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【结 构 式】 
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【分子编号】15547 【品名】4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline 【CA登记号】100-01-6 |
【 分 子 式 】C6H6N2O2 【 分 子 量 】138.12592 【元素组成】C 52.17% H 4.38% N 20.28% O 23.17% |
合成路线1
该中间体在本合成路线中的序号：(I)Diazotization of 4-nitroaniline (I), followed by copper-catalyzed coupling of the resultant diazonium salt (II) with 2-furaldehyde (III) leads to 5-(p-nitrophenyl)-2-furancarboxaldehyde (IV) (1). Cyclization of semicarbazideacetic acid (V) by heating in aqueous sulfuric acid leads to 1-aminohydantoin (VI) (2). This is then condensed with aldehyde (IV) to furnish the furfurylidene aminohydantoin (VII) (1, 2). Treatment of (VII) with sodium methoxide gives rise to the corresponding sodium salt (1).
| 【1】 Frimm, R.; Kovac, S.; Giller, S.A.; Furan derivatives. XXIII. Synthesis and absorption spectra of 5-(nitrophenyl)-2-furaldehyde derivatives. Chem Zvesti 1969, 23, 11-12, 916. |
| 【2】 Snyder, H.R. Jr.; Davis, C.S.; Bickerton, R.K.; Halliday, R.P.; 1-[(5-Arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants. J Med Chem 1967, 10, 5, 807. |
| 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) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (II) | 61431 | 4-nitrobenzenediazonium | C6H4N3O2 | 详情 | 详情 | |
| (III) | 63582 | 2-furaldehyde | C5H4O2 | 详情 | 详情 | |
| (IV) | 63583 | 5-(4-nitrophenyl)-2-furaldehyde | C11H7NO4 | 详情 | 详情 | |
| (V) | 63584 | 2-[1-(aminocarbonyl)hydrazino]acetic acid | C3H7N3O3 | 详情 | 详情 | |
| (VI) | 63585 | 1-amino-2,4-imidazolidinedione | C3H5N3O2 | 详情 | 详情 | |
| (VII) | 63586 | 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione | C14H10N4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)3) The condensation of 2-bromobenzoic acid (XII) with 4-nitroaniline (XIII) by means of SOCl2 in DMF gives the corresponding amide (XIV), which is cyclized with sodium azide and SOCl2 in acetonitrile - DMF, yielding 5-(2-bromophenyl)-1-(4-nitrophenyl)tetrazole (XV). The condensation of (XV) with the boronic acid (VI, Scheme 1) by means of Na2CO3 and tetrakis(triphenylphosphine)palladium in methanol - water - toluene affords 5-(4'-methylbiphenyl-2-yl)-1-(4-nitrophenyl)tetrazole (XVI), which is brominated with NBS and AIBN to the corresponding bromomethyl derivative (XVII). The condensation of (XVII) with quinolone (III, Scheme 1) by means of K2CO3 in hot N-methylpyrrolidone gives 2-ethyl-4-[2'-[1-(4-nitrophenyl)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (XVIII), which is finally deprotected with NaH and propanethiol in N-methylpyrrolidone. 4) The dehydration of the boronic acid (VI), followed by bromination with bromine and AIBN, gives 4-(bromomethyl)boronic anhydride (XIX), which is condensed with quinolone (III) by means of K2CO3 in N-methylpyrrolidone, yielding 4-(2-ethylquinolin-4-yloxymethyl)phenylboronic acid (XX). The condensation of (XX) with the bromophenyl-tetrazole (XV) by means of K2CO3 and tetrakis(triphenylphosphine)palladium in water - methanol - toluene yields compound (XVIII), already obtained (5). Scheme 2. 5) The reaction of the boronic acid (VI) with 2,2-dimethylpropane-1,3-diol (XXI) in refluxing cyclohexane gives the cyclic boronic ester (XXII), which is brominated with BBS as before to the bromomethyl derivative (XXIII). The condensation of (XXIII) with quinolone (III) affords 2-[4-(2-ethylquinolin-4-yloxymethyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane (XXIV), which is condensed with (XV) as before to give (XVIII), already obtained.
