SYI~THESES OF 6-SUBSTITUTED PURINES
Xug. 3, 19%
n'hen acetylation of authentic samples of dihydrocodeine and dihydroisocodeine is carried out as described above but the sodium bicarbonate treatment is omitted, the N,Odiacetates are obtained. Dihydrocodeine N,O-diacetate, m.t.'. 106-108" (from ether). Anal. Calcd. for CZZHZ9NOS: c , 65.49; H, 7.25; X, 3.47. Found: C, 65.43; H , 7.21; N,3.59. Dihydroisocodeine N,O-diacetate, m.p. 162-163' (from ether). Anal. Found: C,65.61; H,7.39; S , 3 . 4 9 . Both give m.p. depressions when admixed with the 0acetates, m . p . 116-117' and 163-164', respectively. Titration of each with sodium methoxide,I4 showed the (11) J. S.Fritz a n d N. M. Lisicki, A r d . Chem., 23, 689 (1961).
[CONTRIBCTIOK FROM
THE
3G93
presence of exactly one mole of acetic acid bound to nitrogen. Saponification of Acetates-General Procedure.-The ester (30 mg.) was dissolved in ethanol (1-3 ml.) and the solution was made up to a volume of 10 ml. with 0.01 N sodium hydroxide solution. Aliquots of 1 ml. each were titrated from time to time with 0.01 N hydrochloric acid (phenolphthalein indicator).
Acknowledgment.-We thank Dr. L. F. Small for samples of all the codeine derivatives which made it possible for us to carry out this work. REHOVOT,ISRAEL
SUTRITIOX A N D PHYSIOLOGY SECTIOS, RESEARCH DIVISIOX,AMERICAN CYANAMID Co., LEDERLE
LABORATORIES]
Syntheses of 6-Substituted Purines BY MILONK. BULLOCK, JOHN J. HAXDAND E. L. R. STOKSTAD RECEIVEDFEBRUARY 1, 1958 Several purine derivatives which are related t o kinetin (6-furfurylaminopurine) have been prepared by condensing 6chloropurine with amines. Analogs in which the 6-amino group was replaced by a sulfur atom have been prepared by treating 6-chloropurine with sodium mercaptides. The ultraviolet absorption spectra of the purine derivatives have been determined in 0.1 N hydrochloric acid, 0 l Nsodium hydroxide and in a neutral solution. Methods for the convenient preparation of some of the intermediates are presented. A modification of the conventional method of lithium aluminum hydride reductions in which only enough water is added to cause the separation of the salts as a solid phase has simplified this method of reducing nitriles. A method for preparing 2-mercaptomethyltetraliydrothiophene directly from tetrahydrofurfuryl alcohol was investigated.
The recent isolation,' structure determination and synthesis2 of kinetin, 6-furfurylaminopurine, the cell division factor from deoxynucleic acid, has prompted us to prepare several analogs with the hope of obtaining an antimetabolite or competitive antagonist to kinetin which would inhibit cell mitosis and possibly be useful for cancer therapy. Miller, et al.,2 synthesized kinetin by the general method of Elion, et u Z . , ~ by treating B-methylmercaptopurine with furfurylamine. I n these Laboratories we have synthesized kinetin and several analogs by a modification of the basic method of Albert and Brown.4 We have found that condensing 6chloropurine with a t least two equivalents of the amine in the presence of a high boiling solvent such as methyl Cellosolve gives excellent yields of pure products. Analogs in which the 6-amino group on the purine nucleus was replaced by a sulfur atom were also conveniently prepared by allowing 6-chloropurine to react with a sodium mercaptide under similar conditions. This method appears to give about the same yields as the method of Elion, Burgi and Hitchings, in which the alkyl halide is condensed with the sodium salt of &mercaptopurine. The melting points and analyses of the G-substituted purine derivatives which were prepared are given in Table I. The letters in the method column refer to the general procedures illustrated in the Experimental section. The biological activities of the compounds will be published elsewhere. The ultraviolet absorption spectra of these com(1)
C. 0. Miller, F. Skoog, AT. H. von Saltza a n d
Since the procedures used to prepare compounds in an)one series are nearly identical, only one example will be given to illustrate each procedure. m-Methylbenzylamine (A).-A solution of 100 g. (0.854 mole) of m-tolylnitrile in 150 ml. of anhydrous ether was added t o a stirred suspension of 38 g. ( 1 mole) of lithium aluminum hydride in 1 liter of ether a t such a rate as to maintain a vigorous reflux. The addition required 30 minutes. The suspension was refluxed a n additional 30 minutes. The heating mantle was replaced by an ice-bath, and 20 ml. of F. 11. Strong, THIS water was added dropwise from a dropping funnel. Sodium hydroxide solution (20yo) was then added until a granular H. yon Saltza and solid second phase was present and the ether solution was
77, 1392 (1933). (2) C. 0. .Miller, F. Skoog, F. S. Okumura, BI. I;. RI. Strong, &bid.,77, 2203 (1955). ( 3 ) (;. H. ISlion, E . llurgi and G. H. Hitchings, ibid., 74, 4 1 1 (1952). (i)A . AIl>eriand 13 I . Urown. . I . ( k m . .?or,, L'(1i;O (l!l.-A).
