Purines, pyrimidines, and imidazoles. Part 61. Reaction of 6-alkylamino-4-chloro-5-nitropyrimidines with diethyl malonate, ethyl cyanoacetate, and ethyl acetoacetate and some derived pyrrolo3,2-dpyrimidines related to the cytokinins

摘要

J. CHEM. SOC. PERKIN TRANS. I 1985 Purines, Pyrimidines, and Imidazoles. Part 61.IReaction of 6-Alkylamino-4-chloro-5-nitropyrimidines with Diethyl Malonate, Ethyl Cyanoacetate, and Ethyl Acetoacetate and some derived Pyrrolo3,2-dpyrimidines related to the Cytoki ni ns Stephen Gregson and Gordon Shaw School of Chemistry, University of Bradford, Bradford, West Yorkshire, BD7 1DP Reaction of 4-chloro-6-methylamino-5-nitropyrimidine (3d) with diethyl malonate and sodium hydroxide afforded diethyl 6-methylamino-5-nitropyrimidin-4-ylmalonate which was reduced to diethyl 5-amino-6-methylaminopyrimidin-4-ylmalonate and this, with sodium carbonate, produced ethyl 6,7-dihydro-4-methylamino-6-oxo-5H-pyrrolo3,2-dpyrimidine-7-carboxylate. Ethyl cyano- acetate and ethyl acetoacetate with (3d) and alkali similarly afforded ethyl 6-methylamino-5-nitro- pyrimidin-4-ylcyano (or aceto) acetate respectively.The latter compound when reduced afforded ethyl 5-amino-6-methylaminopyrimidin-4-ylacetate (48) which was also obtained by treatment of ethyl a-(6-met hylami no- 5-nitropyrimidi n -4-yl) acetoacetate wit h aqueous ammonia to give ethyl 6-methyl-amino-5-nitropyrimidin-4-ylacetate, followed by subsequent hydrogenation of this compound.Cyclisationof (48) with phosphoryl trichloride and dimethylformamide gave, after hydrolysis, 4-methyl- amino-5H-pyrrolo3,2-dpyrimidine-7-carboxylic acid (2g). 4-(trans)-4-t-Butoxy-3-methylbut-2-enylamino)-6-chloro-5-nitropyrimidine in a similar sequence of reactions gave the cytokinin analogue 4-(4-hydroxy-3-methylbutylamino) -5H-pyrrolo3,2-d pyrimidine-7-carboxylic acid (Zj).The cytokinins are a group of substances which stimulate cell division in plant tissues. They are largely 6-alkylaminopurines (1) and include several naturally occurring substances such as trans-zeatin ( dihydrozeatin (Ib),' and the related iso- pentenyl derivative (lc) which also occur as 9-P-~-ribofurano- sides such as zeatin riboside In addition, several simple 6-alkylaminopurines have marked cytokinin activity 'including 6-benzylamino-, 6-furfurylamino-, and 6-pentylamino-purines. As part of a programme designed to prepare compounds structurally related to the cytokinins with potential as anti- cytokinins we have been especially interested to synthesise specific pyrrolo3,2-~fJpyrimidines (2), which are 9-deaza derivatives of the cytokinins, by a method which would ultimately permit the synthesis of 7-substituted t glycosides (2a) which are isosteres of the naturally occurring cytokinin 9- substituted nucleosides.Recently, syntheses of the inosine,' adeno~ine,~and guanosine lo analogues of compounds (2) have been recorded from pyrrole intermediates. An early route to the pyrrolo3,2-dlpyrimidine structure involved the condensation of various 2,6-substituted 4-chloro- 5-nitropyrimidines with diethyl malonate in the presence of sodium hydroxide followed by reduction of the resulting pyrimidinylmalonate to the corresponding aminopyrimidines (4), R3= alkyl, R2 = CH(C0,Et)J and cyclisation of these to pyrrolo3,2-dlpyrimidines.However, the compound we wished to use, namely 4,6-dichloro-S-nitropyrimidine(3a) with a free 2-position, was found l2 to behave anomalously with diethyl malonate and produced the 2-substituted pyrimidine (4a) in which the nitro group is reduced during the reaction. Similar reactions occurred with anions derived from ethyl acetoacetate and acetylacetone. The problem has been over- come in one example l3 by reaction of the dichloro derivative (3a) with ketene diethyl acetal to afford the 2,2-diethoxyvinyl derivative (3b)which, after hydrolysis, gave the ester (3c)which, after amination and reduction, produced the diaminopyrimidine (4b) which was in turn cyclised with phosphoryl trichloride in dimethylformamide (DMF) to the pyrrolo3,2-4jpyrimidines (2b) or (2c).f Pyrrolo3,2-dpyrimidine systematic numbering. I R' (1 1 a; R'= H,R2= trans -CH2CH=CMe.CH20H b; R'= H, R2= CH2CH2CHMe.CH20H c; R'= H, R2= CH2CH= CMe2 d; R1= P-0-ribofuranosyl, RZ = trans-CH2CH=CMe.CH20H R3g:'4 R' (2) a; R' = glycosyl, R2= trans-CH2CH=CMe.CH20H, R3= H b; R' = C02Et R2 = R3= H C; R' = RZ= H, ~3=OH d; R'= C02Et, R2= Me, R3=OH e; R'= H, R2= Me, R3= OH f; R'= C02Et, R2= Me, R3= H g; R'= C02H, R2= Me, R3= H h; R' = C02Et, R2 = CH2C6H,0Me--p, R3= H i; R'= C02Et, R2= CH2CH2CH(Me)CH2OCMe,,R3=H j; R' = CO,H , R2 = CH,CH,CH(Me) CH20H, R3 = H This route does not offer an obvious opportunity to introduce a glycosyl unit so we have re-examined the earlier route in the hope of introducing a malonate or similar residue into the desired 6-position which would ultimately permit C- 188 J. CHEM.SOC. PERKIN TRANS. I 1985 Rrsquo; (3) a; Rrsquo; = R~=CI b; Rrsquo; = CI, R2 = CH =C(OEt)2 C; Rrsquo; = CI, R2 = CH2COzEt d; Rrsquo; = NHMe, R2= CI e; Rrsquo; = NHMe, R2= CH(CO;Et)2 f; Rrsquo; = NHMe, R2= CH(CN)C02Et 9; Rrsquo;= NHMe, R2= CH (COMe)C02Et h; R1= NHMe, R2= CH2C02Et i; Rrsquo; = NHCH,Ph, R2= CH2C02Et j; Rrsquo;= NHCH2C6H40Me-p, R2= CH,CO,Et k; Rrsquo; = trflns-NHCH 2CH=CMe -CH20CMe3, R2= CI I; Rrsquo;= bans -NHCH2CH=CMe .CH20CMe,, R2 CH(COMe)CO,Et m;R1= trans -NHCH2CH=CMe .CH,OCMe,, RL= CH,CO,Et Rrsquo; (4) a; Rrsquo; = R2 = CI, R3 = CH(C02Et 12 b; Rrsquo; = NH2, R2 = CHZCOzEt, R3= H C; Rrsquo; = NHMe, R2=CH(C02Et)2, R3=H d; Rrsquo; = NHMe, R2=CH(CN)C02Et, R3= H eiRrsquo; = NHMe, R2= CH2C02Et, R3= H f;Rrsquo;= NHCH2C6HL0Me--p, R2= CH2C02Et, R3 = H.-9;Rrsquo; = NHCH2CH2CH(Me)CH20CMe3,RL=CH2C02Et,RJ=H glycosylation to be attained on the malonate residue at this position. It should be possible to modify the anomalous reaction of (3a) with the diethyl malonate anion described earlier,I2 and to diminish the potential positive charge at the 2-position of (3a) by replacing one of the chlorine atoms by an alkylamino group of the type required in the final cytokinin analogue. Accord- ingly, in preliminary experiments we have explored the reaction of 4-chloro-6-methylamino-5-nitropyrimidine(3d),14 prepared from the dichloropyrimidine (3a) and methylammonium acetate, with diethyl malonate in acetone and aqueous sodium hydroxide at room temperature when replacement of the chlorine by a malonate residue readily occurred and an excellent yield of the required crystalline malonate derivative (3e)was obtained. Similar reactions of (3d)with anions derived from ethyl cyanoacetate and ethyl acetoacetate gave good yields of the corresponding derivatives (30 and (3g) respectively.Hydrogenation of the malonate (3e) and cyanoacetate (31) derivatives in ethanol solution with a palladium catalyst gave the corresponding aminopyrimidines (4c) and (4)respectively,whereas in contrast the keto ester (3g) gave the pyrimidinyl- acetate derivative (k),the weakly basic solution produced during the hydrogenation clearly being sufficient to cause fission of the acetyl group.The same compound was also pre- pared by treatment of the nitro keto ester (3g)with aqueous ammonia, when acyl fission readily occurred to produce the nitro ester (3h) which, after hydrogenation, then gave the ester (amp;). This is an especially useful route to this last type of compound. Similar compounds prepared by the same route in- clude the benzylamino (3i) and p-methoxybenzylamino (3j) nitropyrimidines and hydrogenation of the latter produced the diaminopyrimidine derivative (40. When the malonate derivative (4c) was heated with aqueous sodium carbonate the pyrrolo3,2-dpyrimidinone (2d) was readily obtained and converted by hot hydrochloric acid into the decarboxylated derivative (2e) which could also be pro-duced directly from the ester (amp;) and 6~-hydrochloric acid.Alternatively, cyclisation of the pyrimidinyl ester (4e) with phosphoryl trichloride in DMF gave the pyrrolo3,2-d-pyrimidine (20 which, with acid, produced the carboxylic acid (2g). The related pyrrolo3,2-dlpyrimidine (2h) was prepared in a similar fashion. H,NCH, CH3 bsol; /c=c Hrsquo; lsquo;CH,0CMe3 (5) Reaction of the dichloronitropyrimidine (3a) with trans-4-amino-l-t-butoxy-2-methylbut-2-ene(5) at 0 ldquo;Cduring 30 min gave the pyrimidine (3k)which smoothly reacted with ethyl acetoacetate in acetone and aqueous sodium hydroxide to produce the ester (31). This was treated immediately with aqueous ammonia to give the ester (3m)which, with palladium catalyst and hydrogen, afforded the aminopyrimidine (4g) in high (74) yield.This readily cyclised with phosphoryl trichloride and DMF to give the pyrrolo3,2-d-jpyrimidine (2i) which, with acid, produced the deblocked carboxylic acid (2j). Experimental Evaporations were carried out with a Buchi rotary evaporator, under water-pump vacuum with a flask temperature 40 ldquo;C. U.V.Absorption spectra were measured with a Unicam SP 800 spectrophotometer, lsquo;H n.m.r. spectra with a JOEL-MH-100 spectrometer (tetramethylsilane as internal standard), and mass spectra with an A.E.I. MS 902 spectrometer. Silica gel (0.05-0.20 mm; 325-370 mesh; Machery Nagel and Co.)was used for column chromatography and silica gel 6OF,,, 0.25 mm precoated glass plates (Merck) were used for t.1.c.with (A) chloroform-methanol (9: l), (B) toluene-ethyl acetate (7:3), (C) ethyl acetate-n-propyl alcohol-water (7:2: l), (D) toluene- ethyl acetate (9: l), or (E) chloroform-methanol (3: 1) as development systems. Light petroleum refers to the fraction boiling in the range 4@-60 ldquo;C. Reaction of 4-Chloro-6-methylamino-5-nitropyrimidine(M) with Diethyl Malonate, Ethyl Cyanoacetate, and Ethyl Aceto- acetate and Hydrogenation of the Products.-The ester (3.9 mmol) was added to a solution of 4-chloro-6-methylamino-5-nitropyrimidine (0.5 g, 2.6 mmol) in acetone (25 ml) at 0deg;C; 1 1M-sodium hydroxide (0.8 ml) was then added dropwise to the stirred mixture during 20 min and the colour of the mixture changed from yellow to red.It was set aside at room temperature for 30 min. (a) Diethyi malonate and ethyl acetoacetate. Water (50ml) and acetic acid (to pH 8) were added and the resultant solution was extracted with ether. The combined extracts were dried (anhyd. Na,S04) and evaporated to dryness. The residue was evaporated several times with toluene to produce a yellow solid. (b) Ethyl cyanoacetate. Water (20ml) was added and the solution was extracted with ether (3 x 50ml). The extracts were discarded. The aqueous phase, on treatment with acetic acid, gave a solid yellow precipitate. Thus prepared were: diethyl6-methylamino-5-nitropyrimidin-4-ylmalonate(3e) (0.58g) from J. CHEM. SOC. PERKIN TRANS. I 1985 method (a) which crystallised from light petroleum (b.p.40- 60"C) as needles, m.p. 78 "C (Found: C, 46.3; H, 5.0; N, 17.7; M+,312. ClzH16N406 requires C, 46.5; H, 5.16; N, 17.94; M, 312); m/z 266 (A4-NO,); ethyl a-cyano-a-(6-methylamino-5-nitropyrimidin-4-yoacetate(39 (0.54 g) from method (b) which crystallised from methanol as needles, m.p. 216 "C (Found: C, 45.7; H, 4.3; N, 26.0; M+, 265. CloHllN,04 re- quires C, 45.3; H, 4.2; N, 26.4; M, 265); and ethyl a-(6- methylamino-5-nitropyrimidin-4-y~acetoacetate(3g) (0.48 g) from method (a) which crystallised from toluene as needles, m.p. 146deg;C (Found: C, 46.75; H, 4.95; N, 19.95; M+, 282. C,,Hl4N4O5 requires C, 46.8; H, 5.0; N, 19.85; M, 282). Solutions of (3)(0.5 g), (39 (0.5 g), and (3g) (0.05 g) in ethanol (15, 200, and 50 ml respectively) with 10 palladium-carbon (0.025, 0.1, and 0.025 g respectively) were shaken in hydrogen for 8 h after which time the reaction was complete 2 h in the case of (3g)l.The mixtures were filtered through Celite and the filtrates were evaporated to dryness and the residues triturated with ether to produce solids. Thus prepared were diethyl 5-amino- 6-me t hy lam inopy r im idin-4- ylmalona te (4c) (0.38 g) which crystallised from toluene as needles, m.p. 162 "C (Found: C, 51.5; H, 6.5; N, 19.7; M+,282. Cl2Hl8N4O4 requires C, 51.05; H, 6.43; N, 19.85; M, 282); ethyl a-cyano-a-(5-amino-6- met hy lam inopy r im idin-4-yoace ta te hem ihy dra te (4)(0.3 g) which crystallised from water as prisms, m.p. 253 "C (Found: C, 49.4 H, 5.5; N, 28.3; M+, 235.CloH,3N502~~H20 requires C, 49.2; H, 5.75; N, 28.7; M, 235); v,,,. 