|
【结 构 式】 
|
【分子编号】21486 【品名】2,4-difluorophenol 【CA登记号】367-27-1 |
【 分 子 式 】C6H4F2O 【 分 子 量 】130.0939664 【元素组成】C 55.4% H 3.1% F 29.21% O 12.3% |
合成路线1
该中间体在本合成路线中的序号：(A)The acetylation of 5-aminoindane (I) with acetic anhydride gives N-(5-indanyl)acetamide (II), which is nitrated with HNO3 in glacial acetic acid yielding N-(6-nitro-5-indanyl)acetamide (III) and a small amount of the isomer (IV). The product (III) is hydrolyzed with HCl to 6-nitro-5-indanylamine (V). This nitroamine can also be obtained by nitration of 5-aminoindane (I). The Sandmeyer reaction of 6-nitro-5-indanylamine (V) with HNO2 and CuBr/NaBr in HBr leads to 6-nitro-5-bromoindane (VI), which reacts with 2,4-difluorophenol in the presence of KOC(CH3)3/CuCl in tert-butanol to yield 6-nitro-5-(2,4-difluorophenoxy)indane (VII). Starting from (VII), CGP-28238 can be prepared by two different routes: a) Condensation of (VII) with tert-butoxy-bis(dimethylamino)methane followed by ozonolysis of the enamine (VIII), and reduction of the nitro group using Raney-Ni and hydrazine hydrate yields 5-amino-6-(2,4-difluorophenoxy)-1-indanone (X). In the last step the intermediate (X) is mesylated with mesylchloride to give CGP-28238. b) Reduction of (VII) using Raney-Ni and hydrazine hydrate gives 5-amino-6-(2,4-difluorophenoxy)indane (XI), which is acetylated with acetic anhydride and oxidized with CrO3 to yield a mixture of indanone (XII) and (XIII). Chromatographic separation and hydrolysis of (XII) with HCl in ethanol gives 5-amino-6-(2,4-difluorophenoxy)-1-indanone (X), which can be mesylated, as before, to CGP-28238.
| 【1】 Schroder, E.; Rufer, C.; Bottcher, I.; Kapp, J.-F. (Schering AG); Novel indanyl derivs., their preparation and use. EP 0056956; US 4375479 . |
| 【2】 Rufer, C.; Bahlmann, F.; Schroder, E.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 8. Antii. Eur J Med Chem 1982, 17, 1, 173-80. |
| 【3】 Schroder, E.; Lehmann, M.; Rufer, C.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 6. Antii. Eur J Med Chem 1982, 17, 1, 35-42. |
| 【4】 Wiesenberg, I.; Ferrini, P.G.; CGP-28238. Drugs Fut 1989, 14, 11, 1035. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 21486 | 2,4-difluorophenol | 367-27-1 | C6H4F2O | 详情 | 详情 |
| (B) | 21487 | N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine | C9H22N2O | 详情 | 详情 | |
| (I) | 21473 | 5-indanamine; 2,3-dihydro-1H-inden-5-ylamine | 24425-40-9 | C9H11N | 详情 | 详情 |
| (II) | 21474 | N-(2,3-dihydro-1H-inden-5-yl)acetamide | C11H13NO | 详情 | 详情 | |
| (III) | 21475 | N-(6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide | C11H12N2O3 | 详情 | 详情 | |
| (IV) | 21476 | N-(4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide | C11H12N2O3 | 详情 | 详情 | |
| (V) | 21477 | 6-nitro-2,3-dihydro-1H-inden-5-ylamine; 6-nitro-5-indanamine | C9H10N2O2 | 详情 | 详情 | |
| (VI) | 21478 | 5-bromo-6-nitroindane | C9H8BrNO2 | 详情 | 详情 | |
| (VII) | 21479 | 5-(2,4-difluorophenoxy)-6-nitroindane | C15H11F2NO3 | 详情 | 详情 | |
| (VIII) | 21480 | N-[[6-(2,4-difluorophenoxy)-5-nitro-2,3-dihydro-1H-inden-1-ylidene]methyl]-N,N-dimethylamine | C18H16F2N2O3 | 详情 | 详情 | |
| (IX) | 21481 | 6-(2,4-difluorophenoxy)-5-nitro-1-indanone | C15H9F2NO4 | 详情 | 详情 | |
| (X) | 21482 | 5-amino-6-(2,4-difluorophenoxy)-1-indanone | C15H11F2NO2 | 详情 | 详情 | |
| (XI) | 21483 | 6-(2,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-ylamine | C15H13F2NO | 详情 | 详情 | |
| (XII) | 21484 | N-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydro-1H-inden-5-yl]acetamide | C17H13F2NO3 | 详情 | 详情 | |
| (XIII) | 21485 | N-[6-(2,4-difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-5-yl]acetamide | C17H13F2NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)This compound has been obtained by two different ways: 1) The oxidation of 4'-amino-3'-chloroacetophenone (I) with NaNO2 and HCl in water gives 3'-chloro-4-nitroacetophenone (II), which is condensed with 2,4-difluorophenol (III) by means of K2CO3 in xylene yielding 3'-(2,4-difluorophenyl)-4'-nitroacetophenone (IV). The reduction of (IV) with Fe and NH4Cl in ethanol affords the corresponding 4'-amino compound (V), which is finally treated with methanesulfonyl chloride and pyridine. 2) The reaction of 4'-aminoacetophenone (VI) with methanesulfonyl chloride as before gives the corresponding sulfonamide (VII), which is brominated with Br2 in acetic acid yielding N-(4-acetyl-3-bromophenyl)methanesulfonamide (VIII). Finally, this compound is condensed with 2,4-difluorophenol (III) by means of K2CO3 and CuCl as before.
