June 20, 1954
3213
NOTES
XI1 was acetylated under conditions similar to those reTesting data on I and current studies on related corded by de Arce, Greene and Cappss for the acetylation compounds with flocculating activity will be reof 5-amino-&bromo-6-methylquinoline; yield 67%, n1.p. ported in forthcoming publications. >330° (uncor.) from 95% ethanol. ExperirnentaF.6 Anal. Calcd. for C12H12Ns02: N, 12.96. Found: N, 13.11. Ethyl 3a-Hydroxy-A11-cholenate (11) .-3a-Hydroxy-A"XI1 was berizoylated under conditions similar to those cholenic acid7.8 was esterified with absolute ethanol essentially according to the method used by Kendall and his associused by de Arce, Greene and Cappss for the benzoylation of ~5-arnino-8-bromo-6-methylquinoline; yield 42%, m.p. > ates for the preparation of the methyl ester.9 However, whereas esterification with methanol is complete in less 315". Anal. Calcd. for C17H14Nn02: N, 10.07. Found: N, than an hour, with ethanol 27% of unreacted acid was recovered even after 22 hours. The ethyl ester did not 10.00. crystallize from aqueous ethanol, but separated satisfac8-Methyl-5-quinoline~usonic Acid (XV) , 2-Chloro-8- torily from purified Skellysolve F as colorless needles melting methyl-5-quinolinearsonic Acid (XVIII) and 2-Hydroxy-8- a t 81-82', [ a I z 8 D 30' (c 2.01, chf.). Anal. Calcd. for methyl-5-quinolinearsonic Acid (XXI) .-The hydrochlorides C2&203: C,77.56; H, 10.52. Found: C,77.3; H, 10.6. of X (12.0 g.), X I (9.0 g.) and XI1 (10.0 g.) were diazotized Ethyl 3P-Chl0ro-A~~-cholenate (I).lO-To a stirred solution and converted into arsonic acids according tcr t h e p r m d r e of 500 mg. of I1 in 28 ml. of chloroform, in a flask equipped reported by Capps and Hamilton" for changing certain 2- with a drying tube and immersed in an ice-bath maintained chloroaminoquinolines into khloroquinolinearsonic acids. a t O', 800 mg. of powdered calcium carbonate and, in two XV, XVIII and XXI resulted in yields of 12.8, 11.9 and portions with a 20-minute interval, 1.2 g. of phosphorus 14 S'%, respectively. X V melted a t 224-226' while XVIII pentachloride were added. Stirring was continued for 100 dud XXI melted above 315" (uncor.). minutes a t 0'. The reaction product was poured into 200 Anal. Ccilctl for CIOHIOASXO~: As, 28.05; N, 5.27. ml. of 5% sodium bicarbonate solution containing ice, and Found: As, 27 92; S , 5.09. Calcd. for CIOH~ASCINO~:ether was added. The resulting mixture was stirred until As, 24 84; S , 4 65. Found: As, 24.69; N, 4.75. Calcd. the ice had melted, transferred to a separatory funnel and H10: As, 24.87; N, 4.65. Found: As, shaken thoroughly. The organic layer, which still retained for CIOHIOASNO~ 24.79; N, 4.67. a small amount of an insoluble, colorless, inorganic solid, was washed with water, dried (Drierite), filtered and evapoD Capps and C. S. Hamilton, THIS JOURNAL, 60, 2105 (11) J rated (reduced pressure) to a colorless residual oil. This oil (1938). dissolved in the minimum amount of warm methanol, on refrigeration for 2 hoours yielded 380 mg. (73%) of colorless Ross CHEMICAL LABORATORY Two recrystallizat$ms from methacrystals m.p. 69-73 INSTITUTE ALABAMA POLYTECHNIC nol gave thin plates melting at 74-76 , [ C Y ] ~ ~ D25" AUBURN, ALABAMA (c 2.05, chf.). Anal. Calcd. for C&,102Cl: C, 74.16; H, 9.82; CL8.42. Found: C, 74.3; H, 9.8; C1,8.8. Catalytic Hydrogenation.-I in acetic acid solution and Seroflocculating Steroids. I. Ethyl 3p-Chlorothe presence of Adams catalyst absorbed 1.03 moles of A1l-cholenate hydrogen within 20 minutes. After removal of catalyst and solvent, two crystallizations of the product from BY FREDERIC e. CAASGA N D DOUGLAS H. S P K U N T methanol gave colorless, feathery crystals, m.p. 59-60.5', R E C E I V EAPRIL D 2, 1954 which did not depress the melting point of ethyl 3p-chlorocholanate (111) prepared from ethyl lithocholatellJ* by the During the course of our study of the relationship same method as used for the unsaturated derivative, crysof steroids2 to ininiunological phenomena associ- tallizing in methanol as colorless needles, m.p. 59-61.5', ~ (c 1.27, chf.). Anal. Calcd. for C2sHtaO&1: ated with injury, we have had the occasion to [ a I z e +18.5" investigate the seroflocculating reagents described C, 73.81; H, 10.24; C1, 8.38. Found: C, 73.5; H, 10.5; c1, 8.2.
