Chemotherapy. X. Antithyroid compounds. Synthesis of 5- and 6-substituted 2-thiouracils from β-oxo esters and thiourea was written by Anderson, George W.;Halverstadt, I. F.;Miller, Wilbur H.;Roblin, Richard O. Jr.. And the article was included in Journal of the American Chemical Society in 1945.Reference of 39083-15-3 The following contents are mentioned in the article:
5- and 6-Substituted 2-thiouracils have been prepared by condensing CS(NH2)2 with β-keto esters. The latter were prepared by one of several methods. As an example of the first, 0.84 mol of AcCHNaCO2Et in 500 mL. ether was treated with 0.84 mol of PrCOCl during 3 h., allowed to stand overnight, treated with 200 cc. H2O, extracted with 600 cc. ether, and treated with 40 g. NH3 gas at 0-25°, giving 39% of Et β-ketocaproate; similarly prepared were Et γ-methyl-β-ketovalerate (41%), Et β-ketoenanthate (40%), Et β-ketocyclohexanepropionate (40%), and Et β-keto-γ-phenylbutyrate (31%). In the 2nd method the reactions involved were: RCOCl + EtOMgCH(CO2Et)CO2CMe3 → RCOCH(CO2Et)CO2CMe3 → RCOCH2CO2Et + CH2:CMe2 + CO2; this method gives the best results when only small quantities are required; the limiting factor is the relative unavailability of tert-BuCH(CO2Et)2; prepared by this method were: Et β-ketovalerate (I) (60%), Et γ-methyl-β-ketocaproate (49%), Et β-(4-chlorophenyl)-β-ketopropionate (82%), and Et β-keto-δ-phenylvalerate (61%). The 3rd method involved the reaction of RAc with NaNH2, followed by Et2CO3; Et γ-methyl-β-ketocaproate (68%), Et γ-γ-dimethyl-β-ketovalerate (43%), Et β-ketocaprylate (57%), and Et β-ketopelargonate (61%) were prepared by this method. The 4th method consisted in the reaction of RCOCH2CO2Et with R’X; AcCHMeCO2Et (45%), AcCHEtCO2Et (58%), and Et α-ethyl-β-ketovalerate, b8 83-5° (75%), were prepared by this method. The 5th method involved the reaction of RCO2Et and R’CH2CO2Et with EtONa or Na; prepared by this method were Et α-methyl-β-ketovalerate (26%) and 2-carbethoxycyclopentanone (71%). Details are given of the reaction of EtMgBr and NCCH2CO2Et, which yields 58% of I. In the preparation of the uracils, 0.1 g.-atom of Na in 50 cc. anhydrous EtOH, 0.07 mol of CS(NH2)2, and 0.05 mol of the keto ester were heated on the steam bath for 6-7 h. and allowed to stand overnight; the solution was evaporated at 40-50°, the residue taken up in 50 cc. H2O, and the product precipitated by addition of 7 cc. concentrated HCl and then AcOH to pH 4; the compounds were crystallized from boiling H2O or AcOH. The m. ps. (corrected), yield (from the ester), and antithyroid activity (thiouracil = 1) are given. 6-Substituted 2-thiouracils: Me, m. above 300°, 63%, 1.0; Et, m. 228.5-30.5°, 78%, 8; Pr, m. 218-19°, 70%, 11; iso-Pr, m. 179-80°, 45%, 9; Bu, m. 207.5-9°, 31%, 3; iso-Bu, m. 220.5-1.5°, 36%, 5; sec-Bu, m. 222-4%, 55%, 6; tert-Bu, m. 178-80°, 43%, 9; Am, m. 153-4.5° and 163-4°, 33%, 1.3; hexyl, m. 144.5-5.5°, 27%, 0.18; cyclohexyl, m. 282-5°, 69%, 1.2; Ph, m. 263-4.5%, 45%, 1; p-chlorophenyl, m. 289-91°, 21%, less than 0.01; benzyl, m. 223-4°, 71%, 10; phenethyl, m. 223.5-5.5°, 41%, 1.2. 5,6-Dimethyl-2-thiouracil, m. 283-5°, 42%, 1.2; 5-methyl-6-Et homolog, m. 223-4°, 48%, 3.5; 5-ethyl-6-Me isomer, m. 216-18°, 53%, 0.9; 5,6-di-Et homolog, m. 214.5-15.5°, 41%, 2.0; trimethylene homolog, m. 336-7° (decomposition), 10%, 0.3; 5-(2-hydroxyethyl)-6-Me compound, m. 265-7, 13%, less than 0.01. BuCO2Et (II) (28.6 g.) and 28.4 g. HCO2Et, added during 4 h. to 4.85 g. Na in 100 cc. ether, the mixture allowed to stand overnight, evaporated in vacuo, treated with 0.75 g. CS(NH2)2 and 85 cc. absolute EtOH, and refluxed 7 h., give 3.4 g. (based on II) of 5-propyl-2-thiouracil, m. 161-3°, 2; 5-iso-Pr isomer, m. 242-4°, 6%, 2.5; 5-Bu homolog, m. 151.5-3.5°, 6%, 0.6; 5-Et homolog, m. 190-2°, 4%, 3.5. Et α-cyano-β-ethoxyacrylate (30 g.), added slowly to 4.22 g. Na in 200 cc. absolute EtOH and 13.5 g. CS(NH2)2, the mixture refluxed 1 h. and allowed to stand overnight, the solution concentrated to 75 cc., diluted with 400 cc. H2O, neutralized to pH 7, the precipitate taken up in 350 cc. H2O and acidified to pH 3, gives 18.9 g. of the Et ester, m. 277° (decomposition), of 2-mercapto-4-amino-5-pyrimidinecarboxylic acid, m. 276-9° (decomposition); the filtrate yields 14% of 5-cyano-2-thiouracil, m. 282-3° (decomposition), activity less than 0.01. The maximum antithyroid activity appears when the alkyl group contains 3 or 4 C atoms. The benzyl derivative was the most active of the aralkyl compounds This study involved multiple reactions and reactants, such as 5-Ethyl-6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (cas: 39083-15-3Reference of 39083-15-3).
5-Ethyl-6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (cas: 39083-15-3) belongs to pyrimidine derivatives. The pyrimidine derivatives can easily interact with enzymes, genetic materials, and bio components within the cell. A Cu-catalyzed and 4-HO-TEMPO-mediated [3 + 3] annulation of commercially available amidines with saturated ketones enables an efficient and facile synthesis of structurally important pyrimidines via a cascade reaction of oxidative dehydrogenation/annulation/oxidative aromatization.Reference of 39083-15-3
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia