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【结 构 式】 
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【分子编号】15248 【品名】1-chloro-2-nitrobenzene 【CA登记号】88-73-3 |
【 分 子 式 】C6H4ClNO2 【 分 子 量 】157.556 【元素组成】C 45.74% H 2.56% Cl 22.5% N 8.89% O 20.31% |
合成路线1
该中间体在本合成路线中的序号：(I)A new synthesis of KB-2413 has been described: The reaction of 2-chloronitrobenzene (I) with 2-ethoxyethylamine (II) gives 1-(2-ethoxyethylamino)-2-nitrobenzene (III), which is reduced with Zn and NaOH to N-(2-ethoxyethyl-o-phenylenediamine (IV). The cyclization of (IV) with urea in amyl alcohol affords 1-(2-ethoxyethyl)benzimidazol-2-one (V), which is treated with refluxing POCl3 yielding 2-chloro-1-(2-ethoxyethyl)benzimidazole (VI). Finally, this compound is condensed with N-methylhexahydro-1,4-diazepine (VII) and treated with fumaric acid.
| 【1】 Awata, N.; Satomi, O.; Synthesis of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-[2-14C]benzimidazole difumarate ([14C]KB-2413). J Label Compd Radiopharm 1987, 24, 3, 331-8. |
| 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) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 20898 | 2-ethoxyethylamine; 2-ethoxy-1-ethanamine | 110-76-9 | C4H11NO | 详情 | 详情 |
| (III) | 20899 | N-(2-ethoxyethyl)-N-(2-nitrophenyl)amine; N-(2-ethoxyethyl)-2-nitroaniline | C10H14N2O3 | 详情 | 详情 | |
| (IV) | 20900 | N(1)-(2-ethoxyethyl)-1,2-benzenediamine; N-(2-aminophenyl)-N-(2-ethoxyethyl)amine | C10H16N2O | 详情 | 详情 | |
| (V) | 20901 | 1-(2-ethoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one | C11H14N2O2 | 详情 | 详情 | |
| (VI) | 20902 | 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole; 2-(2-chloro-1H-benzimidazol-1-yl)ethyl ethyl ether | C11H13ClN2O | 详情 | 详情 | |
| (VII) | 20903 | 1-methyl-1,4-diazepane | 4318-37-0 | C6H14N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of o-chloronitrobenzene (I) with 2-amino-5-methylthiophene-3-carbonitrile (II) by means of lithium hydroxide in DMSO gives 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (III). The reductive cyclization of (III) using stannous chloride in aqueous ethanolic hydrochloric acid gives the primary amidine hydrochloride (IV), which is condensed with N-methylpiperazine (V) in a mixture of 4:1 toluene:DMSO.
| 【1】 Larsen, S.D.; Stephenson, G.A.; Bunnell, C.A.; Reutzel, S.M.; Nichols, J.R. (Eli Lilly and Company); Intermediates and process for preparing olanzapine. US 6020487 . |
| 【2】 Moore, N.A.; Hotten, T.M.; Tupper, D.E.; Olanzapine. Drugs Fut 1994, 19, 2, 114. |
| 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) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 15249 | 5-Amino-4-cyano-2-methylthiophene; 2-amino-5-methyl-3-thiophenecarbonitrile | 138564-58-6 | C6H6N2S | 详情 | 详情 |
| (III) | 15250 | 5-methyl-2-(2-nitroanilino)-3-thiophenecarbonitrile | C12H9N3O2S | 详情 | 详情 | |
| (IV) | 15251 | 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-ylamine hydrochloride; 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine hydrochloride; 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride | 138564-60-0 | C12H12ClN3S | 详情 | 详情 |
| (V) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)By condensation of 2-chloronitrobenzene (I) with 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (II) in refluxing pyridine.
| 【1】 Suzuki, T.; Oka, M.; Maeda, K.; Furusawa, K.; Uesaka, H.; Kataoka, T.; Synthesis and muscarinic activity of novel aniline derivatives with a 1-azabicyclo[3.3.0]octane moiety. Chem Pharm Bull 1999, 47, 1, 28. |
| 【2】 Baba, Y.; Suzuki, T.; Suzuki, T.; Hirooka, K.; Kurono, M.; Sawai, K. (Sanwa Kagaku Kenkyusho Co., Ltd.); 1-Azabicyclo[3.3.0]octane derivs. and their use. EP 0647642; US 5530138 . |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of 2-chloronitrobenzene (I) with 2-hydroxy-4-methoxybenzaldehyde (II) by means of Cu/KOH in refluxing DMF provides derivative (III), which is then oxidized with KMnO4 in pyridine/H2O to afford carboxylic acid (IV). Reduction of the nitro moiety of (IV) by hydrogenation over Pd/C yields amine (V), which is then cyclized at high temperatures to furnish the dibenzo[b,f][1,4]oxazepinone intermediate (VI) (1). O-Demethylation of (VI) by treatment with AlCl3 in ethylmercaptan (EtSH) gives hydroxy derivative (VII), which then reacts with triflic anhydride in CH2Cl2 in the presence of Et3N to provide compound (VIII). Treatment of (VIII) with POCl3 in refluxing toluene in the presence of N,N-dimethylaniline yields chloro derivative (IX), which is finally condensed with N-methylpiperazine (X) in refluxing toluene to give the desired product.
| 【1】 Wikstrom, H.; Liao, Y.; Venhuis, B.J.; Rodenhuis, N.; Timmerman, W.; New (sulfonyloxy)piperazinyldibenzazepines as potential atypical antipsychotics: Chemistry and pharmacological evaluation. J Med Chem 1999, 42, 12, 2235. |
| 【2】 De Boer, P.; Liao, Y.; Wikstrom, H.; New sulfone ester analogues of iso-clozapine and related structures: Atypical neuroleptics. WO 9629316 . |
| 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) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 29301 | 2-hydroxy-5-methoxybenzaldehyde | 672-13-9 | C8H8O3 | 详情 | 详情 |
| (III) | 45965 | 5-methoxy-2-(2-nitrophenoxy)benzaldehyde | C14H11NO5 | 详情 | 详情 | |
| (IV) | 45966 | 5-methoxy-2-(2-nitrophenoxy)benzoic acid | C14H11NO6 | 详情 | 详情 | |
| (V) | 45967 | 2-(2-aminophenoxy)-5-methoxybenzoic acid | C14H13NO4 | 详情 | 详情 | |
| (VI) | 45968 | 2-methoxydibenzo[b,f][1,4]oxazepin-11(10H)-one | C14H11NO3 | 详情 | 详情 | |
| (VII) | 45969 | 2-hydroxydibenzo[b,f][1,4]oxazepin-11(10H)-one | C13H9NO3 | 详情 | 详情 | |
| (VIII) | 45970 | 11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl trifluoromethanesulfonate | C14H8F3NO5S | 详情 | 详情 | |
| (IX) | 45971 | 11-chlorodibenzo[b,f][1,4]oxazepin-2-yl trifluoromethanesulfonate | C14H7ClF3NO4S | 详情 | 详情 | |
| (X) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The condensation of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine (I) with 2-chloronitrobenzene (II) by means of K2CO3 in refluxing butanol gives 1-(2-methoxyphenyl)-4-[2-(2-nitrophenylamino)ethyl]piperazine (III), which is finally condensed with cyclohexylcarbonyl chloride (IV) by means of TEA in dichloroethane to afford the target amide.
| 【1】 Leonardi, A.; Motta, G.; Testa, R.; Riva, C. (Recordati Industria Chimica e Farmaceutica SpA); 1-(N-Phenylaminoalkyl)-piperazine derivs. substd. at position 2 of the phenyl ring. EP 1000047; JP 2001512112; US 6399614; WO 9906384 . |
| 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) | 53508 | 2-[4-(2-methoxyphenyl)-1-piperazinyl]-1-ethanamine; 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamine | n/a | C13H21N3O | 详情 | 详情 |
| (II) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (III) | 53509 | N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-nitrophenyl)amine; N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-2-nitroaniline | n/a | C19H24N4O3 | 详情 | 详情 |
| (IV) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Diethyl malonate (I) was alkylated with 2-bromoethyl ethyl ether (II) in the presence of NaOEt to provide diethyl 2-(ethoxyethyl)malonate (III). Treatment of 2-chloronitrobenzene (IV) with 2,2,2-trifluoroethanol (V) afforded the trifluoroethyl ether (VI). Subsequent reduction of the nitro group of (VI) by means of iron in acetic acid gave aniline (VII), which was condensed with malonate (III) in refluxing diphenyl ether, yielding furoquinoline (VIII). Further reaction of (VIII) with o-toluidine (IX) in boiling diethylene glycol produced the tetrahydropyrroloquinoline (X). Aromatization of the pyrrole ring of (X) to give (XI) was achieved by dehydrogenation in diphenyl ether in the presence of Pd/C. Chloroquinoline (XII) was then obtained by chlorination of (XI) with POCl3. Finally, displacement of the chlorine atom of (XII) by means of ethanolamine at 180 C furnished the title compound.