| 【1】 Roberts, D.A.; Russell, S.T.; Pearce, R.J. (AstraZeneca plc); Quinoline derivs., process for their preparation and their use as medicaments. AU 9160955; EP 0412848; GB 2234748; JP 1991169863; US 5444071 . |
| 【2】 Prous, J.; Castaner, J.; Graul, A.; ICI-D8731. Drugs Fut 1993, 18, 5, 428. |
| 【3】 Bradbury, R.H.; Allott, C.P.; Dennis, M.; et al.; New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives. J Med Chem 1992, 35, 22, 4027. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (XII) | 15546 | 2-bromobenzoic acid; o-bromobenzoic acid | 88-65-3 | C7H5BrO2 | 详情 | 详情 |
| (XIII) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (XIV) | 15548 | 2-bromo-N-(4-nitrophenyl)benzamide | C13H9BrN2O3 | 详情 | 详情 | |
| (XV) | 11451 | 5-(2-Bromophenyl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C13H8BrN5O2 | 详情 | 详情 | |
| (XVI) | 15550 | 5-(4'-methyl[1,1'-biphenyl]-2-yl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C20H15N5O2 | 详情 | 详情 | |
| (XVII) | 15551 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C20H14BrN5O2 | 详情 | 详情 | |
| (XVIII) | 15552 | 2-ethyl-4-quinolinyl [2'-[1-(4-nitrophenyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl ether; 2-ethyl-4-([2'-[1-(4-nitrophenyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methoxy)quinoline | C20H14BrN5O2 | 详情 | 详情 | |
| (XIX) | 15553 | 1,3-bis[4-(bromomethyl)phenyl]-3-hydroxy-1-diboroxanol | C14H14B2Br2O3 | 详情 | 详情 | |
| (XX) | 15554 | 4-[[(2-ethyl-4-quinolinyl)oxy]methyl]phenylboronic acid | C18H18BNO3 | 详情 | 详情 | |
| (XXI) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (XXII) | 15556 | 5,5-dimethyl-2-(4-methylphenyl)-1,3,2-dioxaborinane | C12H17BO2 | 详情 | 详情 | |
| (XXIII) | 15557 | 2-[4-(bromomethyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane | C12H16BBrO2 | 详情 | 详情 | |
| (XXIV) | 15558 | 4-[[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl]oxy]-2-ethylquinoline; 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl 2-ethyl-4-quinolinyl ether | C23H26BNO3 | 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 synthesis of D-23129 is shown in Scheme 22750501a. Reaction of 4-nitroaniline (I) with chloroformic acid ethyl ester gives N-(4-nitrophenyl)carbamic acid ethyl ester (II), which is reduced with H2 over Pd/C in isopropyl acohol, yielding the corresponding 4-amino-derivative (III). This compound is transformed with phthalic acid anhydride in acetic acid into the phthalimide (IV), which is nitrated with fuming nitric acid to the nitro derivative (V). The phthalimide (V) is cleaved up with hydrazine hydrate in dimethoxyethane to the derivative (VI). Condensation of (VI) with 4-fluorobenzaldehyde in refluxing toluene gives the benzylidene aniline derivative (VII), which is reduced with sodium borohydride in DME/ethanol and subsequently with H2/Raney-nickel in dimethoxyethane, yielding D-23129.
| 【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) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (II) | 17139 | Ethyl N-(4-nitrophenyl)carbamate; Ethyl 4-nitrophenylcarbamate | 2621-73-0 | C9H10N2O4 | 详情 | 详情 |
| (III) | 17140 | Ethyl N-(4-aminophenyl)carbamate | C9H12N2O2 | 详情 | 详情 | |
| (IV) | 17141 | ethyl N-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]carbamate | C17H14N2O4 | 详情 | 详情 | |
| (V) | 17142 | ethyl N-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-nitrophenyl]carbamate | C17H13N3O6 | 详情 | 详情 | |
| (VI) | 17143 | ethyl N-(4-amino-2-nitrophenyl)carbamate | C9H11N3O4 | 详情 | 详情 | |
| (VII) | 17144 | ethyl N-(4-[[(E)-(4-fluorophenyl)methylidene]amino]-2-nitrophenyl)carbamate | C16H14FN3O4 | 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 reaction of 5-(dimethylamino)naphthalene-1-sulfonyl chloride (I) with 4-nitroaniline (II) in pyridine gives the corresponding sulfonamide (III), which is reduced at the nitro group with hydrogen over Pd/C in ethanol, yielding the expected amine (IV). Finally, this compound is condensed with 3-hydroxy-2,2-dimethylpropionic acid (V) by means of propylphosphonic anhydride (PRPA) and triethylamine in dichloromethane/ethyl acetate.
