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【结 构 式】 
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【药物名称】GCA-186 【化学名称】6-(3,5-Dimethylbenzyl)-1-(ethoxymethyl)-5-isopropylpyrimidine-1,3-dihydro-2,4-dione 【CA登记号】149950-61-8 【 分 子 式 】C19H26N2O3 【 分 子 量 】330.43067 |
【开发单位】Kagoshima University (Originator), Showa University (Originator), University of Oxford (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors |
合成路线1
Lithiation of 1-(ethoxymethyl)-5-isopropyl-2-thiouracil (I) by means of LDA in cold THF, followed by condensation with 3,5-dimethylbenzaldehyde (II) gave the 6-(alpha-hydroxybenzyl) derivative (III). Oxidative hydrolysis of the thione function of (III) with H2O2 afforded the corresponding uracil (IV). Acetylation of (IV) with Ac2O in pyridine provided acetate ester (V), which was subjected to hydrogenolysis in the presence of Pd/C to furnish the title benzyl derivative.
| 【1】 Walker, R.T.; Baba, M.; De Clerq, E.; Takashima, H.; Inouye, N.; Ubasawa, M.; Miyasaka, T.; Sekiya, K.; Shigeta, S.; Tanaka, H.; Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents. J Med Chem 1995, 38, 15, 2860. |
| 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) | 27026 | 1-(ethoxymethyl)-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C10H16N2O2S | 详情 | 详情 | |
| (II) | 32915 | 3,5-dimethylbenzaldehyde | 5779-95-3 | C9H10O | 详情 | 详情 |
| (III) | 38765 | 6-[(3,5-dimethylphenyl)(hydroxy)methyl]-1-(ethoxymethyl)-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C19H26N2O3S | 详情 | 详情 | |
| (IV) | 38766 | 6-[(3,5-dimethylphenyl)(hydroxy)methyl]-1-(ethoxymethyl)-5-isopropyl-2,4(1H,3H)-pyrimidinedione | C19H26N2O4 | 详情 | 详情 | |
| (V) | 38767 | (3,5-dimethylphenyl)[3-(ethoxymethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl]methyl acetate | C21H28N2O5 | 详情 | 详情 |
合成路线2
In an alternative procedure, condensation of 5-isopropyl-2,4,6-trichloropyrimidine (VI) with 3,5-dimethylbenzylmagnesium chloride (VII) in cold THF produced the 6-benzyl pyrimidine derivative (VIII). Subsequent reaction of (VIII) with sodium methoxide gave dimethoxypyrimidine (IX), which was hydrolyzed to uracil (X) with concentrated HCl. After silylation of (X) with chlorotrimethylsilane and hexamethyldisilazane, alkylation with chloromethyl ethyl ether in the presence of SnCl4 furnished the title compound.
| 【1】 Lee, Y.S.; Kim, Y.H.; Regioselective alkylation and arylation at the 6-position of pyrimidine: Syntheisis of 5-alkyl-6-arylmethyl-2,4-pyrimidinediones. Synth Commun 1999, 29, 9, 1503. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 38768 | 2,4,6-trichloro-5-isopropylpyrimidine | C7H7Cl3N2 | 详情 | 详情 | |
| (VII) | 38769 | chloro(3,5-dimethylbenzyl)magnesium | C9H11ClMg | 详情 | 详情 | |
| (VIII) | 38770 | 2,4-dichloro-6-(3,5-dimethylbenzyl)-5-isopropylpyrimidine | C16H18Cl2N2 | 详情 | 详情 | |
| (IX) | 38771 | 4-(3,5-dimethylbenzyl)-5-isopropyl-6-methoxy-2-pyrimidinyl methyl ether; 4-(3,5-dimethylbenzyl)-5-isopropyl-2,6-dimethoxypyrimidine | C18H24N2O2 | 详情 | 详情 | |
| (X) | 38772 | 6-(3,5-dimethylbenzyl)-5-isopropyl-2,4(1H,3H)-pyrimidinedione | C16H20N2O2 | 详情 | 详情 |