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【结 构 式】 
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【分子编号】33067 【品名】2-amino-5-nitrophenol 【CA登记号】121-88-0 |
【 分 子 式 】C6H6N2O3 【 分 子 量 】154.12532 【元素组成】C 46.76% H 3.92% N 18.18% O 31.14% |
合成路线1
该中间体在本合成路线中的序号：(I)The diazonium salt prepared from 2-amino-5-nitrophenol (I) was subjected to Sandmeyer reaction in the presence of HCl and CuCl to afford the chlorophenol derivative (II). Subsequent alkylation of phenol (II) with prenyl bromide (III) produced ether (IV). Amine (V) was then obtained by reduction of the nitro group of (IV) employing iron powder in the presence of HCl.
| 【1】 Brouwer, W.G.; Osika, E.M.; Pierce, B.J. (Uniroyal Chemical Company, Inc.); Furan- and thiophenecarbothioamide derivs., their preparation and their use as inhibitors of the replication of HIV-1 and HIV-1 mutants. EP 0874839; JP 1999504657; US 5696151; WO 9719940 . |
| 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) | 33067 | 2-amino-5-nitrophenol | 121-88-0 | C6H6N2O3 | 详情 | 详情 |
| (II) | 56028 | 2-chloro-5-nitrophenol | 619-10-3 | C6H4ClNO3 | 详情 | 详情 |
| (III) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (IV) | 56029 | 1-chloro-2-[(3-methyl-2-butenyl)oxy]-4-nitrobenzene; 2-chloro-5-nitrophenyl 3-methyl-2-butenyl ether | C11H12ClNO3 | 详情 | 详情 | |
| (V) | 56030 | 4-chloro-3-[(3-methyl-2-butenyl)oxy]phenylamine; 4-chloro-3-[(3-methyl-2-butenyl)oxy]aniline | C11H14ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Benzoxazinone (IV) was prepared by condensation of 2-amino-5-nitrophenol (I) with either chloroacetyl chloride (II) in the presence of NaHCO3 or ethyl bromoacetate (III) in the presence of KF. Subsequent N-alkylation of (IV) with iodomethane provided (V). After reduction of the nitro group of (V) to amine (VI) by hydrogenation over Pd/C, condensation with benzyl chloroformate afforded carbamate (VII). The chiral oxazolidinone (IX) was obtained by reaction of (VII) with (-)-(R)-glycidyl butyrate (VIII) in the presence of butyllithium in THF at low temperature. Conversion of (IX) to mesylate, followed by displacement with NaN3 gave azide (X). Amine (XI) was then obtained by either hydrogenation of (X) over Pd/C or by reduction with trimethyl phosphite. Finally, reaction of (XI) with acetyl chloride and triethylamine provided the title acetamide.
| 【1】 Haebich, D.; Haerter, M.; Bartel, S.; Riedl, B.; Stolle, A.; Raddatz, S.; Kroll, H.P.; Guarnieri, W.; Endermann, R.; Wild, H.; Rosentreter, U.; Ruppelt, M.; Synthesis and antibacterial activity of novel heteroaryl oxazolidinones: II. Benzoxazinone- and benzthiazinone-oxazolidinones. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F566. |
| 【2】 Shridhar, D.R.; et al.; A facile synthesis of 2-alkyl(aryl)-6- and -7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazines. Synthesis 1982, 986. |
| 【3】 Endermann, R.; Habich, D.; Ruppelt, M.; Raddatz, S.; Rosentreter, U.; Riedl, B.; Bartel, S.; Wild, H.; Stolle, A.; Guarnieri, W.; Kroll, H.-P. (Bayer AG); Novel bicyclene-substd. oxazolidinones. DE 19802239; WO 9937641 . |
| 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) | 33067 | 2-amino-5-nitrophenol | 121-88-0 | C6H6N2O3 | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IV) | 33068 | 7-nitro-2H-1,4-benzoxazin-3(4H)-one | C8H6N2O4 | 详情 | 详情 | |
| (V) | 33069 | 4-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one | C9H8N2O4 | 详情 | 详情 | |
| (VI) | 33070 | 7-amino-4-methyl-2H-1,4-benzoxazin-3(4H)-one | C9H10N2O2 | 详情 | 详情 | |
| (VII) | 33071 | benzyl 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-ylcarbamate | C17H16N2O4 | 详情 | 详情 | |
| (VIII) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (IX) | 33072 | 7-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one | C13H14N2O5 | 详情 | 详情 | |
| (X) | 33073 | 7-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one | C13H13N5O4 | 详情 | 详情 | |
| (XI) | 33074 | 7-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one | C13H15N3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)The intermediate N-(2-ethoxy-4-nitrophenyl)phthalimide (IV) is prepared by N-protection of 2-amino-5-nitrophenol (XVII) with phthalic anhydride (XVIII) in the presence of AcOH at 115-120 °C to give the corresponding phthalimide (XIX), which is then alkylated at the phenolic hydroxyl with ethyl bromide (XX) in the presence of K2CO3 in DMF .
