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【结 构 式】 
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【分子编号】15709 【品名】5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline 【CA登记号】1635-61-6 |
【 分 子 式 】C6H5ClN2O2 【 分 子 量 】172.57068 【元素组成】C 41.76% H 2.92% Cl 20.54% N 16.23% O 18.54% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 5-chloro-2-nitroaniline (I) with imidazole (II) by means of KOH in DMSO gives 5-(1-imidazolyl)-2-nitroaniline (III). Hydrogenation of (III) over Pd/C in 1N HCl gives the diamine (IV), which is condensed with oxalic acid (V) in 4N HCl yielding 6-(1-imidazolyl)quinoxaline-2,3(1H,4H)-dione hydrochloride (VI). Finally, this compound is nitrated with HNO3/H2SO4.
| 【1】 Ngo, J.; Rabasseda, X.; Castaner, J.; YM-900. Drugs Fut 1997, 22, 3, 256. |
| 【2】 Sakamoto, S.; Ohmori, J.; Shimizu-Sasamata, M.; et al.; Imidazolylquinoxaline-2,3-diones: Novel and potent antagonists of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) excitatory amino acid receptor. 12th Int Symp Med Chem (Sept 13-17, Basel) 1992, Abst P-022.A.. |
| 【3】 Ohmori, J.; Sakamoto, S.; Kubota, H.; Shimizu-Sasamata, M.; Okada, M.; Kawasaki, S.; Hidaka, K.; Togami, J.; Furuya, T.; Murase, K.; 6-(1H-Imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) and related compounds: Structure-activity relationships for the AMPA-type non-NMDA receptor. J Med Chem 1994, 37, 4, 467-75. |
| 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) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (II) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (III) | 15711 | 5-(1H-imidazol-1-yl)-2-nitroaniline; 5-(1H-imidazol-1-yl)-2-nitrophenylamine | C9H8N4O2 | 详情 | 详情 | |
| (IV) | 15712 | 4-(1H-imidazol-1-yl)-1,2-benzenediamine; 2-amino-4-(1H-imidazol-1-yl)phenylamine | C9H10N4 | 详情 | 详情 | |
| (V) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (VI) | 15714 | 6-(1H-imidazol-1-yl)-1,4-dihydro-2,3-quinoxalinedione hydrochloride | C11H9ClN4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The acetylation of 3-chloroaniline (I) with refluxing acetic anhydride gives the corresponding anilide (II), which is nitrated with HNO3/H2SO4 yielding 5-chloro-2-nitroacetanilide (III). The hydrolysis of (III) with hot conc. H2SO4 affords 5-chloro-2-nitroaniline (IV), which is treated with NaNO2/HCl to afford the corresponding diazonium salt (V). The reaction of (V) with sodium azide gives 2-nitro-5-chlorophenylazide (VI), which is cyclized to 5-chlorobenzofurazan-3-oxide (VII) in refluxing toluene. The condensation of (VII) with malononitrile (VIII) in DMF in the presence of a catalytic amount of triethylamine afforded a mixture of the isomeric quinoxaline-di-N-oxides (IX and X), which were separated by flash chromatography. The 7-chloro isomer (XI) was then submitted to diazotization with tert-butyl nitrite in acetonitrile in the presence of cupric chloride, which effected a Sandmeyer reaction to give the 2,6-dichloro derivative (XI). N-Alkylation of 3-(N,N-dimethylamino)propylamine (XII) with intermediate (XI) in dichloromethane in the presence of potassium carbonate, followed by treatment with concentrated hydrochloric acid in acetone afforded the title compound.
| 【1】 Monge, A.; et al.; Hypoxia-selective agents derived from quinoxaline 1, 4-di-N-oxides. J Med Chem 1995, 38, 10, 1786. |
| 【2】 Monge, A.; et al.; Hypoxia-selective agents derived from 2-quinoxalinecarbonitrile 1,4-di-N-oxides. 2. J Med Chem 1995, 38, 22, 4488. |
| 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) | 25239 | 3-chloroaniline; 3-chlorophenylamine | 108-42-9 | C6H6ClN | 详情 | 详情 |
| (II) | 25240 | N-(3-chlorophenyl)acetamide | 588-07-8 | C8H8ClNO | 详情 | 详情 |
| (III) | 25241 | N-(5-chloro-2-nitrophenyl)acetamide | 39163-92-3 | C8H7ClN2O3 | 详情 | 详情 |
| (IV) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (V) | 25242 | 5-chloro-2-nitrobenzenediazonium chloride | 2589-71-1 | C6H3Cl2N3O2 | 详情 | 详情 |
| (VI) | 25243 | 2-azido-4-chloro-1-nitrobenzene | C6H3ClN4O2 | 详情 | 详情 | |
| (VII) | 25244 | 7-chloro-4a,8a-dihydro-1-quinoliniumolate | C9H8ClNO | 详情 | 详情 | |
| (VIII) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (IX) | 25245 | 2-amino-6-chloro-3-cyano-1,4-quinoxalinediiumdiolate | C9H5ClN4O2 | 详情 | 详情 | |
| (X) | 25246 | 3-amino-6-chloro-2-cyano-1,4-quinoxalinediiumdiolate | C9H5ClN4O2 | 详情 | 详情 | |
| (XI) | 25247 | 2,6-dichloro-3-cyano-1,4-quinoxalinediiumdiolate | C9H3Cl2N3O2 | 详情 | 详情 | |
| (XII) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The intermediate phenylenediamine (VI) was prepared as follows. Reaction of 5-chloro-2-nitroaniline (I) with sodium methoxide afforded 5-methoxy-2-nitroaniline (II), which was subsequently converted to the N-Boc derivative (III). Methylation of (III) with iodomethane and NaH, followed by acidic treatment of the resulting N-methyl carbamate (IV), produced the N-methyl aniline (V). The nitro group of (V) was then reduced with the combination SnCl2-NaBH4 to furnish the diamine (VI).
| 【1】 Fujita, T.; Wada, K.; Oguchi, M.; Yanagisawa, H.; Fujimoto, K.; Fujiwara, T.; Horikoshi, H.; Yoshioka, T. (Sankyo Co., Ltd.); Benzimidazole derivs., their preparation and their therapeutic use. CA 2177858; EP 0745600; JP 1997295970; JP 2000001487; US 5886014 . |
| 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) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (II) | 42920 | 5-methoxy-2-nitrophenylamine; 5-methoxy-2-nitroaniline | 16133-49-6 | C7H8N2O3 | 详情 | 详情 |
| (III) | 46874 | tert-butyl 5-methoxy-2-nitrophenylcarbamate | C12H16N2O5 | 详情 | 详情 | |
| (IV) | 46875 | tert-butyl 5-methoxy-2-nitrophenyl(methyl)carbamate | C13H18N2O5 | 详情 | 详情 | |
| (V) | 46876 | 5-methoxy-N-methyl-2-nitroaniline; N-(5-methoxy-2-nitrophenyl)-N-methylamine | C8H10N2O3 | 详情 | 详情 | |
| (VI) | 46877 | N-(2-amino-5-methoxyphenyl)-N-methylamine; 4-methoxy-N(2)-methyl-1,2-benzenediamine | C8H12N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The condensation between 4-(acetylamino)thiophenol (I) and 5-chloro-2-nitroaniline (II) produced the diaryl sulfide (III). Nitro group reduction in (III) employing SnCl2 gave the phenylenediamine (IV), which was cyclized to the benzimidazole (VI) upon treatment with N,N'-bis(methoxycarbonyl)-S-methylisothiourea (V). Hydrolysis of the acetamido group of (VI) with HCl in MeOH afforded aniline (VII). This was acylated with N-Boc-alanine (VIII) in the presence of EDC to yield amide (IX). The N-Boc protecting group of (IX) was finally removed by treatment with trifluoroacetic acid.
| 【1】 Lewis, G.S.; Nolan, J.; Davis, P.D.; Naylor, M.A.; Thomson, P.; Hill, S.A.; Benzimidazole carbamates: A new structural class of vascular targeting agents. Proc Amer Assoc Cancer Res 2001, 42, Abst 2000. |
| 【2】 Davis, P.D. (Angiogene Pharmaceuticals Ltd.); Benzimidazole vascular damaging agents. EP 1140078; WO 0041669 . |
| 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) | 34329 | N-(4-sulfanylphenyl)acetamide | 1126-81-4 | C8H9NOS | 详情 | 详情 |
| (II) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (III) | 51869 | N-[4-[(3-amino-4-nitrophenyl)sulfanyl]phenyl]acetamide | C14H13N3O3S | 详情 | 详情 | |
| (IV) | 51870 | N-[4-[(3,4-diaminophenyl)sulfanyl]phenyl]acetamide | C14H15N3OS | 详情 | 详情 | |
| (V) | 28696 | methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C6H10N2O4S | 详情 | 详情 | |
| (VI) | 51871 | methyl 5-[[4-(acetamido)phenyl]sulfanyl]-1H-benzimidazol-2-ylcarbamate | C17H16N4O3S | 详情 | 详情 | |
| (VII) | 51872 | methyl 5-[(4-aminophenyl)sulfanyl]-1H-benzimidazol-2-ylcarbamate | C15H14N4O2S | 详情 | 详情 | |
| (VIII) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (IX) | 51873 | methyl 5-[[4-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)phenyl]sulfanyl]-1H-benzimidazol-2-ylcarbamate | C23H27N5O5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The reaction of 4-chloro-2-amino-1-nitrobenzene (I) with sodium phenylmercaptide (A) in DMF gives 2-amino-4-phenylthio-1-nitrobenzene (II), which is treated with acetic anhydride to yield 2-acetamido-4-phenylthio-1-nitrobenzene (III). This product is oxidized with peracetic acid in methanol giving 2-amino-4-phenylsulfinyl-1-nitrobenzene (V). Then the nitro group is reduced with H2 over Pd/C in methanol yielding 1,2-diamino-4-phenylsulfinylbenzene (VI). This product is finally condensed with N,N'-bis(methoxycarbonyl)-S-methylisothiourea (VII) in ethanol - water - acetic acid. The isothiourea (VII) is obtained by reaction of S-methylisothiouronium sulfate (VIII) with methyl chloroformate (B) by means of KOH in water
| 【1】 Beard, C.C.; et al. (Syntex, Inc.); DE 2363351 . |
| 【2】 Castaner, J.; Bogan, J.A.; Oxfendazole. Drugs Fut 1976, 1, 9, 438. |
| 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) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (A) | 60753 | sodium benzenethiolate | C6H5NaS | 详情 | 详情 | |
| (I) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (II) | 60754 | 2-nitro-5-(phenylsulfanyl)aniline; 2-nitro-5-(phenylsulfanyl)phenylamine | C12H10N2O2S | 详情 | 详情 | |
| (III) | 60755 | N-[2-nitro-5-(phenylsulfanyl)phenyl]acetamide | C14H12N2O3S | 详情 | 详情 | |
| (IV) | 60756 | N-[2-nitro-5-(phenylsulfinyl)phenyl]acetamide | C14H12N2O4S | 详情 | 详情 | |
| (V) | 60757 | 2-nitro-5-(phenylsulfinyl)aniline; 2-nitro-5-(phenylsulfinyl)phenylamine | C12H10N2O3S | 详情 | 详情 | |
| (VI) | 60758 | 4-(phenylsulfinyl)-1,2-benzenediamine; 2-amino-4-(phenylsulfinyl)phenylamine | C12H12N2OS | 详情 | 详情 | |
| (VII) | 28696 | methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C6H10N2O4S | 详情 | 详情 | |
| (VIII) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IIb)Reaction of 2,4-difluoronitrobenzene (I) with liquid ammonia gives 5-fluoro-2-nitroaniline (IIa) , which by subsequent displacement of the remaining fluoride group with N-methylpiperazine (III) in the presence of Et3N in NMP at 100 °C provides the piperazinyl aniline (IV) . Alternatively, nitroaniline (IV) can be prepared by condensation of 5-chloro-2-nitroaniline (IIb) with N-methylpiperazine (III) in hot EtOH , ethylene glycol or aqueous NaCl, optionally in the presence of NaOH . Catalytic hydrogenation of nitroaniline (IV) over Pd/C in EtOH at 40-45 °C yields the phenyldiamine (V) , wh ich by condensa t ion with ethyl 3-ethoxy-3-iminopropionate hydrochloride (VI) at reflux produces benzimidazole (VII) . Cyclocondensation of ethyl ester (VII) with 2-amino-6-fluorobenzonitrile (VIII) by means of LiHMDS , KHMDS or t-BuOK in THF or toluene furnishes dovitinib (IX ) , which is finally treated with racemic lactic acid in EtOH/H2O .
| 【1】 Machajewski, T., Shafer, C., McCrea, B. et al. (Novartis Vaccines and Diagnostics, Inc.). Quinolone derivatives. EP 1317442, EP 1650203, EP 1849782, JP 2004509112, US 2002107392, US 6605617, WO 2002022598. |
| 【2】 Harrison, S.D., Shafer, C.M., Pecchi, S. et al. (Novartis Vaccines and Diagnostics, Inc.). Benzimidazole quinolines and uses thereof. EP 1539754, JP 2006503919, JP 2011162563, US 200409235, US 2013018058, WO 2004018419. |
| 【3】 Renhowe, P.A., Pecchi, S., Machajewski, T.D. (Novartis Vaccines and Diagnostics, Inc.). Quinolone derivatives. JP 2005527587, US 2003028018, WO 2003087095. |
| 【4】 Cai, S., Chou, J., Harwood, E., Machajewski, T.D., Ryckman, D., Shang, X., Zhu, S. (Novartis Vaccines and Diagnostics, Inc.). Pharmaceutically acceptable salts of quinolinone compounds having improved pharmaceutical properties. CN 102225926, EP 1699421, JP 2007522098, JP 2011042687, WO 2005046589. |
| 【5】 Renhowe, P.A., Pecchi, S., Shafer, C.M. et al. Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A novel class of receptor tyrosine kinase inhibitors. J Med Chem 2009, 52(2): 278-92. |
| 【6】 Calvin, G., Harwood, E., Ryckman, D., Zhu, S. (Novartis AG). Methods for synthesizing heterocyclic compounds. EP 1888556, EP 2465857, JP 2008540675, US 2011046376, US 8222413, WO 2006125130. |
| 【7】 Okhamafe, A., Chou, J., Gullapalli, R., Harwood, E., Ryckman, D., Zhu, S.,Shang, X. (Novartis Corp.). Crystalline and other forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid salts. CN 102070614, EP 1904480, EP 2266974, EP 2270000, JP 200854289, US 2011178097, US 2012208825, WO 2006127926. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 67969 | 5-fluoro-2-nitroaniline | 2369-11-1 | C6H5FN2O2 | 详情 | 详情 |
| (IIb) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (I) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (III) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (IV) | 67970 | 5-(4-methylpiperazin-1-yl)-2-nitroaniline | C11H16N4O2 | 详情 | 详情 | |
| (V) | 31430 | 2-amino-4-(4-methyl-1-piperazinyl)phenylamine; 4-(4-methyl-1-piperazinyl)-1,2-benzenediamine | 54998-08-2 | C11H18N4 | 详情 | 详情 |
| (VI) | 67971 | ethyl 3-ethoxy-3-iminopropionate hydrochloride | 2318-25-4 | C7H13NO3.HCl | 详情 | 详情 |
| (VII) | 67972 | ethyl 2-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)acetate | C16H22N4O2 | 详情 | 详情 | |
| (VIII) | 13857 | 5-Amino-2-fluorobenzonitrile; 2-Amino-6-fluorobenzonitrile | 77326-36-4 | C7H5FN2 | 详情 | 详情 |
| (IX) | 67973 | 4-amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one | 405169-16-6 | C21H21FN6O | 详情 | 详情 |