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【结 构 式】 
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【分子编号】11370 【品名】2-Nitrobenzaldehyde 【CA登记号】552-89-6 |
【 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：(II)The condensation of 2-methylpyridine (I) with 2-nitrobenzaldehyde (II) in acetic anhydride gives 2-(2-nitrostyryl)pyridine (III), which is quaternized with methyl iodide in refluxing acetone yielding 2-(2-nitrostyryl)-1-methylpyridinium iodide (IV) . The reduction of (IV) with H2 over PtO2 in ethanol affords 2-(2-aminophenethyl)-1-methylpiperidine (V), which is then acylated with 4-methoxybenzoyl chloride (A) in pyridine.
| 【1】 Dykstra, S.J.; Minielli, J.L.; Substituted piperidines and a process for the preparation thereof. BE 0779951; CA 961038; CH 578529; DE 2210154; FR 2128584; GB 1346261; NL 161443C; NL 7202614 . |
| 【2】 Kendrick, W.D.; Ferguson, H.C.; acid and quimidine analogs. 2-(o-Acylaminophenethyl)piperidines. J Med Chem 1973, 16, 9, 1015. |
| 【3】 Castaner, J.; MJ 9067. Drugs Fut 1977, 2, 3, 176. |
| 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) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (I) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
| (II) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 40197 | 2-[(E)-2-(2-nitrophenyl)ethenyl]pyridine | C13H10N2O2 | 详情 | 详情 | |
| (IV) | 40198 | 1-methyl-2-[(E)-2-(2-nitrophenyl)ethenyl]pyridinium iodide | C14H13IN2O2 | 详情 | 详情 | |
| (V) | 40199 | 2-[2-(1-methyl-2-piperidinyl)ethyl]phenylamine; 2-[2-(1-methyl-2-piperidinyl)ethyl]aniline | C14H22N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：The condensation of Cyclic acetonylphosphonate (II), obtained from bromoacetone and cyclic phosphite (I) by an Arbuzov reaction, with o-nitrobenzaldehyde in the presence of piperidine - AcOH salt in boiling benzene gives benzylidene phosphonale (III), which is cyclized with methyl 3-aminocrotonate (IV) in reflux in 2-propanol affording methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2 oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4 dihydro-pyridine-3 carboxylate.
| 【1】 Kimura, K.; Morita, I. (Nippon Shinyaku Co., Ltd.); 1,4-Dihydropyridine-3-carboxylate derivs.. AU 8541405; BE 0902210; EP 0159040; ES 8606276; FR 2563222; GB 2157695; JP 1985248693; US 5036059 . |
| 【2】 Kimura, K.; DHP-218. Drugs Fut 1987, 12, 3, 212. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 | |
| 20549 | 1-bromoacetone | 598-31-2 | C3H5BrO | 详情 | 详情 | |
| (I) | 22929 | 2-methoxy-1,3,2-dioxaphosphinane | C4H9O3P | 详情 | 详情 | |
| (II) | 20572 | 2-(2-oxopropyl)-1,3,2lambda(5)-dioxaphosphinan-2-one | C6H11O4P | 详情 | 详情 | |
| (III) | 20574 | 2-[(Z)-1-acetyl-2-(2-nitrophenyl)ethenyl]-1,3,2lambda(5)-dioxaphosphinan-2-one | C13H14NO6P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)This compound can be prepared in two related ways: 1) The condensation of diketene (I) with 2,2-(ethylenedioxy)propanol (II) by means of NaH in refluxing benzene gives 2,2-(ethylenedioxy)propyl acetylacetate (III), which is condensed with 2-nitrobenzaldehyde (IV) by means of piperidine and acetic acid in benzene, yielding 2,2-(ethylenedioxy)propyl 2-(2-nitrobenzylidene)acetoacetate (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) in refluxing ethanol affords the protected dihydropyridine (VII), which is finally hydrolyzed with acetic acid in hot water. 2) The reaction of the acetoacetate (III), obtained as before, with ammonia in methanol gives the 3-aminocrotonate (VIII), which is cyclized with methyl 2-(2-nitrobenzylidene)acetoacetate (IX) in refluxing ethanol to afford the dihydropyridine (VII), already obtained.
| 【1】 Ohno, S.; Mizukoshi, K.; Komatsu, O.; Ichiara, K.; Morishima, T. (Maruko Seiyaku); Novel 1,4-dihydropyridines, especially useful as hypotensives. FR 2514761 . |
| 【2】 Castaner, J.; Prous, J.; MPC-1304. Drugs Fut 1991, 16, 1, 25. |
| 【3】 Sumita, T.; Nakamura, Y.; Ichihara, K.; Mizukoshi, K.; Komatsu, O.; Morishima, T.; Ohno, S.; Synthesis of asymmetric 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates with vasodilating and antihypertensive activities. Chem Pharm Bull 1986, 34, 4, 1589-606. |
| 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) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (II) | 11368 | (2-Methyl-1,3-dioxolan-2-yl)methanol | C5H10O3 | 详情 | 详情 | |
| (III) | 11369 | (2-methyl-1,3-dioxolan-2-yl)methyl 3-oxobutanoate | C9H14O5 | 详情 | 详情 | |
| (IV) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 11371 | (2-methyl-1,3-dioxolan-2-yl)methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | C16H17NO7 | 详情 | 详情 | |
| (VI) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VII) | 11373 | 3-methyl 5-[(2-methyl-1,3-dioxolan-2-yl)methyl] 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H24N2O8 | 详情 | 详情 | |
| (VIII) | 11374 | (2-methyl-1,3-dioxolan-2-yl)methyl (E)-3-amino-2-butenoate | C9H15NO4 | 详情 | 详情 | |
| (IX) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Synthesis of Furaldipine (EN:163877)
| 【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 . |
| 【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 . |
| 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) | 14082 | tetrahydro-2-furanylmethyl 3-oxobutanoate | C9H14O4 | 详情 | 详情 | |
| (II) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (IV) | 14085 | tetrahydro-2-furanylmethyl (E)-3-amino-2-butenoate | C9H15NO3 | 详情 | 详情 | |
| (V) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Wittig reaction between 2-nitrobenzyltriphenylphosphonium bromide (I) and pyridine-4-carboxaldehyde (II) provided the olefin adduct (IIIa-b) as a mixture of geometric isomers. After, nitro group reduction employing SnCl2, the desired E-isomer (VII), was isolated from the reaction mixture by fractional crystallization. In an alternative approach to intermediate (VII), condensation between 2-nitrobenzaldehyde (IV) and 4-picoline (V) in refluxing acetic anhydride furnished the E-olefin (VI), which was subsequently reduced with SnCl2 to the desired aniline (VII). Acylation of amine (VII) with 4-methoxybenzenesulfonyl chloride (VIII) in pyridine gave sulfonamide (IX). Subsequent oxidation of the pyridine ring to the corresponding N-oxide (X) was accomplished by treatment with peracetic acid at 70 C. The sulfonamide N was finally acetylated in boiling acetic anhydride.
| 【1】 Matsuura, A.; Matsuda, M. (Nippon Shinyaku Co., Ltd.); Aminostilbazole derivs. and medicine. EP 0754682; WO 9527699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 58544 | 9-amino-3-ethyl-3,7-dihydro-6H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazin-6-one | C10H10N6O | 详情 | 详情 | |
| (IIIb),(VI) | 58555 | 4-[(E)-2-(2-nitrophenyl)ethenyl]pyridine | C13H10N2O2 | 详情 | 详情 | |
| (I) | 58553 | (2-nitrobenzyl)(triphenyl)phosphonium bromide | C25H21BrNO2P | 详情 | 详情 | |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (IV) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 58556 | 2-[(E)-2-(4-pyridinyl)ethenyl]aniline; 2-[(E)-2-(4-pyridinyl)ethenyl]phenylamine | C13H12N2 | 详情 | 详情 | |
| (VIII) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IX) | 58557 | 4-methoxy-N-{2-[(E)-2-(4-pyridinyl)ethenyl]phenyl}benzenesulfonamide | C20H18N2O3S | 详情 | 详情 | |
| (X) | 58558 | 4-[(E)-2-(2-{[(4-methoxyphenyl)sulfonyl]amino}phenyl)ethenyl]-1-pyridiniumolate | C20H18N2O4S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Title compound was prepared by Claisen Schmidt condensation of 2'-nitroacetophenone (I) with 2,3,4-trimethoxybenzaldehyde (II) in EtOH using HCl as the catalyst.
