SEPTEhIBEIt
1961
added to the residue, and the solid collected; wt. 5.9 g. (7.-drositie in 25 nil. of watcr and the solution was heated for I hr. at 70&80", treated with S o r i t and filtered. The filtrate vxs chilled in ice bath md. adjusted t o pH 1 with 6J1 hydrocliloric acid. .\ precipitate formed, which was separated by filtration and n.ashed with 30 ml. of water, yielding 0.08 g. (24:;) of product which did not melt bclow 300". The solid wis recrystallized from 10 ml. of water to give 0.06 g . (18%) of rnatcrial n-hich failed to melt a t 300". It showed 3 single spot with Rhd 0.77 in solvent A, behaving identicnlly lvith a commercial sample of 5-carboxyuraeil ( I V ) hemihydrate in both paper and infrared spectriim; X$:9Ll
2.90 (OH), 3.20 and 3.20 ( S I I ) ,4.10, 4.38-4.46, and 5.18 (carboxyl OH), 5.81 and 5.99 (uracil and carboxyl C-0), 6.19 (C=C), 6.59 (uracil ring), 6.98, 7.46, and 8.41 (COOH). Anal. Calcd. for C5H4N204.1/2HzO: C, 36.3; H, 3.05; N , 16.3. Found: C, 35.5; H, 3.38; ru', 16.3. 5-Azidoacetyluracil (VI). A solution of 0.56 g. (8.7 mmoles) of sodium azide in 10 ml. of water was added to a solution of I .O g. (4.3 mmoles) of the bromoketone ( V ) in 30 ml. of 2niethoxyethanol. After the resalting solution had stood a t room temperature for 2 hr., it was chilled at 0". Thc precipitate, 0.25 g. (30L,6), was sepnratcd and recrystallized from 10 nil. of Imilin: methanol to yield 0.12 g. (1t5c/c)of solid which part,ially decomposed nrar 200" hut did not melt on hrnting 3.21 ( S H ) , 4.75 (Xa),5.80, 5.!J2 and 6.05 (uracil to 300"; A$,: :md ketone C=O), 0% (C=C), 6.57 (uracil ring); Agg;2;:224 ( e 9,300), 287 ( c 11,300). On paper chromatography in solvent A, the product moved as a single spot with R,, 1.21. dlnal. Calcd. for CeH6Ns03:C, 36.9; H, 2.58; S , 35.8. Foiind: C, 37.1: H, 2.78; N, 35.3. On a preparative scale, 15.0 g. of the bromo ketone (V) afforded 10.5 g. (85%) of azide ( V I ) that was suitable for conversion to the amine (VIII), 5-Glycylztracil (VIII) picrule. A. I$/ hydrogenation qf the nzido kelone ( V I ) . .1siispension of 1.0 g. (5.1 mnioles) of tho azido ketone (VI) and 1.0 g. of 5'/'0 palladiiim-on-charcoal catalyst in 100 nil. of 507, aqueous et,hanol containing 4.0 ml. of GJI hydrochloric acid was stirred under 1 atm. of hya t room temperature, during ivhich time drogen for 8 h-. there was no apparent hydrogen uptake. The suspension was filtered and the filtrate evaporated to dryness in z".io, leaving 0.00 g. of amorphous solid Tvhich failed to melt a t 300". A portion of the solid (0.20 p . ) was nddcd to a hot (7080') solution of 0.25 g. (1.09 mmolcs) of pieric acid in 25 ml. of water. The yellow solution mas chilled ( 0 ' ) and n yellow precipitate slowly formed. The precipitate (0.30 g., m.p. 189-191" tiee.) LVRS dissolvcd in 10 ml. of hot water, the solution treated with Sorit, filtrrod and the filtrate chilled t o yield 0.15 g. (23:0 from VI) of pure picrate, n1.p. 198-200" 2.5-3.7 l ( S H 3 + ) , 5.75 and 5.85 (ur:ieil and kedec.; XIdH:C, tone C=O) G.20 (aryl and uracil C=C), 6.56-6.66 (iiraeil ring), 6.40 and 7.50 ( S O * ) . A n a l . Caled. for Ci2HlOS6010: C, 36.2; H, 2.53; S,21.1. Found: C, 36.2, 36.3, IS, 2.92, 2.64; N, 20.5. When a supercooled soliition of the above picrate in water n-as seeded with the second form of the picrate, m.p. 224225" dee., (rf. below), the solution deposited the second form of the picrate, n1.p. 228-226' dec., which possessed an infrared spectrum identicnl with that of the second form and markedly different than that of the l98-20Oo-ine1ting picrate. B. B?/ trmtmcn,t of the azido keione ( V I ) w i t h hydrobromic acid. A siiepension of 0.50 g. (2.56 mmoles) of the azido ketone (L'I) in 7.0 nil. of a 329; solution of hydrogen broniidc in glacial acetic acid was stirred a t room temperature for 20 min. during which time gas evolution Tvas noted m d the solid grad~iallydissolved. K h e n the solution had stood about 10 min. more, a yellow precipitate formed. Ether (40 ml.) was added to precipitate completely the solid, which was theu separated bj, filtration and added to 10 ml. of water. The aqueous niisture was filtered to remove an iinidentified solid and to the hot (60-70") filtrate was added :t hot solution of 0.58 g . (2.56 mmoles) of picric acid in 30 nil. of water. The vellow solution was chilled and seeded with the 198200"-melting,picrate (see Nethod A, above) causing the precipitation of 0.20 y. (2OV0) of yellow solid, m.p. 200-204" dec. This solid was recrystallized from 5 ml. of hot water t o give 0.10 g. (lo',;,) of the analyticd sample, m.p.224-226' u) (KH), 3 . 3 4 . 7 (SH1+), 5.75-5.!12 dec.; A ~ , ~ ~ (3.10-3.18 (uracil and ketone C=O). 6.15 (mj-1 and uracil c=c),6.60 (uracil ring), G.35 and 7.50 ( S O ? ) . .Inai. Calcd. for C,2H10N606: C, 36.2; H, 2.53; 5 , 21.1. Found: C, 36.4; H? 2.82; N, 21.1. 5-Glycyluracil (T'III) hydrochloride. A suspension of 3.0 g. (7.5 mmoles) of 5-glyeyluracil (VIII) picrate, 150 ml. of
henzene, GO ml. of water, and 7.5 nd. of concd. hydrochloric ncid was stirred vigoroilsly for 1 hr. :it room temperatrire. The aqiieons layer 1 ~ 2 ssep:irated and vas extracted n i t h two 50-ml. portions of benzene. On standing at room temperature the aqueous sollition deposited 0.50 g. of the amine hydrocliloride which did not melt hclow 300": XE:TP, 5.1G ( T H ) , 3.59, 3.86, 4.91, and 5.22 (NHz+), 5.60, 5.76, 5.90, 6.10 (uracil anti ketone C=O), 6.27 and 6.36 IC=C and X H s L ) ,6.70 (iir:icil ring and S H 3 + ) ; A$:x 227 ( e 10,20Oj, 285 ( e 12,300); O H 7 ,,,,X, 227 ( e 10,:300), 285 ( 2,500). T h e material streaked tixtlly in sevwal paprr chromat,ographic solvent sj.stema. .Lnol. Cnlcd. for C~H,CIS,OJ:C, 35.0; H, 3.92; C1, 17.2. Found: C, 35.0: H, :3.90; CI, 17.';;. The mother liqiiors from the analytiral sample were evaporated in uacito and left 1 .O g. of solid which did not inclt belaw 300" anti had an infrarcd spectrirm identical with that of the analytical sample. This material was readily recrystallized from 6.11 hydrochloric acid. The total yield of hydrochloride from the picrate was 1.5 g. (97%). f,'onvwsion of 5-qlycyl~~rac.il(VIII) to urrrcil-5-carboxylic acid (IV). A solution of 0.515 g. ( 7 . 2 6 mmolcs) af sodium iritrite in 5 nil. of water was adilrtl to a stirred solution of 0.60 g. (2A2 mmoles) of 5-glycyliiracil (WIT) hydrochloride in 10 ml. of water. The soliition a n s stirred for 3 hr. a t room temperature, during which time a solid, 0.15 g. (40%) and m.p. 285-287' dw., prcv3l)itatd. The solid was recrystallized twice from witer to give 0.05 g. ( I 3 5 & ) of product, m.p. >300". It I V ~ P itlcuticnl in paper chromatographic behavior and in infrarcd sprmruni with :t commercial sainple of the hemihydrate of uracil-5-carbouylic acid (IV). iyt~yliar.a,,il (IX'). A suspension of 0.25 g. f the azido ketone (I,]), 10 nil. of glacial ace. of 5:; ~iall:idium-on-charcortl,and 0.27 g. (2.56 mmolrs) of arctic anhj.dride n':is stirrrd with hydrogen a t room temperatiire for 6 hr., diiring which time there 17-as no visihle uptake of' hydrogen. Methanol (20 ml.) was added to the miutiire, \vhich \vas then heated to boiling on the steam b a t h :ind the niixtrire filtered. The filtrate was evaporntrtl I'~L i i i f ' i t o :it 40-50", leaving a solid residue, m.p. 290205'. 