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【结 构 式】 
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【分子编号】21787 【品名】2,4-dichloro-1-nitrobenzene 【CA登记号】611-06-3 |
【 分 子 式 】C6H3Cl2NO2 【 分 子 量 】192.00076 【元素组成】C 37.53% H 1.57% Cl 36.93% N 7.3% O 16.67% |
合成路线1
该中间体在本合成路线中的序号：(X)The reaction of 2,4-dichloronitrobenzene (X) with sodium diethyl methylmalonate (B) in DMF to diethyl 2-(4-nitro-3-chlorophenyl)-2-methyl-malonate (XI), b.p. 147-8 C/0.25 mm, followed hydrolysis, decarboxylation and esterification to ethyl 2-(3-chloro-4-nitrophenyl)propionate (XII), b.p. 138-42 C /0.25 mm; which, in turn, was reduced as before to ethyl 2-(3-chloro-4-aminophenyl)propionate hydrochloride (VI). Conversely, the diethyl 2-(4-nitro-3-chlorophenyl)-2-methylmalonate (XI), already obtained before, could be hydrogenated first to diethyl 2-(4-amino-3-chlorophenyl)-2-methylmalonate (XIII), b.p. 180-5 C/0.25 mm, and then hydrolyzed, decarboxylated and esterified again to ethyl 2-(3-chloro-4-aminophenyl)propionate hydrochloride (VI).
| 【1】 Carney, R.W.; et al.; Potent nonsteroidal anti-inflammatory agent, 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propionic acid. Experientia 1973, 29, 8, 938. |
| 【2】 Castaner, J.; Pirprofen. Drugs Fut 1977, 1, 1, 23. |
| 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) | 32186 | (E)-1,4-dichloro-2-butene | 110-57-6 | C4H6Cl2 | 详情 | 详情 |
| (B) | 33989 | C8H13NaO4 | 详情 | 详情 | ||
| (VI) | 33987 | ethyl 2-(4-amino-3-chlorophenyl)propanoate | C11H14ClNO2 | 详情 | 详情 | |
| (VII) | 33988 | ethyl 2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl]propanoate | C15H18ClNO2 | 详情 | 详情 | |
| (X) | 21787 | 2,4-dichloro-1-nitrobenzene | 611-06-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (XI) | 33990 | diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate | C14H16ClNO6 | 详情 | 详情 | |
| (XII) | 33991 | ethyl 2-(3-chloro-4-nitrophenyl)propanoate | C11H12ClNO4 | 详情 | 详情 | |
| (XIII) | 33992 | diethyl 2-(4-amino-3-chlorophenyl)-2-methylmalonate | C14H18ClNO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A scaleable process to produce vorozole has been reported: The reaction of 2,4-dichloronitrobenzene (I) with methylamine gives 5-chloro-N-methyl-2-nitroaniline (II), which is condensed with 4-chlorobenzonitrile (III) and oxidized with air to yield 4'-chloro-3-(methylamino)-4-nitrobenzophenone (IV). The hydrogenation of compound (IV), followed by cyclization by means of nitrous acid and reduction of the carbonyl group with NaBH4 affords the benzotriazole (V). Reaction of the OH group of (V) with SOCl2 provides the corresponding chloro derivative (VI), which is treated with acetohydrazide (VII) to give the racemic hydrazine derivative (VIII). Optical resolution of (VIII) by chiral chromatography yields the (S)-isomer (IX), which is finally cyclized with formamidine to afford vorozole.
| 【1】 De Knaep, A.G.M.; Vandendriessche, A.M.J.; Daemen, D.J.E.; et al.; Development summary towards a manufacturable process for R 83842 [(S)-6-[(4-chlorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole]. Org Process Res Dev 2000, 4, 3, 162. |
| 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) | 21787 | 2,4-dichloro-1-nitrobenzene | 611-06-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (II) | 46715 | 5-chloro-N-methyl-2-nitroaniline; N-(5-chloro-2-nitrophenyl)-N-methylamine | 35966-84-8 | C7H7ClN2O2 | 详情 | 详情 |
| (III) | 27360 | 4-chlorobenzonitrile | 623-03-0 | C7H4ClN | 详情 | 详情 |
| (IV) | 46716 | (4-chlorophenyl)[3-(methylamino)-4-nitrophenyl]methanone | C14H11ClN2O3 | 详情 | 详情 | |
| (V) | 14734 | (4-chlorophenyl)(1-methyl-1H-1,2,3-benzotriazol-6-yl)methanol | C14H12ClN3O | 详情 | 详情 | |
| (VI) | 14735 | 6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-1,2,3-benzotriazole | C14H11Cl2N3 | 详情 | 详情 | |
| (VII) | 29262 | acetohydrazide | 1068-57-1 | C2H6N2O | 详情 | 详情 |
| (VIII) | 46717 | 6-[(4-chlorophenyl)(hydrazino)methyl]-1-methyl-1H-1,2,3-benzotriazole | C14H14ClN5 | 详情 | 详情 | |
| (IX) | 46718 | 6-[(S)-(4-chlorophenyl)(hydrazino)methyl]-1-methyl-1H-1,2,3-benzotriazole | C14H14ClN5 | 详情 | 详情 | |
| (X) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Nucleophilic substitution of 2,4-dichloronitrobenzene (I) with 1-methylpiperidin-4-thiol (II) in the presence of K2CO3 provided a mixture of sulfides (III) and (IV), from which the major isomer (IV) was isolated by crystallization from EtOH. The nitro group of (IV) was then reduced with iron under acidic conditions to the corresponding amine (V). Subsequent diazotization of (V) and reduction of the diazonium salt (VI) with EtOH led to the deaminated compound (VII). N-Demethylation of (VII) was achieved by treatment with ethyl chloroformate, yielding the N-ethoxycarbonyl derivative (VIII). Finally, acid hydrolysis of carbamate (VIII) provided the target amine, which was isolated as the hydrochloride salt.
| 【1】 Proska, J.; Radl, S.; Krejci, I.; Hezky, P.; Synthesis and analgesic activity of some deaza derivatives of anpirtoline. Arch Pharm 1999, 332, 1, 13. |
| 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) | 21787 | 2,4-dichloro-1-nitrobenzene | 611-06-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (II) | 21788 | 1-methyl-4-piperidinethiol; 1-methyl-4-piperidinylhydrosulfide | C6H13NS | 详情 | 详情 | |
| (III) | 21789 | 4-[(3-chloro-4-nitrophenyl)sulfanyl]-1-methylpiperidine; 3-chloro-4-nitrophenyl 1-methyl-4-piperidinyl sulfide | C12H15ClN2O2S | 详情 | 详情 | |
| (IV) | 21790 | 4-[(5-chloro-2-nitrophenyl)sulfanyl]-1-methylpiperidine; 5-chloro-2-nitrophenyl 1-methyl-4-piperidinyl sulfide | C12H15ClN2O2S | 详情 | 详情 | |
| (V) | 21791 | 4-chloro-2-[(1-methyl-4-piperidinyl)sulfanyl]phenylamine; 4-chloro-2-[(1-methyl-4-piperidinyl)sulfanyl]aniline | C12H17ClN2S | 详情 | 详情 | |
| (VI) | 21792 | 4-[[5-chloro-2-(1lambda(5)-diazynyl)phenyl]sulfanyl]-1-methylpiperidine; 5-chloro-2-(1lambda(5)-diazynyl)phenyl 1-methyl-4-piperidinyl sulfide | C12H16ClN3S | 详情 | 详情 | |
| (VII) | 21793 | 4-[(3-chlorophenyl)sulfanyl]-1-methylpiperidine; 3-chlorophenyl 1-methyl-4-piperidinyl sulfide | C12H16ClNS | 详情 | 详情 | |
| (VIII) | 21794 | ethyl 4-[(3-chlorophenyl)sulfanyl]-1-piperidinecarboxylate | C14H18ClNO2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXV)Jones oxidation of 2-fluoro-4-methyl-1-nitrobenzene (XVIII) with CrO3 and H2SO4, followed by acetylation with Ac2O in AcOH yields the gemdiacetate (XIX), which by deacetylation with HCl in AcOH at 115 °C provides 3-fluoro-4-nitrobenzaldehyde (XX). Horner-Wadsworth-Emmons reaction of aldehyde (XX) with ethyl (diethoxyphosphoryl)acetate (XXI) using NaH in THF affords the unsaturated ester (XXII), which by fluoride substitution with methylamine (XXIII) in DMSO provides the nitro-aniline derivative (XXIVa) . Alternatively, condensation of 2,4-dichloro-1-nitrobenzene (XXV) with methylamine (XXIII) using Et3N in DMSO or THF yields 5-chloro-N-methyl-2-nitroaniline (XXVI), which is then subjected to Heck coupling with ethyl acrylate (XXVIIa), methyl acrylate (XXVIIb) or butyl acrylate (XXVIIa) in the presence of Pd(OAc)2, LiCl and DIEA in DMAc at 110 °C , or Pd2dba3, t-Bu3P and (c-Hex)2NMe at 110 °C to give the corresponding arylacrylates (XXIVa), (XXIVb) or (XXIVc). Reduction of the nitro group in compounds (XXIVa), (XXIVb) or (XXIVc) by means of SnCl2.2H2O in EtOH at 80 °C , H2 over Raney-Ni in toluene/MeOH or Na2S2O4 and K2CO3 in EtOH/H2O produces the corresponding diaminophenylacrylates (XXVIIIa) , (XXVIIIb) or (XXVIIIc) , which are finally condensed with 1-aminocyclo-butanecarboxylic acid hydrochloride (XXIX) in CH2Cl2 to provide the benzimidazole intermediates (IIIa) , (IIIb) or (XXX), the free base of intermediate (II) .
