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【结 构 式】 
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【药物名称】LM-1484 【化学名称】(E)-8-[2-[4-(4-Phenylbutoxy)phenyl]vinyl]-2-(1H-tetrazol-5-yl)-4H-benzopyran-4-one 【CA登记号】197506-02-8 【 分 子 式 】C28H24N4O3 【 分 子 量 】464.52848 |
【开发单位】Menarini (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Leukotriene CysLT1 (LTD4) Antagonists |
合成路线1
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
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 |