The synthesis of 5-carbethoxyuracils was written by Whitehead, Calvert W.. And the article was included in Journal of the American Chemical Society in 1952.Formula: C9H12N2O4 The following contents are mentioned in the article:
To NaOEt from 2.3 g. Na in 150 cc. EtOH was added 6.0 g. urea, then 21.6 g. EtOCH:CH(CO2Et)2, the mixture let stand 7 days at room temperature, the EtOH removed in vacuo, the residue dissolved in 50 cc. cold H2O, and the solution acidified with dilute HCl to give 6 g. (21.8%) H2NCONHCH: C(CO2Et)2 (I), m. 207-9° (from EtOH). I (23 g.) in 200 cc. absolute EtOH containing 0.1 mol. NaOEt let stand 12 hrs. at room temperature, refluxed 5 hrs., the EtOH removed in vacuo, and the residue in 50 cc. acidified yielded 13 g. (72%) 5-carbethoxyuracil, m. 232° (from EtOH). CO(NHMe)2 (44 g.) and 108 g. I heated 24 hrs. at 120°, and the product recrystallized with charcoal from EtOAc gave 66 g. (62%) 1,3-dimethyl-5-carbethoxyuracil, m. 112° (from EtOH). H2NCONHMe (14.8 g.) and 43.2 g. I gave 16 g. (41%) 3-methyl-5-carbethoxyuracil (II), m. 221° (from EtOH). II (10 g.) and 50 cc. 10% aqueous NaOH heated 2 hrs. on a steam bath, and the mixture acidified with dilute HCl gave 8.5 g. (98%) 3-methyl-5-carboxyuracil (III), m. 242° (from EtOH). III (2 g.) heated 10 min. at 225° yielded 90% 3-methyluracil, m. 174-5° (from EtOH). H2NCONHPr (10.2 g.) and 21.6 g. I heated 12 hrs. at 110° yielded 50% PrNHCONHCH: C(CO2Et)2 (IV), b1 165-70°. IV (14.5 g.) and 2.88 g. NaOMe in 50 cc. MeOH let stand 48 hrs. at room temperature and then heated 6 hrs. at 80° gave 6 g. (56.5%) 3-propyl-5-carbomethoxyuracil, m. 205° (from EtOH). AmNHCONH2 (13.0 g.) and 21.6 g. I heated 24 hrs. at 120°, the resulting sirup added to 200 cc. absolute EtOH containing 0.1 mol. NaOEt, the mixture let stand 24 hrs. at room temperature, the EtOH removed in vacuo, and the residue taken up in 100 cc. H2O and 100 g. ice and acidified with dilute HCl yielded 6.2 g. (24%) 3-amyl-5-carbethoxyuracil, m. 152° (from aqueous EtOH). Similarly were prepared the following compounds (V), where R = H, R’ = Bu (VI), 53%, m. 152°, and R = H, R’ = C6H13, 50%, m. 140°. HOCH2CHEtNHCONH2 (11.6 g.) in 200 cc. absolute EtOH containing 0.1 mol. NaOEt and 21.6 g. I let stand 48 hrs. at room temperature and the mixture worked up as above yielded 21.0 g. (82%) 3-(1-hydroxymethylpropyl)-5-carbethoxyuracil, m. 161° (from EtOAc). Similarly were obtained the following V, where R = H (R’ given): Et, 82%, m. 219°; HO(CH2)2, 79%, m. 175-6°; CH2:CHCH2, 80%, m. 174°; iso-Bu, 62%, m. 167°; cyclohexyl, 49%, m. 282°; p-ClC6H4, 88%, m. 265°; p-MeOC6H4, 90%, m. 185-94°; p-MeC6H4, 97%, m. 235°; PhCH2, 90%, m. 215°; C7H15, 49%, m. 133°; PhCHMe, 77%, m. 130°; Ph(CH2)2, 84%, m. 228°; and C8H17, 48%, m. 130°. PhNHCONH2 (27.2 g.) and 43.2 g. I in 250 cc. absolute EtOH containing 0.2 mol. NaOEt let stand 3 days at room temperature, and the mixture worked up as usual yielded 46 g. (88%) 3-phenyl-5-carbethoxyuracil (VIII), m. 230-1° (from EtOH). VIII (5.2 g.) refluxed 2 hrs. with 100 cc. 