3606
USKOKOVI~, IACOBELLI, AND WENNER
VOL.27
3H-1,4-Benzodiazepine-2,S(lH,4H)-dione and Related Compounds MILANUSKOKOVIE, JEROME IACOBELLI, AND WILHELM WXNNER Research Department of Hoffmann-La Roche Inc., Nutley IO, New Jersey Received May 9, 1986 Synthesis and reactions of 3H-1,4-benzodiazepine-2,5(lH,4H)-dione are described.
There are few reports in the literature about cm.-l), in full agreement with the expected 3Hbenzodiazepine derivatives : Condensation of o- 1,4-benzodiazepine-2,5(lH,4H)-dione (111). phenylenediamine with malonic acrylic The above synthesis did not exclude the possiethyl a~etoacetate,~-'* and acetylacetonels bility that ring closure had led to a cyclic polymeric gave a number of 1,5-benzodiazepine derivatives. substance with the same elementary composition Recently Sternbach and ~o-workers'~ described a and infrared spectrum similar to those expected of number of isomeric 1,4-benzodiazepines, which 111. A molecular weight determination could not possess outstanding psychopharmacologic proper- be used to resolve this problem because of the low ties. l6 The best investigated compound of this solubility of the compound in question. Fortuseries, 7-chloro-2-methylamino-5-phenyl-3H-l,4-nately, this ambiguity was overcome by a difbenzodiazepine 4-oxide has found wide thera- ferent synthesis starting with the methyl ester of peutic application. This led us to investigate N-benzylanthranilic acid (IVb).l7 In this case simpler compounds with the same basic ring system. the N-bromoacetyl derivative (V) could be readily This paper describes the synthesis of 3H-1,4- cyclized with ammonia to 1-benzyl-3H-1,kbenzobenzodiazepine-2,5(1H,4H)-dione (111)l6 and its diazepine-2,5(1H,4H)-dione (VI). The infrared reduction with lithium aluminum hydride to and analytical data, including a molecular weight 1H-2,3,4,t5-tetrahydro-1,4-benzodiazepine (VII). determination supported the assigned structure. Attempts were first directed to the ring closure On hydrogenation in the presence of palladium the of N-(haloacety1)anthranilic esters and amide with benzyl group was removed to give 111. ammonia and other bases, but in every case the Additional support of structure I11 was furnished products were quinazoline-.1(3H)-ones. An alter- by reduction with lithium aluminum hydride to native scheme, starting with o-aminohippuric acid the completely desoxygenated lH-2,3,4,5-tetraethyl ester (I)16 led to the desired compound hydro-1,4-benzodiazepine (VIIa).l8 A minor bythrough the intermediate piperidide (11), which product in the reduction was 1H-2,3-dihydro-1,4was obtained in 50% yield from a hot solution of benzodiazepine (VIII), which was identified by I in piperidine-methanol. On refluxing with acetic analytical data, infrared spectrum (3230 em. -l acid a quantitative ring closure to I11 was effected. for -KH- group and 1630 cm.-' for -C=N-), Direct conversion of I t o I11 was accomplished in ultraviolet spectrum [233-234, 264-265, and 353boiling pyridine solution, but the yield was very 357 m l ) 1, by comparison with its 7-nitro-5-phenyl poor. The infrared spectrum showed absorption analoglg and also by its hydrogenation to VIIa. bands for -SH- (3230 cm.-'), for two carbonyl 3H-1,4-Benzodiazepine-2,5(lH,4H)-dione (111) groups (1710 and 1685 em.-'), and for a methylene is stable in aqueous alkali and glacial acetic acid. group in a-position to a carbonyl (2930 and 1430 In hot 70% sulfuric acid it was degraded to anthranilic acid. It is stable in hot methanolic solution toward ammonia, but methylamine under the (1) R. hleyer, Ann., 827, 1 (1903). same conditions opens the seven-membered ring, (2) R. L. Shriner a n d P. G. Boermann, J. Am. Chem. SOC.,66, 1810 (1944). giving o-aminohippuryl methylamide (IX) . (3) iLI. A. Phiilips, ibid., 64,187 (1942). (1) J. Buchi, H. Dietrich, a n d E. Eichenberger, H e l u . Chim. A c t a , 39, 957 (1956). ( 5 ) 0. E. Bachman a n d L. V. Hesley, J . Am. Chem. Soc., 71, 1985 (1949). (6) W. R i e d a n d G.Urlass, Ber., 86,1101(1953). (7) W. Ried and W. Hohne, tbid., 87,1801 (1954). (8) W.A. Sexton, J . Chem. Soc., 303 (1942). (9) W.Ried a n d W. Hohne, Ber., 87, 1811 (1954). (10) F. B. Wigton a n d M. hf. Joullie, J. Am. Chem. SOC.,81, 5212 (1959). (11) A. Rossi, A. Hunger, J. Kebrle, a n d K. Hoffmann, Helu. Chim. A c t a , 43, 1043,1298(1960). (12) J. Davoll, J . Chem. Soc., 308 (19GO). (13) J. Thiele a n d G. Steimmig, Ber., 40,955 (1907). (14) L. H.Sternbach, U.S. P a t e n t 2,893,992(July 7, 19.59). (15) L. R. Hines. Cur. Ther. Rea., 2,6 (1960). (16) K. Miyatake, S. Kaga, C'hem. Abstr., 47, 2734g [ J . Phorm. SOC.J a p a n . 72, llG0 (1952) I.
Experimentalz0 o-Aminohippuric Acid Piperidide (11) from o-Aminohippuric Acid Ethyl Ester (I).-The solution of 15 g. of I in 100 ml. of methanol and 100 ml. of piperidine was refluxed (17) J. Houben a n d W. Brassert, Ber., 39, 3233 (1906). (18) S. Archer, J. R. Lewis, M. J. Unaer, J. 0. Hoppe, a n d H. Lape, J . Am. Chem. Sac., 79,5783,1957. (19) J. A. Hill, A. W. Johnson, a n d T. J. King, J . Cham. Sac., 4480 (1961). (20) All melting points a r e uncorrected. Elemental microsnalysea were performed b y Dr. 8. Steyermark. Ultraviolet spectra were taken on a Cary Model 1 4 M spectrophotometer. Infrared spectra were taken o n a Perkin-Elmer hfodel 21 spectrophotometer.
OCTOBER,1962
3G07
aNHz 0''' I\
c=o I
\
C00C2H5 I C-NH-CHz
C --N H-CHZ I
n
0
II
II
0
I1
I CHz I
