【结 构 式】 |
【分子编号】41739 【品名】3-phenyl-2-propynal 【CA登记号】2579-22-8 |
【 分 子 式 】C9H6O 【 分 子 量 】130.14604 【元素组成】C 83.06% H 4.65% O 12.29% |
合成路线1
该中间体在本合成路线中的序号:(VI)A new practical synthesis of FK-453, suitable for large scale manufacture is described: Bromination of cinnamic aldehyde (I) with Br2 in HOAc gives the dibromoderivative (II), which is treated with NaHSO3 and triethylamine yielding alpha-bromocinnamic aldehyde (III). The reaction of (III) with triethyl orthoformate affords the corresponding acetal (IV), which is treated with KOH in hot ethanol to give the acetylenic acetal (V). Acidic hydrolysis of the acetal (V) with sulfuric acid in refluxing water affords phenylpropargyl aldehyde (VI), which by a Horner-Emmons condensation with the phosphonate (VII) by means of KOH in DMSO gives 5-phenylpent-2(E)-en-4-ynoic acid ethyl ester (VIII). The 1,3-dipolar cycloaddition of (VIII) with 1-aminopyridinium iodide (IX) by means of KOH and K2CO3 in the same solvent yields 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (X), which is hydrolyzed with NaOH in hot methanol affording the corresponding free acid (XI). Reaction of (XI) with SOCl2 and DMF gives the activated acyl chloride (XII), which is condensed with the silylated chiral piperidineethanol (XIII) [obtained by silylation of the chiral piperidineethanol (XIV) with N,N'-bis(trimethylsilyl)urea (BSU)] by means of Et3N and DMAP in CH2Cl2, yielding the silylated target compound (XV). Finally, this compound is desilylated by means of K2CO3 in methanol.
【1】 Morinaga, Y.; Zanka, A.; Uematsu, R.; Yamazaki, H.; Yasuda, H.; Process development of a novel-xanthine adenosine A1 receptor antagonist. Org Process Res Dev 1999, 3, 6, 389. |
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) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
(II) | 41735 | 2,3-dibromo-3-phenylpropanal | C9H8Br2O | 详情 | 详情 | |
(III) | 41736 | (Z)-2-bromo-3-phenyl-2-propenal | 5443-49-2 | C9H7BrO | 详情 | 详情 |
(IV) | 41737 | (Z)-2-bromo-1-ethoxy-3-phenyl-2-propenyl ethyl ether; 1-[(Z)-2-bromo-3,3-diethoxy-1-propenyl]benzene | C13H17BrO2 | 详情 | 详情 | |
(V) | 41738 | 1-(3,3-diethoxy-1-propynyl)benzene; 1-ethoxy-3-phenyl-2-propynyl ethyl ether | 6142-95-6 | C13H16O2 | 详情 | 详情 |
(VI) | 41739 | 3-phenyl-2-propynal | 2579-22-8 | C9H6O | 详情 | 详情 |
(VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
(VIII) | 41740 | ethyl (E)-5-phenyl-2-penten-4-ynoate | C13H12O2 | 详情 | 详情 | |
(IX) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
(X) | 13273 | methyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C17H14N2O2 | 详情 | 详情 | |
(XI) | 13274 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid | C16H12N2O2 | 详情 | 详情 | |
(XII) | 13275 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride | C16H11ClN2O | 详情 | 详情 | |
(XIII) | 41741 | (2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidine; 2-[(2R)piperidinyl]ethyl trimethylsilyl ether | C10H23NOSi | 详情 | 详情 | |
(XIV) | 13276 | 2-[(2R)Piperidinyl]-1-ethanol | C7H15NO | 详情 | 详情 | |
(XV) | 41742 | (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1-((2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidinyl)-2-propen-1-one | C26H33N3O2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(II)Phenylenediamine (I) was condensed with phenylpropargyl aldehyde (II) in the presence of formic acid to generate the benzimidazole derivative (III). Subsequent N-alkylation of (III) with trimethyloxonium tetrafluoroborate gave the title benzimidazolium salt.
【1】 Kerwin, S.M.; et al.; DNA cleavage chemistry of 1-methyl-2-phenylethynyl-3-(prop-2-ynyl)-3H-benzoimidazolium salts. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 146. |
【2】 David, W.M.; et al.; Synthesis of a heterocyclic aza-enediyne and its DNA-cleavage properties. Bioorg Med Chem Lett 2000, 10, 22, 2509. |
【3】 Kerwin, S.M.; David, W. (Research Development Foundation ; University of Texas System); Novel DNA-cleaving antitumor agents. EP 1109552; US 6297284; WO 0003709; WO 0170217 . |