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【结 构 式】 
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【分子编号】27290 【品名】1-(2-hydroxy-3-iodophenyl)-1-ethanone 【CA登记号】 |
【 分 子 式 】C8H7IO2 【 分 子 量 】262.04685 【元素组成】C 36.67% H 2.69% I 48.43% O 12.21% |
合成路线1
该中间体在本合成路线中的序号：(VI)4-Bromophenol (I) was acetylated with Ac2O and Et3N, and the resulting 4-bromophenyl acetate (II) was rearranged to 5'-bromo-2'-hydroxyacetophenone (III) in the presence of AlCl3 at 120 C. Subsequent nitration of (III) produced the 3'-nitroacetophenone (IV). The catalytic hydrogenation of the nitro group of (IV), with simultaneous halogen hydrogenolysis, furnished 3'-amino-2'-hydroxyacetophe-none (V). Then, diazotization of the amine group of (V), followed by treatment with KI and Cu powder gave iodide (VI). Coupling of 4-phenyl-1-butanol (VII) with 4-hydroxybenzaldehyde (VIII) under Mitsunobu conditions provided 4-(4-phenylbutoxy)benzaldehyde (IX). Further Wittig reaction of (IX) with methylene triphenylphosphorane (X) gave the styrene (XI). This was condensed with the iodoacetophenone (VI) in the presence of Pd(OAc)2 to produce the stilbene derivative (XII). The benzopyranone (XIII) was prepared by condensation of hydroxyacetophenone (XII) with diethyl oxalate in the presence of NaOEt, followed by acid cyclization. After conversion of the ester function of (XIII) to the corresponding amide with methanolic ammonia, dehydration using POCl3 in DMF afforded nitrile (XIV). The required tetrazole ring was finally obtained by reaction with NaN3 and NH4Cl in DMF at 100 C.
| 【1】 Carganico, G.; Mauleon Casellas, D.; Pascual Avellana, J.; Garcia Perez, M.L.; Palomer Benet, A. (Menarini Industrie Farma Riunite srl); Benzopyran derivs. having leukotriene-antagonistic action. EP 0888327; ES 2127106; JP 2000506878; US 5990142; WO 9734885 . |
| 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) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (II) | 27286 | 4-bromophenyl acetate | C8H7BrO2 | 详情 | 详情 | |
| (III) | 27287 | 1-(5-bromo-2-hydroxyphenyl)-1-ethanone | 1450-75-5 | C8H7BrO2 | 详情 | 详情 |
| (IV) | 27288 | 1-(5-bromo-2-hydroxy-3-nitrophenyl)-1-ethanone | C8H6BrNO4 | 详情 | 详情 | |
| (V) | 27289 | 1-(3-amino-2-hydroxyphenyl)-1-ethanone | C8H9NO2 | 详情 | 详情 | |
| (VI) | 27290 | 1-(2-hydroxy-3-iodophenyl)-1-ethanone | C8H7IO2 | 详情 | 详情 | |
| (VII) | 27291 | 4-phenyl-1-butanol | 3360-41-6 | C10H14O | 详情 | 详情 |
| (VIII) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (IX) | 27292 | 4-(4-phenylbutoxy)benzaldehyde | C17H18O2 | 详情 | 详情 | |
| (X) | 27301 | methylene(triphenyl)phosphorane | C19H17P | 详情 | 详情 | |
| (XI) | 27293 | 1-(4-phenylbutoxy)-4-vinylbenzene | C18H20O | 详情 | 详情 | |
| (XII) | 27294 | 1-(2-hydroxy-3-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethenyl]phenyl)-1-ethanone | C26H26O3 | 详情 | 详情 | |
| (XIII) | 27295 | ethyl 4-oxo-8-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethenyl]-4H-chromene-2-carboxylate | C30H28O5 | 详情 | 详情 | |
| (XIV) | 27296 | 4-oxo-8-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethenyl]-4H-chromene-2-carbonitrile | C28H23NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)In a related synthesis, styrene (XV) was coupled with iodoacetophenone (VI) to afford stilbene (XVI). The benzopyranone system (XVII) was constructed by condensation with diethyl oxalate, followed by acid cyclization. Subsequent alkylation of the phenolic hydroxyl group with 4-phenylbutyl bromide (XVIII) gave the previously described ether (XIII), which was then converted into the target compound using the same reaction sequence as before.