'l'hc prodiict \V:LS recrystallized from 30 ml. of hot g. ( i 4 ( ' ; ) of a solid which did not melt ,(E, 3.18, 3.28 (XH), 5.81, 5.95, and 6.22 C=O) amide C=O, and C=C); there was a hro:id, nnassigiietl band a t 3.70-3.8" p . 0 1 1 paper c1irom:itogr:iphv i r i solvents ;1 and I3 thc compoiind \\-as hoinogenwus with I300"; A:E$,) ( S H ) : 4.05 ( S C S j , 5.77 and 5.96 (uracil and ketone C=Oj. ti.25 (C=C). On paper chromatography in watcxr, the com~ pound moved as a single spot with R A1.87. A r d . Calcd. for C,H,S,O,S: C, 39.8; H,2 Foiind: C! 40.0; H , 2.58; S , 19.5. ~~-(2-.~lethi/i-~-thintoi!/l!irrnril ( X I I ) . T o a ivarni (50") solution of 0.23 g. i 1 .0 mmole) of the bromo kctnnr, ( V ) in 3.5 ml. of 2-nic,t,hoxyethanol w:is added 0.09 g. (1.12 mmolesj of thioacetamide. 7Vithin 1 min. the sollition began to di,posit a crystalline, white precipitate. After it had stood a t room temperature for 1 hr., the mixtiire was chillctl ant1 filtered, yielding 0.18 g. (87L;10) of solid which failed t o melt bclow 300" and whose infrared spectrum was identical with that of the analytical sample. The material was recrptallized (--N-S),
(24) If the solution was dloiveci to evaporate to dryness, the infrared diazo band was weak or missing in the resulta~it solid,
1)). dissolving it in 20 ml. of hot (90") ,Ir,,V-dimeth~~lform:imide, diluting the solution with 7 ml. of water, and chilling, 3.01, 3.18, t o yield the analytical sample, m.p. >300°; A$:), 3.22 (NH), 5.82 and 5.95 (uracil C=O), 6.05 (C=S), 6.22 (C=C); there were strong, unassigned bands a t 8.09 and 8.22 p and unexplained, broad absorptions a t 3.6-4.2 p ; X$~, 233 ( f 9,700), 274 ( t 11,500); A&:,; 249 ( e 11,800), 285 ( e 8,700), 294 (shoulder, e 7,500); X E ~ r i $ l 249 (broad, e 11,700), 307 (broad, e 9,700). On paper chromatography i n solvents A and C, the product moved as a single spot \\.it11 R A1.28 ~ and 1.08, respectively. Anal. Calcd. for C8HjS,O3S: C, Xi!); H, 3.38; S , 20.1. Found: C, 46.1; H, 3.56; S , 19.5. 5-(8-dwnino-~-thiazolyl)uracil (XIV) and the hyt/?ob?"tie and picrate salts. A mixture of 0.27 g. ( 1 2 0 mmoles) of 5bromoacetyluracil (V), 0.92 g. (12.0 mmoles) of thiourea, and 10 ml. of 2-methoxyethanol was heated a t 70-80" for 1 hr., during which time a heavy solid formed. This was separated by filtration and washed with cold water, leaving 0.30 g. (870/,) of the hydrobromide salt of XIV which did not melt below 300". The solid was recrystallized from 300 ml. of hot water, yielding 0.27 g. ( 7 8 % ) of product, m.p. >300"; X$:) 3.00-3.22 ( X H ) , 3.6-4.2 (broad absorptions, possibly SHs+), 5.81 and 5.93 (uracil C=O), 6.14 (C=C and C=S or C=S+); X;zx:, 242 ( E 12,800); X;~x~,,,pl 243 ( 6 12,000); ,,,,,,X, pH 13 241 (broad, e 13,400),316 ( ~ 8 , 0 0 0 On ) . paper chroinatography in solvent C, the product' moved as a single spot with R A d 0.83. Anal. Calcd. for C?H&40&3.HBr: C, 28.9; H, 2.43; S, 11.0. Found: C. 28.8,29.2; H, 3.02, 3.02; S, 10.9, 10.7. A solution of 0.200 g. of