| 【1】 Chew, W., Papamichelakis, M. (Wyeth). Methods of preparing 3-cyanoquinolines and intermediates made thereby. WO 2006127205. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 69192 | 2-(2-ethoxy-4-nitrophenyl)isoindoline-1,3-dione | C16H12N2O5 | 详情 | 详情 | |
| (XVII) | 33067 | 2-amino-5-nitrophenol | 121-88-0 | C6H6N2O3 | 详情 | 详情 |
| (XVIII) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (XIX) | 69202 | 2-(2-hydroxy-4-nitrophenyl)isoindoline-1,3-dione | C14H8N2O5 | 详情 | 详情 | |
| (XX) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVII)N-Protection of 2-amino-5-nitrophenol (XVII) with Ac2O in the presence of AcOH gives N-(2-hydroxy-4-nitrophenyl)acetamide (XXI), which upon O-alkylation with ethyl bromide (XX) in the presence of K2CO3 in DMF at 60 °C affords N-(2-ethoxy-4-nitrophenyl) acetamide (XXII). Reduction of the nitro derivative (XXII) with H2 over Pd/C in THF furnishes the corresponding aniline (XXIII), which by condensation with ethyl 2-cyano-3-ethoxy-2-propenoate (XXIV) at reflux produces enamine (XXV). Thermal cyclization of enamino ester (XXV) in Dowtherm at 250 °C then yields 4-hydroxyquinoline derivative (XXVI) , which upon chlorination with POCl3 in 1,2-diethoxyethane at 80-85 °C affords N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (VII) . Alternatively, condensation of ethyl cyanoacetate (II) with morpholine (XXVII) at 100-110 °C gives 4-(cyanoacetyl)morpholine (XXVIII), which after coupling with 4-acetamido-3-ethoxyaniline (XXIII) in the presence of triethyl orthoformate in i-PrOH at 50-60 °C produces the arylamino propenamide (XXIX). Finally, cyclization of (XXIX) in the presence of POCl3 in acetonitrile at 60-65 °C then leads to the target intermediate (VII) .
| 【1】 Wissner, A., Rabindran, S.K., Tsou, H.-R. (Wyeth). Substituted quinolines as protein tyrosine kinase enzyme inhibitors. EP 1670473, WO 2005034955. |
| 【2】 Rabindran, S.K., Tsou, H.-R., Wissner, A. (Wyeth). Protein tyrosine kinase enzyme inhibitors. US 2005059678, US 7399865, WO 2005028443. |
| 【3】 Bernier, C., Shaw, C.-C. (Wyeth). Method of preparing 4-halogenated quinoline intermediates. WO 2009139797. |
| 【4】 Wang, Y., Warren, C. Papamichelakis, M. (Wyeth). Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof. WO 2005070890. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (VII) | 69196 | 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile;4-Chloro-3-cyano-7-ethoxy-6-(acetylamino)quinoline | 848133-76-6 | C14H12ClN3O2 | 详情 | 详情 |
| (XVII) | 33067 | 2-amino-5-nitrophenol | 121-88-0 | C6H6N2O3 | 详情 | 详情 |
| (XX) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
| (XXI) | 69203 | N-(2-hydroxy-4-nitrophenyl)acetamide | C8H8N2O4 | 详情 | 详情 | |
| (XXII) | 69204 | N-(2-ethoxy-4-nitrophenyl)acetamide | C10H12N2O4 | 详情 | 详情 | |
| (XXIII) | 69205 | N-(4-amino-2-ethoxyphenyl)acetamide | C10H14N2O2 | 详情 | 详情 | |
| (XXIV) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (XXV) | 69206 | (E)-ethyl 3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanoacrylate | C16H19N3O4 | 详情 | 详情 | |
| (XXVI) | 69207 | N-(3-cyano-7-ethoxy-4-hydroxyquinolin-6-yl)acetamide | C14H13N3O3 | 详情 | 详情 | |
| (XXVII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XXVIII) | 69208 | 4-(cyanoacetyl)morpholine;Cyanoacetic acid morpholide;N-(Cyanoacetyl)morpholine;3-Morpholin-4-yl-3-oxopropionitrile;3-(4-Morpholinyl)-3-oxopropanenitrile;(Morpholinocarbonyl)acetonitrile;(Morpholin-4-ylcarbonyl)acetonitrile | 15029-32-0 | C7H10N2O2 | 详情 | 详情 |
| (XXIX) | 69209 | (E)-N-(4-((2-cyano-3-morpholino-3-oxoprop-1-en-1-yl)amino)-2-ethoxyphenyl)acetamide | C18H22N4O4 | 详情 | 详情 |