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【结 构 式】 
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【分子编号】42876 【品名】methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate 【CA登记号】 |
【 分 子 式 】C22H20N2O6 【 分 子 量 】408.41068 【元素组成】C 64.7% H 4.94% N 6.86% O 23.5% |
合成路线1
该中间体在本合成路线中的序号：(IV)The common intermediate (IV) was obtained by coupling of 4-formylbenzoic acid (I) with methyl 2-L-amino-5-phthalimidopentanoate.HCl (III) via the mixed anhydride (II).
| 【1】 Rosowsky, A.; Vaidya, C.M.; Wright, J.E.; Forsch, R.A.; Bader, H.; Analogues of the potent nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity. J Med Chem 2000, 43, 8, 1620. |
| 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) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (II) | 42874 | C13H14O5 | 详情 | 详情 | ||
| (III) | 42875 | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C14H16N2O4 | 详情 | 详情 | |
| (IV) | 42876 | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate | C22H20N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The first synthetic method started from 2,4-diamino-6-(hydroxymethyl)-pteridine (V). Conversion of (V) into the corresponding bromide (VI) was achieved by treatment with triphenylphosphine dibromide. Ylide (VII) was then prepared by reaction of bromide (VI) with triphenylphosphine, followed by deprotonation using potassium tert-butoxide. Wittig reaction between ylide (VII) and aldehyde (IV) produced the olefin (VIII), assumed to be a mixture of geometric isomers. Catalytic hydrogenation of olefin (VIII), followed by reoxidation of the pteridine ring with H2O2, yielded (IX). Finally, hydrolysis of (IX) with NaOH gave rise to the title compound.
| 【1】 Rosowsky, A.; Vaidya, C.M.; Wright, J.E.; Forsch, R.A.; Bader, H.; Analogues of the potent nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity. J Med Chem 2000, 43, 8, 1620. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 42878 | methyl (2S)-2-([4-[(E)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H26N8O5 | 详情 | 详情 | |
| (VIIIb) | 42879 | methyl (2S)-2-([4-[(Z)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H26N8O5 | 详情 | 详情 | |
| (IV) | 42876 | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate | C22H20N2O6 | 详情 | 详情 | |
| (V) | 20068 | (2,4-diamino-6-pteridinyl)methanol | 945-24-4 | C7H8N6O | 详情 | 详情 |
| (VI) | 11006 | 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine | 52853-40-4 | C7H7BrN6 | 详情 | 详情 |
| (VII) | 42877 | triphenyl-N-[2-[(triphenylphosphoranylidene)amino]-6-[(triphenylphosphoranylidene)methyl]-4-pteridinyl]phosphine imide; 2,4-bis[(triphenylphosphoranylidene)amino]-6-[(triphenylphosphoranylidene)methyl]pteridine | C61H47N6P3 | 详情 | 详情 | |
| (IX) | 42880 | methyl (2S)-2-([4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H28N8O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)An alternative route involved a Wittig reaction between aldehyde (IV) and ylide (XI), generated from 2-amino-3-cyanopyrazin-5-ylmethyltriphenylphosphonium chloride (X). The resulting adduct (XII) was then cyclized and partly hydrolyzed to pteridine (XIV) upon refluxing with guanidine (XIII) in MeOH. Catalytic hydrogenation and further reoxidation of (XIV) yielded (XV). The methyl ester group of (XV) was finally hydrolyzed by treatment with NaOH in DMSO.
| 【1】 Rosowsky, A.; Vaidya, C.M.; Wright, J.E.; Forsch, R.A.; Bader, H.; Analogues of the potent nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity. J Med Chem 2000, 43, 8, 1620. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIa) | 42883 | methyl (2S)-2-([4-[(E)-2-(5-amino-6-cyano-2-pyrazinyl)ethenyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C28H24N6O5 | 详情 | 详情 | |
| (XIVa) | 42885 | 2-([[(4S)-4-([4-[(E)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-methoxy-5-oxopentyl]amino]carbonyl)benzoic acid | C29H28N8O6 | 详情 | 详情 | |
| (XIVb) | 42886 | 2-([[(4S)-4-([4-[(Z)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-methoxy-5-oxopentyl]amino]carbonyl)benzoic acid | C29H28N8O6 | 详情 | 详情 | |
| (XIIb) | 42887 | 2-([[(4S)-4-([4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoyl]amino)-5-methoxy-5-oxopentyl]amino]carbonyl)benzoic acid | C29H30N8O6 | 详情 | 详情 | |
| (IV) | 42876 | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate | C22H20N2O6 | 详情 | 详情 | |
| (X) | 42881 | [(5-amino-6-cyano-2-pyrazinyl)methyl](triphenyl)phosphonium chloride | C24H20ClN4P | 详情 | 详情 | |
| (XI) | 42882 | 3-amino-6-[(triphenylphosphoranylidene)methyl]-2-pyrazinecarbonitrile | C24H19N4P | 详情 | 详情 | |
| (XIII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (XV) | 42887 | 2-([[(4S)-4-([4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoyl]amino)-5-methoxy-5-oxopentyl]amino]carbonyl)benzoic acid | C29H30N8O6 | 详情 | 详情 |