Noveiiiber 1965
883
SEW' ~ O & l P O G S D S
progesterone (5.0 g.) was dissolved in 20 nil. of hot methanol and the Clauberg te>t, Iiitac~tS e w Zealaiid rabbits meightreated with 1.8 ml. of pyrrolidine. The mixture was heated on a ing approximately 1 kg. were primed for 6 days with steam bath for 5 min. and then allowed to cool. The crystals 3 y of 176-estradiol (s.c.)/day. On the following were filtered off and recrystallized from methanol to give 5.1 g. day, daily (oral) treatment was begun with test com(89.5%) of product, m.p. 167-170'. General Method. Borohydride Reduction. 3p-( 1-Pyrrolidy1)pound and continued for 5 days. On the day after 6-methyl-17a-acetoxypregn-5-en-20-one. - 3- [ 1-Pyrrolidinyl]-6the last treatnient the rabbits were sacrificed and a rnethyl-lia-acetoxypregna-3,5-dien-20-one (2.0 g.) was disuteri tie qegnieiit wa- taken for histological exaininasolved in methanol and treated with 1.5 g. of KBH4. The mixtion. The uteri were graded froni 0-4 according t o the ture was stirred a t room temperature for 12 hr., then poured into standard wale of llcPhail.lo The compounds, 3p-(lice and water and extracted with ethyl acetate. The organic layer was washed with 10%; HC1 solution and the acid extracts 1)yrrolidyl) - 17a-acet oxypregii-3-en-20-one (5), 3p-( 1were combined and neutralized with cold loc/;. KOH solution. pyrrolidyl) - 17a-et hynylandrost-3-en-17p-ol (7), and 3pThe crystals thus precipitated were once again extracted with (l-pyrrolidyl)-17a-ethynyl- 19 - norandrost-5 - en- 176-01 ethyl acetate. The ethyl acetate layer was washed with water, (8) (Table 11) were inactive at 0.5-, 1.0-, arid 5.0-mg. dried (Na2S04),and evaporated to give a yellow oil. Recrystaldose. However, 3~-(l-pyrrolidyl)-l7~~acetoxy-6-meth-lization from ethyl acetate gave 1.2 g. (60%) of material: m.p. 183-186"; ::A: 5.75, 5.82, and 7.99 g. ylpregn-5-en-20-one (6) qhowed a XcPhail grading of 3.1 at the higheit (5.0nig.) dohe level.
Experimental Section General Method. Dienamines. 3- [ 1-Pyrrolidinyl]-6-methyl17~~-acetoxypregna-3,5-dien-%O-one.-6~u-~let hpl- 1 i a - a ce t oxy(10) C. W. Emmens. "Hormone .issay," C. Press Inc.. S e w s 1-ork, K. Y., 1950.
W.Einmens, Ed., .icademic
Acknowledgment.-I wish to thank Dr. I. Scheer for his encouragement and interest, Dr. R. P. Blye of our Division of Pharmacology for the biological data, and N r . C. H. Harper and N r . J. Grodsky for technical assistance.
New Compounds Some 3,4,5-Trimethoxyphenyl Analogs of Anticonvulsantsla asas as^ S. PALKAR'~ ASD PIERRE F. SMXPH
Department of Pharmaceictical Chemistry, Cniversaty of Rhode Island, Kingston, Rhode Island Receiced J u n e 18, 1965 The possible iiiflrience of the 3,4,5-trimethoxyphenyl groiip on drugs having varying types of central nervoiis system activity has been evident i n such diverse cnomporinds as mescaline, reserpiiie, colvhiriiie, and trinieglamide (3,4,5-trimethoxybenzoylglycine diethylamide). As part of a continuing study, 3,4,5triniethoxyphenyl analogs of diphenylhydantoin, phensuximide (S-niethy1-2-phenylsucciniInide), and related intermediates were prepared.