5% aqueous NaOH, and the mixture cooled, filtered, and acidified yielded 2.5 g. 3-phenyl-5-carboxyuracil (IX), m. 243° (decomposition). IX (1.0 g.) heated 15 min. at 243° gave 0.6 g. 3-phenyluracil, m. 242-6° (from H2O). VI (20 g.) stirred vigorously at 40° with 3.4 g. NaOH in 150 cc. H2O and 12.9 g. Et2SO4 added dropwise during 1 hr., the mixture stirred another hr., the H2O removed in vacuo, and the residue extracted gave 14.5 g. (65%) 1-ethyl-3-butyl-5-carbethoxyuracil, m. 41-3°. Similarly were prepared from the corresponding monoalkyl derivatives of V the following V (R and R’ given): Me, Et, 76%, m. 116°; Me, iso-Pr, 78%, m. 98°; Me, Bu, < 50%, m. 60°; Me, iso-Bu, 72%, m. 119°; Et, iso-Bu, 65%, m. 90-90.5°; Me, p-ClC6H4, – , m. 141°; and Me, PhCH2, 76%, m. 79°. The above V heated 24-48 hrs. with 10% excess of an amine, the mixture cooled, and the product recrystallized from hot EtOAc gave the following 5-carbamyluracils (X) (R, R’, and Y given): Me, Me, NHMe, 100%, m. 196°; Me, Me, NHEt(XI), 95%, m. 158°; H, Pr, NHCONH2, (50%), m. 234°; H, HO(CH2)2, NHEt, 75%, m. 222° Me, Me, NH(CH2)2OH (XII), 100%, m. 151°; H, HO(CH2)2, NH(CH2)2OH, 60%, m. 185°; Me, Et, NH(CH2)2OH, 57%, m. 179°; Et, Me, NH(CH2)2OH, 70%, m. 123°; Me, Me, NHBu, 100%, m. 125°; Me, Me, NHCH2CHMe2 (XIII), 100%, m. 150.5°; Me, iso-Pr, NH(CH2)2OH (XIV), 93%, m. 114°; Me, Me, N(CH2CH2OH)2 (XV), 45%, m. 122°; Me, Me, NHAm, 100%, m. 115.5°; Me, iso-Bu, NH(CH2)2OH, 49%, m. 142°; Me, Me, NH(CH23N Me2, 86%, m. 89°; H, cyclohexyl, NH(CH2)2OH, 89%, m. 232°; Me, Me, NHC6H13, 79%, m. 121°; Me, Me, NH(CH2)3NEt2, 66%, m. 69.5°; and Me, Me, NHC7H15, 87%, m. 107°. Alk. hydrolysis of the above V with refluxing 5% aqueous NaOH gave the following XVI (R and R’ given): Me, Me (XVII), 90%, m. 183°; H, Et, 70%, m. 179°; H, Pr, 90%, m. 172-3°; Me, Et, 70%, m. 172°; H, iso-Pr, 69%, m. 192°; Me, CH2:CHCH2, 70%, m. 161-2°; H, iso-Bu, 80%, m. 211°; H, HOCH2CHEt, 90%, m. 166°; Me, Bu, 80%, m. 148°; Et, Bu, 95%, m. 107°; Me, Am, 74%, m. 152° H, p-ClC6H4, 98%, m. 255° (decomposition); H, p-MeC6H4, 90%, m. 240° (decomposition); and Me, C6H13, 66%, m. 151°. XII and XVII showed moderate diuresis in dogs with oral doses of 0.5-1 g.; XI, XIII, and XIV with intravenous doses of 5-10 mg.; XII caused marked diuresis with oral doses of 0.5-1 g.; and XII and XV with intravenous doses of 5-10 mg./kg. This study involved multiple reactions and reactants, such as Ethyl 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (cas: 39513-47-8Formula: C9H12N2O4).
Ethyl 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (cas: 39513-47-8) belongs to pyrimidine derivatives. The pyrimidine nitrogenous bases are derived from the organic compound pyrimidine through the addition of various functional groups. As nucleotides in DNA and RNA, pyrimidine nucleotide derivatives have a wide range of biological applications. For example, pyrimidine derivatives are useful in DNA repair studies involving cancer and epigenetics.Formula: C9H12N2O4
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia