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【结 构 式】 
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【分子编号】24135 【品名】2-hydroxy-1,2-diphenyl-1-ethanone; benzoin 【CA登记号】579-44-2 |
【 分 子 式 】C14H12O2 【 分 子 量 】212.24808 【元素组成】C 79.23% H 5.7% O 15.08% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of benzoin (I) with succinic anhydride (II) by heating at 120 C gives benzoin hemisuccinate (III), which is cyclized with ammonium acetate in refluxing acetic acid.
| 【1】 Brown, K. (Wyeth-Ayerst Laboratories); Oxazoles. GB 1206403; YU 244367; YU 249673 . |
| 【2】 Brown, K. (Wyeth-Ayerst Laboratories); Oxazoles. US 3578671 . |
| 【3】 Arrigoni-Martelli, E.; Castaner, J.; Oxaprozin. Drugs Fut 1978, 3, 7, 539. |
合成路线2
该中间体在本合成路线中的序号：(I)Condensation of benzoin (I) and phenylurea in a boiling mixture of glacial acetic acid and 63% hydrobromic acid yields 1,4,5-triphenyl-4-imidazolin-2-one (III), which can be converted to octimibate (VI) and octimibate sodium by two procedures (A, B): Procedure A: (III) is converted to 2-chloro-1,4,5-triphenylimidazole (II) on treatment with phosphorus oxytrichloride at 100 C. Octimibate is prepared by treatment of (II) with the dipotassium salt of 8-hydroxyoctanoic acid in boiling dimethylformamide. Procedure B: The sodium salt of (III) is formed by treatment with sodium hydride in dimetbylformamide. The reaction of this salt with 8-bromooctanoic acid ethyl ester gives 8-[(1,4,5-triphenylimidazol-2yl)oxy]octanoic acid ethyl ester (IV) after purification using column chromatography. Saponification of (IV) yields octimibate (V), which is converted to octimibate sodium.
| 【1】 Brekle, A.; Hilboll, G.; Lautenschlager, H.-H.; Prop, G.; Welter, A.; Winkelmann, J.; Zierenberg, O. (A. Nattermann & Cie. GmbH); Octanoic acids. DE 3228271; EP 0104342; US 4460598 . |
| 【2】 Niemann, R.; Lautenschlager, H.H.; Prop, G.; Octimibate Sodium. Drugs Fut 1986, 11, 1, 26. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 55672 | Phenylurea | C7H8N2O | 详情 | 详情 | ||
| 55673 | 8-Hydroxyoctanoic acid | C8H16O3 | 详情 | 详情 | ||
| 55674 | Ethyl 8-bromooctanoate; 8-Bromooctanoic acid ethyl ester | C10H19BrO2 | 详情 | 详情 | ||
| (I) | 24135 | 2-hydroxy-1,2-diphenyl-1-ethanone; benzoin | 579-44-2 | C14H12O2 | 详情 | 详情 |
| (II) | 24136 | 2-chloro-1,4,5-triphenyl-2,3-dihydro-1H-imidazole | C21H17ClN2 | 详情 | 详情 | |
| (III) | 24137 | 1,4,5-triphenyl-1,3-dihydro-2H-imidazol-2-one | C21H16N2O | 详情 | 详情 | |
| (IV) | 24138 | ethyl 8-[(1,4,5-triphenyl-1H-imidazol-2-yl)oxy]octanoate | C31H34N2O3 | 详情 | 详情 | |
| (V) | 24139 | 8-[(1,4,5-triphenyl-1H-imidazol-2-yl)oxy]octanal | C29H30N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)The reduction of benzoin (XIII) with NaBH4 in ethanol/water gives the diol (XIV), which by a pinacol rearrangement by means of H2SO4 in hot acetic acid yields the diphenylacetaldehyde (XXV). The cyclization of (XV) with methyl vinyl ketone (XVI) by means of KOH in ethanol affords the cyclohexenone (XVII), which is reduced first with H2 over Pd/C in THF and then with NaBH4 in ethanol/water giving the 4,4-diphenylcyclohexanol (IX). The reaction of (IX) with PCl3 in THF yields the dichlorophosphite (XVIII), which is treated with imidazole (XIX) in THF affording the bis imidophosphite (XX). The condensation of (XX) with the previously obtained penta tert-butyl acetate compound (VI) in THF/heptane gives the imidophosphite (XXI), which is oxidized with sodium periodate yielding the phosphoric acid diester (XXII). Finally, the hydrolysis of (XXII) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII).
| 【1】 Amedio, J.C. Jr.; et al.; A practical preparation of 4,4-diphenylcyclohexanol: A key intermediate in the synthesis of MS-325. Synth Commun 1998, 28, 20, 3895. |
| 【2】 Dunham, S.O.; Lauffer, R.B. (Epix Medical, Inc.); Contrast-enhanced diagnostic imaging method for monitoring interventional therapies. WO 9917809 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 30317 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-(hydroxymethyl)-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C35H65N3O11 | 详情 | 详情 | |
| (IX) | 30319 | 4,4-diphenylcyclohexanol | C18H20O | 详情 | 详情 | |
| (XII) | 30322 | 3,6,9-Tris(carboxymethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid | C33H44N3O14P | 详情 | 详情 | |
| (XIII) | 24135 | 2-hydroxy-1,2-diphenyl-1-ethanone; benzoin | 579-44-2 | C14H12O2 | 详情 | 详情 |
| (XIV) | 30331 | Hydrobenzoin; 1,2-diphenyl-1,2-ethanediol | 655-48-1 | C14H14O2 | 详情 | 详情 |
| (XV) | 30323 | 2,2-diphenylacetaldehyde | 947-91-1 | C14H12O | 详情 | 详情 |
| (XVI) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (XVII) | 30325 | 4,4-diphenyl-2-cyclohexen-1-one | C18H16O | 详情 | 详情 | |
| (XVIII) | 30326 | Dichlorophosphorous acid 4,4-diphenylcyclohexyl ester | C18H19Cl2OP | 详情 | 详情 | |
| (XIX) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (XX) | 30327 | 4,4-diphenylcyclohexyl di(1H-imidazol-1-yl)phosphinite | C24H25N4OP | 详情 | 详情 | |
| (XXI) | 30328 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(1-imidazolyl)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C56H86N5O12P | 详情 | 详情 | |
| (XXII) | 30329 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C53H84N3O14P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Treatment of benzoin (I) with methanesulfonyl chloride and LiCl, followed by condensation with thioacetamide afforded 2-methyl-3,4-diphenylthiazole (II). Subsequent selective chlorosulfonation at the most reactive 5-phenyl group of (II) provided sulfonyl chloride (III). This was finally converted to the target sulfonamide upon treatment with ammonium hydroxide.
| 【1】 Talley, J.J.; Carter, J.S.; Kramer, S.; et al.; Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1999, 9, 8, 1171. |
| 【2】 Talley, J.J.; Carter, J.S.; Collins, P.W.; Kramer, S.W.; Penning, T.D.; Rogier, D.J. Jr.; Rogers, R.S. (Pharmacia Corp.); Substd. thiazoles for the treatment of inflammation. EP 0772606; JP 1998504542; US 5668161; WO 9603392 . |