| 【1】 Nielsen, S.F.; Christensen, S.B.; Gruciani, G.; Kharazmi, A.; Liljefors, T.; Antileishmanial chalcones: Statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis. J Med Chem 1998, 41, 24, 4819. |
合成路线7
该中间体在本合成路线中的序号：(I)Condensation of 2-nitrobenzaldehyde (I) with methyl phenylacetate (II) in the presence of lithium diisopropylamide in cold THF provided hydroxyester (III). Reduction of the nitro group of (III) with concomitant cyclization by hydrogenation over Pd/C in EtOAc produced the dihydroquinolinone (IV). Further hydrogenolysis of the hydroxyl group of (IV) over Pd/C in AcOH gave (V), which was finally alkylated with benzyl bromide and NaH to yield the N-benzylquinolinone.
| 【1】 Cho, W.-J.; Lee, J.Y.; Chung, B.-H.; Kim, T.S.; Choi, B.-G.; Cheon, S.H.; Studies on the synthesis and in vitro antitumor activity of the isoquinolone derivatives. Arch Pharmacal Res 1999, 22, 2, 179. |
| 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) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 32831 | methyl 2-phenylacetate | 101-41-7 | C9H10O2 | 详情 | 详情 |
| (III) | 32832 | methyl 3-hydroxy-3-(2-nitrophenyl)-2-phenylpropanoate | C16H15NO5 | 详情 | 详情 | |
| (IV) | 32833 | 4-hydroxy-3-phenyl-3,4-dihydro-2(1H)-quinolinone | C15H13NO2 | 详情 | 详情 | |
| (V) | 32834 | 3-phenyl-3,4-dihydro-2(1H)-quinolinone | C15H13NO | 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 reductive amination of 2-nitrobenzaldehyde (I) with 4-amino-1-benzylpiperidine (II) in the presence of NaBH4 gave amine (III). Subsequent hydrogenation of the nitro group of (III) over Rh/C afforded (IV), which was converted to oxoquinazoline (V) upon treatment with carbonyl diimidazole in hot DMF. Hydrogenolysis of the benzyl protecting group of (V) yielded intermediate (VI).
| 【1】 Eberlein, W.; Wienen, W.; Doods, H.; Rudolf, K.; Entzeroth, M.; Pieper, H.; Engel, W.; Hallermayer, G. (Dr. Karl Thomae GmbH); Modified aminoacids, pharmaceuticals containing these cpds. and methods for their production. JP 2000505100; WO 9811128 . |
| 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) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (III) | 39269 | 1-benzyl-N-(2-nitrobenzyl)-4-piperidinamine; N-(1-benzyl-4-piperidinyl)-N-(2-nitrobenzyl)amine | C19H23N3O2 | 详情 | 详情 | |
| (IV) | 39270 | N-(2-aminobenzyl)-N-(1-benzyl-4-piperidinyl)amine; N-(2-aminobenzyl)-1-benzyl-4-piperidinamine | C19H25N3 | 详情 | 详情 | |
| (V) | 39271 | 3-(1-benzyl-4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone | C20H23N3O | 详情 | 详情 | |
| (VI) | 39272 | 3-(4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone | C13H17N3O | 详情 | 详情 |