| 【1】 Hallenberger, S.; Weber, O.; Bender, W.; Eckenberg, P.; Reefschlaeger, J.; Goldmann, S.; Trappe, J.; Haerter, M.; A novel nonnucleosidic inhibitor of human cytomegalovirus replication. Intersci Conf Antimicrob Agents Chemother 1999, Abst F940. |
| 【2】 Leeson, P.A.; Sorbera, L.A.; Castañer, J.; Bay-38-4766. Drugs Fut 1999, 24, 12, 1297. |
| 【3】 Trappe, J.; Weber, O.; Eckenberg, P.; Hallenberger, S.; Bender, W.; Goldmann, S.; Harter, M.; Reefschlager, J. (Bayer AG); Novel naphthyl-substd. and anilide-substd. sulfonamides. WO 9937609 . |
| 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) | 19027 | 5-(dimethylamino)-1-naphthalenesulfonyl chloride | 605-65-2 | C12H12ClNO2S | 详情 | 详情 |
| (II) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (III) | 30616 | 5-(dimethylamino)-N-(4-nitrophenyl)-1-naphthalenesulfonamide | C18H17N3O4S | 详情 | 详情 | |
| (IV) | 30617 | N-(4-aminophenyl)-5-(dimethylamino)-1-naphthalenesulfonamide | C18H19N3O2S | 详情 | 详情 | |
| (V) | 30618 | 3-hydroxy-2,2-dimethylpropionic acid | 4835-90-9 | C5H10O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The condensation between 4-fluoronitrobenzene (I) and tetrazole (II) provided a mixture of regioisomeric (4-nitrophenyl)tetrazoles (III) and (IV). Reduction of this mixture employing hydrazine and FeCl3 gave the corresponding mixture of amino derivatives from which the required isomer (V) was isolated by column chromatography. Alternatively, 4-nitroaniline (VI) was converted into the desired (4-nitrophenyl)tetrazole regioisomer (III) by reaction with sodium azide and trimethyl orthoformate in HOAc. Subsequent reduction of the nitro group of (III) employing hydrazine and FeCl3 gave aniline (V). This compound was also obtained by another alternative procedure consisting in protection of 4-nitroaniline (VI) as the N,N-dibenzyl amine (VII), followed by reduction of the nitro group and cyclization with NaN3 and trimethyl orthoformate to afford tetrazole (VIII). Further hydrogenolysis of the benzyl protecting groups of (VIII) yielded 1-(4-aminophenyl)tetrazole (V). Aniline (V) was then converted to the intermediate phenyl carbamate (IX) by treatment with phenyl chloroformate in pyridine. Optionally, the intermediate phenyl carbamate (IX) was converted into the aryl imidazolone (XII) by condensation with 2,2-diethoxyethylamine (X) and then acid-catalyzed cyclization of the resulting N-(2,2-diethoxyethyl)urea (XI) to give (XII).
| 【4】 Itoh, K.; Okonogi, K.; Tasaka, A. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0809640; JP 1997183769; WO 9625410 . |
| 【5】 Kitazaki, T.; Matsushita, Y.; Hosono, H.; Itoh, K.; Mitsudera, H. (Takeda Chemical Industries, Ltd.); Triazole derivs. and their production. EP 0884311 . |
| 【1】 Ichikawa, T.; Matsushita, Y.; Yamada, M.; Tasaka, A.; Yamaguchi, M.; Itoh, K.; Okonogi, K.; Kitazaki, T.; TAK-456 and the water-soluble prodrug TAK-457, new antifungal triazoles: Synthesis and in vitro antifungal activity. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1085. |
| 【2】 Ichikawa, T.; et al.; Optically active antifungal azoles. XI. An alternative synthetic route for 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456) and its analog. Chem Pharm Bull 2000, 48, 12, 1947. |
| 【3】 Hosono, H.; Itoh, K.; Kitazaki, T.; Ichikawa, T.; Okonogi, K.; Tasaka, A.; Matsushita, Y.; Hayashi, R.; Optically active antifungal azoles. X. Synthesis and antifungal activity of N-[4-(azolyl)phenyl] and N-[4-(azolylmethyl)phenyl]-N'[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H,1,2,4-triazol-1-yl)propyl]-azolones. Chem Pharm Bull 2000, 48, 12, 1935. |
