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【结 构 式】 
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【分子编号】25623 【品名】2-Thiobarbituric acid; 4,5-Dihydroxy-2-mercaptopyrimidine; 2-sulfanyl-4,6-pyrimidinediol 【CA登记号】504-17-6 |
【 分 子 式 】C4H4N2O2S 【 分 子 量 】144.15404 【元素组成】C 33.33% H 2.8% N 19.43% O 22.2% S 22.24% |
合成路线1
该中间体在本合成路线中的序号：(I)Alkylation of 4,6-dihydroxy-2-mercaptopyrimidine (I) with 4-methoxybenzyl chloride (II) provided methoxybenzyl sulfide (III). This was treated with POCl3 and 2-picoline to give dichloropyrimidine (IV). Then, ammonolysis with NH4OH in acetonitrile produced aminopyrimidine (V). Removal of the methoxybenzyl protecting group orf (V) was accomplished by treatment with methanesulfonic acid in CH2Cl2 to provide (VI). 4-Chlorocrotonyl chloride (VII) was condensed with diethylamine to yield chloro amide (VIII) (1). The title compound was then obtained by alkylation of mercaptopyrimidine (VI) with chloro amide (VIII) in the presence of NaOH in aqueous ethanol.
| 【1】 Murphy, M.J.; Schlachter, S.T.; Nugent, R.A.; et al.; Pyrimidine thioethers: A novel class of HIV-1 reverse transcriptase inhibitors with activity against BHAP-resistant HIV. J Med Chem 1998, 41, 20, 3793. |
| 【2】 Nugent, R.A.; et al. (Pharmacia & Upjohn AB); Alpha-substituted pyrimidine-thioalkyl and alkylester compounds as inhibitors of viral reverse transcriptase. EP 0824524; WO 9635678 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 25623 | 2-Thiobarbituric acid; 4,5-Dihydroxy-2-mercaptopyrimidine; 2-sulfanyl-4,6-pyrimidinediol | 504-17-6 | C4H4N2O2S | 详情 | 详情 |
| (II) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (III) | 25624 | 2-[(4-methoxybenzyl)sulfanyl]-4,6-pyrimidinediol | C12H12N2O3S | 详情 | 详情 | |
| (IV) | 25625 | 4,6-dichloro-2-[(4-methoxybenzyl)sulfanyl]pyrimidine | C12H10Cl2N2OS | 详情 | 详情 | |
| (V) | 25626 | 6-chloro-2-[(4-methoxybenzyl)sulfanyl]-4-pyrimidinamine | C12H12ClN3OS | 详情 | 详情 | |
| (VI) | 25627 | 4-amino-6-chloro-2-pyrimidinylhydrosulfide | C4H4ClN3S | 详情 | 详情 | |
| (VII) | 25629 | (E)-4-chloro-2-butenoyl chloride | C4H4Cl2O | 详情 | 详情 | |
| (VIII) | 25628 | (E)-4-chloro-N,N-diethyl-2-butenamide | C8H14ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 2-thiobarbituric acid (I) with ethyl bromoacetate (II) by means of NaHCO3 in ethanol - water gives ethyl-(4,6-dihydroxy-2-pyrimidinylthio)acetate (III), which by halogenation with POCl3 and N,N-diethylaniline yields ethyl (4,6-dichloro-2-pyrimidinylthio)acetate (IV). The condensation of (IV) with 2,3-dimethylaniline (V) by means of Na2CO3 in refluxing ethanol affords ethyl [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetate (VI), which is finally hydrolyzed with Na2CO3 in refluxing ethanol. Description.- Crystals, m.p. 146-51 C; Na salt, m.p. 183 C (decomp.).
| 【1】 Castaner, J.; Paton, D.M.; Wy - 14643. Drugs Fut 1978, 3, 5, 404. |
| 【2】 Santilli, A.A.; et al.; Natural product resveratrol: Novel sensitizer of tumor cells for TRAIL- or cytotoxic drug-induced apoptosis by cell cycle-mediated survivin depletion. Experientia 1974, 30, 10, 1110. |
| 【3】 Santilli, A.A.; et al.; US 3940394 . |
| 【4】 Santilli, A.A.; et al. (American Home Products Corp.); US 3910910 . |
| 【5】 Santilli, A.A.; et al. (American Home Products Corp.); CA 967571; DE 2314160; FR 2182917; GB 1413892; US 3814761; US 3876789; US 3896129; ZA 7301526 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 25623 | 2-Thiobarbituric acid; 4,5-Dihydroxy-2-mercaptopyrimidine; 2-sulfanyl-4,6-pyrimidinediol | 504-17-6 | C4H4N2O2S | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 61116 | ethyl 2-[(4,6-dihydroxy-2-pyrimidinyl)sulfanyl]acetate | C8H10N2O4S | 详情 | 详情 | |
| (IV) | 61117 | ethyl 2-[(4,6-dichloro-2-pyrimidinyl)sulfanyl]acetate | C8H8Cl2N2O2S | 详情 | 详情 | |
| (V) | 23025 | 2,3-Dimethylphenylamine; 2,3-Dimethylaniline; 2,3-Xylidine | 87-59-2 | C8H11N | 详情 | 详情 |
| (VI) | 61118 | ethyl 2-{[4-chloro-6-(2,3-dimethylanilino)-2-pyrimidinyl]sulfanyl}acetate | C16H18ClN3O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)In an alternative method, 2-thiobarbituric acid (XIII) is alkylated with 1-iodopropane and NaOH in N-methylpyrrolidone to afford the 2-(propylsulfanyl)pyrimidine (XIV). Diazotization of p-toluidine (XV) with NaNO2 and HCl, followed by coupling of the intermediate diazonium salt with pyrimidine (XIV) in the presence of NaOAc, produces the diazo adduct (XVI). After chlorination of (XVI) with POCl3, reductive cleavage of the diazo compound (XVII) with H2 and Pt/C gives 5-amino-4,6-dichloro-2-(propylsulfanyl)pyrimidine (XVIII). Subsequent condensation of (XVIII) with the cyclopentylamino compound (XIX) in ethanolic triethylamine at 120 °C in a pressure vessel provides the diaminopyrimidine (XX), which is further converted to the azapurine (XXI) by treatment with NaNO2 in acetic acid. Then, substitution of chloride (XXI) with 2-(3,4-difluorophenyl)cyclopropylamine (X) in the presence of triethylamine in acetonitrile affords the acetonide (XII), which is finally hydrolyzed to the title compound as in the above method (3). Scheme 2.
| 【3】 Larsson, U., Magnusson, M., Musil, T., Palmgren, A. (AstraZeneca AB). Triazolo pyrimidine compounds. CA 2408914, EP 1299390, JP 2003535093, US 2003148888, US 2006041132, US 2007049755, US 7067663, WO 0192263. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 65451 | (1R,2S)-rel-2-(3,4-Difluorophenyl)cyclopropanamine | 1006614-49-8 | C9H9F2N | 详情 | 详情 |
| (XII) | 65453 | 2-[[(3aS,4R,6S,6aR)-4-[7-[[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy]ethanol | 274693-26-4 | C26H32F2N6O4S | 详情 | 详情 |
| (XIII) | 25623 | 2-Thiobarbituric acid; 4,5-Dihydroxy-2-mercaptopyrimidine; 2-sulfanyl-4,6-pyrimidinediol | 504-17-6 | C4H4N2O2S | 详情 | 详情 |
| (XIV) | 65454 | 6-Hydroxy-2-(Propylsulfanyl)-4(3H)-Pyrimidinone | 145783-12-6 | C7H10N2O2S | 详情 | 详情 |
| (XV) | 31228 | p-toluidine; 4-methylphenylamine | 106-49-0 | C7H9N | 详情 | 详情 |
| (XVI) | 65455 | C14H16N4O2S | 详情 | 详情 | ||
| (XVII) | 65456 | C14H14Cl2N4S | 详情 | 详情 | ||
| (XVIII) | 65457 | 5-amino-4,6-dichloro-2-(propylsulfanyl)pyrimidine | 145783-15-9 | C7H9Cl2N3S | 详情 | 详情 |
| (XIX) | 65458 | 2-[[(3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol | 274693-55-9 | C10H19NO4 | 详情 | 详情 |
| (XX) | 65459 | 2-[[(3aR,4S,6R,6aS)-6-[[5-Amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol | 376608-74-1 | C17H27ClN4O4S | 详情 | 详情 |
| (XXI) | 65460 | 2-[[(3aR,4S,6R,6aS)-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol | 376608-75-2 | C17H24ClN5O4S | 详情 | 详情 |