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【结 构 式】 
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【分子编号】40643 【品名】5-(3-iodo-4,5-dimethoxybenzyl)-2,4-pyrimidinediamine; 2-amino-5-(3-iodo-4,5-dimethoxybenzyl)-4-pyrimidinylamine 【CA登记号】 |
【 分 子 式 】C13H15IN4O2 【 分 子 量 】386.19233 【元素组成】C 40.43% H 3.91% I 32.86% N 14.51% O 8.29% |
合成路线1
该中间体在本合成路线中的序号：(VI)Methylation of 5-iodovanillin (I) with dimethyl sulfate and K2CO3 afforded dimethoxy derivative (II). This was condensed with 3-anilinopropionitrile (III) in the presence of potassium tert-butoxide yielding the enamino nitrile (IV). Subsequent cyclization of (IV) with guanidine hydrochloride (V) produced diaminopyrimidine (VI).
| 【1】 Guerry, P.; Locher, H.H.; Hubschwerlen, C.; Wyss, P.C.; Jolidon, S.; Hartman, P.G.; Stalder, H.; Specklin, J.L.; Anti-MRSA dihydrofolate reductase inhibitors: Synthesis and SAR. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F1800. |
| 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) | 12758 | 4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin | 5438-36-8 | C8H7IO3 | 详情 | 详情 |
| (II) | 40641 | 3-iodo-4,5-dimethoxybenzaldehyde | 32024-15-0 | C9H9IO3 | 详情 | 详情 |
| (III) | 27195 | 3-anilinopropanenitrile | 1075-76-9 | C9H10N2 | 详情 | 详情 |
| (IV) | 40642 | (Z)-3-anilino-2-(3-iodo-4,5-dimethoxybenzyl)-2-propenenitrile | C18H17IN2O2 | 详情 | 详情 | |
| (V) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (VI) | 40643 | 5-(3-iodo-4,5-dimethoxybenzyl)-2,4-pyrimidinediamine; 2-amino-5-(3-iodo-4,5-dimethoxybenzyl)-4-pyrimidinylamine | C13H15IN4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The condensation between ethyl picolinate (VII) and phenethylamine (VIII) at 180 C produced amide (IX), which was subsequently cyclized to dihydroisoquinoline (X) either by heating with polyphosphoric acid or by chlorination with PCl5, followed by cyclization in the presence of AlCl3. Catalytic hydrogenation of (X) gave rise to the racemic tetrahydroisoquinoline, which was resolved employing D-(-)-tartaric acid. The desired (R)-enantiomer (XI) was acylated with acryloyl chloride (XII) to produce acrylamide (XIII). Finally, palladium-catalyzed coupling of (XIII) with aryl iodide (VI) furnished the title compound.
| 【1】 Guerry, P.; Locher, H.H.; Hubschwerlen, C.; Wyss, P.C.; Jolidon, S.; Hartman, P.G.; Stalder, H.; Specklin, J.L.; Anti-MRSA dihydrofolate reductase inhibitors: Synthesis and SAR. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F1800. |
| 【2】 Guerry, P.; Stalder, H.; Wyss, P.-C. (F. Hoffmann-La Roche AG); 2,4-Diaminopyrimidine derivs.. EP 0901488; JP 1999511749; US 5866583; WO 9743277 . |
| 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) | 40643 | 5-(3-iodo-4,5-dimethoxybenzyl)-2,4-pyrimidinediamine; 2-amino-5-(3-iodo-4,5-dimethoxybenzyl)-4-pyrimidinylamine | C13H15IN4O2 | 详情 | 详情 | |
| (VII) | 40644 | ethyl 2-pyridinecarboxylate | 2524-52-9 | C8H9NO2 | 详情 | 详情 |
| (VIII) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (IX) | 40645 | N-phenethyl-2-pyridinecarboxamide | C14H14N2O | 详情 | 详情 | |
| (X) | 40646 | 1-(2-pyridinyl)-3,4-dihydroisoquinoline | C14H12N2 | 详情 | 详情 | |
| (XI) | 40647 | (1R)-1-(2-pyridinyl)-1,2,3,4-tetrahydroisoquinoline | C14H14N2 | 详情 | 详情 | |
| (XII) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XIII) | 40648 | 1-[(1R)-1-(2-pyridinyl)-3,4-dihydro-2(1H)-isoquinolinyl]-2-propen-1-one | C17H16N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Methylation of 5-iodovanillin (I) with dimethyl sulfate and K2CO3 afforded dimethoxy derivative (II). This was condensed with 3-anilinopropionitrile (III) in the presence of potassium tert-butoxide yielding the enamino nitrile (IV). Subsequent cyclization of (IV) with guanidine hydrochloride (V) produced diaminopyrimidine (VI). Cinnamate derivative (VIII) was then obtained by palladium-catalyzed coupling of (VI) with ethyl acrylate (VII).
| 【1】 Guerry, P.; Locher, H.H.; Hubschwerlen, C.; Wyss, P.C.; Jolidon, S.; Hartman, P.G.; Stalder, H.; Specklin, J.L.; Anti-MRSA dihydrofolate reductase inhibitors: Synthesis and SAR. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F1800. |
| 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) | 12758 | 4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin | 5438-36-8 | C8H7IO3 | 详情 | 详情 |
| (II) | 40641 | 3-iodo-4,5-dimethoxybenzaldehyde | 32024-15-0 | C9H9IO3 | 详情 | 详情 |
| (III) | 27195 | 3-anilinopropanenitrile | 1075-76-9 | C9H10N2 | 详情 | 详情 |
| (IV) | 40642 | (Z)-3-anilino-2-(3-iodo-4,5-dimethoxybenzyl)-2-propenenitrile | C18H17IN2O2 | 详情 | 详情 | |
| (V) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (VI) | 40643 | 5-(3-iodo-4,5-dimethoxybenzyl)-2,4-pyrimidinediamine; 2-amino-5-(3-iodo-4,5-dimethoxybenzyl)-4-pyrimidinylamine | C13H15IN4O2 | 详情 | 详情 | |
| (VII) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (VIII) | 40649 | ethyl (E)-3-[5-[(2,4-diamino-5-pyrimidinyl)methyl]-2,3-dimethoxyphenyl]-2-propenoate | C18H22N4O4 | 详情 | 详情 |