Experimental Section'
5 4 3,4,5-Trimethoxyphenyl)-5-phenylhydantoin.-3,4,5-Trimethoxybenzophenones (18.0 g., 0.067 mole), KCN (12.0 g., 0.18 mole), (NH4)&03 (60.0 g., 0.62 mole), and 60% ethanol (500 nil.) were mixed together and stirred vigorously. The teniperat,ure of the reaction mixture was gradually increased from 23 to 63". I t was maintained a t 54-56" for about 70 hr., 58-.59' for about 50 hr., and finally 60-63" for another 50 hr. hboilt one-third of the solvent was removed under vacuiim and the reaction mixtiire was made acidic ( 10Tc HCI). The yellowish white solid thus precipitated was separated by filtration and treat,ed with 5yo aqueous XaOH. ,4 part. of the solid which ( l ) ( a ) This work xas supported by C. S.Public Health Service Research Grant M H 04132, Xational Institute of Mental Health. (b) Institute of Agriculture, Department of Biochemistry, University of hlinnesota, St. Paul. l l i n n . (2) l l e l t i n g points u-ere determined on a Fisher-Johns block and are uncorrected. Cornhiistion analyses were carried out b y hlicro-hnalysis Inc., Wilinington, Del. Infrared spectra were r u n on a Beckman Model I R 8 as K B r wafers. ( 3 ) C. l'. Iioelsch a n d R. S . Flesch. J . Ovg. Chem., 10, 1275 (1955).
remained insoluble (10.8 g.) was identified as the starting ketoiie. The greenish alkaline filtrate on acidification ( 10ccHC1) in the cold gave a white solid; yield 8.9 g. (407,). Upon crystallization from ethanol (50%), white fluffy crystals, m.p. 102-104", were obtained. Anal. Calcd. for C18H181L'j?Oj: C, 63.15; H, 5.26; K, 8.19. Found: C,62.55; H , 5.27; IL',7.97. 4-Hydroxy-3,5-dimethoxyphenylsuccinicAcid (I).-To a s o h tion of 3,4,5-trimethoxybenzaldehyde(19.6 g., 0.1 mole) and ethyl cganoacetate (11.3 g., 0.1 mole) in 60% ethanol (50 ml.) was added a little piperidine4 (1 ml.). The mixture was stirred niechanically. The addition of piperidine clarified the solution, and the t,emperatnre rose to about 35' from 20". The clear solution became turbid (yellowish) in 10 niin., and aboiit 20 min. later, a yellowish solid separated. Water (20 ml.) and 600/; ethanol (100 ml.) were now added to the mixture and then NaCN (4.$) g., 0.1 mole) was added within 20 min. The stirring was continned until the solrition again clarified. The solritioti was acaidified (10% HCI) and the oil that. precipitated was stirred overiiight, rintil it solidified. The solid (27.5 g.) was hydrolyzed with concentrated HC1 (50 ml.) by vigorous refluxing for over 6 hr. until the mixture clarified to a brown solution. The white solid, 15.0 g. (56yc) crystallized on cooling, was recrystallized from boiling water after decolorization with Yorit A. Fine fluffy cryst,als were obtained, m.p. 198-200". Anal. Calcd. for C12Hi40i: C, 53.33; H , 5.18; 0, 41.48. Found: C, 53.17; H,4.85; 0,41.35. 3,4,5-TrimethoxyphenylsuecinieAcid (II).-Compound I ( 15.0 g., 0.056 mole) was dissolved in 10FGaqueous NaOH (100 ml.). Dimethyl sulfate (10 ml.) was added dropwise to the hot solution with stirring. The solut,ion was refluxed for aboiit 4 hr. In order to hydrolyze any ester formed at this stage, the solutioii was further refluxed for over 2 hr. with the addition of KaOH pellets (10 g.) and ethanol (80 nil.). The ethanol was removed by distillation and the sodium salt thiis separated was dissolved in as little water as possible and acidified in t,he cold ( l0Yc HC1). The precipkate weighed 12.3 g. ( 7 8 % ) , white fluffy crystals from boiling water, m.p. 185-187'. Anal. Calcd. for C13H160,:C, 54.93; H, 5.63. Found: C, 55.04; H I 5.47. N-Methyl-2-( 3,4,5-trimethoxyphenyl)succinimide(III).Compound I1 (10 g., 0.035 mole) was added to 40Yc aqueous (1) .I. Lapnorth and J. A . McRae, J
Chem. Soc., 117, 1704 (1922).