the hydrobromide salt of XIV in 25 ml. of hot water was adjusted t o pH 7 with solid sodium bicarbonate, causing the precipitation of 0.125 g. (91%) of the free base ( X I I ) as a solid which did not melt below 300". The solid was recrystallized from 40 ml. of hot water t o yield 2.92, 3.02 and 0.075 g. (557,) of product, m.p. >300°; A$:) 3.12 (XH), 5.81 and 5.92 (uracil C=O), 6.14 (C=S and C=C); there was a strong, unassigned band a t 8.30 p . On paper chromatography in solvents A and C, the compound moved as a single spot n i t h R A d 0.81 and 0.81, respectively. Anal. Calcd. for C7H6K402.1/2 H2O: C, 38.4; H , 3.22; K, 25.6. Found: C, 39.0, 39.2; H, 3.41, 3.40; X, 25.2. To a hot solution of 0.137 g. (0.600 mmole) of picric acid in 40 ml. of methanol was added 0.105 g. (0.500 mmole) of t)he free base (XIV). The hot solution was filtered and the filtrate was chilled overnight t o cause precipitation of the piccrate. The yellow solid was recrystallized twice from hot methanol t o give a crystallinr solid which decomposed with$:) 2.84, 2.98, 3.13 ( N H ) , 3.22 out melting near 260"; V ( N H and aryl), 5.76 and 5.86 (uracil C=O), 6.08 (aryl and C=N +), 6.44, 7.46 and 7.56 ( NOp). Anal. Calcd. for C13H9X709S: C, 35.5; H, 2.06; X, 22.3. Found: C, 36.0; H, 2.59; S , 22.6. 5- [Bis(2-hydros~ethyl)anzinoacetyl] uracil (XV). To a warm (55-60") solution of 1.50 g. (6.44 mmoles) of 5-bromoacetyluracil (V) in 150 inl. of methanol was added 1.68 g. (16.1 mmoles) of 2,2'-iminodiethanol. Thc solution was warmed at, 55-60" for 5 min. and was then evaporated in vacuo, leaving a brown sirup. Water (30 ml.) was added t o the residuc. and the mixture was heated a t 65-70" for 15 min. The solution was chilled and the flask scratched, caiising the precipitation of 1.15 g. (705,G)of crystalline solid, m.p. 135-137". The solid was recrystallized from 25 ml. of hot m-atcr, yielding 1.0 g. ( 6 0 5 ~ ~of) product, ni.1). t16-14io with darkriiing around 135". From a previous run, a sample was obtained, after recrystallization froin water, which had m.p. 144-146" \vit)h prior darkening; A E ~ x 2.03, ~ ~ l 2.99, and t3.11 (OH, NH), 3.24 (XH), 6.00, 6.08, 6.20 (uracil and kctoiic C=O and C=C), 9.12, 9.27 and 9.43 (C-OH); 258 ( e 7,700), 287 (shoulder, e 3,500); XL:x:n,,) 250 ( e 0,430), 302 ( t 5,5iO); x ~ 13 H 244 ( E 8,270), 302 ( e 15,900). On paper chromatography in solvents A and D,. the compound moved as a single spot with R A0.40 ~ and 1.10, respectively.
. 4 n d Calcd. for CluHli,S,10j.H20: C , 4:.lpj.ruvate diethyl acetal (XXI),2* 6.!)3 g. (0.158 ~nolc)of sodirini hydride (as a 54.571 suspc&on in mineral oil), and 103 g. (0.1 18 mole) of eth>,lncrtate and thc. tc~nnprr:ttiirr)for. I mixture \vas stirred a t 20-25" (m~atc~r-hilth hr. IfiiiicC H ) . On paper chromatography i l l solvrnt B, t h r ( - o i i i ~ ) o r i i i dinoved as a singlc spot with Rid 1.65. .I!itri. C a l d for Ct,,H16S?OJS: C, 49.1. H, 6.59. P, 13.1. F'ountl: C, 49.7; H, 6.8!); S, I2.(i. 6-. I wt~J-2-thio~cracil( X I X ) . A inixtiire of 18.0 g. ( 7 7 . 