| 【1】 Zanka, A.; et al.; Process development of a novel anti-inflammatory agent. The regiospecific bromination of 4'-acetylmethanesulfonanilide. Org Process Res Dev 1998, 2, 2, 71. |
| 【2】 Tsuji, K.; et al.; Studies on antiinflammatory agents. I. Synthesis and pharmacological properties of 2'-phenoxymethanesulfonanilide derivatives. Chem Pharm Bull 1992, 40, 9, 2399. |
| 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) | 33161 | 1-(4-amino-3-chlorophenyl)-1-ethanone | C8H8ClNO | 详情 | 详情 | |
| (II) | 33162 | 1-(3-chloro-4-nitrophenyl)-1-ethanone | C8H6ClNO3 | 详情 | 详情 | |
| (III) | 21486 | 2,4-difluorophenol | 367-27-1 | C6H4F2O | 详情 | 详情 |
| (IV) | 33163 | 1-[3-(2,4-difluorophenoxy)-4-nitrophenyl]-1-ethanone | C14H9F2NO4 | 详情 | 详情 | |
| (V) | 33164 | 1-[4-amino-3-(2,4-difluorophenoxy)phenyl]-1-ethanone | C14H11F2NO2 | 详情 | 详情 | |
| (VI) | 27847 | 1-(4-aminophenyl)-1-ethanone | 99-92-3 | C8H9NO | 详情 | 详情 |
| (VII) | 33165 | N-(4-acetylphenyl)methanesulfonamide | C9H11NO3S | 详情 | 详情 | |
| (VIII) | 33166 | N-(4-acetyl-2-bromophenyl)methanesulfonamide | C9H10BrNO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Synthesis of intermediate (XI): Treatment of 2,4-difluorophenol (I) with triethylamine and ethyl chloroformate (II) in dichloromethane yields O-ethoxycarbonyl-2,4-difluorophenol (III), which is then nitrated by means of HNO3/H2SO4 and hydrolyzed with Na2CO3 or NaHCO3 in MeOH/H2O to provide (IV). The nitro group of (IV) is then hydrogenated over Pd/C in EtOAc to afford 5-amino-2,4-difluorophenol (V), which is N-protected by reaction with pivaloyl chloride (VI) in pyridine to furnish pivaloylamino derivative (VII). Treatment of (VII) with 3,4-dihydro-2H pyran (VIII) and camphorsulfonic acid (CSA) in dichloromethane gives O-protected derivative (IX), which is converted into ethyl benzoate (X) by first reaction in THF with hexamethylphosphoric triamide (HMPA) and n-BuLi in hexane, followed by treatment with ethyl chloroformate (II). Finally, methylation of (X) by means of iodomethane (MeI) and LDA in THF/hexane yields intermediate (XI). Alternatively, intermediate (XI) can be also obtained by following this pathway: lithiation of derivative (IX) with LDA followed by treatment with TMSCl in THF affords trimethylsilylated compound (XII), which is converted into ethyl benzoate (XIII) by reaction with BuLi and ethyl chloroformate (II). Finally, TMS removal of (XIII) is achieved by treatment with tetrabutyl ammonium fluoride (TBAF) in THF to furnish derivative (X), which is methylated as described above.
| 【1】 Akama, T.; et al.; Synthesis of an ethyl 6-amino-3,5-difluorosalicylate derivative by sequential regioselective direct ortho-metalation; a practical synthesis of 4',5-diamino-3',6,8-trifluoroflavone, a potent antitumor agent. Synthesis 1997, 1446. |
| 【2】 Saito, H.; Ishida, H.; Akama, T.; Kimura, U.; Gomi, K.; Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent. J Med Chem 1998, 41, 12, 2056. |
| 【3】 Akama, T.; Ikeda, S.; Ishida, H.; Kimura, U.; Gomi, K.; Saito, H. (Kyowa Hakko Kogyo Co., Ltd.); 5-Aminoflavone derivs., their preparation and their use as antibacterial, anti-estrogenic and/or antitumor agent. EP 0638566; JP 1995109268 . |
| 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) | 21486 | 2,4-difluorophenol | 367-27-1 | C6H4F2O | 详情 | 详情 |
| (II) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (III) | 46822 | 2,4-difluorophenyl ethyl carbonate | C9H8F2O3 | 详情 | 详情 | |
| (IV) | 46823 | 2,4-difluoro-5-nitrophenol | C6H3F2NO3 | 详情 | 详情 | |
| (V) | 46824 | 5-amino-2,4-difluorophenol | C6H5F2NO | 详情 | 详情 | |
| (VI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VII) | 46825 | N-(2,4-difluoro-5-hydroxyphenyl)-2,2-dimethylpropanamide | C11H13F2NO2 | 详情 | 详情 | |
| (VIII) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (IX) | 46826 | N-[2,4-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,2-dimethylpropanamide | C16H21F2NO3 | 详情 | 详情 | |
| (X) | 46827 | ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-6-(tetrahydro-2H-pyran-2-yloxy)benzoate | C19H25F2NO5 | 详情 | 详情 | |
| (XI) | 46828 | ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)benzoate | C20H27F2NO5 | 详情 | 详情 | |
| (XII) | 46829 | N-[2,4-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)-3-(trimethylsilyl)phenyl]-2,2-dimethylpropanamide | C19H29F2NO3Si | 详情 | 详情 | |
| (XIII) | 46830 | ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-6-(tetrahydro-2H-pyran-2-yloxy)-4-(trimethylsilyl)benzoate | C22H33F2NO5Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Alkylation of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (I) with 1,3-dibromopropane (II) in the presence of K2CO3 produced the bromopropyl ether (III). Subsequent displacement of the remaining bromine of (III) with 3-picolylamine (IV) furnished the secondary amine (V). The ester group of (V) was then reduced to alcohol (VI) with LiAlH4. Finally, Mitsunobu coupling of alcohol (VI) with 2,4-difluorophenol (VII) in the presence of 1,1'-(azodicarbonyl)dipiperidine and tributylphosphine gave rise to the target difluorophenyl ether.
| 【1】 Ebiike, H.; Masubuchi, M.; Liu, P.; Kawasaki, K.,-I.; Morikami, K.; Sogabe, S.; Hayase, M.; Fujii, T.; Sakata, K.; Shindoh, H.; Shiratori, Y.; Aoki, Y.; Ohtsuka, T.; Shimma, N.; Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 2. Bioorg Med Chem Lett 2002, 12, 4, 607. |
| 【2】 Fujii, T.; Tsujii, S.; Liu, P.; Ohtsuka, T.; Ebiike, H.; Masubuchi, M.; Aoki, Y.; Kawasaki, K. (F. Hoffmann-La Roche AG); Novel bicyclic cpds.. US 6376491; WO 0037464 . |
| 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) | 52126 | ethyl 4-hydroxy-3-methyl-1-benzofuran-2-carboxylate | C12H12O4 | 详情 | 详情 | |
| (II) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (III) | 52127 | ethyl 4-(3-bromopropoxy)-3-methyl-1-benzofuran-2-carboxylate | C15H17BrO4 | 详情 | 详情 | |
| (IV) | 18731 | 3-pyridinylmethanamine; 3-pyridinylmethylamine | 3731-52-0 | C6H8N2 | 详情 | 详情 |
| (V) | 52875 | ethyl 3-methyl-4-{3-[(3-pyridinylmethyl)amino]propoxy}-1-benzofuran-2-carboxylate | C21H24N2O4 | 详情 | 详情 | |
| (VI) | 52876 | (3-methyl-4-{3-[(3-pyridinylmethyl)amino]propoxy}-1-benzofuran-2-yl)methanol | C19H22N2O3 | 详情 | 详情 | |
| (VII) | 21486 | 2,4-difluorophenol | 367-27-1 | C6H4F2O | 详情 | 详情 |