A new, general synthesis of purines

摘要

1976 1547A New, General Synthesis of PurinesBy Fumio Yoneda and Tomohisa Magamatsu, Faculty of Pharmaceutical Sciences, Kumamoto University,Oe- honrnachi, Kumamoto 862, JapanReactions of 6-arnino-5-nitrosouracil derivatives with the I ,I -dimethylhydrazones of a wide variety of aldehydesin dirnethylformamide led to the corresponding xanthine derivatives. Alkylation of 9-substituted 1 -methyl-xanthines with an excess of alkyl halide in dirnethylforrnamide in the presence of potassium carbonate gave thecorresponding 3.7-dialkyl-1 -methylxanthine, with elimination of the 9-substituent. Treatment of 6-amino-4-hydroxy-5-nitroso-2-phenylpyrimidines with aldehyde 1 ,I -dimethylhydrazones also gave the correspondingpurines.DIRECT syntheses of purines by condensation-cyclizationof 6-amino-5-nitrosopyrimidines with several carbonsources, such as alkylamines,l ben~ylideneaniline,~?~aromatic aldehyde^,^ quaternized Mannich bases: Vils-meier reagent^,^ and amide aceta1s,6 have been thesubject of recent investigations.We now report a newapproach to xanthines which is widely applicable andespecially convenient for the synthesis of 9-substitutedxanthines.'This route consists of treatment of 6-amino-5-nitroso-uracils with 1 ,l-dimethylhydrazones of a wide varietyof aldehydes. For example, heating 3-methyl-6-methyl-amino-5-nitrosouracil (IIa) under reflux with a slightexcess of benzaldehyde 1, l-dimethylhydrazone for 5 hin dimethylformarnide gave 1,9-dimethyl-S-phenyl-xanthine (IIId) in good yield.This reaction is equallyapplicable to other 6-alkylamino-3-methyl-5-nitroso-uracils (IIb-e) and to other aldehyde 1,l-dimethyl-hydrazones, giving the respective 8,9-disubstituted3-methylxanthines (111)-(VII) (see Table 1).When G-benzylamino- (IId) and B-phenethylamino-3-methyl-5-nitrosouracil (IIe) were used as the startingmaterials, significant amounts (10-25%) of the intra-molecular condensation products, 8-phenyl- (VIIIc) and8-benzyl-l-methylxanthine (VIIId), were obtained asby-products.The formation of 8-phenyltheophylline by treatmentof 6-amino-l,3-dimethyl-5-nitrosouracil (Ic) with benz-aldehyde in dimethylformamide has been r e p ~ r t e d . ~However, the reaction of the uracil (IIa) with benz-aldehyde in dimethylformarnide did not give the purine(IIId) ; the starting material was recovered.Reactionsof the 6-n-propylamino- (IIb) and 6-n-butylamino-uracil(IIc) with benzaldehyde in dimethylformamide did notgive the 9-n-propyl- (IVd) or 9-n-butyl-xanthine (Vd),but only the product of intramolecular condensation,8-ethyl- (VI IIa) or 8-n-propyl-l-methylxanthine (VIIIb) ,respectively (see later), Furthermore, the uracil (IIa)did not react with 1 ,l-dimethylhydrazine (which mightH. Goldner, G. Dietz, and E. Carstens, Annalen, 1966, 691,142.G. M. Timmis, J. Cooke. and R. G. W. Spickett, ' Ciba;Foundation Symposium on the Chemistry and Biology of Purines,Churchill, London, 1957, p. 139.E. C. Taylor and E. E. Garcia, J . Amer. Chem. SOL, 1964,86, 4721.E. C. Taylor and E.E. Garcia, J . Amer. Chem. SOC., 1964,86, 4720.be liberated from their hydrazones during reaction) ;starting material was recovered.From these facts, this new purine synthesis is bestrationalized in terms of initial nucleophilic attack of theelectron-rich a-carbon atom of the hydrazone on thenitroso-group of the pyrimidine to form a hydroxylamineintennediat e, followed by intramolecular cyclizat ioninvolving addition of the o-amino-substituent to the anilcarbon atom. Elimination of 1, l-dimethylhydrazineand deoxygenation of the resulting xanthine 7-oxide bythe 1 ,I-dimethylhydrazine (thermal deoxygenation isalso conceivable) would then yield the xanthine.Treatment of 6-amino- (Ia), 6-amino-l-methyl- (Ib),and 6-amino-l,3-dimethyl-5-nitrosouracil (Ic) with alde-hyde 1, l-dimethylhydrazones under the same conditionsgave, as expected, the corresponding 8-substitutedxanthine derivatives (Table 1).The xanthine deriva-tives (IX), (X), and (XIIIa) thus obtained were allmethylated with an excess of methyl iodide in dimethyl-formamide in the presence of potassium carbonate togive 8-phenylcaff eine (XI).Alkylation of the 9-substituted 1-methylxanthineswith an excess of alkyl halide in dimethylformamide gavethe corresponding 3,7-dialkyl- 1 -meth ylxant hines, withelimination of the 9-substituent. For example, treat-ment of the xanthines (IIId), (IVd), and (VIId) with anexcess of methyl iodide in dimethylformamide in thepresence (or in the absence) of potassium carbonate ineach case gave 8-phenylcaffeine (XI).Treatment of(IIId) with an excess of ethyl iodide in dimethyl-formamide in the presence of potassium carbonate gave3,7-diethyl-l-methyl-8-phenylxanthine (XII) in highyield.A possible mechanism for 9-dealkylation presumablyinvolves initial full alkylation of the 9-alkyl-l-methylxanthine. It is possible that quaternization of theimidazole ring then takes place with simultaneous lossof the 9-alkyl group to give the thermodynamically morest able 7-alkylxant hine.(a) F. Yoneda, T. Matsumura, and K. Senga, J.C.S. Chem.Comm., 1972, 606; (b) F. Yoneda, M. Higuchi, T. Matsumura,and K. Senga, Bull. Chem. SOC. Japan, 1973, 46, 1836; (c)F. Yoneda and M. Higuchi, Chem. and Pharm. Bull. (Japan),1974, 22, 1658.F.Yoneda, M. Higuchi, and A. Hayakawa, Synthesis, 1975,264.7 Preliminary report, F. Yoneda, K. Ogiwara, M. Kanahori,and S. Nishigaki, Chem. Conzm., 1970, 10681548 J.C.S. Perkin IThe scope of the new purine synthesis has beenextended by the following reactions. Treatment of[ I J a; R': R2: R3-Hb; R ' =R3: H, R2: Mec; R ' =R2= Me, R3: H(Illa; R' :R3= Me,R2: Hb; R':MeJR2: ti, R3=Prnc; 'R' - Me, R2: H , R 3 = Bund; R': Me,R2-H ,R3:CH2Phe; R ' = Me,R2= H,R3=[CH2I2 Ph.IN$.=. AN NHR3RzM e N y L RZILUIa; R':Me, R2:HAN' If?'b; R': R2: Mec; R': Me, R2- Pr"d; R': Me, R2- Phe; R' : Me , R2- 4 - c I C 6 t - f ~f ; R': Me, R2: 4 - Me00 C ~ H LO H9; R'=Me, R2= 3,4 -1CH,O2)C6H3(El a; R'=Pr",R2:Hb; R ' : Pr", R2=MeC; R1:R2: Prnd; R':Prn,R2=Phe; R':Pr",R2;4-C(C6HLf ; R' : Pr" RZ= 4 - Me0.C6H~9; R'=prn, R2:3,4-(CH20~)C6H3(P 1 a; RI = BU", R~:Hb; R' = BunJ R2:Mec; R ' = Bun, R2=Prne; R': BunJ R2=4 -CIC~HLf ; R'= Bun, R': 4 -MeO.C,jHc9; R': BunJ R2:?,4 - (CH,O,)C6H3b; R'-CH2PhJR2: Mec; R':CH2Ph,R2: Pr"d; R': CH2Ph,R2: Phe ; R ' = CH2Ph,R2=4-ClC6HLf ; R': C H2 Ph,R2= 4 - MeO- C6H4gJ R' : C H, Ph,R2= 3,L- ( C H ~ O ~ ) C S H ~d; R ' z Bu", R2: Ph(PI) a; R': CH,Ph ,R2: HIPIIJa; R': [CH2I2 Ph, R2=Hb; R' : [CH, 3, P h, R2= MeC ; R': [CH2I2 Ph, R2= Prnd ; R': [CH2I2 Ph, R2=Phe; R ' = [C!i2I2 Ph, R2:4-CIC6HLf ; R': [CH212 Ph, R2=4-MeO* C6H49; R': [CH,], Ph, R 2 : 3 , 4 - !CH202)C6H,6-amino-4-hydroxy-5-nitroso-2-phenylpyrimidine (XIV)with benzaldehyde 1, l-dimethylhydrazone in dimethyl-formamide gave 6-hydroxy-2,8-diphenylpurine (XVI) .