1722
NOTES
was obtained 50.3 g. (47.4%) ofwater-white liquid of an unpleasant odor; b.p. 69' at 0.8 mm:' S-Meth@nemaptoacetic acid chloride. The preparation of alkyl mercapto acid chlorides (Method D) reported by Mooradian et uZ.'O waa followed. From freshly &tilled Sm e t h y h e r c a p h e t i c acid and freshly distilled and purified thionyl chloridelxa pale red oil waa obtained. A double distillation in vacuo gave 56.1 g. (95.5%) of a pale yellow oil; b.p. 49-50' at 14 mm.l0 N - ( n - T e t r a ~ ~ l ) m e t h ~ l m r ~ p t o a c eI tna amflask ~ . were placed 7.0 g. (0.033mole) of freshly vacuum &tilled n-tetradecyl amine, 11 d.(0.137mole) of pyridine, and 600 ml. of anhydrous ether. The flask was placed in an ice bath and mixed until the contents had cooled to 5". Slowly, and with good agitation, 4.1 g. (0.033 mole) of freshly distilled Smethyhercaptoacetic acid chloride were added dropwise over a period of 15 min. A white precipitate formed immediately and the solution turned yellow. Agitation continued for 5 hr., while the contents of the flask slowly warmed up to room temperature. The mixture waa extracted several times with a 5% hydrochloric acid solution until the washings were acid. The ether solution waa washed with water until neutral, and the ether evaporated. The dry waxy reaidue was taken up in hot 95% ethanol. After cooling down in an ice bath a white waxy material was atered off. It was recrystallized from acetone and 5.9 g. (60%) of white waxy material with a faint pungent odor were obtained. A mixture melting point of this material with that previously prepared gave no depression. Infrared absorption curves showed the products obtained from both methods to be identical. N - ( n - O ~ l ) m e t h y l m r m p ~ ~ m &In. a similar fashion this compound was prepared in 79% yield. A mixture melting point and infrared absorption curves showed the product obtained from both methods to be. identical. N-(n-But~l)methylmermptoacetam&.This compound waa similarly prepared. The product obtained waa a yellow oil, of u n p l w n t odor; b.p. 123-124' at 7 mm.,ny 1.49400, d:' 1.020, MD 46.03 (calcd. 45.89). An examination of the infrared absorption curves shows both products exhibit a band for the thioether group at 737 cm.-', and bands for a monosubstituted amide at 1545, 1660, and 3280 cm.-I Anal. Calcd. for GHuNSO: C, 52.13; H, 9.38. Found: C, 51.90;H, 9.21.
VOL.
22
ture I. These substances were of interest for testing as possible hypnotic agents because of their close structural resemblance to the well known barbituric acids (11).In the past a number of diketopyridines (111) have been synthesized' and reported t o possess hypnotic properties.lJ The compounds I11 differ from the barbiturates structurally in that a CO-NH portion of the ring system is replaced by CH=CR. Since the compounds I11 appear to possess a rather low order of hypnotic activity, we believed it desirable to prepare and test the related compounds, I, which differ from the barbiturate structure only in the replacement of a NH of the ring by CHR. Indeed Ib has been described, previo ~ s l ybut , ~ its pharmacological activity has not been well documented.
I a, R = C1; b, R = H
I11
I1
The sequence of reactions for the synthesis of I and related types started from the known pyridinedionecarboxylic ester (IV).4 The reaction of the amide (V) with hypochlorite gave the chloro compound (VI), which was hydrolyzed to 2-chloro-4,4diethy1-3-oxoglutarimide (Ia) by boiling with concentrated hydrochloric acid. To avoid the introduction of halogen, IV was converted through the hydrazide (VII) t o the azide, and this, after decomposition and hydrolysis of the resulting product with hydrochloric acid, gave Ib.3 These compounds were Acknowledgment. The authors wish to thank the remarkably stable toward long heating with conColgate Palmolive Co. for the use of their facilities centrated acid. and the staff of the Analytical Division of the Re0 search and Development Department for instrumental and microchemical analyses. Thanks axe also due to Evans Chemetics, Inc., for a generous sample of mercaptoacetic acid. DEPARTM~ENT OF CHEMISTRY POLYTECHNIC INSTITUTE OF BROOKLYN BROOKLYN, N. Y.
(10) A. Mooradian, C. J. Cavallito, A. J. Bergman, E. J. Lawson, and C. M. Suter, J. Am. Chem. SOC.,71, 3372 (1949). (11)E.Lareson, Ber., 63, 1347 (1930). (12) L. F. Fieser, Experiments in Organic Chemistry, D. C, Heath and Co., Boston, Maas., 2nd ed., 1941,p. 381.
Some 2,2-Diethyl-3-oxoglutarimides W. N. CANNON AND R. G. JONES Received May 1, 1967
This paper is concerned with the preparation of several compomds of the type represented by struc-
V
+
IV J,
VI1
VI
(1) 0.Schinder, H.Frick, and A. H. Lutz, Experientia, 10,135(1954). (2) A. Krautwald, G. Kuschinsky, and H. Riedel, Arch. exptl. Pathol. Phamkol., 193, 219 (1939); [Chem. Ab&.,
34,3367 (194O)l.T.Kopanyi, R. P. Herwick, C. R. Linegar, and R. H. I(. Foster, Arch. intern. phmacd2/namie, 64, 123 (1940);[Chem. Abstr., 34,5937(1940)l. (3) H. Erlenmeyer and H. Meyenburg, Heb. Chim. Acta., 20, 1388 (1937).H.Rijhnert, Ber. 90, 118 (1957). (4) German Pat. 658489,Dec. 5, 1938; [Chm. Ahstr., 33, 2150 (1939)l.
DECEMBER 1957
NOTES
1723
A w l . Calcd. for CBH12C1NOU: C, 49.66;H, 5.51;N, 6.43. Found: C, 49.60; H, 5.60; N, 6.61. 3,3-DiethyM,4dioxo-l ,W,S,4-tetrahydropyridyl-6-earbox~lic acid hydrazide (VII). To a solution of 56.3 g. (0.25mole) of the methyl ester in 200 ml. of ethanol was added 13.7 g. (0.275 mole) of hydrazine hydrate. The clear solution was heated under reflux for 1 hr. and the ethanol then removed in vacuo. The reaidue was recrystallized from hot water to give 29.5 g. (52.5%) of a yellow solid; m.p. 159-162'. A sample was recrystallized twice from ethanol; m.p. 162EXPERIMENTAL 163'. Diethyl $ ~ d i e t h y l S , 6 d i o x o ~ ~ a ~ d i c a r b o x y ~ t eThis - l , 6 . ~ Anal. Calcd. for CloH1i"aOs: C, 53.32;H, 6.71;N, 18.66. was prepared on a one-mole scale by condensation of ethyl Found: C, 53.59;H, 6.91;N, 18.74. oxalate with ethyl cu,a-diethylacetoacetate6 using sodium d1d-DieUay~3-ozogZutarimide(Ib). The hydrazide, 11.3 g. sand in toluene a t 50'. The product was a liquid; b.p. 180- (0.05 mole), was dissolved in 75 ml. of cold water containing 182' (14mm.), 172' (11 mm.); n y 1.4675;yield 71%. 8 ml. of 6N hydrochloric acid. To this was added 100 ml. of Anal. Calcd. for C1dHlzOs: C, 58.73; H, 7.75. Found: C, ethyl ether and the mixture was stirred vigorously. A solu58.61;H, 7.86. tion of 3.8 g. of sodium nitrite in 10 ml. of water was added Diethyl d , d d i e t h y ~ ~ x o S - a m i ~ h e x e ~ - 4 d i ~ r while b o x ykeeping ~~ the temperature below 10" by adding ice di1,6.4 This compound was obtained by treating the above rectly to the reaction mixture. The mixture was stirred for ester with excess 15% alcoholic ammonia, followed by heab 10 min., then the ether layer was separated. The aqueous ing the resulting salt at 60' for 1.5 hr. to effect dehydration. layer was extracted once with more ether. The combined The liquid product was distilled; b.p. 180-185' (14 mm.), ether solutions were washed with dilute aqueous sodium 177' (10 mm.); n y 1.4775;yield 59%. bicarbonate, water, then dried over anhydrous calcium Anal. Calcd. for CldH~N06: C, 58.93;H, 8.13.Found: C, chloride. The ether was decanted into a flask containing 58.90;H, 8.01. 100 ml. of ethanol. The ether was distilled off slowly on the Methyl d,4dwx~,Sdiethyl-l,d,S,4-tetrahydrohydropy~- steam bath and the remaining ethanol solution warmed for dine-6-carboxylate (IV).' This was obtained in very poor 1 hr. to complete decomposition of the azide. The ethanol was yield by heating diethyl 2,2-diethyl-3-keto-5-aminohexene- removed in vacuo to give a yellow, glassy residue. A mixture 4-dicarboxylate-1,6 with one equivalent of sodium methoxide of 20 ml. of concentrated hydrochloric acid and 10 ml. of in methanol. It was obtained as a yellow crystalline solid, glacial acetic acid was added and the mixture was heated m.p. 79-80', after recrystallization from water. at reflux for 1 hr., and then heated on the steam bath overAnal. Calcd. for CnH16N04:N, 6.22.Found: N, 6.33. night. The solvents were removed in vacuo and the residue S,3-Diethyl-d,4dwx6-diozo-l , d , d 1 4 - ~ t r a h y d r o p y r i d ~ ~ ~ r b treated oxwith 100 ml. of warm water. A water-insoluble solid am& (V). A small quantity, ca. 5 g., of the methyl wter was separated; 1.9 g.; m.p. 225-227'. The aqueous filtrate was added to 50 ml. of liquid ammonia. The ester dissolved was evaporated to give a second solid; 3.6 g.; m.p. 135-145' immediately, forming a clear yellow solution. The ammonia with gas evolution. A sample of this material on redissolving was allowed to evaporate. The viscous residue was dissolved in water gave a precipitate with silver nitrate, indicating the in 50 ml. of warm ether and 10 ml. of chloroform was added. presence of ionic chlorine. This water-soluble material was The crystalline precipitate was collected by filtration and added to 50 ml. of 1:1 hydrochloric acid and water and the dried on a porous plate; m.p. 118-120". A sample on re- mixture refluxed for 6 hr. The solvents were removed in crystallization from water melted at 119-119.5'. vacuo to give a SezQi-crystalline residue. This was dissolved Anal. Calcd. for CL~H14N20s: C, 57.13;H, 6.71;N, 13.33. in a small volume of dilute aqueous sodium hydroxide, Found: C, 56.95;H, 6.62;N, 13.19. filtered, and the filtrate acidified with concentrated hydro~ - A m i ~ - c h l o r o d , 6 d i e t h y ~ ~ , 6 d i o x o - l , ~ , 6 , 6 - t e t r a h y chloric d r o - acid. Chilling and scratching produced a white, granpyridine (VI). A solution of sodium hypochlorite was pre- ular precipitate. This was removed by atration and dried; pared by adding 3.1 g. of chlorine to a mixture of 14 g. of m.p. 224226'. A mixture melting point with the water insodium hydroxide in 14 ml. of water containing 25 g. of soluble hydrolysis product from above showed no deprescrushed ice. To this was added 45 g. of ice, followed by 8.4 sion.The combined solids were dissolved in aqueous sodium g. (0.04 mole) of the amide. The amide dissolved immedi- hydroxide, filtered, and the atrate acidified. The white ately and the mixture was allowed to warm to room tem- solid was collected by filtration, washed with cold water, and perature. The solution was heated on the steam bath for dried; m.p. 225-226". A sample on recrystallization from 30 min., cooled, and the pH adjusted to 7.1 by addition ethanol showed no increase in melting point. of concentrated hydrochloric acid. The yellow solid which Anal. Calcd. for C&&&O8: C, 59.00;H,7.15.Found: C, was formed was collected by filtration, washed with cold 59.17;H, 7.35. water, and air dried. This material weighed 3.8 g. (52%); THELILLYRESEARCH LABORATORIES m.p. 286-290" dec. A sample was recrystallized twice from ELI LILLY& COMPANY ethanol; m.p. 290' dec. INDIANAPOLIS, IND. Anal. Calcd. for C&&M&&: C, 49.89;H,6.05;N, 12.93; C1, 16.32. Found: C, 50.16;H, 0.02;N, 12.69;C1, 16.59. s C h l o r o - 4 , 4 - d i e ~ y ~ ~ o g l ~ r(Ia). i m ~ Ae mixture of 10.8 g. (0.05mole) of the amino compound in 50 ml. of conPyrolysis of 5,5-Bis(chloromethyl)-1,3,2centrated hydrochloric acid was heated under reflux for 24 dioxathiane 2-Oxide hr. The hot solution was filtered to remove a small amount of insoluble material, and the filtrate on chilling and scratching precipitated a tan, granular solid. This was collected by ALBERTS. MATLACK AND DAVIDS. BRESLOW filtration, washed with cold water, and dried. There was obtained 10.3 g. (gt?~q/~) of solid; m.p. 184-186'. A small sample, Received May 6 , 1967 on sublimation at 225'/1 mm., gave a white crystalline solid; m.p. 188'.
Compounds Ia, Ib, V, VI, and VI1 as well as the ester IV were tested in rats for both hypnotic and anticonvulsant activities. All were inactive except the amide (V), which had both hypnotic and anticonvulsant properties but the activity was too low t o have any practical value.
(5) F.J. Marshall and W. N.' Cannon, J . Org. Chem., 21, 245 (1956).
The pyrolysis of cyclic sulfites of 172-glycolshas been studied by Denivelle' and by Price and (1) L. Denivelle, Compt. rend., 208, 1024 (1939).