+
.
+
by Penn and his associate^.^ These reagents4 (5) Microanalyses by the Microchemical Laboratory of New York cause flocculation in a high percentage of the sera University. of patients with cancer and other diseases. (6) Melting points were taken on an electrically heated micro Our investigation of the flocculating reaction hot-stage and are uncorrected. led us to prepare ethyl 3P-~hloro-A~~-cholenate (7) J. Press and T. Reichstein, Helu. Chim. Acla, 26, 878 (1912); (I) which in preliminary testing we have found to B. F. McKenzie, W. F. McGuckin and E. C. Kendall, J. Biol. Chcm., 555 (1946) be a very satisfactory flocculating reagent. The 162, (8) Generously supplied by Merck and Co. through the kindness of conipuund. is crysta.liirse a d stable -m&ror&my Dr: M;rx Tishier conditions. I r e will discuss in detail elsewhere (9) L. L. Engle, V. R. Mattox, B. F. McKenzie, W. F. McGuckin implications of general significance in this field sug- and E. C. Kendall, J. B i d . Chem., 162, 565 (1946). (10) Although a double bond shift is considered unlikely under the gested to us by this finding. conditions of this reaction. experiments are under way to confirm the 'Treatmext of ethyl 3a-hydroxy-A1Wiolenate position of unsaturation. ( I 1) with phosphorus pentachloride in chloroforni (11) F. Reindel and K. Niederlander, Bey., 68, 1969 (1935). (12) We are indebted to Ciba Pharmaceutical Products, Inc.. and at 0" yielded ethyl 3~-chloro-A11-cholenate(I), which could be quantitatively hydrogenated to Dr. H. B. MacPhillamy for a supply of lithocholic acid. AND ethyl 3,b-chlorocholanate (111). The latter was DIVISIONOF CHEMISTRY, DiVi310N O F PATHOLOGY AND- BACTERIOLOGY found- to be identicar by meiting point comparison UNIVERSITY O F TENNESSEE with the product of reaction between ethyl litho- MEMPHIS,TENNESSEE cholate and phosphorus pentachloride. (1) Aided in part by a grant from the United States Public Ifealth Service. (2) D. 1%.Sprunt, A. D. Dulaney and R. P. Conger, Cancer Research, 2 , 282 (1951). (3) H. S.Penn. J . S n l l C Q J I C P Y ~12, I S ~1389 . , (1952); A. H. Dowdy, H S. Penn, C i . Hall and A. Brllamy, Proc. A m . Assoc. for Cancer R P s r i l r < h . 1, I2 (19.54).
( 4 ) We wish to thank 131s. D o w d y and Penn aud their group for their coijperation in making available to us procedures for preparing and testing both the liver and desoxycholic acid-derived flocculating reagents which they designate as "antigens."
The Preparation of Sarcosine and Methyl Methylamino-0- (3-indolyl)-propionate
CY-
BY F. F. BLICKEA N D PAULE. NORRIS RECEIVED FEBRUARY 15, 1954
The preparation of methyl a-methylaniino-P-(3indoly1)-propionate was undertaken since a supply of this ester was required as an intermediate.