*Similarly, treatment of 4-hydroxy-6-methylamino-5-nitroso-2-phenylpyrimidine (XV) with 1,l-dimethyl-F. Yoneda, M.Higuchi, and T. Nagamatsu, J . Amev. Chem.SOC., 1974, 96, 5607.hydrazones of benzaldehyde and p-chlorobenzaldehydegave the corresponding 8-substituted 6-hydroxy-9-methyl-2-plienylpurines (XVIIa and b) .CEDI) a ;R :Etb ; R =Prnc ; R :Phd ; R :CH,PhR21lX) R':R2=R3:HJRL:Ph1x1 R'=R3- H,R2:MeJ RL=Ph(XI1 R'=R2= R 3 - Me, RL:Phl x i l l R':MeJR2r.R3=Et,RL:Ph(XULal R':R?: Me,R3: H,RL:PhCXm b 1 R' :R2: Me , R3= H , R L : 4 - C l C c H LCXIlc 1 R' :Rz = Me, R3= H, RL: 3 ,L-C12CcH3( X m d 1 R' =R2: MeJR3=H, RL: 4 - MeQCsHLThese products were sometimes accompanied by smallamounts of intramolecular condensation products, asdescribed above.Some of the latter were synthesizedfor identification purposes. Refluxing the uracils (IIb,0Q0 O-H0 O-HR 31976 1549c, and e) in dimethylformamide for 4 h gave %ethyl-(VIIIa), 8-n-propyl- (VIIIb), and 8-benzyl-l-methyl-xanthine (VIIId), respectively.The structures of the purines obtained were estab-lished by elemental analyses and mo€ecular weightdeterminations (by mass spectrometry), and confirmedby n.m.r. spectra [available as Supplementary Public-ation No. SUP 21769 (3 pp.)].?EXPERIMENTALM.p.s were determined with a Yanagimoto micro-material (8 g, 0.044 mol) was dissolved in acetic acid(150 ml) and saturated aqueous sodium nitrite (4.4 g,0.064 mol) was added drop by drop with cooling at 10 O C .The crystals were collected, washed with water and re-crystallized from ethanol to give the nitroso-derivative its apale orange powder (86%), m.p.242' (Found: C, 45.35;H, 5.75; N, 26.55. C,H,,N,O, requires C, 45.3; H, 5.7;N, 26.4%).Similarly, 6-chloro-3-methyluracil and phenethylaminegave 3-methyl-6-$henethylaminoztraciZ (87 %) , m.p. 238'(Found: C, 63.45; H, 6.3; N, 17.05. C13Hl,N30, requiresC, 63.65; H, 6.15; N, 17.2%), which was nitrosated toN.m.r. spectra were determined with a JEOL give 3-methyl-5-nitroso-6-phenethyZa?ninouraciZ (IIe), paleXanthine derivatives* - - Recrvst. Found (yo) Required (%)M.p. ("C)352340340375362 360356285315231335363319335257282202295370332330325337293356287288296242241229331357326304 360 360 360 360 360 360Yield (%)5147547176686726404243465450284036404553472122313734283130333631353639656361586670' C45.749.6554.161.0553.7558.6555.951.9554.257.763.556.560.9558.654.055.957.164.357.762.359.560.8562.264.468.6562.166.163.662.263.3565.569.263.267.064.357.7559.653.748.358.6H4.45.36.354.63.64.94.15.96.357.35.554.75.74.96.46.758.26.35.155.955.44.65.36.24.84.155.14.45.35.46.255.054.45.14.73.44.23.73.154.85" Formula15.5 C7H8N40228.7 C8H10N40225.0 C10H14N40219.35 C1,H11CLN40219.3 C14H14N40321.85 C13H12N40218.35 Cl4HI2N4O426.75 C,H12N40225.05 C1,H14N40222.2 C12H18N40219.55 C15H16N4O217.7 C15H15C1N40217.8 C16H18N40317.2 C16H16N40423.6 c11H16N40222.0 C13H20N40218.8 C16H18N40216.8 C16H17C1N40217.0 C17H20N40316.2 C17H18N40426.35 Cl,H14N40221.65 Cl3H1,N4O220.85 C14H14N40218.65 C1,H1,N40216.6 C19H16N40215.0 C1SH15C1N40215.4 C20H18N40320.8 C14H14N40214.85 C20Hl,N40419.85 Cl,Hl,N40217.85 C17H2,N,0216.35 C2,H18N40214.95 C2,H,,ClN4O214.6 C21H20N40314.5 C21H18N40424.4 C11H8N40223.4 C1!ZH10N402C13H1ZN40219.1 C13H11C1N40217.05 C,,H1,C1,N40,19.35 C14H14N403C45.6549.554.0560.9553.758.7556.051.954.0557.663.3556.561.1558.5554.0555.957.164.457.7562.259.6560.9562.264.468.6562.266.363.862.263.3565.3569.3563.0567.064.657.959.560.9553.748.058.75H4.45.26.354.73.84.954.055.86.357.255.654.755.754.96.356.858.06.15.156.155.34.75.26.14.854.15.04.35.25.656.455.254.55.354.653.554.154.73.53.14.95N15.2528.8525.221.8519.2519.5518.6526.925.222.419.717.617.8517.0525.223.722.218.7516.8517.0516.3521.8520.7518.7516.8515.315.4514.920.7519.717.9516.214.714.914.3524.5523.1521.8519.2517.2519.55solveit *DMF-EtOHDMF-EtOHDMFDMFDMFDMFDMFEtOHEtOHEtOHDMFDMFDMFDMFEtOHEtOHE t O HDMFDMFDMFDMFEtOHEtOHDMFDMFDMFDMFDMFEtOHEtOHEtOHDMFDMFDMFDMFDMFDMFDMFDMFDMFDMFW. Pfleiderer and G.Nubel, Annalen, 1961, 647, 155. b Ref. 3.* DMF = dimethylformamide.JNM 3H-60 spectrometer, with tetramethylsilane asinternal standard.3-Methyl-5-nitroso-6-n-~ro~ylaminourac~Z (IIb) .-A mix-ture of 6-chloro-3-methyluracil (15 g, 0.09 mol) and n-propylamine (11 g, 0.185 mol) in n-butyl alcohol (100 ml)was refluxed for 4 h. After cooling, the crystalline materialwas collected, washed with water, and recrystallized fromethanol to give needles of 3-methyl-6-n-propylaminouraciZ(73%), m.p.243' (Found: C, 52.3; H, 7.3; N, 22.75.C,H,,N,O, requires C, 52.45; H, 7.15; N, 22.95%). Thist For details of Supplementary Publications, see Notice toAuthors No. 7 in J.C.S. Pevkin I , 1975, Index issue.violet crystals (goyo), m.p. 225' (Found: C, 56.8; H, 5.25;N, 20.2. Cl,Hl,N40, requires C, 56.95; H, 5.15; N,20.45%).General Pyocedure.-A mixture of a 6-amino-5-nitrosouracil (0.005 mol), analdehyde (0.007 mol), and 1, l-dimethylhydrazine (0.007mol) in dimethylformamide (30 ml) was refluxed for 5-7 h.The solution was evaporated under reduced pressure andthe residue was diluted with ethanol and set aside overnightor for several days. The $yoduct which separated wasfiltered off, washed with a small amount of ethanol, andrecrystallized (Table 1).Xanthine Derivatives (111)-(VII) 1550I n the preparations of 8-unsubstituted or %methylderivatives, an excess of 37 % formaldehyde or acetaldehyde(0.015 mol) and 1, l-dimethylhydrazine (0.015 mol) wereused.8-Phenylcaffeine (XI).-Method A .A mixture of 3-methyl-8-phenylxanthine (X) (0.5 g, 0.002 mol), methyliodide (2.8 g, 0.02 mol), and potassium carbonate (0.5 g) indimethylformamide (20 ml) was refluxed for 2 h. Thesolution was evaporated t o dryness and the residue wasdiluted with water to precipitate crystals (65%), m.p. 185"(from ethanol), M+ 270 (Found: C, 62.4; H, 5.25; N,20.6. C1.&14N402 requires C, 62.2; H, 5.2; N, 20.75%).A mixture of l-methyl-9-n-propyl-8-phenyl-xanthine (IVd) (0.25 g, 0.0009 mol), methyl iodide (1.24 g,0.009 mol), and potassium carbonate (0.5 g) in dimethyl-formamide (20 ml) was refluxed for 2 h, then evaporatedunder reduced pressure to dryness.The residue wasdiluted with water t o precipitate crystals (7 1 yo).3,7-Diethyl-l-methy1-8-phenylxanth~ne (XII) .-A mixtureof the purine (IIId) (0.4 g, 0.0016 mol), ethyl iodide (1 g,0.0064 mol), and potassium carbonate (1 g) in dimethyl-formamide (30 ml) was treated as above to give needles(68%), m.p. 150", M+ 298 (Found: C, 64.35; H, 6.2; N,18.85.8-Ethyl-l-methylxanthine (VIIIa) .