884 riiethyl:tniiiie5 ( 2 U nil. 1. The fiask was heated uiitil t h e ternperature of the cwitents reached about 210". The residue (viscwus brown oil) was cwoled, dissolved in hot MC; ethanol. decolorized with Xorit -4,and filtered. On cooliiig, 5.5 g. (56c; ) Is, 1n.p. 147-150", was obtained. TWU rec,rystalli~atioiisfrom the same solvent raised the melting point to 154-155° (short woolly needles). .Inal. Calrd. for ClaH17SOj:C, 60.21 : H , 6.10: S , 5 . I ) l . Foiiiid: C, 60.82; H, 6.30: N , 5.21. N-Methyl-2-( 3,5-dimethoxy-4-hydroxyphenyl)succinimide (IV).-The reartion was mrried out as for 111. From I (10 g., O.OX7 mole), IT: (6.4 g., S6C; ) \vas obtained as yellowish white crystals, i i 1 . p . lS: nip ( e 16,700). T h e arinlyticxl snnlplp \$-:IS tl o i i w more from ethanol. i l d . for CIl,H,3N10s:C, 42.40: H , 4.t;:;: N. 24.72. F o i i I l k C', 42.42: H. 4 , 7 7 : S , 24.94.
of Py rimidines and Purines'
Quinoxaline Sulfonamides
Hecaiise of interest, i i i orotic' arid aiialogs iii this laboratory,Y 6-?;-hSdroxylamiiioiiracil ( I ) and iiwcil-6-hydroxamic acid (11) have been synthesized. 6-4-Hydroxylamiiiopriririe ribonucleoside (111)was regarded as an analog of adenosine, becarise 6-Kc'hydroxylaminopiiriiie3 is active as an analog of both adenine arid hypoxanthine. 2,4-l)imet hoxy-6-c~hloropyriniidiiie~~~ failed t o react with hydroxylamine; however, the demethylated derivative, 6-c:hloroiiracil,i rewted smoothly with hydroxylamine to give I. Compound I1 was prepared from methyl orotate,8 whereas 111 was prepared from 6-chlornpiiriiie rihoriiic~leo~ide~ and hydroxylamine.
Experimental Section'" 6-N-Hydroxylaminouracil (I).--A solution of KOH ( 11.2 g., 0.2 mole) in ethanol (40 nil.) was added to a solution of hydroxylamine hydrochloride (12 g., 0.17 mole) in boiling ethanol (200 nil.). The precipihted KC1 was filtered. 6-Chlorourac*i17 ( 1 g., 0.007 mole) was added t o the soliition of hydro The mixtiire was refliixed for 1 hr. and allowed to cool to room iemperatiire with stirring ( 1 hr. j. The prodiicbt, which separated as a solid, was washed with water and ethanol to give aiialytically pure I (0.73 g., i4!;), m.p. 280" der., 264 r n M ( e 6250). Anal. Calcd. for CJHJ,O~: C, 33.57, H, 3 . 5 2 ; N, 29.36. Foiind: C, 33.56; H , 3 . 7 7 ; Ti,29.25. Uracil-G-hydroxamic Acid (II).---A mixture of methyl orotatex (1.25 g., 0.0074 mole), ?jH,OH. H C l ( l . 4 g., 0.02 mole), and water (10 nil.) was cvoled to 0". JI'ith stirring, S a O H (12.5 AY,3.6 ml.) was added t o the mixtiire dropwise a t '3". The now clear solri( 1 ) This uork was suiiported l)y a grant (C.\-02817) from the S a t i o n a l ('ancer Institute. U. A . Public Health Service. ( 2 ) K . F:. Handschiimaclier. Cancer Res., 28, 6-13 (1963). ( 3 ) A . Qiner-Horolla and .II3endich. . .I. A m . Chem. Soc., 80, 3932 (1858). artorelli. .\. I,. Richer, P. K. Clianr, a n d G . .i.Fischer, Bior.lrc.m. I'harmarol., 13,507 (196-1). ( 5 ) 11. .J. Fisher a n d T. 13. .Johnson. .J. , i m Clirm. Soi,., 54, 727 (1832). (6) S. 1%. Greenliaum a n d W . I,. Holinep, ihid.. 76, 28Y9 ( 1 9 5 4 ) . ( 7 ) .T. P.H o r w i t z and .\. .J. Tomson, . I . Oru. Chem., 26, 3392 (1862). (8) .I. .J. 1:os. h-. T u n g , and I . \\-empen. B i o c h e m . B i o p h y s . Acta. 23, 2!93 (l!IR7), ($1) I