3214
Vol. i(i
NOTES
1-Nethylhydantoin,' which had been synthesized 50 cc. of absolute methanol was cooled iii i t i i ice-bath aiit1 from sarcosine (M-methylglycine) a n d potassium saturated with hydrogen- chloride. The mixture was Alowed to-remain- a t room temperature- whereupon the acid cyanate, was condensed with indole-3-aldehyde2to slowly dissolved. By slow evaporation of the solvent from forni 1-inethyl-5-(3'-indolal) -hydantoin.' This hy- the solution, under reduced pressure in a desiccator which dantoin had been heated with ammonium sulfide in contained calcium chloride, a crystalline residue \vas obtained. It was covered with methanol aut1 the solvent \v:t\ a sealed tube a t 100" for 3 days, by Miller and Rob- removed in the manner just described. If necessary, this son,l in order to reduce i t to l-methyl-5-(3'-indo- process was repeated in order to remove the odor of hydrolylinethyl] -hyd-antoin. ne found- that this reduc- gen chloride. The hydrochloride, which was slightly contion could be carried out a t 40-50" by the use of taminated by a light violet impurity, nielted a t 185-188". ilnal. Calcd. for C13Hii02XZCl: N, 10.42: CI, 13.20. Raney nickel, and could be completed in 5-6 hours. &h'en the last-mentioned hydantoin was refluxed Found: N, 10.41; C1, 13.56. The finely powdered hydrochloride was suspeiitletl in abwith barium hydroxide, according to the directions solute ether, the mixture was cooled and saturated with dry, in the literature, a-methylamino-/3-(3-indolyl)-pro-gaseous ammonia. After 10 minutes, thc mixture 1va5 pionic acid was obtained. We converted this acid filtered through a sintered glass funnel and the solvent wa5 into the methyl ester hydrochloride, in quantita- removed from the filtrate in the manner described above; tive- yield; by the use of methanol and hydrogen the residue, the ester base, melted a t 70-72"; yield 2.3 g. chloride. T h e ester base was formed when the (45%). Anal. Calcd. for CljH:;OeX~: C, 67.21; 11, (!.%; S, salt was treated with ammonia. 12.06. Found: C, 67.34; H, 6.84; N, 12.28. I t was discovered t h a t sarcosine could be preThe picrate was obtained when the cstcr was treatctl w i t h p a r d by a much simpler method than t h a t which an alcoholic solution of picric acid; m.p. 180-182O. The hydrobrornide precipitated when a n ethereal solutioil has been dcscribedl3namely, by interaction of chloof the ester was treated with hydrogen broinidc; m . p . 163roacetic acid and methylamine. 165" after recrystallization from absolutc ethanol-ether. Experimental COLLEGEOF PHARMACY Sarcosine.-Two liters of 30% aqueous methylaniine \vas CSIVERSITY O F %CIIIGAX stirred and 47.5 g. of chloroacetic acid, dissolved in 30 cc. of Asx ARBOR,hIICIlIG.4S water, was added slowly. After 24 huurs, t h e swlutim- \vaconcentrated under reduced pressure to a thick sirup which \vas diluted with absolute ethanol until the volume was The Preparation of 2-Disubstituted Amino-5,5-diabout 210 cc. The alcoholic solutio11 was then kept a t phenyl-4(5H)-imidazolonesI about -10" for 13 hours, the crystalline precipitate wa5 removed by filtration and the filtrate was diluted with abBY C. E;. CAINAYD SARAI(. SAEGELE solute ethanol until the volume mas about 225 cc. h;hen RECEIVED DECEMBER 4, 19% the solution was cooled t o -lo", and maintained at that temperature, more crystalline material deposited. The In spite of the large number of 5,3-disubstitutetl combined precipitates were recrystallized twice from 95% hydantoiris which have been prepared and studied ethanol; m.p. 212-215°,4 yield 18.0 g. (40.5%). l-Methy1-5-(3'-indolylmethyl)-hydantoin.