2 180 cm-' (CN); and ethyl 5-amino-6-methylaminopyrimidin-4-ylacetate(4e) (0.033 g) which crystallised from benzene as prisms, m.p. 172 "C (Found: C, 51.4; H, 6.7; N, 26.2; M+, 210. C9H14N402 requires C, 5 1.42; H, 6.71; N, 26.65; M, 210). The latter compound (0.1 g) in 98 formic acid (5 ml) was heated on a steam-bath for 45 min after which time starting material had been replaced by a product (RF0.52, System E). The solution was evaporated to afford a gum which was purified by silica gel chromatography with chloroform-methanol (3:1) as eluant. Fractions corres- ponding to the product were combined and evaporated to leave a solid.Ethyl 5-formamido-6-methylaminopyrimidin-4-ylacetate (0.06 g) crystallised from benzene as needles, m.p. 153 "C (Found: C, 50.25; H, 5.8; N, 23.6; M+, 238. CloH14N403 requires C, 50.4; H, 5.9; N, 23.5; M,238). Ethyl 6-Methylamino-5-nitropyrimidin-4-ylacetate(3h).-A suspension of ethyl a-(6-methylamino-5-nitropyrimidin-4-y1)-acetoacetate (3g) (3.5 g) in 2~-ammonium hydroxide (75 ml) was shaken at room temperature for 5 h. The resulting solid precipitate was collected, washed with water, and dried. The pyrimidine (3h) (3.07 g) crystallised from toluene as needles, m.p. 152 "C (Found: C, 45.5; H, 5.2; N, 23.2; M+,240. C9H12N404 requires C, 45.0; H, 5.05;N, 23.35; M, 240); v,,,. 1 740 cm-' (CO); G(CDC1,) 1.32 (3 H, t, CH,CH,), 3.3 (3 H, d, CH,N), 4.23 (2 H, m, CH,CH,), 4.35 (2 H, s, CH,CO), and 8.2 (1 H, s, 2-H). Catalytic hydrogenation of compound (3h) (0.2 g) with palladium-carbon was complete in 4 h and gave ethyl 5-amino- 6-methylaminopyrimidin-4-ylacetate(4e) (0.12 g), m.p.172 "C, identical i.r., t.1.c. (System A), and mass spectral analysis with the sample prepared above. Similarly prepared were ethyl 6- benzylamino-5-nitropyrimidin-4-yZacetate(3i) (64 yield) which crystallised from aqueous ethanol as needles, m.p. 114 "C (Found: C, 57.5; H, 5.1; N, 18.0; M+, 316. Cl,H,,N4O4 re-quires C, 57.0; H, 5.1; N, 17.7; M, 316); and ethyl 6-(p- methoxybenzylamino)-5-nitropyrimidin-4-yZacetate(3j) (52 yield) which crystallised from aqueous ethanol as needles, m.p.130 "c (Found: c,55.8; H, 5.5; N, 16.0;M+,346. Cl6HI8N4o5 requires C, 55.5; H, 5.25; N, 16.2; M, 346). The latter com- pound after hydrogenation gave ethyl 5-amino-6-(p-methoxy- benzylamino)pyrimidin-4-ylacetate(49 (83 yield) which cry- stallised from benzene as prisms, m.p. 132 "C (Found: C, 60.7; H, 6.4; N, 17.7; M+,316. C16H20N403 requires C, 60.74; H, 6.37; N, 17.71; M, 316); G(CDC1,) 1.3 (3 H, t, CH,CH,), 3.57 (3 H,s,OCH,),4.1(2 H,m,CHzCH,).4.55(2 H,s,CH,CO),7.4 (4 H, m, C6H4), and 8.2 (1 H, s, CH=N). With 90 formic acid at 100 "C for 30 min, compound (40 gave the Ngormyl derivative which crystallised from benzene as prisms, m.p. 115 "C (Found: C, 59.15; H, 5.8; N, 15.9; M+,344. Cl,H20N,04 requires C, 59.3; H, 5.8;N, 16.28; M, 344).Ethyl 6,7-Dihydro-4-methylamino-6-oxo-5H-pyrrolo3,2-d-pyrimidine-7-carboxylate (2d).