 (a) A -cyclohexenyZ-isoamylacetyl chloride- A solution of 44 g. (0.21 m.) of .A -cyclohexenyl-isoamylacetic acid in 36.3 cc. of thionyl chloride is warmed at 50 C. until the reaction is complete. The excess thionyl chloride is removed at reduced pressure and the product is distilled giving about 45 g. (94%) of M-cyclohexenyl-isoamylacetyl chloride, B. P. 85 C. (0.07 mm.); n =1.4800; d4 =1.0017.
(b) Beta-dimethylaminoethyl A -cyclohezcenylisoamylacetate and its hydroohlorida-Beta-dimethylaminoethanol (7.8 g., 0.088 m.) is dissolved in 70 cc. of dry pyridine and 20 g. (0.088 m.) of A -cyclohexenyl-isoamylacetyl chloride is added, and the mixture is' allowed to stand for a few minutes and finally heated on a steam bath for four hours. After cooling the mixture, it is shaken with a solution of 8 g. of sodium carbonate monohydrate in 150cc. of water and the water layer is separated and extracted with ether.
"The combined organic layers are concentrated using a water aspirator and the residue distilled at reduced pressure, giving about 21.7 g. (89%) of beta-dimethylaminoethyl A -cyclohexenylisoamylacetate, B. P. 93 C. (0.015 mm.)
The hydrochloride is prepared in the manner described in Example 1, part d by passing dry hydrogen chloride gas through a solution of the basic ester in anhydrous ether. The hydrochloride is obtained in about 46% yield and has the M. P. 114-115 C.
EXAMPLE 3 Beta- (N-piperidyl) -ethyl A -cycIohewenyZ-isoamylacetate.-This is prepared by the same method described in Example 2, using as starting materials A -cyclohexenyl-isoamylacetyl chloride and beta-(N-piperidyl) -ethanol.' The product is obtained in about 77% yield and has the B. P. 130 C. (0.01 mm.); n =1.4832; d4= =0.9768.
The hydrochloride of beta-(N-piperidyl) -ethyl A -cyclohexenyl-isoamylacetate is prepared in the usual manner from the free basic ester and hydrogen chloride gas in ether solution. It is obtained in about 76% yield and has the M. P.
urated sodium chloride solution and dried over anhydrous sodium sulfate. After removing the solvent, the product is distilled at reduced pressure, first from a Claisen flask and then through a 12-inch column packed with %-inch glass helices, giving about 110 g. of ethyl A -cyclohexenyl-sec-butylcyanoacetate, B. P. 94 C. (0.02 mm.); n =1.4'750; d4= =1.0015.
(b) A -cyclohexenyl-sec-butylacetic acid.A mixture of 40 g. (0.16 m.) of ethyl M-cyclohexenyl-sec-butylcyanoacetate with a solution of '70 g. of potassium hydroxide in 120 cc. of 90% ethanol is heated in a bomb in an oil bath at 140-180 C. for 43 hours. After cooling, the contents of the bomb are diluted with water, extracted with ether to remove considerable neutral material, and acidified. The acidic oil is extracted with ether, washed three times with water and once with saturated sodium chloride solution containing a little sodium bicarbonate, and finally dried over anhydrous sodium sulfate. After removal of solvent, the product is distilled at reduced pressure from a Claisen flask, giving about 21.6 g. (69%) of N-cyclohexenyl-sec-buty1- acetic acid, B. P. 92 (0.01 mm.); n =1.4800; d4* =0.9912. I
(c) Beta-diethylaminoethyl A -cyclohexenylsec-butylacetate and its hydrochlorida-This is prepared from the substituted acetic acid using sodium ethoxide and beta-diethylaminoethyl chloride according to the method shown in Example 1, part d- Nine and six-tenths grams of acid results in about 8.6 g. (60%) of beta-diethylaminoethyl A cyclohexenyl sec butylacetate, B. P. 109 C. (0.04 mm.) n =1.4701;
The hydrochloride is prepared in the usual manner from the basic-ester and dry hydrogen chloride gas in ether solution. When recrystallized from methyl isobutyl ketone, the hydrochloride melts at 105-110 C.
Additional compounds have been made by the methods outlined in the preceding examples and are disclosed in the following table.
TABLE I A. Malonates Oocoooimn it B B. P. O.( mm.) m)" d4" CH1(CH1): (0.09) 1.4638 1.0071
CBhCHCHaCHr- 07 (0. 02) 1. 4643 0. 9993 CHaCHaCHCHa- 98 (0.018) 1. 4848 1. 0071 CHIOHICHCHr- 100 (0. 026) 1. 4684 0. 9984 OH; H]
B. Cyanoacetates ON 61-0 0 0 01H 1:
R B. P. O. mm.) up" (14" emotion.- 02 0.05) 1. 4127' 0. 9913 CHaCHaCK- 94 (0. 02) 1. 4750 l. 0016 CHgCHaCHgCH- 101 (0.05) 1.4750 0.9882
. CHsCH-CH- 96 (0. 045) 1. 4778 0. 9974 O. Acetic acids OCH-C 0 on R B. P. C.( mm.) no" d4" CHKCHDF' 102 (0. 006) 1. 4770 0. 9818 CHaCHCHzCHr: 104 (0.07) 1. 4746 0.9669
HI CHQCHgCHCHi- 103 (0. 03) 1. 4758 0.9715
H: CHaCIfiCH-Cfir- 111 (0. 026) 1. 4775 0. 9600 CH: Ha I CHICHCHI- (0. 013) 1. 4754 0. 9810 a CHsCHaCH- 92 (0. 01) 1. 48m 0. 0912 0 HI CH'CHCHCH 106 (0. 046) 1. 4790 0. 0778 H: CHgOH-CH- 108 (0. 04) I 1. 4806 TABLE I; Basic eaten as; R -5158 CHQOHI l CBKCHnh- I 5-CHQCH5N 118 (0.2)
omen:
2 cmcncm- CH1CH|N 108 (0.01)
n, omen:
omen,
a cmcncmcnr- -CH|0H 100(0020) H1 CH1CH:
CH0 4. cmcrrcmcm- -CH1OHiN 93(0015 H: CHa
011103: 6.. cmcncmcm- 0H,c11,1-1 cm 130 (0.01) Hz CHgC:
cmcm
a. cmcmcn- CH|CH: 100 (0.04
H: CHaCHI CHSCHI 7 cmcmcncm- CHCH2N 11001025 H, cmcm a cmcmcmca- CH:CH1N 130 (0.5)
(1H0 CHaCHa CHzCHa 9 cmcn-on- 4321:0115 124(015) H: H, 035cm CHzCH: v
10.- cmcnwncm- CH:CH;N 1140.010)
OH: H: CHsCH:
N=B is a tertiary-amino group of the class Hydw consisting of di-lower-alkylamino, piperidyl and Compound "D a." chloride morpholinyl radicals; and acid addition and quaternary ammonium salts thereof.
2. A substance of the group consisting of basic 103-10415 esters of the formula 0. 9324 102-104 OH-CO OYN wherein R is an alkyl group of 4-6 carbon atoms,
We-clalm: Y is an alkylene bridge of 2-5 carbon atoms and R and R" are lower alkyl groups and acid 1. Asubstance f the u 0 ns t f esters of the fomgula gm p 0 15 mg 0 baslc addit1on and quaternary ammonium salts thereof.
3. A substance of the group consisting of basic esters of the formula wherein R is an alkyl group of 4-6 carbon atoms, 76 Y is an alkylene bridge of 2-5 carbon atoms and 1; CH5.
wherein R is an alkyl group of 4-6 carbon atoms and Y is an alkylene bridge of 2-5 carbon atoms; and acid addition and quaternary ammonium salts thereof.
4. A substance of the group consisting of the formula CHaCHs CH-COO-CHaCHz- CHaCHa wherein R is an alkyl group of 4-6 carbon atoms, and acid addition and quaternary ammonium salts thereof.
5. A substance of the group consisting of betadiethylaminoethyl A -cyclohexenyl-isobutylacetate of the formula CHsCHa CH-COO CHaCHaN Hr-CH-CH: CHaCH:
and acid addition and quaternary ammonium salts thereof.
6. A substance of the group consisting of betadiethylaminoethyl A -cyclohexenyl-isoamylacetate of the formula CHxCHa CH-C O O CHaCHaN (JHaCHaCI-ICH; CHICK:
and acid addition and quaternary ammonium salts thereof.
7. A substance of the group consisting of beta- (N-piperidyl) -ethyl A -cyclohexenyl-isoamylacetate of the formula CHICHI CH-COO CHICHIN CH2 HaCHaGHCH: OHaC and acid addition and quaternary ammonium salts thereof.
10 8. A substance of the group consisting of betadiethylaminoethyl A -cyclohexenyl-(1,2-dimethy1propyl)-acetate of the formula CHaCHI CH-C O O CHICHIN H-CH-CH: CHlCHI CH-CO 0 CHaCHs (JHQCHzCHCHs OH:
and acid addition and quaternary ammonium salts thereof.
ROBERT BRUCE MOFFE'IT. CHARLOTTE ANNE HART.
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Number Name Date 1,677,123 Adams July 1'7, 1928 1,693,801 Adams Dec. 4, 1928 2,265,184 Miescher et a1. Dec. 9, 1941 2,351,833 Northey et al. June 20, 1944 2,417,208 Martin et a1 Mar. 11, 1947 FOREIGN PATENTS Number 9 Country Date 532,943 Great Britain Feb. 4, 1941 220,975 Switzerland Aug. 1, 1942 221,219 Switzerland Aug. 17, 1942 221,519 Switzerland Sept. 1, 1942 93,341 Sweden Nov. 19, 1938 70,567 Norway June 26, 1946 m one Perkins et al., Chem. Abstracts, vol. 21 (1927), page 901.
Arvin et al., Chem. Abstracts, vol. 22 (1929),, page 228.
Certificate of Correction Patent No. 2,538,794
ROBERT BRUCE MOFFETT ET AL.
January 23, 1951 It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:
Column 2, line 33, for alladium-on-chamoal read palladium-on-charooal column 9, line 5, after of, second occurrence, insert a compound of;
and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice.
Signed and sealed this 3rd day of April, A. D, 1951.
THOMAS F. MURPHY,
Assistant Oommissz'oner of Patents.