| 【1】 Cabre,M.; Borras, L.; Pascual, J.; et al.; Novel stilbene derivatives as LTD4 antagonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.53. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIIII) | 27300 | 1-(4-bromobutyl)benzene; (4-bromobutyl)benzene | 13633-25-5 | C10H13Br | 详情 | 详情 |
| (VI) | 27290 | 1-(2-hydroxy-3-iodophenyl)-1-ethanone | C8H7IO2 | 详情 | 详情 | |
| (XIII) | 27295 | ethyl 4-oxo-8-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethenyl]-4H-chromene-2-carboxylate | C30H28O5 | 详情 | 详情 | |
| (XIV) | 27296 | 4-oxo-8-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethenyl]-4H-chromene-2-carbonitrile | C28H23NO3 | 详情 | 详情 | |
| (XV) | 27297 | 4-vinylphenyl acetate | 2628-16-2 | C10H10O2 | 详情 | 详情 |
| (XVI) | 27298 | 4-[(E)-2-(3-acetyl-2-hydroxyphenyl)ethenyl]phenyl acetate | C18H16O4 | 详情 | 详情 | |
| (XVII) | 27299 | ethyl 8-[(E)-2-(4-hydroxyphenyl)ethenyl]-4-oxo-4H-chromene-2-carboxylate | C20H16O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Reduction of 3-(4-fluorobenzoyl)propionic acid (I) by means of AlCl3 in CH2Cl2 and borane/tert-butylamine complex yields alcohol (II), which is then converted into aldehyde (IV) by reaction with 4-hydroxybenzaldehyde (III) in presence of PPh3 in THF and diethyl azodicarboxylate. Treatment of (IV) with a solution of methyltriphenylphosphonium bromide in THF and a solution of n-BuLi in hexane affords styrene derivative (V), which couples with 2’-hydroxy-3’-iodoacetophenone (VI) in presence of Et3N and Pd(OAc)2 in CH3CN to provide (VII). Cyclization of (VII) by means of a first treatment with NaOEt in EtOH followed by reaction with diethyl oxalate in Et2O/EtOH yields benzopyrane derivative (VIII) which is then hydrolyzed with NaOH in THF/MeOH to give (IX). Carboxylic acid (IX) is first converted into carboxamide (X) by treatment with a saturated NH3 solution in MeOH and then into carbonitrile (XI) by means of POCl3 in DMF. Finally, treatment of (XI) with a solution of NaN3, NH4Cl and DMF leads to the formation of the desired product.
| 【1】 Carganico, G.; Mauleon Casellas, D.; Pascual Avellana, J.; Garcia Perez, M.L.; Palomer Benet, A. (Menarini Industrie Farma Riunite srl); Benzopyran derivs. having leukotriene-antagonistic action. EP 0888327; ES 2127106; JP 2000506878; US 5990142; WO 9734885 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (A) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (I) | 39863 | 4-(4-fluorophenyl)-4-oxobutyric acid | 366-77-8 | C10H9FO3 | 详情 | 详情 |
| (II) | 41474 | 4-(4-fluorophenyl)-1-butanol | C10H13FO | 详情 | 详情 | |
| (III) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (IV) | 41475 | 4-[4-(4-fluorophenyl)butoxy]benzaldehyde | C17H17FO2 | 详情 | 详情 | |
| (V) | 41476 | 1-fluoro-4-[4-(4-vinylphenoxy)butyl]benzene; 4-(4-fluorophenyl)butyl 4-vinylphenyl ether | C18H19FO | 详情 | 详情 | |
| (VI) | 27290 | 1-(2-hydroxy-3-iodophenyl)-1-ethanone | C8H7IO2 | 详情 | 详情 | |
| (VII) | 41477 | 1-[3-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-2-hydroxyphenyl]-1-ethanone | C26H25FO3 | 详情 | 详情 | |
| (VIII) | 41478 | ethyl 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxylate | C30H27FO5 | 详情 | 详情 | |
| (IX) | 41479 | 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxylic acid | C28H23FO5 | 详情 | 详情 | |
| (X) | 41480 | 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxamide | C28H24FNO4 | 详情 | 详情 | |
| (XI) | 41481 | 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carbonitrile | C28H22FNO3 | 详情 | 详情 |