-Five grains pharmacologically, the corresponding 2-imino coliiof activated Raney nickel5 was added t o a mixture of 5.0 g. pounds (glycocyaniidines) have received little of l-metliyl-5-(3'-indolal)-hpdantoin1 and 100 cc. of 1 A: attention. Recently Hoffniann2 reported the prepsotliuin hydroxide solution. The mixture was hydrogenated aration of 3,3-diphenyl-2-iminohydantoin(5,sa t 10-50° under :in initial pressure of 40 pounds. After coiiii~letetlrctluctioii (5-6 hours), the catalyst was removed diphenylglycocyainidine) (formula I) aiid Deliwala !>y filtratioii aiic! :he filtrate :va.;at(!jus,tcd to a pE of 6.5 ~ v i t ! ~ and iiajagopaiari' described the synrhesis of- a few 1 : I hytlrochloric acid. T h e product, which separnted related compounds. No examples could be found froiii the cooled mixture, \veighecl 4.5 g. (90%); m.1). 2132113O.6
~Methylamino-~-(3-indolyl)-propionic Acid.7-This suhstance was obtained by treatment of l-methyl-5-(3'i n t l o l ~ - l i n e t h ~ - l ) - l i ~ - d a ~with ~ t o i barium n hydroxide solution by the procedure of Miller and Robson'in 8070 yield; m . p . 272-375" ~ I e c . ~ AI^. C d c d . for CI2HlaO2S2:C, 65.53; H, 6.46. Fuund: C, 65.19; H, 6.63. T h e hydrochloride, prepared according t o the directioiis ill the literature,' melted at 220-222D.9 Thc picrate, prepared by a described method,'O melted a t 185-186O dec." and HyMethyl ~-Methylamino-~-(3-indolyl)-propionate drochloride.--A mixture of 5.0 g. of the propionic acid and _.
E. J . l f i l l e r and W. R o b a o n , J . Cheirz. S O L . 1910 , (1938). J Elks, D. IT, Elliot and B. A . Hems, ibid., 029.(191.1). U'. Cocker, i b i i l . . 1693 (1937). Reference 3, m . p . 211-212°. A. A , Pavlic and H. Adkins, THIS J O U R N A L , 68, 1171 (19.16). ( 6 ) Reference 1, m.p. 211-212'. fl) (2j (B) (-I) (31
(T) The name N-methyltryptophan, which has been used for this compound, is an unsatisfactory one as has been pointed out by hliller and Rson.' ( 8 ) Relerence 1, m 1). 2-13'; \V. G. Gordon and l < , \V Jncksrln (.I 14iol. C h e ~ z . 110, , 1.74 (1935)), in 1). 2 ! ! 7 O rlrc. (9) Itefcrence 1, m.p. 192-193'; N. Ghatak (Buil Actrd SCi C'iziled Pvouinces.Agrn O z l d k , India, 3, 295 (1934); C . A . , 29, 33-11 (1933)), m.p. 221-222'. f l n ) \\'. If.Cahill and R. W.Jackson, J Gir~lCiicibi , 126, 20 (1938). 1 1 I i?Lr,.r,,,lcc, li!, ~n 11 lS.i-lRI;o d c r
in the literature of compounds containing a disubstituted amino group attached to the carbo11 atom between the two nitrogen atoins of the ring (formula 11). Such a structure is of interest since the existence of the tautomeric forni involving a double bond between carbon atom 2 and the cxocyclic atom attached to i t is not possible, at lcast in neutral or basic medium. H O=C-- --SH
I
o=c-..-
h-
I1
Several 2-disubstituted aiiiino-5,3-dipheiiyl-~(5~~ j iiiiidazolones have been prepared in good yields by the reaction of 2-rnethylinercapto-5,3-diphenq.l4(5H)-imidazolone with an excess of R secondary amine (Table I ) . Diisopropylalnilic failed to give any detectable reaction under thc coiitlitions tried. ( 1 ) I'resentetl lieiiire t h e l)ivisi