JOURXAL,
pounds have been determined with a Cary recording spectrophotometer in 0.1 N sodium hydroxide, 0.1 N hydrochloric acid and in water or ethanol. Many of the compounds are so insoluble in water that the determination of the absorption spectrum in this medium was impractical. The molecular extinctions are summarized in Table 11. Most of the amines which were required as intermediates in this work and which were unavailable comniercially were prepared by reducing the corresponding nitrile with lithium aluminum hydride in ether. 3-Aminomethylpyridine was prepared by reducing 3-cyanopyridine catalytically since the lithium aluminum hydride reduction was unsatisfactory. N-Methylfurfurylamine was prepared by a slight modification of the method of S c h w a b b a ~ e r . ~The methods of preparation, yields and physical constants of the amines are summarized in Table 111. Acknowledgments.-The authors are indebted to Mr. L. Brancone and staff for the microanalyses and to Mr. H . Lewry for the ultraviolet absorption spectra. Experimental6
(.?I G.Schwabbauer, Ber., 36,410
(1902)
(ti) Melting points are iinrorrectrd.
11. L\-. BBULLOCK, J . J. H.mm
36Y4
AND
E. L.K. STOKST.\D
TABLE I SUBSTITUTED PURISES Yield,
Purine &Furfurylamino-" 6-(x-Methylfurfurylamino). 6-ThenyIamin0-~ 6-Ben~yIamino-~ G- (o-1lethylbenzj.lamino)6- (m-hlethylbenzslamino)6- (P-hlethylbenzylamino). 0- (S-Benzylmethylamino)A- (a-Pheny1ethylamino)6- (2-Pyridylmethylamino)-r 6 - (3-Pyridylmethylamino)-' (i-(4-Pyridylmethylamino)-c 6- (Carbomethoxymethylamino) ti-FurfurylthioG-Tetrahydrothenylthio6-Benzylthio-
Procedure D E B E D E 11
u
&i.p., C. 95,5 2ii7-26Sb 80.2 210-211b 87.5 '2441.5-242 92.,5 231 7 9 , .i 243-24qb 91 233-234 88 3 203 ri3.5 114.5-113 70 199-202 JJ 245-24li 70 3 237 39 250-231 41 238 80 178-178.5 79 192.5-194 t45.3 193-194
%
03.98 51.93 57.63 (i3.36 65.25 1,3, 25 1,3.25 (i5.25 58.39 38,39 38.39 46,37 51.71 47.54 39.48
__
D I)
D D I
ether was added, portionwise, 23.2 g. (0.1 mole) of 5-ethyl5-phenJ.lbarbituric acid.5 The mixture was stirred and rcfluxed for 44 hr. H>-drolysis was effected as previously 0 1 I1 outlined a n d the snlids were extracted by boiling with f o u r The reaction was extended to some barbituric 2dO-ml.portions of ethanol.4 There !vas obtained 12 g. i d acid derivatives to give hexahydro-2-pyrimidinones material melting a t 19j-108°. Two crystallizations froill B and one from ethanol-Skelly B gave (Table 11),to some 2-thiouracils to produce 1,2,3,&- 9chlorofr)rni-Skelly g. (-My0) melting a t 1!)5-196.5".
tetrahydro-2-pyrimidinethionesand to &methyl4,3-dihydro-3(2H)pyridazinoneto obtain the tetrahydropyridazine. The only unsuccessful reactions were those involving 5-ethyl-6-phenyl- and Aphenyluracil. This may well have been due to the greater insolubility of the uracils in ether. No further investigation was made of this point. 1 IJnpiihli~hrdst,iilie\, the5e lalioraturies. 8 2 , I J \Vilk and \V J . Clirir, ./ 0 , g . ( ' h c v . , 16, 1021) ll!J,7ll>
(
( 3 ) Prepared according t o the method of H. R . Henze and K . 1 Speer, THISJ O U R X A L , 64, 5 2 2 (1942), as were all the hydantoins with t h e exception of t h e >,>-diphenylderivative which was prepareii I>? the procedure of H. Biltz, Be?., 41, 1391 (1908). (4) X'ith t h e dialkyl derivatives t h e ether contained some prnrIiicL a n d t h e extractions were preferably carried o u t with benzene. ( 3 ) XImt of the barbituric acids were kindly slipplied b y Xlr IV I . DordtL of the