| 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) | 14153 | 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene | 350-46-9 | C6H4FNO2 | 详情 | 详情 |
| (II) | 32408 | 1H-1,2,3,4-tetraazole; Tetrazole | 288-94-8 | CH2N4 | 详情 | 详情 |
| (III) | 45555 | 1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C7H5N5O2 | 详情 | 详情 | |
| (IV) | 45556 | 2-(4-nitrophenyl)-2H-1,2,3,4-tetraazole | 67-97-0 | C7H5N5O2 | 详情 | 详情 |
| (V) | 45557 | 4-(1H-1,2,3,4-tetraazol-1-yl)phenylamine; 4-(1H-1,2,3,4-tetraazol-1-yl)aniline | C7H7N5 | 详情 | 详情 | |
| (VI) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (VII) | 45558 | N,N-dibenzyl-N-(4-nitrophenyl)amine; N,N-dibenzyl-4-nitroaniline | C20H18N2O2 | 详情 | 详情 | |
| (VIII) | 45559 | N,N-dibenzyl-N-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]amine; N,N-dibenzyl-4-(1H-1,2,3,4-tetraazol-1-yl)aniline | C21H19N5 | 详情 | 详情 | |
| (IX) | 45560 | phenyl 4-(1H-1,2,3,4-tetraazol-1-yl)phenylcarbamate | C14H11N5O2 | 详情 | 详情 | |
| (X) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
| (XI) | 45561 | N-(2,2-diethoxyethyl)-N'-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]urea | C14H20N6O3 | 详情 | 详情 | |
| (XII) | 45562 | 1-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C10H8N6O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Acylation of 4-nitroaniline (I) with 4-fluorobenzoyl chloride (II) affords benzanilide (III). Catalytic hydrogenation of the nitro group of (III) employing Pt/C then gives amine (IV). Diazotization of (IV), followed by reduction with SnCl2 leads to hydrazine (V). Reaction of 5-chloro-2-pentanone (VI) with dimethylamine yields the amino ketone (VII). Finally, the title compound is obtained by Fisher indole synthesis from aryl hydrazine (V) and ketone (VII) under acidic conditions.
| 【1】 Xu, Y.-C.; Johnson, K.W.; Phebus, L.A.; et al.; N-[3-(2-Dimethylaminoethyl)-2-methyl-1-H-indol-5-yl]-4-fluorobenzamide: A potent, selective, and orally active 5-HT1F receptor agonist potentially useful for migraine therapy. J Med Chem 2001, 44, 24, 4031. |
| 【2】 Johnson, K.W.; Phebus, L.A. (Eli Lilly and Company); Use of a serotonin 5-HT1F agonist in the manufacture of a medicament for treating or ameliorating the symptoms of common cold or allergic rhinitis. EP 0824917; US 5962473; WO 9806402 . |
| 【3】 Fritz, J.E.; Hahn, P.J.; Kaldor, S.W.; Siegel, M.G.; Xu, Y.-C. (Eli Lilly and Company); N-[2-Substd.-3-(2-aminoethyl)-1H-indol-5-yl]-amides: New 5-HT1F agonists. EP 0768301; JP 1999513666; WO 9713512 . |
| 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) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (II) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (III) | 60456 | 4-fluoro-N-(4-nitrophenyl)benzamide | C13H9FN2O3 | 详情 | 详情 | |
| (IV) | 60457 | N-(4-aminophenyl)-4-fluorobenzamide | C13H11FN2O | 详情 | 详情 | |
| (V) | 60458 | 4-fluoro-N-(4-hydrazinophenyl)benzamide | C13H12FN3O | 详情 | 详情 | |
| (VI) | 60460 | 5-chloro-2-pentanone | C5H9ClO | 详情 | 详情 | |
| (VII) | 60459 | 5-(dimethylamino)-2-pentanone | C7H15NO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)In an alternative method, p-nitroaniline (I) is reacted with ethylene oxide (II) to afford diol (III). This compound can also be prepared by condensation of 1-fluoro-4-nitrobenzene (IV) with diethanolamine (V). Chlorination of diol (III) to provide (VI) is accomplished with either mesyl chloride or SOCl2 in the presence of pyridine. Then, nitro group reduction in (VI) by means of iron and HCl affords aniline (VII).
