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Aminoalcohol Esters of Crotonic Acid*,†
Aminoalcohol Esters of Crotonic Acid*,t By T O N Y EVERETT JONES$ and CHARLES 0. WILSONS
'The hydrochloride salts of p-diethylaminoethyl, 4-morpholinoethyl, and piperidinoethyl esters of crotonic acid were prepared. None of these salts had been reported previOuslYThree new diethylaminopropyl sorbate, 4-rnorpholinoethyl sorbate, piperidinoethyl and the previously reported diethylaminoethyl sorbate were prepared. Vinylacrylic acid and its m i n o alcohol have also been studied. most often synthesized for local C anesthetic purposes are the alkylaminoalkanol esters of aromatic acids. In most corn. OMPOUNDS
pounds having local anesthetic activity, the carbony1 group is attached to a conjugated system (1); e. g., procaine, an ester of p-aminobenzoic acid, possesses good local anesthetic activity. However, when a methylene group separates the carbonyl of the ester from the conjugated system of the aromatic phenyl group, as is the case with esters of phenylacetic acid, no local anesthetic activity is observed (1). In contrast, it has been pointed out that the alkylaminoalkanol esters of cinnamic acid possess local anesthetic activity (2). Therefore, it has been postulated that local anesthetic activity is due, a t least in pkrt, to the conjugation of the carbonyl group being attached to a conjugated system (i. e., aromatic nucleus). It has been shown that alkylaminoalkanol esters of simple saturated aliphatic acids exert no local anesthetic effect (3). However, when alkylaminoalkanol esters are prepared from unsaturated acids which have a double bond attached to the a-carbon atom, they show a definite local anesthetic effect (4). This type of compound is represented by the diethylaminoethanol ester of acrylic acid (4). The local anesthetic activity of this compound, as com])"red to that of eslers of aroinatic acids, is t l i o u g l i t to be due to conjugation of the carl)onyl group with the oleliriic double boiitl of U i e uiisaturated acid. None of the unsaturated aliphatic acid esters have shown sufficient local anesthetic activity to be of practical value. *Received August 22, 1952, from the Department of Pharmaceutical Chemistry, College of Pharmacy, The University of Texas, Austin. t Abstracted from a thesis presented to the Graduate Faculty of The University of Texas by Tony Everett Jones in partial fulfillment of the requirements for the degree of Master of Science. Instructor of Pharmaceutical Chemistry, College of Pharmacy, University of Texas, Austin. 5 Professor of Pha nlaceutical Chemistry, College (JI Pharmacy, University Texas, Austin.
Crotonic acid, CHaCH=CHCOOH, has both liquid and solid forms. The solid is trans-2-butenoic acid, which is crotonic acid in a strict sense. I t is colorless, melts at 72', and has a boiling point of 189'. The liquid form is the stereoisomeric cis-2-butenoic acid. This is a colorless liquid that forms crystals at 140 and has a boiling point of 172'. All reports on the preparation of crotonic acid are modifications of the synthesis made by Kekuli: (5). Crotonic acid has been studied extensively in the field of polymers and in the manufacture of threonine and vitamin A. The diethylaminoethanol esters of 2-chlorocrotonic acid and 3aminocrotonic acid have been prepared ( 6 ) . These compounds were tested and found to possess no local anesthetic activity (Table I).
EXPERIMENTAL Crotonic Acid Chloride.-This compound was prepared according to the method of Auwers and Wissebach (7) from crotonic acid' (20 Gm.) and thionyl chloride (40 cc.). The crude product was distilled at 4043'/20 mm. The crotonic acid chloride was a colorless oil-like liquid that formed crystals at 0'. The liquid was dried in t h e presence of soda lime for two hours and then was redistilled at 4245'/20 mm. Consistent yields of 37% were obtained. 2-Diethylaminoethyl Crotonate Hydrochloride.Crotonic acid chloride (10 Gm.) dissolved in dry benzene (20 cc.) was cooled in an ice bath and a solution of 2-diethylaminoethano1' (5 Gm.) in dry benzene (10 cc.) was added slowly. A white crystalline product formed when all of the aminoalcohol and benzene solution had been added. The crude product in benzene was refluxed for two hours. White crystals formed in the benzene solution after cooling. A yield of 4.6 Gin. (51Yo) of a crystalliiie componiitl with a melting point of 102-104° was obtaiiictl. The product w a s recrystallizctl froill hot beiizciie: in. p., 103-105°.
2-(4-Morpholino)-ethanol.- This uiiiiiioalrohol was obtaiiietl by a iiiodificatioll of tlic niethtwl hy Leffler and Brill (8). 4-Morpholine (62 Gm.) and ethylene chlorohydrin (60 Gm.) were dissolved in benzene (120 cc.) and refluxed for two hours. The crystalline product that formed was removed by filtration and dissolved in a saturated solution of potassium hydroxide in alcohol (50 cc.). After filtering off the potassium chloride that formed, the alcohol solution of the amine was distilled. The free aminoalcohol was collected at 100-130"/30 mm. The product, a brownish, thin, oil-like liquid,
&
3-10
I
Ihstman Kidak Co.
