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【结 构 式】 
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【分子编号】18184 【品名】4-Nitrobenzaldehyde 【CA登记号】555-16-8 |
【 分 子 式 】C7H5NO3 【 分 子 量 】151.12164 【元素组成】C 55.64% H 3.33% N 9.27% O 31.76% |
合成路线1
该中间体在本合成路线中的序号：(C)3) By reaction of 4-methoxybenzylamine (I) with methyl isothiocyanate (B) in ether to yield N-(4-methoxybenzyl)-N'-methylthiourea (III), which is then methylated with MeI in refluxing methanol affording N-(4-methoxybenzyl)-N',S-dimethylisothiourea (IV). Finally, this compound is treated first with methylamine in refluxing methanol and then with H2SO4.
| 【1】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【2】 Christensen, B.G.; Ratcliffe, R.W.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates. Tetrahedron Lett 1973, 46, 4645-48. |
| 【3】 Christensen, B.G.; Ratcliffe, R.W.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin. Tetrahedron Lett 1973, 46, 4649-52. |
| 【4】 Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.); 7-Azido-cephalosporin compounds and their preparation. DE 2365406; FR 2182953; GB 1424373; JP 49014488 . |
| 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) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (A) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (I) | 39815 | 1,3,5-tribenzyl-1,3,5-triazinane | 2547-66-2 | C24H27N3 | 详情 | 详情 |
| (II) | 39816 | diethyl (benzylamino)methylphosphonate | C12H20NO3P | 详情 | 详情 | |
| (III) | 39817 | diethyl aminomethylphosphonate | C5H14NO3P | 详情 | 详情 | |
| (IV) | 39818 | diethyl [[(E)-benzylidene]amino]methylphosphonate | 50917-73-2 | C12H18NO3P | 详情 | 详情 |
| (V) | 39819 | 1-[[(chlorocarbonyl)oxy]methyl]-4-methoxybenzene | C9H9ClO3 | 详情 | 详情 | |
| (VI) | 39820 | 4-methoxybenzyl 2-(diethoxyphosphoryl)-2-[[(E)-benzylidene]amino]acetate | C21H26NO6P | 详情 | 详情 | |
| (VII) | 39821 | 4-methoxybenzyl 2-amino-2-(diethoxyphosphoryl)acetate | C14H22NO6P | 详情 | 详情 | |
| (VIII) | 39822 | O-ethyl thioformate | C3H6OS | 详情 | 详情 | |
| (IX) | 39823 | 4-methoxybenzyl 2-(diethoxyphosphoryl)-2-(thioformylamino)acetate | C15H22NO6PS | 详情 | 详情 | |
| (X) | 39824 | 3-chloro-2-oxopropyl acetate | 40235-68-5 | C5H7ClO3 | 详情 | 详情 |
| (XI) | 39825 | 4-methoxybenzyl 5-[(acetoxy)methyl]-6H-1,3-thiazine-4-carboxylate | C16H17NO5S | 详情 | 详情 | |
| (XII) | 39826 | 2-azidoacetyl chloride | C2H2ClN3O | 详情 | 详情 | |
| (XIII) | 39827 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-azido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H18N4O6S | 详情 | 详情 | |
| (XIV) | 39828 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H20N2O6S | 详情 | 详情 | |
| (XV) | 39829 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-[[(E)-(4-nitrophenyl)methylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C25H23N3O8S | 详情 | 详情 | |
| (C) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)1-(3,4-Dimethoxyphenyl)-2-propanol (I) is condensed with 4-nitrobenzaldehyde. The resulting 1-(4-nitrophenyl)-3-methyl-6,7-dimethoxyisochromane (II) is oxidized with Jones reagent to obtain 2-acetonyl-4,5-dimethoxy-4'-nitrobenzophenone (III). Then 1-(4-nitrophenyl)-3-methyl-6,7-dimethoxy-2-benzopyrylium perchlorate (IV) is produced by the conventional procedure, from which intermediary, with the help of hydrazine hydrate and reduction. GYKI-52322 is prepared.
| 【1】 Lang, T.; Korösi, J.; Andrási, F.; Botka, P.; Hámori, T.; Berzsenyi, P.; Goldschmidt, K.; Zólyomi, G.; Elekes, I.; Láng, Z. (Egis Pharmaceuticals Ltd.); 5H-2,3-Benzodiazepine derivs. and pharmaceutical c. BE 0902953; CH 667090; DE 3527117; ES 8608494; FR 2568252; GB 2162184; JP 1986043174; US 4614740 . |
| 【2】 Somogyi, G.; Balogh, T.; Botka, P.; Lang, T.; Hamori, T.; Lang, T.; Zolyomi, G.; Koeroesi, J. (Gyogyszerkutato Intezet Kft.); New process for producing 2-aroyl-phenylacetone derivs.. HU 194529 . |
| 【3】 Hamori, T.; Botka, P.; Zolyomi, G.; Koeroesi, J.; Lang, T.; Lang, T. (Gyogyszerkutato Intezet Kft.); Process for preparing isochromane derivs.. HU 194550 . |
| 【4】 Andrasi, F.; GYKI-52322. Drugs Fut 1988, 13, 4, 308. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (I) | 22077 | 1-(3,4-dimethoxyphenyl)-2-propanol | 161121-02-4 | C11H16O3 | 详情 | 详情 |
| (II) | 22078 | 6,7-dimethoxy-3-methyl-1-(4-nitrophenyl)-3,4-dihydro-1H-isochromene; 6-methoxy-3-methyl-1-(4-nitrophenyl)-3,4-dihydro-1H-isochromen-7-yl methyl ether | C18H19NO5 | 详情 | 详情 | |
| (III) | 22079 | 1-[4,5-dimethoxy-2-(4-nitrobenzoyl)phenyl]acetone | C18H17NO6 | 详情 | 详情 | |
| (IV) | 22080 | 6,7-dimethoxy-3-methyl-1-(4-nitrophenyl)isochromenium | C18H16NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Treatment of a benzenic solution of 4-piperidone hydrate (I) with anhydrous AlCl3 provided 4,4-diphenylpiperidine (II). Then, conjugate addition of acrylonitrile (III) in the presence of triethylamine in ethanol gave the cyanoethylpiperidine (IV), which was reduced with borane in THF to afford the intermediate primary amine (V). Dihydropyridine (IX) was prepared by Hantzsch synthesis by condensation of 3-aminocrotonamide (VI), 4-nitrobenzaldehyde (VII) and cyanoethyl acetoacetate (VIII) in refluxing ethanol. Cyanoethyl ester was then cleaved with dilute KOH at 0 C to give acid (X), which was finally coupled with amine (V) by treatment with DEC to yield the target amide.
| 【1】 Cox, E.D.; et al.; Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate. J Med Chem 1998, 41, 14, 2643. |
| 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) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (II) | 13154 | 4,4-Diphenylpiperidine | C17H19N | 详情 | 详情 | |
| (III) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (IV) | 18181 | 3-(4,4-diphenyl-1-piperidinyl)propanenitrile | C20H22N2 | 详情 | 详情 | |
| (V) | 18182 | 3-(4,4-diphenyl-1-piperidinyl)-1-propanamine; 3-(4,4-diphenyl-1-piperidinyl)propylamine | C20H26N2 | 详情 | 详情 | |
| (VI) | 18183 | (E)-3-amino-2-butenamide | C4H8N2O | 详情 | 详情 | |
| (VII) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (VIII) | 13993 | 2-cyanoethyl 3-oxobutanoate | C7H9NO3 | 详情 | 详情 | |
| (IX) | 18186 | 2-cyanoethyl 5-(aminocarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate | C18H18N4O5 | 详情 | 详情 | |
| (X) | 18187 | 5-(aminocarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C15H15N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The reaction of 5-bromo-1,3-benzodioxole (I) with (S)-(-)-propylene oxide (II) by means of sec-butyllithium in THF gives the (S)-isopropanol derivative (IV) (also obtained by stereoselective reduction of 1-(1,3-benzodioxol-5-yl)-2-propanone (III) with Z. rouxii ATCC 14462 in a phosphate buffer). The cyclization of (IV) with 4-nitrobenzaldehyde (V) by means of HCl in hot toluene yields the benzopyran (VI), which is oxidized with air in aqueous NaOH affording the carbinol (VII). The reaction of (VII) with acetohydrazide (VIII) and HCl in refluxing ethanol gives the acetyl hydrazone (IX), which is mesylated at the secondary OH group with methanesulfonyl chloride and TEA in dichloromethane yielding the mesylate (X). The cyclization of (X) by means of NaOH in methanol provides the nitro benzodiazepine (XI), which is finally reduced with potassium formate and Pd/C in ethanol/water.