-A solution of 3-methyl-5-nitroso-6-n-propylaminouraci1 (IIb) (0.7 g, 0.0033mol) in dimethylformamide (20 ml) was refluxed for 6 h.After cooling, the crystals were filtered off, washed withethanol, and recrystallized from dimethylformamide ; yield71%; m.p.370°; M+ 194 (Found: C, 49.2; H, 5.2;N 29.0. C,Hl,N402 requires C, 49.5; H, 5.2; N, 28.85%).Similarly, compound (IIc) gave l-methyl-8-n-pro~yl-xanthine (VIIIb) (70%), m.p. 362", M+ 208 (Found: C51.75; H, 5.8; N, 26.65. C,Hl,N402 requires C, 51.9;H, 5.8; N, 26.9%). Compound (IIe) gave 8-benzyl-l-methylxanthine (VIIId) (85y0), m.p. 374", M+ 256 (Found:C 60.95; H, 4.75; N, 21.95. C,,H12N402 requires C,60.95; H, 4.7; N, 21.85%).4-Hydroxy- 6-methyZamino-5-nitvoso-2-pheny Zpyrinzidine(XV) .-To a mixture of concentrated hydrochloric acid(30 ml) and n-butyl alcohol (50 ml) was added 4,6-dichloro-2-phenylpyrimidine (5.8 g, 0.026 mol), and the mixture wasrefluxed for 3 h.After cooling, the crystals were filteredoff, washed with water, and dried. Recrystallization fromMethod B.Cl,H,,N402 requires C, 64.4; H, 6.1; N, 18.8%).J.C.S. Perkin Iethanol gave needles of 6-chloro-4-hydroxy-2-phenyl-pyrimidine @ ( s a x ) , m.p. 226' (Found: C, 57.9; H, 3.4;N, 13.4. Calc. for Cl,H7C1N20: C, 58.1; H, 3.4; N,13.56%).This material (3.77 g, 0.018 mol) and 40% aqueousmethylamine (20 ml) were heated in an autoclave at 150 "Cfor 5 h. The mixture was evaporated to dryness and theresidue was crushed in hot water to give crystals. Re-crystallization from ethanol gave 4-hydvoxy-6-methylamino-2-fihenylpyrimidine (73%), m.p. 270" (Found: C, 65.55;H, 5.4; N, 20.9. Cl1HllN30 requires C, 65.65; H, 5.5;N, 20.9%).A mixture of the 6-methylaminopyrimidine (2.3 g, 0.01mol) and sodium nitrite (1.6 g, 0.02 mol) in water (20 ml)was heated at 95 "C for 10 min with stirring.The mixturewas then acidified with acetic acid and the green crystalswhich separated were filtered off, washed with water, andrecrystallized from ethanol to give a pale green powder(XV) (95.5y0), m.p. 253" (Found: C, 67.45; H, 4.6; N,24.2. Cl1H,,N4O2 requires C, 57.4; H, 4.4; N, 24.35%).9-Methyl-2, 8-diphenyl-6-hydroxypurine (XVIIa) .-A mix-ture of the 5-nitrosopyrimidine (XV) (1 g, 0.0044 mol),benzaldehyde (0.64 g, 0.006 mol), and 1, l-dimethyl-hydrazine (0.45 g, 0.0075 mol) in dimethylformamide (30 ml)was refluxed for 8 h. The solution was evaporated t odryness and the residue was diluted with ethanol. Thecrystals which separated were filtered off and recrystallizedfrom dimethylformamide-ethanol; yield 29% ; m.p. 240"(decomp.); M+ 302 (Found: C, 71.4; H, 4.8; N, 18.4.C,,H14N,0 requires C, 71.5; H, 4.65; N, 18.55%).6-Hydroxy-2,8-diphenyZpurine (XVI) was prepared simi-larly from 6-amino-5-nitroso-2-phenylpyrimidine and benz-aldehyde 1, l-dimethylhydrazone. Recrystallization fromdimethylformamide-ethanol gave prisms (asyo), m.p.360", M+ 288 (Found: C, 70.55; H, 4.3; hT, 19.55.C17H1,N,0 requires C. 70.8; H 4.2; N, 19.45%).(XVIIb) was prepared as above and recrystallized fromdimethylformamide; yield 35% ; m.p. 320"; M+ 336(Found: C, 64.35; H, 3.75; N, 16.7. C1,H,,ClNO,requiresC, 64.2; H, 3.9; H, 16.650/,).8- (4-ChZorophenyl)-6-~ydroxy-9-~~etPlyZ-2-phe~~ylpurine[6/077 Received, 12th January, 19761Q H. C . Carrington, F. H. S. Curd, and D. N. Richardson,J . Chem. SOL, 1955, 1858