| 【1】 Kim, H.-J.; Kim, S.-S.; Yoo, Y.-K.; Kang, S.-K.; Cheon, H.-G.; Choi, J.-K.; Yum, E.-K. (Korea Research Institute of Chemical Technology); Pyrrolo[3,2-c]quinoline derivs. containing haloalkoxy group and pharmaceutically acceptable salts thereof. CA 2268166; EP 0966466; JP 2000504352; US 6011044; WO 9909029 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 | |
| (I) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (II) | 34659 | 2-bromoethyl ethyl ether; 1-bromo-2-ethoxyethane | 592-55-2 | C4H9BrO | 详情 | 详情 |
| (III) | 34660 | diethyl 2-(2-ethoxyethyl)malonate | C11H20O5 | 详情 | 详情 | |
| (IV) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (V) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
| (VI) | 29562 | 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene | C8H6F3NO3 | 详情 | 详情 | |
| (VII) | 29563 | 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine | C8H8F3NO | 详情 | 详情 | |
| (VIII) | 34661 | 6-(2,2,2-trifluoroethoxy)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one | C13H10F3NO3 | 详情 | 详情 | |
| (IX) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (X) | 34662 | 1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-c]quinolin-4-one | C20H17F3N2O2 | 详情 | 详情 | |
| (XI) | 34663 | 1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one | C20H15F3N2O2 | 详情 | 详情 | |
| (XII) | 34664 | 4-chloro-1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]quinoline; 4-chloro-1-(2-methylphenyl)-1H-pyrrolo[3,2-c]quinolin-6-yl 2,2,2-trifluoroethyl ether | C20H14ClF3N2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Reaction of 2-chloronitrobenzene (I) with the sodium alkoxide of 2,2,2-trifluoroethanol (II) in cold THF afforded trifluoroethyl ether (III). The nitro group of (III) was then reduced by means of iron and AcOH to produce 2-(trifluoroethoxy)aniline (IV). Condensation of (IV) with diethyl (2-ethoxyethyl)malonate (V) in boiling diphenyl ether led to the furoquinolinone system (VI), and subsequent reaction of (VI) with 2-methyl-4-methoxyaniline (VII) in refluxing diethylene glycol generated the pyrroloquinolinone (VIII). Chlorination of (VIII) with POCl3 gave chloropyrroloquinoline (IX). Finally, displacement of the chlorine of (IX) by ethanolamine at 180 C yielded the title compound.
| 【1】 Kim, H.-J.; Kim, S.-S.; Yoo, Y.-K.; Kang, S.-K.; Cheon, H.-G.; Choi, J.-K.; Yum, E.-K. (Korea Research Institute of Chemical Technology); Pyrrolo[3,2-c]quinoline derivs. containing haloalkoxy group and pharmaceutically acceptable salts thereof. CA 2268166; EP 0966466; JP 2000504352; US 6011044; WO 9909029 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 | |
| (I) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
| (III) | 29562 | 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene | C8H6F3NO3 | 详情 | 详情 | |
| (IV) | 29563 | 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine | C8H8F3NO | 详情 | 详情 | |
| (V) | 34660 | diethyl 2-(2-ethoxyethyl)malonate | C11H20O5 | 详情 | 详情 | |
| (VI) | 34661 | 6-(2,2,2-trifluoroethoxy)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one | C13H10F3NO3 | 详情 | 详情 | |
| (VII) | 40006 | 4-methoxy-2-methylphenylamine; 4-methoxy-2-methylaniline | 102-50-1 | C8H11NO | 详情 | 详情 |
| (VIII) | 40007 | 1-(4-methoxy-2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-c]quinolin-4-one | C21H19F3N2O3 | 详情 | 详情 | |
| (IX) | 40008 | 4-chloro-1-(4-methoxy-2-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-6-yl 2,2,2-trifluoroethyl ether; 4-chloro-1-(4-methoxy-2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline | C21H18ClF3N2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)The reaction of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (I) with 4-aminopyridine (II) gives the corresponding pyridinium salt (III), which is reduced with NaBH4 to 2-[3-(4-aminopiperidyl)propyl]-2-(4-fluorophenyl)-1,3-dioxolane (IV). The condensation of (IV) with 2-chloronitrobenzene (V) yields 2-[3-[4-(2-nitroanilino)piperidyl]propyl]-2-(4-fluorophenyl)-1,3-dioxolane (VI), which is hydrogenated with H2 over Raney-Ni affording the corresponding amino compound (VII). Finally this compound is cyclized with carbon disulfide and KOH
| 【1】 JP 76095096 . |
| 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) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (II) | 25661 | 4-pyridinamine; 4-aminopyridine | 5044-74-5 | C5H6N2 | 详情 | 详情 |
| (III) | 60701 | 4-amino-1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}pyridinium chloride | C17H20ClFN2O2 | 详情 | 详情 | |
| (IV) | 60702 | 1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinamine; 1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinylamine | C17H25FN2O2 | 详情 | 详情 | |
| (V) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (VI) | 60703 | 1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-(2-nitrophenyl)-4-piperidinamine; N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-N-(2-nitrophenyl)amine | C23H28FN3O4 | 详情 | 详情 | |
| (VII) | 60704 | N-(2-aminophenyl)-N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)amine; N~1~-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-1,2-benzenediamine | C23H30FN3O2 | 详情 | 详情 |