Oct., 1941
8-(2- AND 4-hIDYLALKYL)-AMINES
2771
[CONTRIBUTION FROM THE RESBARC~ LABORATORIES OF THE MALTBIECHEMICAL Co. I
6-Q- and 4-Pyridylalkyl)-amines1 BY L. A. WALTER,WILLIAMH. HUNT AND RUSSELJ. FOSBINDER
Certain j3-(2- and 4-pyridylethyl and propyl) amines have been synthesized for the purpose of investigating their pharmacological properties. Some of the 2-pyridyl compounds were first prepared and described by L ~ f f l e r . ~A, ~ second method, illustrated below, also was used for the preparation of the &(2- and 4-pyridylethy1)amines and their quaternary methochloride hydrochlorides. PyCHs +PyCHzCHOHCCla ----f PyCH=CHCOOH --+ PyCH2CHzCONH2 + Py CHzCHzNHCOOCHs +
J.
Py CHzCHzNHz +PyCHzCH2NHz’HCl PYCH~CH~NHCOOCH~ CHsI A CHaCl
active agents in gammas per cc. which, in contact with the tissues, produced near-maximal contraction of the muscle. With the exception of /3-(2pyridy1)-ethyldiethylamine the activity of these derivatives approached that of histamine phosphate. All of the j3-(2-pyridyl)-alkylamines and histamine phosphate exerted a stimulative effect on rabbit uterus and intestine; this tissue was far less sensitive as doses of the compounds 40 to 100-fold those used in the guinea pig work were required to produce sub-maximal contractions. All of the compounds were found to be less toxic than histamine on intravenous injection in the rabbit. TABLEI CONCENTRATIONS OF THE AMINES PRODUCING NEARMAXIMAL CONTBACTIONS IN GUINEAPIG UTERUSAND INTESTINE
Pharmacological Results Guinea pig Guinea pig The pyridyl alkylamines described in this paper uterus, intestine, gammas gammas were originally investigated with the object of Compound per c c per cc. ascetaining whether or not they would exhibit sym- j3-(2-Pyridyl)-ethyldiethylpathomimetic activity. H a r t ~ n gin , ~an excellent amine hydrochloride 80 6 review on epinephrin and related compounds, ,%(2-Pyridyl)-ethylmethylamine hydrochloride 1 2-3 concluded that: “The aromatic portion of the 1-(2-Pyridyl)-2-methylaminomolecule need not necessarily be a phenyl or subpropane hydrochloride 1 1 stituted phenyl group. Various naphthalene and &(2-Pyridyl)-ethylamine heterocyclic derivatives also possess pressor ac4 1 hydrochloride Histamine phosphate 0.2 0.2 tivity.” All of the compounds investigated] with the The pharmacological findings, which are to be exception of j3-(4-pyridyl)-ethylamine hydrochlo- described in detail elsewhere, reveal that /3-(2ride and the N-methochlorides, produced a mod- pyridy1)-alkylamines exhibit a physiological acerate or marked fall in blood pressure following tion similar to histamine, while the action of 8intravenous administration to anesthetized cats, (4-pyridyl)-ethylamine resembles epinephrin. while in rabbits a rise in blood pressure was always This interesting and striking relationship may be observed. In the case of 8-(4-pyridyl)-ethyl- explained] we believe, by a comparison of the amine hydrochloride, a definite but transitory rise structural formulas of histamine, j3-(2-pyridyl)in blood pressure was observed with a typical ethylamine and p- (4-pyridyl)-ethylamhe. “epinephrin reversal” noted following the injection of ergotamine tartrate. These unexpected results led us to investigate the action of the compounds on isolated strips of smooth muscle such as guinea pig and rabbit uterus and intestine, using the familiar method of Magnus. Histamine (1) ,9-(2-Pyridyl)-ethylamine(2) Table I shows the concentrations of the various CHzCHzNHt (1) Presented before the Division of Medicinal Chemistry at the Detroit meeting of the American Chemical Society, September, 1940. (2) Lomsr, EW., 87, 161 (1904). (3) Lotiler and Kirschner, ibid., 88,8330(1906). (4) Hartung, them.&u., 0, as9 (1981).
HCRTCH
@-(4-Pyridyl)-ethylPminee (a)
L. A. WALTER,WILLIAM H. HUNTAND RUSSELJ. FOSBINDER
2772
An obvious similarity in structure exists between (1) and ( 2 ) while (3) resembles an aromatic alkylamine and would be expected to have epinephrin-like activity.
Vol. 63
give an additional small quantity; m. p. 129-130"; yield from the ester 95%. A n d 6 Calcd. for C8HloON2: C, 63.98; H, 6.71. Found: C, 64.34; H, 6.71. This amide was also prepared by refluxing p-(2-pyridyl)ethyl bromide with sodium cyanide in 80% alcohol for Experimental p-( 2-Pyridylethyl)-methylamine.1-This compound was seven hours to give a 65% yield of p-(2-pyridyl)-propionitrile, b. p. 85-87' (1 mm.). Twenty-three grams of this purified by crystallization of the dihydrochloride from nitrile, 2.3 g. of potassium hydroxide, 150 cc. of water, and absolute alcohol. The salt was not hygroscopic when pure; 100 g. of 30% hydrogen peroxide were vigorously stirred, m. p. 148-149". carefully warmed t o 40" and kept a t that temperature by Anal. Calcd. for CsHlrNaC12: C1, 33.90. Found': immersion in an ice-bath until the temperature dropped to C1,34.03. 30' without external cooling. The solution was treated p-( 2-Pyridylethyl)-diethylamine.2-This compound was with 4 cc. of concentrated hydrochloric acid and evapoalso purified by crystallization of its dihydrochloride; m. p. rated to a volume of 100 cc. in a vacuum. On cooling over171-172 night 17.5 g. of crystals melting sharply a t 76-77" sepaAnal. Calcd. for CllHroNaCln: C1, 28.22. Found: rated. When crystallized from hexone the material melted a t 129-130" and gave no melting point depression when C1, 28.42. l-(2-Pyridyl)-2-propanol.-Only 4-6% yields are ob- mixed with a sample prepared by the other method. p-( 2-Pyridyl)-ethylamine-methylurethan.-Fifteen tained by heating 2-picoline with acetaldehyde.3~6 To a well-stirred suspension of 6.9 g. of lithium filings in grams of the above amide was added to a cold solution of 500 cc. of dry ether under an atmosphere of nitrogen was 4.6 g. of sodium in 150 cc. of absolute methanol. The slowly added 79 g. of bromobenzene. This mixture was mixture was stirred and kept below 0" while 16 g. of dry stirred overnight, 46 g. of 2-picoline was added and after bromine was added drop by drop. When all the amide had stirring for one hour at room temperature a dark red solu- dissolved the solution was refluxed one hour, the alcohol tion of picolyl-lithium resulted. The flask was immersed distilled and the residue treated with 75 cc. of water. The in an ice-salt mixture and acetaldehyde slowly distilled urethan was extracted with ethyl acetate and crystallized into the flask until the red color disappeared. After fifteen from ether-petroleum ether. The yield was 15 g.; m. p. minutes 100 cc. of water was slowly added followed by 100 53-54 O. A n d 6 Calcd. for CgH130eN~: C, 59.98; H, 6.71. cc. of concentrated hydrochloric acid. When all the solid had dissolved the aqueous layer was separated and poured Found: C, 59.81; H, 6.48. with stirring into a solution of 200 g. of sodium carbonate p-(2-Pyridyl)-ethylamine Dihydrochl0ride.-The above decahydrate in 100 cc. of water. The lithium carbonate urethan was hydrolyzed with hydrochloric acid, evaporated was filtered off and washed well with chloroform. The to dryness and crystallized from alcohol; m. p. 185-186 '. filtrate was extracted with chloroform and the combined Anal. Calcd. for CIH12N2C12: CL36.33. Found: C1, fractions distilled to give 40 g. of product; b. p. 110-111" 36.48. (10 mm.). j3-(2-Pyridyl)-ethylarnine-methylurethanMethiodide.1-(2-Pyridyl)-2-methylaminopropane.-This compound A solution of the urethan and excess methyl iodide in ether was obtained in 75% yield from 1-(2-pyridy1)-2-bromowas kept a t room temperature for several weeks. The propane3 and excess absolute alcoholic methylamine at reaction proceeded very slowly. The semi-solid precipi100". The product distilled a t 72" (2 mm.) and was extate was separated by decantation and crystallized from tremely hygroscopic. butanol to give bright yellow crystals; m. p. 110-111". A n d 6 Calcd. for GH1,Nz: N, 18.65. Found: N, Anal. Calcd. for C I ~ H I ~ O ~ NI,~39.38. I: Found: I, 18.71. 38.87. This amine was purified by crystallization of its di~-(2-Pyridyl)-ethylamine-methochoride Hydrochloride. hydrochloride, m. p. 158-158.5'. -The above methiodide was dissolved in water and shaken Anal. Calcd. for CoHl&N2Cll: C1,31.78. Found: C1. with a n excess of freshly precipitated silver chloride until 32.03. the filtrate no longer gave a test for iodide ion. An equal p-( 2-Pyridyl)-propionamide.-p-( 2-Pyridyl)-acrylic volume of hydrochloric acid was added and the mixture acid' was hydrogenated in aqueous alkali with Raney refluxed and evaporated to dryness. The product was nickel and hydrogen a t 40-lb. pressure. After removal of crystallized from alcohol and melted at 191-193 '. the catalyst the solution was acidified with hydrochloric Anal. Calcd. for CsHlaN2C1~: C1,33.91. Found: C1, acid, evaporated to dryness and the acid esterified in the 34.05. usual manner with methanol and hydrogen chloride. p-(4-Pyridyl)-propionamide.-&( 4-Pyridyl)-acrylic The methyl ester, b. p. 102-103" (2 mm.), was treated acid* (the intermediate l,l,l-trichloro-3(4-pyridyl) -2with five volumes of aqueous ammonia saturated a t 0 ', and kept in an icebox for several days. The amide was filtered propanol was obtained in much better yields (35%) by treating chloral with three times its weight of pyridine base off and the filtrate evaporated t o a small volume in 'uacuoto fraction b. p. 142-144' as described, and removing the ex( 5 ) Meisenheirnet and Mahler, Ann., 464, 301 (1928). cess a t 10 mm. on a water-bath before working up the
'.
