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【结 构 式】

【分子编号】17203

【品名】4-Pyridinecarboxaldehyde; isonicotinaldehyde

【CA登记号】872-85-5

【 分 子 式 】C6H5NO

【 分 子 量 】107.11184

【元素组成】C 67.28% H 4.71% N 13.08% O 14.94%
与该中间体有关的原料药合成路线共 23 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23

合成路线1

该中间体在本合成路线中的序号：(VII)

The reaction of 5-methoxyindole-2-carboxylic acid (I) with thionyl chloride gives the acid chloride (II), which is condensed with dimethylamine to afford the amide (III). Reduction of (III) by LiAlH4 leads to the dimethylamino derivative (IV), which is quaternized by methyl iodide to give (V). The ammonium salt (V) is transformed into the corresponding phosphonium iodide (VI) by means of triphenyl phosphine. The successive steps from (I) to the phosphonium iodide (VI) give an overall yield of 50-60%. The condensation of (VI) with 4-formyl pyridine (VII) gives a mixture of 70% cis-(Z-VIII) and 30% trans-(E-VIII) isomers. The mixture of indolyl-pyridylethylenes (Z-VIII) and (E-VIII) is cyclized to 10-methoxy-7H-pyrido[4,3-c]carbazole (IX) by irradiation for 90 h in a Rayonet photoreactor at 350 nm in the presence of iodine (40% yield). Dimerization of (IX) is achieved by strirring in DMF two equivalents of (IX) with one equivalent of 1,1'-bis(2-chloroethyl)-4,4'-bipiperidine dihydrochloride (X) at 85 C for 18 h and recrystallization in EtOH/H20 (40/60).

参考文献 中间体
合成目标
【1】 Bible, R.; Yuan, J.J.; Yang, D.-C.; Zhang, J.Y.; Findlay, J.W.; Karim, A.; Compt Rend Acad Sci 1976, 283, 9, 1109-1112.
【2】 Pelaprat. D.; et al.; DNA intercalating comnpounds as potential antitumor agents. 2. Preparation and properties of 7H-pyridocarbazole dimers. J Med Chem 1980, 23, 12, 1336-1343.
【3】 Pelaprat. D.; et al.; DNA intercalating comnpounds as potential antitumor agents. 1. Preparation and properties of 7H-pyridocarbazoles. J Med Chem 1980, 23, 12, 1330-1335.
【4】 Serradell, M.N.; Castaner, J.; Ditercalinium Chloride. Drugs Fut 1985, 10, 2, 116.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Z-VIII) 28891 5-methoxy-2-[(Z)-2-(4-pyridinyl)ethenyl]-1H-indole C16H14N2O 详情 详情
(E-VIII) 28892 5-methoxy-2-[(E)-2-(4-pyridinyl)ethenyl]-1H-indole C16H14N2O 详情 详情
(I) 28885 5-methoxy-1H-indole-2-carboxylic acid 4382-54-1 C10H9NO3 详情 详情
(II) 28885 5-methoxy-1H-indole-2-carboxylic acid 4382-54-1 C10H9NO3 详情 详情
(III) 28887 5-methoxy-N,N-dimethyl-1H-indole-2-carboxamide C12H14N2O2 详情 详情
(IV) 28888 (5-methoxy-1H-indol-2-yl)-N,N-dimethylmethanamine C12H16N2O 详情 详情
(V) 28889 (5-methoxy-1H-indol-2-yl)-N,N,N-trimethylmethanaminium iodide C13H19IN2O 详情 详情
(VI) 28890 [(5-methoxy-1H-indol-2-yl)methyl](triphenyl)phosphonium iodide C28H25INOP 详情 详情
(VII) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(IX) 28893 10-methoxy-7H-pyrido[3,4-c]carbazole C16H12N2O 详情 详情
(X) 28894 1,1'-Bis-(2-chloro-ethyl)-[4,4']bipiperidinyl C14H26Cl2N2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