| 【1】 Andrasi, F.; Talampanel. Drugs Fut 2001, 26, 8, 754. |
| 【2】 Anderson, B.A.; et al.; Application of a practical biocatalytic reduction to an enantioselective synthesis of the 5H-2, 3-benzodiazepine LY300164. J Am Chem Soc 1995, 117, 49, 12358. |
| 【3】 Andrasi, F.; Berzsenyi, P.; Botka, P.; Farkas, S.; Goldschmidt, K.; Hamori, T.; Korosi, J.; Moravcsik, I.; Tarnawa, I. (Gyogyszerkutato Intezet Kft.); N-Acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0492485; JP 1993070463; US 5519019; US 5521174; US 5536832; US 5604223; US 5639751 . |
| 【4】 Varie, D.L.; Hansen, M.M.; Anderson, B.; Vicenzi, J.T.; Zmijewski, M.J. (Eli Lilly and Company); Stereoselective process for producing dihydro-2,3-benzodiazepine derivs.. EP 0699677; US 5665878 . |
| 【5】 Zmijewski, M.J. Jr.; Varie, D.L.; Hansen, M.M.; Vicenzi, J.T.; Anderson, B.A. (Eli Lilly and Company); Physical form of dihidro-2,3-benzodiazepine deriv.. EP 0699676 . |
| 【6】 Hansen, M.M.; Vicenzi, J.T.; Groleau, E.G.; Varie, D.L.; Zmijewski, M.J.; Anderson, B.A. (Eli Lilly and Company); Crystalline form of dihydro-2,3-benzodiazepine deriv.. EP 0699678 . |
| 【7】 Anderson, B.A.; Varie, D.L.; Vicenzi, J.T.; Zmijewski, M.J.; Hansen, M.M. (Eli Lilly and Company); Stereoselective process for producing dihydro-2,3-benzodiazepine derivs.. US 5919954 . |
| 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) | 10124 | 5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene | 2635-13-4 | C7H5BrO2 | 详情 | 详情 |
| (II) | 29268 | (2S)-2-methyloxirane | 16088-62-3 | C3H6O | 详情 | 详情 |
| (III) | 28466 | 1-(1,3-benzodioxol-5-yl)acetone | 4676-39-5 | C10H10O3 | 详情 | 详情 |
| (IV) | 29259 | (2S)-1-(1,3-benzodioxol-5-yl)-2-propanol | C10H12O3 | 详情 | 详情 | |
| (V) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (VI) | 29260 | (7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene | C17H15NO5 | 详情 | 详情 | |
| (VII) | 29261 | (7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol | C17H15NO6 | 详情 | 详情 | |
| (VIII) | 29262 | acetohydrazide | 1068-57-1 | C2H6N2O | 详情 | 详情 |
| (IX) | 29263 | N'-[(E)-[6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methylidene]acetohydrazide | C19H19N3O6 | 详情 | 详情 | |
| (X) | 29264 | N'-[(E)-[6-((2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]propyl)-1,3-benzodioxol-5-yl](4-nitrophenyl)methylidene]acetohydrazide | C22H25N3O6S | 详情 | 详情 | |
| (XI) | 29265 | 1-[(8R)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-7-yl]-1-ethanone | C19H17N3O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The hydrolysis of the ketoester (I) with NaOH gives the corresponding ketoacid (II), which is condensed with 4-nitrobenzaldehyde (III) by means of pyridine to yield the hydroxyketone (IV). The reaction of (IV) with acetic anhydride and pyridine affords the acetoxy compound (V), which is dehydrated by means of hot pyridine to provide the enone (VI). The condensation of (VI) with benzyl acetate (VII) by means of LDA gives 3-hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester (VIII), which is fully hydrogenated with H2 over Pd(OH)2 to yield the amino acid (IX). Finally, (IX) is treated with acetic anhydride to afford the target 5-(4-acetamidophenyl)-3-hydroxy-3-isopropylpentanoic acid intermediate (X).
| 【1】 Deering, C.F.; et al.; Application of the Schöpf method to optimization of the synthesis of 3-[2-(p-N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid: Simultaneous reduction of three functional groups to maximine yield and throughput. Org Process Res Dev 2000, 4, 6, 596. |
| 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) | 43331 | methyl 4-methyl-3-oxopentanoate | 42558-54-3 | C7H12O3 | 详情 | 详情 |
| (II) | 50030 | 4-methyl-3-oxopentanoic acid | C6H10O3 | 详情 | 详情 | |
| (III) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (IV) | 50031 | 1-hydroxy-4-methyl-1-(4-nitrophenyl)-3-pentanone | C12H15NO4 | 详情 | 详情 | |
| (V) | 50032 | 4-methyl-1-(4-nitrophenyl)-3-oxopentyl acetate | C14H17NO5 | 详情 | 详情 | |
| (VI) | 50033 | (E)-4-methyl-1-(4-nitrophenyl)-1-penten-3-one | C12H13NO3 | 详情 | 详情 | |
| (VII) | 35457 | benzyl acetate | 140-11-4 | C9H10O2 | 详情 | 详情 |
| (VIII) | 50034 | benzyl (E)-3-hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoate | C21H23NO5 | 详情 | 详情 | |
| (IX) | 50035 | 3-(4-aminophenethyl)-3-hydroxy-4-methylpentanoic acid | C14H21NO3 | 详情 | 详情 | |
| (X) | 50036 | 3-[4-(acetamido)phenethyl]-3-hydroxy-4-methylpentanoic acid | C16H23NO4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Condensation of 4-nitrobenzaldehyde (I) with N-methyl acetoacetamide (II) in the presence of piperidine acetate gave benzylideneacetoacetamide (III). This was further condensed with 2-cyanoethyl 3-amino-2-butenoate (IV) to provide dihydropyridine (V), which was resolved into the enantiomers using chiral HPLC. Then, basic hydrolysis of the cyanoethyl ester from the appropriate enantiomer of (V) yielded carboxylic acid (VI). The aminopropyl piperidine (X) was obtained by esterification of 4-phenyl-4-piperidinecarboxylic acid (VII) with MeOH and H2SO4, followed by alkylation of piperidine (VIII) with 3-bromopropylamine (IX). Finally, amine (X) was coupled to acid (VI) by means of EDC and DMAP to furnish the target compound.
| 【1】 Nagarathnam, D.; Wetzel, J.M.; Miao, S.W.; Marzabadi, M.R.; Chiu, G.; Wong, W.C.; Hong, X.; Fang, J.; Forray, C.; Branchek, T.A.; Heydorn, W.E.; Chang, R.S.; Broten, T.; Schorn, T.W.; Gluchowski, C.; Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 1998, 41, 26, 5320. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (II) | 25443 | N-methyl-3-oxobutanamide | 20306-75-6 | C5H9NO2 | 详情 | 详情 |
| (III) | 25444 | (Z)-2-acetyl-N-methyl-3-(4-nitrophenyl)-2-propenamide | C12H12N2O4 | 详情 | 详情 | |
| (IV) | 13987 | 2-cyanoethyl (E)-3-amino-2-butenoate | C7H10N2O2 | 详情 | 详情 | |
| (V) | 25445 | 2-cyanoethyl 2,6-dimethyl-5-[(methylamino)carbonyl]-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate | C19H20N4O5 | 详情 | 详情 | |
| (VI) | 25446 | 2,6-dimethyl-5-[(methylamino)carbonyl]-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H17N3O5 | 详情 | 详情 | |
| (VII) | 25447 | 4-phenyl-4-piperidinecarboxylic acid | 3627-45-0 | C12H15NO2 | 详情 | 详情 |
| (VIII) | 25448 | methyl 4-phenyl-4-piperidinecarboxylate | C13H17NO2 | 详情 | 详情 | |
| (IX) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (X) | 25450 | methyl 1-(3-aminopropyl)-4-phenyl-4-piperidinecarboxylate | C16H24N2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Condensation of 2-(4-chlorophenyl)ethanol (I) with 4-nitrobenzaldehyde (II) by means of ZnCl2 and HCl produced isochromane (III). Subsequent oxidative cleavage of (III) employing Jones reagent in acetone afforded ketoacid (IV). Conversion of (IV) to the corresponding hydrazone (V), followed by cyclization in the presence of dicyclohexylcarbodiimide yielded benzodiazepinone (VI). After conversion of (VI) to the benzodiazepine thione (VII) by treatment with P2S5, condensation with 2-(1-aminoethyl)-1,3-dioxolane (VIII) employing HgO as the desulfurizing reagent furnished (IX). Further acid-catalyzed cyclization of (IX) gave rise to the imidazobenzodiazepine (X). Finally, the nitro group of (X) was reduced by transfer hydrogenation using hydrazine and Raney Nickel.
| 【1】 Csuazdi, E.; Solyom, S.; Abraham, G.; et al.; New non competitive AMPA antagonists. Bioorg Med Chem 2000, 8, 8, 2127. |
| 【2】 Csuzdi, E.; Ling, I.; Berzsenyi, P.; Horvath, K.; Abraham, G.; Andrasi, F.; Hamori, T.; Moravcsik, I.; Simay, A.; Tarnawa, I.; Pallagi, I.; Solyom, S. (Gyogyszerkutato Intezet Kft.); New 2,3-benzodiazepine derivs.. EP 1001956; WO 9906408 . |
| 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) | 33783 | 2-(4-chlorophenyl)-1-ethanol | 1875-88-3 | C8H9ClO | 详情 | 详情 |
| (II) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (III) | 33784 | 7-chloro-1-(4-nitrophenyl)-3,4-dihydro-1H-isochromene | C15H12ClNO3 | 详情 | 详情 | |
| (IV) | 33785 | 2-[4-chloro-2-(4-nitrobenzoyl)phenyl]acetic acid | C15H10ClNO5 | 详情 | 详情 | |
| (V) | 33786 | 2-[4-chloro-2-[(Z)hydrazono(4-nitrophenyl)methyl]phenyl]acetic acid | C15H12ClN3O4 | 详情 | 详情 | |
| (VI) | 33787 | 8-chloro-1-(4-nitrophenyl)-3,5-dihydro-4H-2,3-benzodiazepin-4-one | C15H10ClN3O3 | 详情 | 详情 | |
| (VII) | 33788 | 8-chloro-1-(4-nitrophenyl)-3,5-dihydro-4H-2,3-benzodiazepine-4-thione | C15H10ClN3O2S | 详情 | 详情 | |
| (VIII) | 33789 | 1-(1,3-dioxolan-2-yl)-1-ethanamine; 1-(1,3-dioxolan-2-yl)ethylamine | C5H11NO2 | 详情 | 详情 | |
| (IX) | 33790 | 8-chloro-N-[1-(1,3-dioxolan-2-yl)ethyl]-1-(4-nitrophenyl)-5H-2,3-benzodiazepin-4-amine; N-[8-chloro-1-(4-nitrophenyl)-5H-2,3-benzodiazepin-4-yl]-N-[1-(1,3-dioxolan-2-yl)ethyl]amine | C20H19ClN4O4 | 详情 | 详情 | |
| (X) | 33791 | 8-chloro-2-methyl-6-(4-nitrophenyl)-11H-imidazo[1,2-c][2,3]benzodiazepine | C18H13ClN4O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The title compound was synthesized through Baylis-Hillman reaction of p-nitrobenzaldehyde (I) with acrylonitrile (II) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) and NaI.
合成路线9
该中间体在本合成路线中的序号：(I)Oxidative oxidation of p-nitrobenzaldehyde (I) and 1,2-phenylenediamine (II) in DMF in the presence of nitrobenzene produced benzimidazole (III). Subsequent reduction of the nitro group of (III) by means of NaBH4 and CuCl afforded aniline (IV). Bromide (VI) was prepared by treatment of 4'-demethyl epipodophyllotoxin (V) with HBr. The title compound was then obtained by coupling aniline (IV) with bromide (VI) using BaCO3 in 1,2-dichloroethane.
| 【1】 Cheng, H.-H.; Guan, J.; Zhu, X.-K.; Cheng, Y.-C.; Tachibana, Y.; Bastow, K.F.; Lee, K.-H.; Gurwith, M.; Cho, S.J.; Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles. J Med Chem 1999, 42, 13, 2441. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (II) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (III) | 33735 | 2-(4-nitrophenyl)-1H-benzimidazole | C13H9N3O2 | 详情 | 详情 | |
| (IV) | 33736 | 4-(1H-benzimidazol-2-yl)aniline; 4-(1H-benzimidazol-2-yl)phenylamine | C13H11N3 | 详情 | 详情 | |
| (V) | 13053 | (5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | 6559-91-7 | C21H20O8 | 详情 | 详情 |
| (VI) | 14609 | (5R,5aR,8aR,9S)-9-bromo-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | C21H19BrO7 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(V)The chiral intermediate (S)-alpha-methyl-1,3-benzodioxole-5-ethanol (IV) was prepared by microbiological reduction of 3,4-methylenedioxyphenyl acetone (I) or, alternatively, by lithiation of 4-bromo-1,2-(methylenedioxy)benzene (II) with sec-butyllithium, followed by addition to (S)-propylene oxide (III). Hydrochloric acid-promoted condensation of (IV) with p-nitrobenzaldehyde (V) in hot toluene gave rise to the dioxolobenzopyran system (VIa-b), which was hydroxylated to (VIIa-b) by air oxidation under alkaline conditions. Hydrazone (IXa-b) was obtained as a mixture of E,Z isomers upon treatment of (VIIa-b) with 2-hydrazinopyridine (VIII) in refluxing EtOH. After mesylation of the alcohol group of (IXa-b) with methanesulfonyl chloride and triethylamine, the resulting mesylate (Xa-b) was cyclized to the dioxolo benzodiazepine (XI) using lithium tert-butoxide in THF. The nitro group of (XI) was finally reduced to the target aniline by transfer hydrogenation with potassium formate in the presence of Pd/C.
| 【1】 Anderson, B.A.; Harkness, A.R.; Hansen, M.V.; Harn, N.K.; Lodge, D.; Leander, J.D.; Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazepine AMPA antagonists. Bioorg Med Chem Lett 1999, 9, 14, 1953. |
| 【2】 Anderson, B.A.; Hansen, M.M.; Vicenzi, J.T.; Varie, D.L.; Zmijewski, M.J. Jr.; Harkness, A.R. (Eli Lilly and Company); Physical form of dihydro-2,3-benzodiazepine deriv.. EP 0699676; JP 1996081468; JP 1996081469; JP 1996092255; JP 1998505066; US 5795886 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 34410 | (5R,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene | C17H15NO5 | 详情 | 详情 | |
| (VIb) | 34411 | (5S,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene | C17H15NO5 | 详情 | 详情 | |
| (VIIa) | 34412 | (5R,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol | C17H15NO6 | 详情 | 详情 | |
| (VIIb) | 34413 | (5S,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol | C17H15NO6 | 详情 | 详情 | |
| (IXa) | 34415 | [6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methanone N-(2-pyridinyl)hydrazone | C22H20N4O5 | 详情 | 详情 | |
| (IXb) | 34416 | [6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methanone N-phenylhydrazone | C23H21N3O5 | 详情 | 详情 | |
| (Xa) | 34417 | (1S)-1-methyl-2-(6-[(4-nitrophenyl)[(E)-2-(2-pyridinyl)hydrazono]methyl]-1,3-benzodioxol-5-yl)ethyl methanesulfonate | C23H22N4O7S | 详情 | 详情 | |
| (Xb) | 34418 | (1S)-1-methyl-2-(6-[(4-nitrophenyl)[(Z)-2-phenylhydrazono]methyl]-1,3-benzodioxol-5-yl)ethyl methanesulfonate | C24H23N3O7S | 详情 | 详情 | |
| (I) | 28466 | 1-(1,3-benzodioxol-5-yl)acetone | 4676-39-5 | C10H10O3 | 详情 | 详情 |
| (II) | 10124 | 5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene | 2635-13-4 | C7H5BrO2 | 详情 | 详情 |
| (III) | 29268 | (2S)-2-methyloxirane | 16088-62-3 | C3H6O | 详情 | 详情 |
| (IV) | 29259 | (2S)-1-(1,3-benzodioxol-5-yl)-2-propanol | C10H12O3 | 详情 | 详情 | |
| (V) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (VIII) | 34414 | 2-hydrazinopyridine | C5H7N3 | 详情 | 详情 | |
| (XI) | 34419 | (8R)-8-methyl-5-(4-nitrophenyl)-7-(2-pyridinyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine | C22H18N4O4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)The precursor aldehyde (VI) was prepared as follows. 4-Nitrobenzaldehyde (I) was protected as the ethylene acetal (II) and subsequently reduced by catalytic hydrogenation in the presence of PtO2 to furnish aniline (III). Acylation of (III) with 2-thiophenecarbonyl chloride (IV) provided amide (V). The ethylene acetal group of (V) was then hydrolyzed to the target aldehyde (VI) under acidic conditions.