SCIENTIFIC EDITION
June, 1953
34 1
TABLE I.-ESTERS OF CROTONIC ACID^‘ 0
I1
R-&C-CH=CH-CH3 R
(CzH6)zNCHzCHz.HCl O( CzHA)zNCH&H2.HCl CsHioNCH2CHyHCl
M. P..
Yield,
%
Formula
103-105 144-146 140-142
51 28 26
CaH16OzNCI CioHis03NCl CiIHzo0,h'Cl
c.
%-
--Carbon, Calcd.
Found
54.06 50.85 56.89
53.42 50.65 56.97
--Hydrogen, %Calcd. Found
9.09 7.63 8.62
9.28 7.70 8.79
All melting and boiling points are uncorrected.
was obtained in a yield of 60 Gm. (61%). The compound was redistilled a t 130-132"/30 mm. with a yield of 52%. 2-(4-Morpholino)-ethyl Crotonate Hydrochloride.-Crotonic acid chloride (10 Gm.) was dissolved in dry benzene (20 c ~ . )and a solution of 2-(4-mwpholino)-ethanol ( 5 Gm.) in dry benzene (10 cc.) was added slowly. This solution was refluxed for one hour and became filled with a crystalline product. After the solution had cooled, the crystals were removed by filtration. A yield of 2.6 Gm. (28%) was obtained; m. p., 144-146'. After recrystallization from absolute alcohol ( 5 cc.) and dry ether (10 cc.), the melting point was still 144146". 2-( 1-Piperidin0)-ethanol.-This compound was prepared from a modification of the method used by Leffler and Brill (8). Piperidine (63 Gm.) and ethylene chlorohydrin (60Gm.) were dissolved in benzene (100 cc.). The solution was refluxed for two hours and fifteen minutes. The crystals that formed throughout the solution were removed by filtration and dissolved in a saturated solution of potassium hydroxide in alcohol (50 cc.). The potassium chloride precipitate was removed by filtration, and the free aminoalcohol solution was distilled under reduced pressure (28 mm.). The distillate, a liquid with a slight brownish color, was collected at 100145'/28 mm. A yield of 52 Gm. (70%) was obtained. The compound was redistilled at 140-145'/ 28 mm. with a yield of 54%. 2-( 1-Piperidin0)-ethyl Crotonate Hydroehloride.-Crotonic acid chloride (4 Gm.) was dissolved in dry benzene (10 cc.), and to this solution was added a solution of 2-( l-piperidino)-ethano1(3 Gm.) dissolved in dry benzene (10 cc.). A white crystalline precipitate formed after the two solutions were mixed. The crystalline product was removed by filtration and dissolved in a 30% aqueous sodium hydroxide solution (3 cc.). Ether (30 cc.) was used to extract the free amine from the aqueous solution,
and the ethereal solution was dried over anhydrous sodium sulfate and then filtered. Dry hydrogen chloride in an anhydrous ether solution was added and a white crystalline precipitate formed immediately in a yield of 1.2 Gm. (26%). The product, recrystallized from absolute alcohol (6 cc.) and anhydrous ether (10 cc.), melted at 140-142'.
DISCUSSION 2-Diethylaminoethyl crotonate hydrochloride possessed hygroscopic properties when purified by recrystallization from absolute alcohol and anhydrous ether, but when recrystallized from benzene, the compound was stable. The 2-(4-morpholino)-ethanol and 2-( l-piperidine)-ethanol esters of crotonic acid hydrochloride were stable compounds when recrystallized from absolute alcohol and anhydrous ether. None of the compounds have been tested pharmacologically. However, no evidence of local anesthetic activity was observed when small amounts of each ester were placed on the tongue and lips.
SUMMARY
The hydrochlorides of 2-diethylaminoethyl, 2(4-morpholino)-ethyl, a n d 2- (1-piperidino) -ethyl crotonate were prepared. REFERENCES (1) Kamm 0. J . A m . Chem. Soc., 42, 1030(1920). (2) Gilman' H: and Pickens R. M ibid. 47 245(1925). (3) Brill H. C.'and BWIOW.'T.A. ';bid. 55 i059(1933).
(4) Gilman, H.,'Heckert, L. C.. and Mcdracken, R., ibid., 50 4i17(1928). i5) Kekulb. A,, Ber., 2, 365(1869). (6) Shriner, R.L., and Keyser, L. S., J . A m . Chem. SOC.,60,
286(1938). (7) Auwers. K. V.. and Wissebach, H. Ber. 56 715(1923). (8) Leffler, M. T., and Brill, H. C . , J.'Am. khLnz. SOL.,55, 305(1933).
'The hydrochloride salts of p-diethylaminoethyl, 4-morpholinoethyl, and piperidinoethyl esters of crotonic acid were prepared. None of these salts had been reported previOuslYThree new diethylaminopropyl sorbate, 4-rnorpholinoethyl sorbate, piperidinoethyl and the previously reported diethylaminoethyl sorbate were prepared. Vinylacrylic acid and its m i n o alcohol have also been studied. most often synthesized for local C anesthetic purposes are the alkylaminoalkanol esters of aromatic acids. In most corn. OMPOUNDS
pounds having local anesthetic activity, the carbony1 group is attached to a conjugated system (1); e. g., procaine, an ester of p-aminobenzoic acid, possesses good local anesthetic activity. However, when a methylene group separates the carbonyl of the ester from the conjugated system of the aromatic phenyl group, as is the case with esters of phenylacetic acid, no local anesthetic activity is observed (1). In contrast, it has been pointed out that the alkylaminoalkanol esters of cinnamic acid possess local anesthetic activity (2). Therefore, it has been postulated that local anesthetic activity is due, a t least in pkrt, to the conjugation of the carbonyl group being attached to a conjugated system (i. e., aromatic nucleus). It has been shown that alkylaminoalkanol esters of simple saturated aliphatic acids exert no local anesthetic effect (3). However, when alkylaminoalkanol esters are prepared from unsaturated acids which have a double bond attached to the a-carbon atom, they show a definite local anesthetic effect (4). This type of compound is represented by the diethylaminoethanol ester of acrylic acid (4). The local anesthetic activity of this compound, as com])"red to that of eslers of aroinatic acids, is t l i o u g l i t to be due to conjugation of the carl)onyl group with the oleliriic double boiitl of U i e uiisaturated acid. None of the unsaturated aliphatic acid esters have shown sufficient local anesthetic activity to be of practical value. *Received August 22, 1952, from the Department of Pharmaceutical Chemistry, College of Pharmacy, The University of Texas, Austin. t Abstracted from a thesis presented to the Graduate Faculty of The University of Texas by Tony Everett Jones in partial fulfillment of the requirements for the degree of Master of Science. Instructor of Pharmaceutical Chemistry, College of Pharmacy, University of Texas, Austin. 5 Professor of Pha nlaceutical Chemistry, College (JI Pharmacy, University Texas, Austin.
Crotonic acid, CHaCH=CHCOOH, has both liquid and solid forms. The solid is trans-2-butenoic acid, which is crotonic acid in a strict sense. I t is colorless, melts at 72', and has a boiling point of 189'. The liquid form is the stereoisomeric cis-2-butenoic acid. This is a colorless liquid that forms crystals at 140 and has a boiling point of 172'. All reports on the preparation of crotonic acid are modifications of the synthesis made by Kekuli: (5). Crotonic acid has been studied extensively in the field of polymers and in the manufacture of threonine and vitamin A. The diethylaminoethanol esters of 2-chlorocrotonic acid and 3aminocrotonic acid have been prepared ( 6 ) . These compounds were tested and found to possess no local anesthetic activity (Table I).
EXPERIMENTAL Crotonic Acid Chloride.-This compound was prepared according to the method of Auwers and Wissebach (7) from crotonic acid' (20 Gm.) and thionyl chloride (40 cc.). The crude product was distilled at 4043'/20 mm. The crotonic acid chloride was a colorless oil-like liquid that formed crystals at 0'. The liquid was dried in t h e presence of soda lime for two hours and then was redistilled at 4245'/20 mm. Consistent yields of 37% were obtained. 2-Diethylaminoethyl Crotonate Hydrochloride.Crotonic acid chloride (10 Gm.) dissolved in dry benzene (20 cc.) was cooled in an ice bath and a solution of 2-diethylaminoethano1' (5 Gm.) in dry benzene (10 cc.) was added slowly. A white crystalline product formed when all of the aminoalcohol and benzene solution had been added. The crude product in benzene was refluxed for two hours. White crystals formed in the benzene solution after cooling. A yield of 4.6 Gin. (51Yo) of a crystalliiie componiitl with a melting point of 102-104° was obtaiiictl. The product w a s recrystallizctl froill hot beiizciie: in. p., 103-105°.
2-(4-Morpholino)-ethanol.- This uiiiiiioalrohol was obtaiiietl by a iiiodificatioll of tlic niethtwl hy Leffler and Brill (8). 4-Morpholine (62 Gm.) and ethylene chlorohydrin (60 Gm.) were dissolved in benzene (120 cc.) and refluxed for two hours. The crystalline product that formed was removed by filtration and dissolved in a saturated solution of potassium hydroxide in alcohol (50 cc.). After filtering off the potassium chloride that formed, the alcohol solution of the amine was distilled. The free aminoalcohol was collected at 100-130"/30 mm. The product, a brownish, thin, oil-like liquid,
&
3-10
I
Ihstman Kidak Co.
SCIENTIFIC EDITION
June, 1953
34 1
TABLE I.-ESTERS OF CROTONIC ACID^‘ 0
I1
R-&C-CH=CH-CH3 R
(CzH6)zNCHzCHz.HCl O( CzHA)zNCH&H2.HCl CsHioNCH2CHyHCl
M. P..
Yield,
%
Formula
103-105 144-146 140-142
51 28 26
CaH16OzNCI CioHis03NCl CiIHzo0,h'Cl
c.
%-
--Carbon, Calcd.
Found
54.06 50.85 56.89
53.42 50.65 56.97
--Hydrogen, %Calcd. Found
9.09 7.63 8.62
9.28 7.70 8.79
All melting and boiling points are uncorrected.
was obtained in a yield of 60 Gm. (61%). The compound was redistilled a t 130-132"/30 mm. with a yield of 52%. 2-(4-Morpholino)-ethyl Crotonate Hydrochloride.-Crotonic acid chloride (10 Gm.) was dissolved in dry benzene (20 c ~ . )and a solution of 2-(4-mwpholino)-ethanol ( 5 Gm.) in dry benzene (10 cc.) was added slowly. This solution was refluxed for one hour and became filled with a crystalline product. After the solution had cooled, the crystals were removed by filtration. A yield of 2.6 Gm. (28%) was obtained; m. p., 144-146'. After recrystallization from absolute alcohol ( 5 cc.) and dry ether (10 cc.), the melting point was still 144146". 2-( 1-Piperidin0)-ethanol.-This compound was prepared from a modification of the method used by Leffler and Brill (8). Piperidine (63 Gm.) and ethylene chlorohydrin (60Gm.) were dissolved in benzene (100 cc.). The solution was refluxed for two hours and fifteen minutes. The crystals that formed throughout the solution were removed by filtration and dissolved in a saturated solution of potassium hydroxide in alcohol (50 cc.). The potassium chloride precipitate was removed by filtration, and the free aminoalcohol solution was distilled under reduced pressure (28 mm.). The distillate, a liquid with a slight brownish color, was collected at 100145'/28 mm. A yield of 52 Gm. (70%) was obtained. The compound was redistilled at 140-145'/ 28 mm. with a yield of 54%. 2-( 1-Piperidin0)-ethyl Crotonate Hydroehloride.-Crotonic acid chloride (4 Gm.) was dissolved in dry benzene (10 cc.), and to this solution was added a solution of 2-( l-piperidino)-ethano1(3 Gm.) dissolved in dry benzene (10 cc.). A white crystalline precipitate formed after the two solutions were mixed. The crystalline product was removed by filtration and dissolved in a 30% aqueous sodium hydroxide solution (3 cc.). Ether (30 cc.) was used to extract the free amine from the aqueous solution,
and the ethereal solution was dried over anhydrous sodium sulfate and then filtered. Dry hydrogen chloride in an anhydrous ether solution was added and a white crystalline precipitate formed immediately in a yield of 1.2 Gm. (26%). The product, recrystallized from absolute alcohol (6 cc.) and anhydrous ether (10 cc.), melted at 140-142'.
DISCUSSION 2-Diethylaminoethyl crotonate hydrochloride possessed hygroscopic properties when purified by recrystallization from absolute alcohol and anhydrous ether, but when recrystallized from benzene, the compound was stable. The 2-(4-morpholino)-ethanol and 2-( l-piperidine)-ethanol esters of crotonic acid hydrochloride were stable compounds when recrystallized from absolute alcohol and anhydrous ether. None of the compounds have been tested pharmacologically. However, no evidence of local anesthetic activity was observed when small amounts of each ester were placed on the tongue and lips.
SUMMARY
The hydrochlorides of 2-diethylaminoethyl, 2(4-morpholino)-ethyl, a n d 2- (1-piperidino) -ethyl crotonate were prepared. REFERENCES (1) Kamm 0. J . A m . Chem. Soc., 42, 1030(1920). (2) Gilman' H: and Pickens R. M ibid. 47 245(1925). (3) Brill H. C.'and BWIOW.'T.A. ';bid. 55 i059(1933).
(4) Gilman, H.,'Heckert, L. C.. and Mcdracken, R., ibid., 50 4i17(1928). i5) Kekulb. A,, Ber., 2, 365(1869). (6) Shriner, R.L., and Keyser, L. S., J . A m . Chem. SOC.,60,
286(1938). (7) Auwers. K. V.. and Wissebach, H. Ber. 56 715(1923). (8) Leffler, M. T., and Brill, H. C . , J.'Am. khLnz. SOL.,55, 305(1933).