| 【1】 Jordan, A.M.; Khan, T.H.; Malkin, H.; Osborn, H.M.I.; Synthesis and analysis of urea and carbamate prodrugs as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT). Bioorg Med Chem 2002, 10, 8, 2625. |
| 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) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (II) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (III) | 64080 | 2-[(2-hydroxyethyl)-4-nitroanilino]-1-ethanol | C10H14N2O4 | 详情 | 详情 | |
| (IV) | 14153 | 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene | 350-46-9 | C6H4FNO2 | 详情 | 详情 |
| (V) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (VI) | 64081 | N,N-bis(2-chloroethyl)-4-nitroaniline; N,N-bis(2-chloroethyl)-N-(4-nitrophenyl)amine | C10H12Cl2N2O2 | 详情 | 详情 | |
| (VII) | 64082 | N~1~,N~1~-bis(2-chloroethyl)-1,4-benzenediamine; N-(4-aminophenyl)-N,N-bis(2-chloroethyl)amine | C10H14Cl2N2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Diazotization of 4-nitroaniline (I) with NaNO2 in cold concentrated HCl produces diazonium salt (II), which is subsequently coupled to 1,4-benzoquinone (III) in the presence of NaHCO3 to furnish the target 2-aryl benzoquinone.
| 【1】 Reynolds, K.; et al.; The identification of nanomolar 1,4-benzoquinone inhibitors of shikimate kinase. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-745. |
合成路线9
该中间体在本合成路线中的序号：(XVA)The precursor dihydropyridones (IIa) and (IIb) can be synthesized as follows. Acylation of either 4-nitroaniline (XVa) (1) or 4-iodoaniline (XVb) (2) with 5-bromovaleryl chloride (V) affords the corresponding bromoamides (XVIa) and (XVIb), which are cyclized to piperidones (XVIIa) and (XVIIb) upon treatment with potassium tert-butoxide or with potassium hydroxide under phase-transfer conditions. Piperidones (XVIIa/b) are then chlorinated by means of phosphorus pentachloride in chlorobenzene or chloroform to form the geminal dichlorides (XVIIIa) and (XVIIIb) (1, 2). Dehydrohalogenation of (XVIIIa) by means of lithium carbonate and lithium chloride in DMF at 105-110 °C then provides the chloro dihydropyridone (IIa) (1). Alternatively, the dichloro derivative (XVIIIb) is refluxed with neat morpholine (XIX) to furnish intermediate (IIb) (2). Scheme 3.
| 【1】 Shapiro, R., Rossano, L.T., Mudryk, B.M. et al. (Bristol-Myers Squibb Co.). Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO 2007001385. |
| 【2】 Pinto, D., Quan, M., Orwat, M. et al. (Bristol-Myers Squibb Co.). Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. EP 1427415, JP 2005507889, WO 03026652. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVA) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (XVB) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (XVIa) | 65620 | C11H13BrN2O3 | 详情 | 详情 | ||
| (XVIb) | 65621 | C11H13BrINO | 详情 | 详情 | ||
| (XVIIa) | 65622 | 1-(4-Nitrophenyl)-2-piperidinone | 38560-30-4 | C11H12N2O3 | 详情 | 详情 |
| (XVIIb) | 65618 | 1-(4-Iodophenyl)-2-piperidinone | 385425-15-0 | C11H12INO | 详情 | 详情 |
| (XVIIIa) | 65623 | 3,3-Dichloro-1-(4-nitrophenyl)-2-piperidinone | 881386-01-2 | C11H10Cl2N2O3 | 详情 | 详情 |
| (XVIIIb) | 65624 | 3,3-Dichloro-1-(4-iodophenyl)piperidin-2-one | 545445-10-1 | C11H10Cl2INO | 详情 | 详情 |
| (IIA) | 65610 | 3-Chloro-5,6-dihydro-1-(4-nitrophenyl)-2(1H)-pyridinone | 536760-29-9 | C11H9ClN2O3 | 详情 | 详情 |
| (IIB) | 65611 | 1-(4-Iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one; N-(4-Iodophenyl)-3-morpholino-5,6-dihydro-2H-pyridin-2-one | 473927-69-4 | C15H17IN2O2 | 详情 | 详情 |
| (V) | 39700 | 5-bromopentanoyl chloride | 4509-90-4 | C5H8BrClO | 详情 | 详情 |
| (XIX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |