【结 构 式】 |
【分子编号】25468 【品名】tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate 【CA登记号】 |
【 分 子 式 】C23H31NO5 【 分 子 量 】401.50288 【元素组成】C 68.8% H 7.78% N 3.49% O 19.92% |
合成路线1
该中间体在本合成路线中的序号:(VIII)2-Chloro-4-propionylpyridine (I) was protected as the cyclic ketal (II) with 1,3-propanediol and p-toluenesulfonic acid in refluxing toluene with azeotropical removal of water. Subsequent halogen displacement in (II) with sodium methoxide in boiling acetonitrile gave methoxypyridine (III). Lithiation of (III) with mesityllithium, followed by condensation with dimethylformamide provided formylpyridine (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. The hydroxyl group of (V) was protected as the benzyl ether (VI), and the ketal group was then hydrolyzed to ketone (VII) with aqueous trifluoroacetic acid. Reformatskii reaction of (VII) with tert-butyl bromoacetate and zinc afforded the beta-hydroxyester (VIII). Further hydrogenolysis of benzyl ether of (VIII) over Pd/C gave alcohol (IX). Then, treatment of (IX) with trifluoroacetic acid produced lactone (X), and hydrolysis of the methoxy group of (X) with aqueous HCl furnished pyridone (XI). Condensation of 3,4-difluoroacetanilide (XII) with Vilsmeier reagent yielded quinolinecarboxaldehyde (XIII), which was reduced to alcohol (XIV) with NaBH4. This was then coupled with pyridone (XI) under Mitsunobu conditions to give (XV). Finally, Heck reaction of (XV) with palladium acetate and triphenyl phosphine generated the target pentacyclic compound.
【1】 Lavergne, O.; Lesuer-Ginot, L.; Pla Rodas, F.; Kasprzyk, P.G.; Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D.C.; Homocamptothecins: Synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem 1998, 41, 27, 5410. |
【2】 Bigg, D.; Lavergne, O.; Pla Rodas, F.; Pommier, J.; Ulibarri, G. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Novel camptothecin analogues, preparation methods therefor, use thereof as drugs, and pharmaceutical compsns. containing said analogues. EP 0835258; JP 1999508249; US 5981542; WO 9700876 . |
【3】 Lanco, C.; Rolland, A.; Bigg, D.; Lavergne, O.; Harnett, J.; Liberatore, A.-M. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Pro-drugs and counterparts of camptothecin, their application as medicines . EP 0946566; WO 9828304 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 | |
17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
(I) | 25461 | 1-(2-chloro-4-pyridinyl)-1-propanone | C8H8ClNO | 详情 | 详情 | |
(II) | 25462 | 2-chloro-4-(2-ethyl-1,3-dioxan-2-yl)pyridine | C11H14ClNO2 | 详情 | 详情 | |
(III) | 25463 | 4-(2-ethyl-1,3-dioxan-2-yl)-2-pyridinyl methyl ether; 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine | C12H17NO3 | 详情 | 详情 | |
(IV) | 25464 | 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxynicotinaldehyde | C13H17NO4 | 详情 | 详情 | |
(V) | 25465 | [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methanol | C13H19NO4 | 详情 | 详情 | |
(VI) | 25466 | 3-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine; benzyl [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methyl ether | C20H25NO4 | 详情 | 详情 | |
(VII) | 25467 | 1-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-1-propanone | C17H19NO3 | 详情 | 详情 | |
(VIII) | 25468 | tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate | C23H31NO5 | 详情 | 详情 | |
(IX) | 25469 | tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate | C16H25NO5 | 详情 | 详情 | |
(X) | 25470 | 5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H15NO4 | 详情 | 详情 | |
(XI) | 25471 | 5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H13NO4 | 详情 | 详情 | |
(XII) | 25472 | N-(3,4-difluorophenyl)acetamide | 458-11-7 | C8H7F2NO | 详情 | 详情 |
(XIII) | 25473 | 2-chloro-6,7-difluoro-3-quinolinecarbaldehyde | C10H4ClF2NO | 详情 | 详情 | |
(XIV) | 25474 | (2-chloro-6,7-difluoro-3-quinolinyl)methanol | C10H6ClF2NO | 详情 | 详情 | |
(XV) | 25475 | 8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C21H17ClF2N2O4 | 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 synthesis of the intermediate oxepinopyridinone (VI) is detailed in Scheme 27517601a: The racemic acid (II), obtained by cleavage of tert-butyl ester (I) with trifluoroacetic acid, was resolved with quinidine to furnish the required (+)-(R)-enantiomer (III). Subsequent debenzylation of (III) by transfer hydrogenation with ammonium formate and Pd/C gave alcohol (IV), which was cyclized to the corresponding lactone (V) employing DCC in hot THF. Dealkylation of the methyl ether group by means of iodotrimethylsilane, generated from Me3SiCl and NaI, produced the intermediate pyridinone (VI).
【1】 Coulomb, H.; Huchet, M.; Harnett, J.; Rolland, A.; Lanco, C.; Lavergne, O.; Demarquay, D.; Lesueur-Ginot, L.; Bigg, D.C.H.; BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 1999, 9, 17, 2599. |
【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 . |
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) | 25468 | tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate | C23H31NO5 | 详情 | 详情 | |
(II) | 33096 | 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoic acid | C19H23NO5 | 详情 | 详情 | |
(III) | 33097 | (3R)-3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoic acid | C19H23NO5 | 详情 | 详情 | |
(IV) | 33098 | (3R)-3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoic acid | C12H17NO5 | 详情 | 详情 | |
(V) | 33099 | (5R)-5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H15NO4 | 详情 | 详情 | |
(VI) | 33100 | (5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H13NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)The synthesis of the intermediate oxepinopyridinone (VI) is detailed in Scheme 27517701a: The racemic acid (II), obtained by cleavage of tert-butyl ester (I) with trifluoroacetic acid, was resolved with quinidine to furnish the required (+)-(R)-enantiomer (III). Subsequent debenzylation of (III) by transfer hydrogenation with ammonium formate and Pd/C gave alcohol (IV), which was cyclized to the corresponding lactone (V) employing DCC in hot THF. Dealkylation of the methyl ether group by means of iodotrimethylsilane, generated from Me3SiCl and NaI, produced the intermediate pyridinone (VI).
【1】 Coulomb, H.; Huchet, M.; Harnett, J.; Rolland, A.; Lanco, C.; Lavergne, O.; Demarquay, D.; Lesueur-Ginot, L.; Bigg, D.C.H.; BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 1999, 9, 17, 2599. |
【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 . |
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) | 25468 | tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate | C23H31NO5 | 详情 | 详情 | |
(II) | 33096 | 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoic acid | C19H23NO5 | 详情 | 详情 | |
(III) | 33097 | (3R)-3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoic acid | C19H23NO5 | 详情 | 详情 | |
(IV) | 33098 | (3R)-3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoic acid | C12H17NO5 | 详情 | 详情 | |
(V) | 33099 | (5R)-5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H15NO4 | 详情 | 详情 | |
(VI) | 33100 | (5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H13NO4 | 详情 | 详情 |