Claims (1)

1. A SUBSTANCE OF THE GROUP CONSISTING OF BASIC ESTERS OF THE FORMULA
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Cited By (8)

* Cited by examiner, † Cited by third party
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US2686186A (en) * 1951-07-21 1954-08-10 Warner Hudnut Inc Aminopropyl-2-thienyl-cycloalkenyl acetate
DE941908C (en) * 1953-01-23 1956-04-19 Basf Ag Process for the production of basic ethers
DE961349C (en) * 1951-07-20 1957-04-04 Sterling Drug Inc Process for the production of highly effective anticholinergic compounds
DE1016705B (en) * 1953-12-18 1957-10-03 Schering Corp Process for the preparation of therapeutically active substituted 4-dimethylaminocyclohexylcarbinols
US2868786A (en) * 1954-12-27 1959-01-13 Ravensberg G M B H Esters of phenyl acetic acids and a process of making same
US2987517A (en) * 1954-04-20 1961-06-06 Cilag Chemie Alpha aryl-3-methyl-pentanoic acid-nu-lower alkyl heterocyclic esters
US3018222A (en) * 1956-08-28 1962-01-23 Ravensberg G M B H Central stimulant and appetite depressant composition
DE1248039B (en) * 1963-03-18 1967-08-24 Heilmittelwerke Wien Ges Mit B Process for the production of antispasmodic quaternary ammonium compounds of alpha-cyclohexylbutyric acid aminoethyl ester

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US1677123A (en) * 1927-08-25 1928-07-17 Abbott Lab Cyclopentenyl alkyl acetic acid
US1693801A (en) * 1926-07-24 1928-12-04 Abbott Lab Cyclohexyl-substituted aliphatic acids
GB532943A (en) * 1938-08-05 1941-02-04 Chem Ind Basel Manufacture of alkamine esters and quaternary salts thereof
CH220975A (en) * 1938-08-05 1942-04-30 Chem Ind Basel Process for the preparation of a basic ester.
CH221219A (en) * 1938-08-05 1942-05-15 Chem Ind Basel Process for the preparation of a basic ester.
US2351833A (en) * 1942-04-08 1944-06-20 American Cyanamid Co N(alkyl,beta-4-morpholylalkyl) aminoalkanol esters
US2417208A (en) * 1943-08-04 1947-03-11 Geigy Ag J R Basic esters of monoalkyl isobutyl acetic acids

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US1693801A (en) * 1926-07-24 1928-12-04 Abbott Lab Cyclohexyl-substituted aliphatic acids
US1677123A (en) * 1927-08-25 1928-07-17 Abbott Lab Cyclopentenyl alkyl acetic acid
GB532943A (en) * 1938-08-05 1941-02-04 Chem Ind Basel Manufacture of alkamine esters and quaternary salts thereof
US2265184A (en) * 1938-08-05 1941-12-09 Ciba Pharm Prod Inc Basic esters and process of preparing same
CH220975A (en) * 1938-08-05 1942-04-30 Chem Ind Basel Process for the preparation of a basic ester.
CH221219A (en) * 1938-08-05 1942-05-15 Chem Ind Basel Process for the preparation of a basic ester.
CH221519A (en) * 1938-08-05 1942-05-31 Chem Ind Basel Process for the preparation of a basic ester.
US2351833A (en) * 1942-04-08 1944-06-20 American Cyanamid Co N(alkyl,beta-4-morpholylalkyl) aminoalkanol esters
US2417208A (en) * 1943-08-04 1947-03-11 Geigy Ag J R Basic esters of monoalkyl isobutyl acetic acids

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE961349C (en) * 1951-07-20 1957-04-04 Sterling Drug Inc Process for the production of highly effective anticholinergic compounds
US2686186A (en) * 1951-07-21 1954-08-10 Warner Hudnut Inc Aminopropyl-2-thienyl-cycloalkenyl acetate
DE941908C (en) * 1953-01-23 1956-04-19 Basf Ag Process for the production of basic ethers
DE1016705B (en) * 1953-12-18 1957-10-03 Schering Corp Process for the preparation of therapeutically active substituted 4-dimethylaminocyclohexylcarbinols
US2987517A (en) * 1954-04-20 1961-06-06 Cilag Chemie Alpha aryl-3-methyl-pentanoic acid-nu-lower alkyl heterocyclic esters
US2868786A (en) * 1954-12-27 1959-01-13 Ravensberg G M B H Esters of phenyl acetic acids and a process of making same
US3018222A (en) * 1956-08-28 1962-01-23 Ravensberg G M B H Central stimulant and appetite depressant composition
DE1248039B (en) * 1963-03-18 1967-08-24 Heilmittelwerke Wien Ges Mit B Process for the production of antispasmodic quaternary ammonium compounds of alpha-cyclohexylbutyric acid aminoethyl ester

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