5 inniolvs) of the P-keto ester ( X S I I ) , !).go g. (0.183 mole) of d i u m methoside, 11.8g. (0.155 mole) of thiourea, and 90 inl. of ahsolute ethanol n-as stirred for 14 hr. at room trnipcmtiirr. The solution was heated under rrfltis for t i hr. and tw~poratcrlin aaruo. K a t c r ('10 ml.) was addrd to the resitliic, the solrition filtwed and the filtrate adjiipted to pH 3 with 6.1.I h\,tlrochloric arid. The acid solution W H S hrated 011 the stcttrn bath for 30 min., during which time cr>~stallixation hegan. Aftrr rhilling the mixtiirr, 8.50 g (51 c ; , ) of prodiivt \\as olitainetl with m.p. 274-2763' der.: this prodrict \v:ts iticnticnl \vit,h that prepared froin S V I I I . Prcvioiisl>., l)y heating a inistiire of 0.20 p. 10.82 imnolc) of thts tlirth~~1krta.l (Si'III), 5 drops of 6Ilr hydrorhloric 1 5 1111. of water a t 70-80 for 30 Inin., n yellou-, prodiict, 0.14 g. (!Uyo), m.p. 278-280" t l c v . , had iiod. This was rerrystallizcd from 35 ml. of ljoiling Lvittcr with the aid of Norit to yield 0.060 g. (58r,,) of solid, m.p. 278-2880' dec.; )$:,A 3.78 anti 3.22 ( N H ) , 55.!)I (thioiirncil : m t i Iit~to~ie C-0), 6.15 (C=C), ii.-IO-(i.50 (pyrimidine ring), 8.57 (C=S), 1 1 . i O (olefinic CH) ; h ~ n ~ ! y ~2, in2, , ~( e "PI 260 ( e 13!400)I x 2 6 i ( e 14,700). On :itogr:il)hy in solvcri ant1 H, thv prodrict inovc:tl :is :t singlc spot with R . ~ ,1.14 I and 1.46, respcactivel>r. .Inul. Calcd. for CsH6S20,S:C, 12.3; H, 3.54:S, 18.8. Foiind: C, 42.5; H: 3.64; X. 18.!). ~
6-.1c.el$icrnci.l
( S X ) . -4.Prom fi-(1,1-dr'pthor!jrlhyl)-d-
thioltracil (XVIII). A stirrpil .wspension of 0.22 g. (0.r)o
nunole) of the diethylketal ( S V I I I ) , 0.43 g. (4.5 mmolex) of rhloroacetic acid, and 5 nil. of water was heated under reflux for 6 hr. The solution was chilled, causihg the precipitat>ionof 0.094 g. (68'7r) of product, m.p. 259-260' dec. Thifi was recrystallized from 5 ml. of hot) water, yielding 0.080 g. (58y0)of solid, m.p. 265~266" der. (lit.20 m.p 2555-260" 3.00 and 3.19 ( S H ) ; 5.82 and 5.03 (uracil and 0). 6.10 (C=C), 11.50 (olefinic C H ) ; 2!6 ( e 6,600) ; Afn~,~~,, 295 ( e 5,400). On paper chroinatograph!. in solvents A and B, the compound moved :is a single spot with It,{ 0.97 and 0.92, respectively. .Inal. Calrd. for CsHsN?03: C, 46.6; H, 3.92. Foiirid: C , 46.5; H, 4.05. In the same manner, the t'reatnient of 7.0 g. of 6-aretyl-2thiouracil ( X I X ) with a solution of 13.6 g. of chloroacetir arid in 130 ml. of water heated at reflux for 5 hr. gave 4.0 g. (6:30&) of 6-aret-yluraril (SX), 1n.p. 264-265' tiec., with infrared spectrum and paprr chromatographic hrhavior identicd to those of the analytical sample. 13. Froin 2-nmino-fi-acetyl-Q(3H)-pyrimidinone (XXIII) To a stirrrd mixture of 2.00 g. (13.0 mmoles) of the aminop>~imidinonr!( X X I I I ) , 10 nil. of 6 J I hydrochloric acid, 5 i n l . of roncd. snlfuric arid, and 15 ml. of water a t room t,rmpPratur(: was added dropwise a solution of 8.58 g. ( 5 2 mmoles) of sodiiim nitritr in I O ml. of water ovcr a period of 10 min. Th(>iiiixt\irr was stirred at room temperature 1.5 hr. and rhillrd to yicld 1.40 g. (697;) of crystalline 6-aretyluracil (IS), m.p. 257-260" dec., which was identical with the analj~tiralsample in infrared spectrum and paper chromatographic behavior.
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.4 clinoiulcdgmcnt. 'The authors are indebtled to Tlr. l'eter T,im for iiit'erpretatmioiiof t'he iufrared spcrtru and to his staff for the paper chromatography. They also wish t,o t,haiik Mr. 0. 1). Creivs aiid his st,aff for the large-scale preparation of rertain intermediates. h1ESl,U PARK,
C.4LIF.
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[C~lSTltIB~l'I(JS YH(lM TIIE 1 ) I V I h I O s s 01,' Tl EOI'R(1TBIS CHEhfISTHY AS11 fi>SI'ERIMEST.II. (:H&.MOTHER.IPY, l