| 【1】 Folkes, A.; et al.; Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1. Bioorg Med Chem Lett 2001, 11, 19, 2589. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (II) | 53126 | 2-(4-nitrophenyl)-1,3-dioxolane | n/a | C9H9NO4 | 详情 | 详情 |
| (III) | 53127 | 4-(1,3-dioxolan-2-yl)aniline; 4-(1,3-dioxolan-2-yl)phenylamine | n/a | C9H11NO2 | 详情 | 详情 |
| (IV) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (V) | 53128 | N-[4-(1,3-dioxolan-2-yl)phenyl]-2-thiophenecarboxamide | n/a | C14H13NO3S | 详情 | 详情 |
| (VI) | 53129 | N-(4-formylphenyl)-2-thiophenecarboxamide | n/a | C12H9NO2S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)The intermediate benzaldehyde (XII) has been obtained as follows: The reduction of 4-nitrobenzaldehyde (I) with NaBH4 and NiCl2 gives 4-aminobenzyl alcohol (II), which is treated with benzyl chloroformate to yield the carbamate (III). The protection of the OH group of (III) with Tbdms-Cl affords the silyl ether (IV). The cyclization of (IV) with glycidyl butyrate (V) by means of BuLi provides the hydroxymethyl oxazolidinone (VI), which is treated with MsCl and TEA to give the mesylate (VII). The reaction of (VII) with NaN3 yields the azidomethyl compound (VIII), which is condensed with thioacetic acid (IX) to afford the acetamide (X). The cleavage of the Tbdms protecting group of (X) by means of TBAF provides the benzyl alcohol (XI), which is oxidized with PDC to furnish the target benzaldehyde intermediate (XII)
| 【1】 Selvakumar, N.; et al.; Synthesis and antibacterial activity of novel chalcone oxazolidinone hybrids. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1323. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (II) | 34431 | diallyl (2S)-2-isocyanatopentanedioate | C12H15NO5 | 详情 | 详情 | |
| (III) | 61803 | benzyl 4-(hydroxymethyl)phenylcarbamate | C15H15NO3 | 详情 | 详情 | |
| (IV) | 61804 | benzyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenylcarbamate | C21H29NO3Si | 详情 | 详情 | |
| (V) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (VI) | 61805 | (5R)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C17H27NO4Si | 详情 | 详情 | |
| (VII) | 61806 | {(5R)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate | C18H29NO6SSi | 详情 | 详情 | |
| (VIII) | 61807 | (5R)-5-(azidomethyl)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-1,3-oxazolidin-2-one | C17H26N4O3Si | 详情 | 详情 | |
| (IX) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | |
| (X) | 61808 | N-({(5S)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide | C19H30N2O4Si | 详情 | 详情 | |
| (XI) | 61809 | N-({(5S)-3-[4-(hydroxymethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide | C13H16N2O4 | 详情 | 详情 | |
| (XII) | 61812 | N-{[(5S)-3-(4-formylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide | C13H14N2O4 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(II)The cyclization of 3,4-diaminobenzoic acid (I) with 4-nitrobenzaldehyde (II) in nitrobenzene at 160 C gives 2-(4-nitrophenyl)-1H-benzimidazole-5-carboxylic acid (III), which is condensed with 2-aminopyridine (IV) by means of CDI in DMF to yield the corresponding amide (V). The reduction of the nitro group of (V) with H2 over Pd/C in methanol affords 2-(4-aminophenyl)-N-(2-pyridinyl)-1H-benzimidazole-5-carboxamide (VI). Finally, this compound is condensed with adamantane-1-carboxylic acid (VII) to provide the target diamide.
| 【1】 Sircar, J.C.; Richards, M.L.; Major, M.W. (Avanir Pharmaceuticals); Benzimidazole cpds. for modulating IgE and inhibiting cellular proliferation. EP 1368028; WO 0272090 . |
| 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) | 62528 | C7H8N2O2 | 详情 | 详情 | ||
| (II) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (III) | 64591 | 2-(4-nitrophenyl)-1H-benzimidazole-5-carboxylic acid | C14H9N3O4 | 详情 | 详情 | |
| (IV) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (V) | 64592 | 2-(4-nitrophenyl)-N-(2-pyridinyl)-1H-benzimidazole-5-carboxamide | C19H13N5O3 | 详情 | 详情 | |
| (VI) | 64593 | 2-(4-aminophenyl)-N-(2-pyridinyl)-1H-benzimidazole-5-carboxamide | C19H15N5O | 详情 | 详情 | |
| (VII) | 64594 | tricyclo[3.3.1.1~3,7~]decane-1-carbonyl chloride | C11H15ClO | 详情 | 详情 |