-A suspension of diethyl 5-amino-6-methylaminopyrimidin-4-ylmalonate(4c) (0.05 g, 0.18 mmol) and anhydrous sodium carbonate (0.6 g, 0.56 mmol) in water (5 ml) was heated on a steam-bath until all the solid dissolved; the solution changed from colourless to orange- yellow in colour. Addition of acetic acid (to pH 7) precipitated a solid which was collected by filtration, washed with water, and dried. The pyrrolopyrimidine hydrate (2d) (0.038 g) crystallised from water as needles, m.p. 230 "C (Found: C, 47.2; H, 5.6; N, 21.5; M+,236. Cl,HlzN40,~H,0 requires C, 47.25; H, 5.55; N, 22.05; M, 236). 6,7- Dihydro-4-met hylamino-5H-pyrroloC 3,2-dpyrimidin-6- one (2e).-(a) A solution of ethyl 5-amino-6-methylamino- pyrimidin-4-ylacetate (4e) (0.02 g, 0.095 mmol) in 6whydro- chloric acid (2 ml) was heated on a steam-bath for 15 min then evaporated to dryness.The residue, on treatment with ether, precipitated a solid which was collected by filtration, washed with ether, and dried in uacuo.The pyrimidinone hydrochloride (2e)eHCl (0.01 g) had m.p. 280 "C and was homogeneous on t.1.c. (Found: C, 41.85; H, 4.7; N, 28.2; C1, 17.4; M', 164. C7H8N40-HCl requires C, 41.9; H, 4.53; N, 27.95; C1, 17.7; M, 164). (b) Ethyl 6,7-dihydro-4-methylamino-6-oxo-5H-pyrrolo3,2-dpyrimidine-7-carboxylate (2d) (0.1 g) and 6~-hydrochloric acid (10 ml) were heated together on a steam-bath for 1 h.The solution, on evaporation to dryness, gave the pyrimidinone hydrochloride (0.1 g), identical (i.r., m.p. and mixed m.p.) with the compound prepared under (a) above. 4- Me th ylam ino- 5H -py rr 0101 3,2 -dlpy r imidine- 7-carboxy lic Acid (2g).-Phosphoryl trichloride (0.7 ml, 7 mmol) was added to a stirred, ice-cold solution of ethyl 5-amino-6-methylamino- pyrimidin-4-ylacetate (4e) (0.3 g, 1.4 mmol) in anhydrous DMF (20 ml). The reaction mixture was set aside at room temperature overnight, when t.1.c. examination (System E) revealed the absence of starting material and the presence of a single pro- duct at RF0.51. The solution was evaporated to dryness and water (20 ml) was added. The aqueous solution was set aside at 4 "C for 3 h then extracted with ethyl acetate (3 x 20 ml).The extract was dried (anhyd. NazS04) and evaporated to give ethyl 6,7-dihydro-4-methylamino-5H-pyrrolo3,2-(11pyrim-idine-7-carboxylate hydrochloride (0.155 g) as a glass which was homogeneous on t.1.c. (Found: M+,220. CloH 1zN4Oz requires M, 220). A suspension of the foregoing ester (0.05 g, 0.23 mmol) in 6~- hydrochloric acid (2 ml) was heated on a steam-bath. T.1.c. examination (System E) revealed that after 30 min all the starting material had been replaced by a product (RF0.61). The mixture was heated with charcoal, filtered through Celite, and the filtrate was evaporated to afford a gum which, when triturated with ether, gave the carboxylic acid hydrochloride (2g)oHCl as a white solid (0.028 g) which was collected by filtration and dried in uacuo.It had m.p. 250 "C (Found: C, 41.95; H, 3.7; N, 24.0; cl, 15.2; M+, 192. C8H8N40z*HCl requires C, 42.0 H, 3.95; N, 24.54; C1, 15.55; M, 192). Similarly, ethyZ 4-(p-methoxybenzyfurnino)-5H-pyrrofo3,2-dlpyrimidine-7-carboxylatehydrochloride (2h)aHCl (60 yield) was obtained as a hard glass (Found: C, 56.1; H, 5.5; N, 15.2;C1, 9.9; M', 326, C1,Hl8N40,.HC1 requires C, 56.25; H, 5.3;N, 15.45;C1, 9.8; M, 326). 4-(trans)-4-t-Butoxy-3-methylbut-2-enylamino-6-chloro-5-nitropyrimidine (3k).-To an ice-cold solution of 4,6-dichloro-5- nitropyrimidine (313)(1 g, 5 mmol) in n-butyl alcohol (70ml) were added triethylamine (0.52 g, 5 mmol) and trans-4-amino-l-t-butoxy-2-methylbut-2-ene (0.8 g, 5 mmol) (from the phthaloyl derivative and hydrazine).The mixture was stirred at 0 "C and after 30 min the starting material (RF0.62) (System B)had been replaced by a product (RF0.55).The solution was evaporated to dryness and ice-cold water (50 ml) was added to the residue which was immediately extracted with ethyl acetate (3 x 50 ml) and the combined extracts dried (anhyd. Na,SO,), filtered, and evaporated to afford a red gum which was applied to a silica gel column and eluted with toluene-ethyl acetate (7:3). Evaporation of the combined major u.v.-absorbing fraction afforded the pyrimidine (3k) (1.2 g, 76) which crystallised from light petroleum as pale yellow plates, m.p. 52 "C (Found: C, 49.6; H, 6.1; N, 17.7; C1, 11.4; M', 314.C1,H1,C1N,O, requires C, 49.6; H, 6.1; N, 17.8; C1, 11.28; M, 314); m/z 241 (M -OC,H,); G(CDC1,) 1.2 (9 H, s, CMe,), 1.65 (3 H, s, CH,), 3.1-3.4 (2 H, m, CH,NH), 3.76 (2 H, s, CHlO), 5.5 (1 H, t, CHS), 8.2 (1 H, S, 2-H). Ethyl 6-(trans)-4-t-Butoxy-3-methylbut-2-enylamino)-5-nitropyr imidin-4-ylace ta te (3m).-E thyl acet oace ta te (0.22 g, 1.7 mmol) was added to an ice-cold solution of 4-(truns)-4-t-butoxy-3-methylbut-2-enylamino-6-chloro-5-nitrop yrimidine (0.2 g, 0.5 mmol) in freshly distilled acetone (10 ml). The temperature was maintained at 0 "C whilst 1 lM-sodium hydroxide (0.3 ml) was added dropwise during 20 min. The mixture was stirred for 30 min, then water (20 ml) and acetic acid (to pH 7) were added.The mixture was extracted with chloroform(3 x 50 ml) and the extracts dried (anhyd. Na,SO,) and evaporated to afford a gum which was applied to a silica-gel column and eluted with toluen-thy1 acetate (7 :3). Fractions corresponding to the acetoacetate product (31) (RF0.31; System B) were collected and evaporated and the residue was dissolved in 2~-aqueous ammonium hydroxide (10 ml), the solution was shaken at room temperature for 30 min, and the resulting yellow solid precipitate was collected. The pyrimidinylacetate hemihydrate (3m) (0.186 g, 85) crystallised from aqueous ethanol as needles, m.p. 108 "C (Found: C, 54.3; H, 7.0; N, 15.0; M', 366. C,,H,6N405~~H20requires C, 54.4; H, 7.2; N, 14.9; M, 366); G(CDC1,) 1.2 (9 H, s, CMe,), 1.3 (3 H, t, CH,CH,), 1.65 (3 H, s, CH,), 3.1-3.4 (2 H, m, CH,OBu'), 3.75 (2 H,s,CH,N),4.2(2 H,m,CH,CH,),4.35(2 H,s,CH,CO),5.6 (1 H, t, CH=C), and 8.2 (1 H, s, 2-H).E thy1 5-Amino-6-(4-t-butoxy-3-methylbuty1amino)pyrimidin-4-ylacetare (4g).-A solution of the foregoing nitropyrimidine (3m) (0.03 g, 0.08 mmol) in ethanol (30 ml) was shaken with palladium-carbon catalyst (10 Pd; 0.015 g) in an atmosphere of hydrogen for 3 h after which time the starting material (RF 0.8) had been replaced by a product (RF0.66;System C). The filtered solution was evaporated, the residue was dissolved in ethanol (10ml), and hydrogen chloride gas was passed into this solution for 1 min. After evaporation of the solvent to low volume, diethyl ether was added dropwise to give a white solid which was collected by filtration, washed with ether, and dried J.CHEM. SOC. PERKIN TRANS. I 1985 in uucuo. The pyrimidine hydrochloride (4g)oHCl (0.02 g) had m.p. 230 "C (Found: C, 54.3; H, 8.3;N, 14.7;C1,9.25;M', 338. C17H30N403-HClrequires C, 54.46; 8.35; N, 14.94; C1, 9.47; M, 338) S(CD,),SO 1.17 (9 H, s, CMe,), 1.22 (3 H, d, CH,), 1.4 (3 H, t, CH,CH,), 1.9-2.2 (3 H, m, CH,CH,CH), 3.45 (2 H, d, CH,OBu'), 3.9 (2 H, m, CH,N), 4.1 (2 H, m, CH,CH,), 4.3 (2 H, s, CH2CO), and 8.4 (1 H, s, 2-H). 4-(4-Hydroxy-3-methylbutylumino)-5H-pyrrolo3,2-dlpyrirn-idine-7-curboxylic Acid (2j).-Phosphoryl trichloride (0.5 ml, 5 mmol) was added slowly to a stirred, ice-cold solution of the foregoing pyrimidine hydrochloride (4g)HCl (0.35 g, 1 mmol) in anhydrous DMF (20 ml).The reaction mixture was set aside at room temperature overnight. The excess of solvent was evaporated off,water (10 ml) was added to the cooled, stirred residue, the mixture was extracted with ethyl acetate (3 x 20 ml), and the extracts were dried (anhyd. Na,SO,) and evaporated to afford a glass which was homogeneous on t.1.c. (System A); ethyl 4-(4-t-butoxy-3-methylbutylamino)-5H-pyrrolo 3,2-dJpyrimidine-7-carboxylate(2i) was obtained as a glass (0.16 g) (Found: M+, 348. C,8H28N40, requires M, 348); m/z 291 (M -CMe,). A suspension of the ester (2i)(0.2 g, 0.57 mmol) in 6~-hydrochloric acid (10 ml) was heated on a steam-bath for 4 h. After evaporation of the mixture to low volume under reduced pressure the resulting solid was collected by filtration, washed with water, and dried in uucuo.The pyrrolopyrimidine hydro- chloride (2j)HCl (0.13 g, 86) had m.p. 280 "C (Found: C, 47.95; H, 5.6; N, 18.8; C1, 11.75; M', 264. CI,H16N,O3-HC1 requires C, 47.9; H, 5.7; N, 18.65; Cl, 11.8; M, 264); S(CD,)SO 0.9 (3 H, d, CH,), 1.8-2.4 (3 H, m, CH,CH,CH), 3.3 (2 H, d, CH,O), 3.8 (2 H, m, CH2N), 51-64 (2 H, br, OH and NH, exch. with D20 with difficulty), 8.4 (1 H, d, 6-H), 8.75 (1 H, s, 2-H), and carboxyl absorption obscured. Acknowledgements We thank S.E.R.C. for a research grant (to S. G.). References 1 R.Alonso, G. Shaw, and D. Wright, J, Chem. SOC., Perkin Trans. 1, 1984, 2795. 2 D. S. Letham, J. S.Shannon, and I. R. McDonald, Proc. Chem. SOC., 1964,230. 3 G. Shaw and D. V. Wilson, Proc. Chem. SOC.,1964, 231. 4 G. Shaw, B. M. Smallwood, and D. V. Wilson, f.Chem. SOC.C, 1966, 921. 5 K. Koshimizu, T. Kusaki, and T. Mitsui, Tetrahedron Lett., 1967, 1317. 6 J. P.Helgeson and N. J. Leonard, Proc. Natl. Acad. Sci. USA, 1966, 56,60. 7 S. Matsubara, Phytochemistry, 1980, 19,2239. 8 M. I. Lim, R. S.Klein, and J. J. Fox,Tetrahedron Lett., 1980,21,1013. 9 M. I. Lim and R.S. Klein, Tetrahedron Lett., 1981, 22, 25. 10 M. 1. Lim, W. Y. Ren, B. A. Otter, arid R. S.Klein, J. Org. Chem., 1983,48, 780. 1 1 F. L. Rose, J. Chem. Soc., 1954, 41 16. 12 F. L. Rose and D. J. Brown, f. Chem. Soc., 1956, 1953. 13 J. A. Montgomery and K. A. Hewson, J. Org. Chem.,1965,30,1528. 14 D. J. Brown, f.Appl. Chem., 1957, 7, 109. Received 8th June 1984; Paper 41953