(6) Analyses by Arlington Laboratories, Chagrin Falls, Ohio. (7) Tullock and McElvain, TXISJOURNAL, 61, 961 (1939).
( 8 ) Alberts and Bachman,ibid.,67, 1286 (1935).
Oct., 1941
2773
P-CHLORO-P-(2-METHYL-1-NAPHTHYL)-ACRYLIC ACIDS
mixture) was converted t o the amide as described for the 2pyridyl analog. The intermediate methyl ester distilled a t 95" (2 mm.). The amide, m. p. 166-167", was crystallized from alcohol. Anal. Calcd. for C ~ H I O N ~ OC,~ : 63.98; H, 6.71. Found: C, 63.99; H , 6.90. The following compounds were prepared as described for the 2-pyridyl analogs. p (4-Pyridyl)-ethylamine-methylurethanHydrochloride. -The urethan could not be obtained crystalline and decomposed on attempted distillation. The crude material was converted to the hydrochloride with dry hydrogen chloride in ethyl acetate and crystallized from methanolether, m. p. 132-133". Anal. Calcd. for C9H1802NnCI: C1, 16.36. Found: C1, 16.46. ,9-(4-Pyridyl)-ethylaine Dihydrochloride.-M. p. 222'.
[CONTRIBUTION FROM
THE NOYES
Anal. Calcd. for C1, 36.43.
GHlzNtClz: C1, 36.33. Found:
@-(4-Pyridyl)-ethylamine-methyluethan Methiodide.M. p. 121-122'. Anal. Calcd. for C1~H1502NJ:I, 39.38. Found: I, 39.04. p-(4-Pyridyl)-ethylamine-methochloride Hydrochloride. -M. p. 186-187". Anal. Calcd. for C8Hl,N1C12. C1, 33.91. Found: C1, 34.05.
Summary The preparation as well as the chemical and pharmacological properties of some 6-(2-, and 4pyridylethyl and propyl)-amines have been described. NEWARK,N. J.
RECEIVED AUGUST 2, 1941
CHEMICAL LABORATORY, UNIVERSITY OF ILLINOIS]
Restricted Rotation in Aryl Olefins. 111. Preparation and Resolution of 8-Chloro6- (2-methyl- 1-naphthyl)-acrylic Acids' BY ROGERADAMSAND L. 0. BINDER^ Among the aryl olefins with restricted rotation between the benzene ring and an acrylic acid residue reported in previous articleslJ in this series are compounds I and 11.
C1 CHI
C1 H
C=C-COOH
C=C-COOH
i
I11
I
IT
Both of these molecules were resolved readily. Compound I did not racemize in boiling n-butanol; compound I1 under similar conditions had a half-life of about two hundred minutes. Although no direct chemical proof was offered for the relative placement of the side-chain methyl and carboxyl groups in I or the hydrogen and carboxyl groups in 11, by indirect deductions the structures assigned them appear to%be the more likely. A series of analogous derivatives of this type has been under investigation in order to compare the effects of various groups on the restricted rotation. The corresponding naphthalene compounds have now been synthesized and their structures are shown in formulas I11 and IV. (1) For previous paper see
Adams, Anderson and Miller, THIS
JOUBNAL, 68, 1589 (1941).
(2) An abstract of e thesis submitted in partial fulfillment for the degree of Doctor of Philosophy in Chemistry. ( 8 ) A d a m and Miller, TEIUJOURNAL. 63, 53 (1940).
l
I
I
IV
Compounds 111 and I V are assumed to have the same geometric configuration as compounds I and I1 since they were formed from the appropriate ketones by exactly the same process used for the benzene derivatives. Evidence deduced from previous work in this field would lead to the conclusion that the two methyls adjacent to the acrylic acid side-chain in I and I1 and the methyl and the aromatic grouping -CH= adjacent to the side-chain in 111 and I V represent the bulk of the hindrance contributed by the aromatic part of the molecules. A direct comparison of the steric effect of the methyl and -CH= groups is thus possible. Although many substituted binaphthyls and biphenyls have been prepared and resolved, none has been synthesized which allows a direct comparison of these groups just mentioned. Compound I11 had a half-life in boiling nbutanol of seventy hours in contrast to compound I which did not racemize a t all in boiling n-butanol. Compound IV had a half-life of about seventy