Similarly, intermediate (II) can be obtained by condensation of the diaminophenylacrylate (XXVIIIc) with N-Boc-1-aminocyclobutanecarboxylic acid (XXXI) using DCC in toluene, followed by N-deprotection and cyclization of the resulting amino amide (XXXII) with HCl in BuOH at 75 °C .
| 【1】 Boecher, W., Haefner, C., Kukolj, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Combination therapy for treating HCV infection. CN 103228278, EP 2621495, JP 2013540112, KR 2013116245, US 2012135949, WO 2012041771. |
| 【2】 Brickl, R.-S., Chen, S., Chung, J. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Solid state forms of a potent HCV inhibitor. CN 103153987, EP 2621921, JP 2013543495, KR 2013108326, US 2012122887, US 8598183, US 2014057928, WO 2012044520. |
| 【3】 Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749. |
| 【4】 Mensa, F. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient sub-population. WO 2013147750. |
| 【5】 LaPlante, S.R., Boes, M., Brochu, C. et al. Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors. Discovery of deleobuvir (BI 207127). J Med Chem 2014, 57(5): 1845-54. |
| 【6】 Tsantrizos, Y.S., Chabot, C., Beaulieu, P. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Viral polymerase inhibitors. CN 102911161, CN 103304541, CN 103319464, CN 103333162, EP 1718608, EP 2626354, JP 2007523094, JP 2010195818, JP 2010280740, KR 2012091276, US 2005222236, US 8030309, WO 2005080388. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIVa) | 67786 | (E)-ethyl 3-(3-(methylamino)-4-nitrophenyl)acrylate | C12H14N2O4 | 详情 | 详情 | |
| (XXIVb) | 67787 | (E)-methyl 3-(3-(methylamino)-4-nitrophenyl)acrylate | C11H12N2O4 | 详情 | 详情 | |
| (XXIVc) | 67788 | (E)-butyl 3-(3-(methylamino)-4-nitrophenyl)acrylate | C14H18N2O4 | 详情 | 详情 | |
| (XXVIIa) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XXVIIb) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XXVIIc) | 67789 | butyl acrylate | C7H12O2 | 详情 | 详情 | |
| (XXVIIIa) | 67791 | (E)-ethyl 3-(4-amino-3-(methylamino)phenyl)acrylate | C12H16N2O2 | 详情 | 详情 | |
| (XXVIIIb) | 67792 | (E)-methyl 3-(4-amino-3-(methylamino)phenyl)acrylate | C11H14N2O2 | 详情 | 详情 | |
| (XXVIIIc) | 67790 | (E)-butyl 3-(4-amino-3-(methylamino)phenyl)acrylate | C14H20N2O2 | 详情 | 详情 | |
| (IIIa) | 67765 | (E)-methyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C16H19N3O2 | 详情 | 详情 | |
| (IIIb) | 67766 | (E)-ethyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C17H21N3O2 | 详情 | 详情 | |
| (II) | 67764 | (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate dihydrochloride | C19H25N3O2.2HCl | 详情 | 详情 | |
| (XVIII) | 39366 | 2-fluoro-4-methyl-1-nitrobenzene | 446-34-4 | C7H6FNO2 | 详情 | 详情 |
| (XIX) | 67783 | (3-fluoro-4-nitrophenyl)methylene diacetate | C11H10FNO6 | 详情 | 详情 | |
| (XX) | 67784 | 3-fluoro-4-nitrobenzaldehyde | C7H4FNO3 | 详情 | 详情 | |
| (XXI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (XXII) | 67785 | (E)-ethyl 3-(3-fluoro-4-nitrophenyl)acrylate | C11H10FNO4 | 详情 | 详情 | |
| (XXIII) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (XXV) | 21787 | 2,4-dichloro-1-nitrobenzene | 611-06-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (XXVI) | 46715 | 5-chloro-N-methyl-2-nitroaniline; N-(5-chloro-2-nitrophenyl)-N-methylamine | 35966-84-8 | C7H7ClN2O2 | 详情 | 详情 |
| (XXIX) | 67793 | 1-aminocyclo-butanecarboxylic acid hydrochloride | 98071-16-0 | C5H9NO2.HCl | 详情 | 详情 |
| (XXX) | 67794 | (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C19H25N3O2 | 详情 | 详情 | |
| (XXXI) | 67795 | 1-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (XXXII) | 67796 | (E)-butyl 3-(4-amino-3-(1-((tert-butoxycarbonyl)amino)-N-methylcyclobutanecarboxamido)phenyl)acrylate | C24H35N3O5 | 详情 | 详情 |