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【结 构 式】

【分子编号】25461

【品名】1-(2-chloro-4-pyridinyl)-1-propanone

【CA登记号】

【 分 子 式 】C8H8ClNO

【 分 子 量 】169.61036

【元素组成】C 56.65% H 4.75% Cl 20.9% N 8.26% O 9.43%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(I)

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
Extended Information