3-(Chloromethyl)benzothiophene (II) was prepared by condensation of benzothiophene (I) with paraformaldehyde in the presence of HCl. Subsequent treatment of (II) with KCN produced nitrile (III). This was condensed with pyridine-4-carboxaldehyde (IV) to yield adduct (V). Oxidative photochemical cyclization of (V) furnished the benzothienoisoquinoline tetracyclic system (VI). Hydrolysis of the nitrile group of (VI) to carboxylic acid (VII) was achieved by treatment with KOH in hot glycerol. After conversion of (VII) to methyl ester (VIII), displacement by hydrazine gave rise to hydrazide (IX). Nitrosation of (IX), followed by rearrangement of the resulting acyl azide produced an intermediate isocyanate, that was further converted to ethyl carbamate (X) in boiling EtOH. Alternatively, Curtius rearrangement of carboxylic acid (VII) upon treatment with diphenylphosphoryl azide, and further reaction with tert-butanol furnished tert-butyl carbamate (XI). The title amine was then obtained by either hydrolysis of ethyl carbamate (X) with KOH or by trifluoroacetic acid promoted cleavage of carbamate (XI).

参考文献 中间体
合成目标
【1】 Reist, E.J. (SRI International); Novel benzothiophene analogs as antiviral agents. EP 0712404; JP 1997500386; US 5424315; WO 9504059 .
【2】 Smee, D.F.; Zaveri, N.; Sidwell, R.W.; Reist, E.; Huffman, J.H.; Bradford, W.W.; Benzthieno[3,2-h]isoquinolines as novel nonnucleoside inhibitors of human cytomegalovirus. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 130.
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) 25578 1-benzothiophene 95-15-8 C8H6S 详情 详情
(II) 40956 3-(chloromethyl)-1-benzothiophene C9H7ClS 详情 详情
(III) 40957 2-(1-benzothiophen-3-yl)acetonitrile 3216-48-6 C10H7NS 详情 详情
(IV) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(V) 40958 (E)-2-(1-benzothiophen-3-yl)-3-(4-pyridinyl)-2-propenenitrile C16H10N2S 详情 详情
(VI) 40959 [1]benzothieno[3,2-h]isoquinoline-6-carbonitrile C16H8N2S 详情 详情
(VII) 40960 [1]benzothieno[3,2-h]isoquinoline-6-carboxylic acid C16H9NO2S 详情 详情
(VIII) 40961 methyl [1]benzothieno[3,2-h]isoquinoline-6-carboxylate C17H11NO2S 详情 详情
(IX) 40962 [1]benzothieno[3,2-h]isoquinoline-6-carbohydrazide C16H11N3OS 详情 详情
(X) 40963 ethyl [1]benzothieno[3,2-h]isoquinolin-6-ylcarbamate C18H14N2O2S 详情 详情
(XI) 40964 tert-butyl [1]benzothieno[3,2-h]isoquinolin-6-ylcarbamate C20H18N2O2S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IV)

3-(Chloromethyl)benzothiophene (II) was prepared by condensation of benzothiophene (I) with paraformaldehyde in the presence of HCl. Subsequent treatment of (II) with KCN produced nitrile (III). This was condensed with pyridine-4-carboxaldehyde (IV) to yield adduct (V). Oxidative photochemical cyclization of (V) furnished the benzothienoisoquinoline tetracyclic system (VI). Hydrolysis of the nitrile grroup of (VI) to carboxylic acid (VII) was achieved by treatment with KOH in hot glycerol. After conversion of (VII) to methyl ester (VIII), displacement by hydrazine gave rise to hydrazide (IX). Nitrosation of (IX), followed by rearrangement of the resulting acyl azide produced an intermediate isocyanate, that was further converted to ethyl carbamate (X) in boiling EtOH. Alternatively, Curtius rearrangement of carboxylic acid (VII) upon treatment with diphenylphosphoryl azide, and further reaction with tert-butanol furnished tert-butyl carbamate (XI). Amine (XII) was obtained by either hydrolysis of ethyl carbamate (X) with KOH or by trifluoroacetic acid promoted cleavage of carbamate (XI). Finally, acylation of (XII) with trifluoroacetic anhydride furnished the title trifluoroacetamide.

参考文献 中间体
合成目标
【1】 Reist, E.J. (SRI International); Novel benzothiophene analogs as antiviral agents. EP 0712404; JP 1997500386; US 5424315; WO 9504059 .
【2】 Smee, D.F.; Zaveri, N.; Sidwell, R.W.; Reist, E.; Huffman, J.H.; Bradford, W.W.; Benzthieno[3,2-h]isoquinolines as novel nonnucleoside inhibitors of human cytomegalovirus. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 130.
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) 25578 1-benzothiophene 95-15-8 C8H6S 详情 详情
(II) 40956 3-(chloromethyl)-1-benzothiophene C9H7ClS 详情 详情
(III) 40957 2-(1-benzothiophen-3-yl)acetonitrile 3216-48-6 C10H7NS 详情 详情
(IV) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(V) 40958 (E)-2-(1-benzothiophen-3-yl)-3-(4-pyridinyl)-2-propenenitrile C16H10N2S 详情 详情
(VI) 40959 [1]benzothieno[3,2-h]isoquinoline-6-carbonitrile C16H8N2S 详情 详情
(VII) 40960 [1]benzothieno[3,2-h]isoquinoline-6-carboxylic acid C16H9NO2S 详情 详情
(VIII) 40961 methyl [1]benzothieno[3,2-h]isoquinoline-6-carboxylate C17H11NO2S 详情 详情
(IX) 40962 [1]benzothieno[3,2-h]isoquinoline-6-carbohydrazide C16H11N3OS 详情 详情
(X) 40963 ethyl [1]benzothieno[3,2-h]isoquinolin-6-ylcarbamate C18H14N2O2S 详情 详情
(XI) 40964 tert-butyl [1]benzothieno[3,2-h]isoquinolin-6-ylcarbamate C20H18N2O2S 详情 详情
(XII) 40965 [1]benzothieno[3,2-h]isoquinolin-6-ylamine; [1]benzothieno[3,2-h]isoquinolin-6-amine C15H10N2S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

Condensation of 1,3-acetonedicarboxylic acid (I) with pyridine-4-carboxaldehyde (II) and subsequent acid decarboxylation produced 1,5-dipyridylpentadienone (III), which was reduced to the saturated ketone (IV) by transfer hydrogenation using formic acid and Pd/C. Condensation of (IV) with benzyl amine (V) in benzene with azeotropical removal of water, followed by reduction of the intermediate imine with NaBH4 gave rise to the secondary amine (VI). Coupling of (VI) with N-Boc-N-methyl-L-4-chlorophenylalanine (VII) in the presence of EDC afforded amide (VIII). After Boc deprotection of (VIII) with trifluoroacetic acid, the resulting amine (IX) was coupled with 3,4,5-trimethoxybenzoylformic acid (X) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Zelle, R.E.; Harding, M.W. (Vertex Pharmaceuticals Inc.); Novel amino acid derivs. with improved multi-drug resistance activity. EP 0797567; JP 1998509151; US 5543423; WO 9615101 .
【2】 Zelle, R.E. (Vertex Pharmaceuticals Inc.); Methods and compsns. for stimulating neurite growth using cpds. with affinity for FKBP2 in combination with neurotrophic factors. WO 9820891 .
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) 15530 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid 542-05-2 C5H6O5 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 30040 (1E,4E)-1,5-di(4-pyridinyl)-1,4-pentadien-3-one C15H12N2O 详情 详情
(IV) 30041 1,5-di(4-pyridinyl)-3-pentanone C15H16N2O 详情 详情
(V) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(VI) 30042 N-benzyl-1,5-di(4-pyridinyl)-3-pentanamine; N-benzyl-N-[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]amine C22H25N3 详情 详情
(VII) 30043 (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(4-chlorophenyl)propionic acid 125324-00-7 C15H20ClNO4 详情 详情
(VIII) 30044 tert-butyl (1S)-2-(benzyl[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]amino)-1-(4-chlorobenzyl)-2-oxoethyl(methyl)carbamate C37H43ClN4O3 详情 详情
(IX) 30045 (2S)-N-benzyl-3-(4-chlorophenyl)-2-(methylamino)-N-[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]propanamide C32H35ClN4O 详情 详情
(X) 30046 2-oxo-2-(3,4,5-trimethoxyphenyl)acetic acid C11H12O6 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 2-bromo-4,5-diethoxybenzaldehyde dimethyl ketal (I) with pyridine-4-carbaldehyde (II) by means of NaH in THF gives the expected addition product (III), which by treatment with acetic acid in refluxing toluene yields the isobenzofuran (IV) (unstable, not isolated compound) that is submitted immediately to a Diels-Alder cyclization with dimethyl maleate (V) to afford the epoxy-tetrahydronaphthalene (VI). The aromatization of (VI) with trifluoroacetic acid (TFA) in chloroform, or with BF3/ethyl ether in acetonitrile gives 6,7-diethoxy-1-(4-pyridyl)naphthalene-2,3-dicarboxylic acid dimethyl ester (VII). The oxidation of (VII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane gives the corresponding N-oxide (VIII), which is isomerized to the pyridone (IX) by refluxing in acetic anhydride. The condensation of (IX) with 2-chloroethyl methyl ether (X) by means of NaH or Li in DMF affords the N-substituted pyridone (XI), which is finally reduced with NaBH4 in THF.

参考文献 中间体
合成目标
【1】 Graul, A.; Leeson, P.; Castañer, J.; T-440. Drugs Fut 1997, 22, 7, 729.
【2】 Iwasaki, T.; Kondo, K.; Kuroda, T.; Moritani, Y.; Yamagata, S.; Sugiura, M.; Kikkawa, H.; Kaminuma, O.; Ikezawa, K.; Novel selective PDE IV inhibitors as antiasthmatic agents. Synthesis and biological activities of a series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans. J Med Chem 1996, 39, 14, 2696-704.
【3】 Iwasaki, T.; Kondo, K.; Ikezawa, K.; Kikkawa, H.; Yamagata, S. (Tanabe Seiyaku Co., Ltd.); Naphthalene derivs. processes for preparing the same, and synthetic intermediates thereof. EP 0557016; JP 1993229987; US 5342941 .
【4】 Iwasaki, T.; Kondo, K.; Ikesawa, I.; Yoshikawa, H.; Yamashina, S. (Tanabe Seiyaku Co., Ltd.); Antiasthma agent. JP 1995101861 .
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) 17202 (2-bromo-4,5-diethoxyphenyl)(methoxy)methyl methyl ether; 1-bromo-2-(dimethoxymethyl)-4,5-diethoxybenzene C13H19BrO4 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 17204 [6-(dimethoxymethyl)-3,4-diethoxy-2,4-cyclohexadien-1-yl](4-pyridinyl)methanol C19H27NO5 详情 详情
(IV) 17205 6-ethoxy-1-(4-pyridinyl)-2-benzofuran-5-yl ethyl ether; 4-(5,6-diethoxy-2-benzofuran-1-yl)pyridine C17H17NO3 详情 详情
(V) 17206 dimethyl (Z)-2-butenedioate; Dimethyl Maleate 23055-10-9 C6H8O4 详情 详情
(VI) 17207 dimethyl 4,5-diethoxy-1-(4-pyridinyl)-11-oxatricyclo[6.2.1.0(2,7)]undeca-2,4,6-triene-9,10-dicarboxylate C23H25NO7 详情 详情
(VII) 17208 dimethyl 6,7-diethoxy-1-(4-pyridinyl)-2,3-naphthalenedicarboxylate C23H23NO6 详情 详情
(VIII) 17209 4-[6,7-diethoxy-2,3-bis(methoxycarbonyl)-1-naphthyl]-1-pyridiniumolate C23H23NO7 详情 详情
(IX) 17210 dimethyl 6,7-diethoxy-1-(2-oxo-1,2-dihydro-4-pyridinyl)-2,3-naphthalenedicarboxylate C23H23NO7 详情 详情
(X) 17211 1-Chloro-2-methoxyethane; 2-Chloroethyl methyl ether 627-42-9 C3H7ClO 详情 详情
(XI) 17212 dimethyl 6,7-diethoxy-1-[1-(2-methoxyethyl)-2-oxo-1,2-dihydro-4-pyridinyl]-2,3-naphthalenedicarboxylate C26H29NO8 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

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.

参考文献 中间体
合成目标
【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7

该中间体在本合成路线中的序号：(XIII)

Methyl 6-methylnicotinate (XII) was condensed with 4-pyridinecarboxaldehyde (XIII) in AcOH-Ac2O at 120 C to produce (XIV). Then, ester group was reduced with LiAlH4 to alcohol (XV), and this was subsequently oxidized with DMSO and SO3-pyridine complex to give aldehyde (XVI). Wittig reaction with phosphorane (XVII) afforded ester (XVIII), which was saponified to yield acid (XIX). Finally, coupling of acid (XIX) with amine (XI) in the presence of EDC and HOBt provided the title amide.

参考文献 中间体
合成目标
【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C.; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a]pyridine moiety. J Med Chem 1998, 41, 21, 4062.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 18600 2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide C20H19Cl2N3O2 详情 详情
(XII) 14160 methyl 6-methylnicotinate 5470-70-2 C8H9NO2 详情 详情
(XIII) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(XIV) 18603 methyl 6-[(E)-2-(4-pyridinyl)ethenyl]nicotinate C14H12N2O2 详情 详情
(XV) 18604 [6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]methanol C13H12N2O 详情 详情
(XVI) 18605 6-[(E)-2-(4-pyridinyl)ethenyl]nicotinaldehyde C13H10N2O 详情 详情
(XVII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XVIII) 18607 methyl (E)-3-[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]-2-propenoate C16H14N2O2 详情 详情
(XIX) 18608 (E)-3-[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]-2-propenoic acid C15H12N2O2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

Title compound was prepared by condensation of tetrahydroindolizinone (I) with pyridine-4-carboxyaldehyde (II) under phase transfer conditions using NaOH and tetrabutyl hydrogensulfate in a mixture of H2O and CH2Cl2.

参考文献 中间体
合成目标
【1】 Sonnet, P.; Guillon, J.; Enguehard, C.; Dallemagne, P.; Bureau, R.; Rault, S.; Auvray, P.; Moslemi, S.; Sourdiane, P.; Galopin, S.; Seralini, G.E.; Design and synthesis of a new type of non steroidal human aromatase inhibitors. Bioorg Med Chem Lett 1998, 8, 9, 1041.
【2】 Sonnet, P.; Dallemagne, P.; Guillon, J.; et al.; New aromatase inhibitors. Synthesis and biological activity of aryl-substituted pyrrolizine and indolizine derivatives. Bioorg Med Chem 2000, 8, 5, 945.
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) 18742 6-(4-chlorophenyl)-6,7-dihydro-8(5H)-indolizinone C14H12ClNO 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情

合成路线9

该中间体在本合成路线中的序号：(V)

The cyclization of the amino group of 4-amino-3-(4-chlorophenyl)butyric acid (I) with 2,5-dimethoxytetrahydrofuran (II) by means of AcOH in THF gives the corresponding pyrrole (III), which is cyclized by means of TEA, ClCOOEt, pyrrolidine and POCl3 in toluene yielding the pyrrolopyridone (IV). Finally, this compound is condensed with pyridine-4-carbaldehyde (V) by means of tetrabutylammonium bisulfate and NaOH in water.

参考文献 中间体
合成目标
【1】 Moslemi, S.; Dallemagne, P.; Enguehard, C.; Sonnet, P.; Séralini, G.-E.; Bureau, R.; Auvray, P.; Sourdaine, P.; Guillon, J.; Rault, S.; MR 20492 and MR 20494: Two indolizinone derivatives that strongly inhibit human aromatase. J Steroid Biochem Mol Biol 1999, 70, 1-3, 59.
【2】 Sonnet, P.; Dallemagne, P.; Guillon, J.; et al.; New aromatase inhibitors. Synthesis and biological activity of aryl-substituted pyrrolizine and indolizine derivatives. Bioorg Med Chem 2000, 8, 5, 945.
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) 36490 4-amino-3-(4-chlorophenyl)butyric acid 1134-47-0 C10H12ClNO2 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 36491 3-(4-chlorophenyl)-4-(1H-pyrrol-1-yl)butyric acid C14H14ClNO2 详情 详情
(IV) 18742 6-(4-chlorophenyl)-6,7-dihydro-8(5H)-indolizinone C14H12ClNO 详情 详情
(V) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

The condensation of pyridine-4-carbaldehyde (I) with 4-(methylsulfinyl)acetophenone (II) by means of diethylamine in pyridine gives the chalcone (III), which is treated with 4-fluorobenzaldehyde (IV) and NaCN in DMF to afford the butanedione (V). Finally, this compound is cyclized with ammonium acetate in refluxing acetic acid.

参考文献 中间体
合成目标
【1】 Pyrroles and other heterocycles as inhibitors of P. Bioorg Med Chem Lett 1998, 8, 19, 2689.
【2】 De Laszlo, S.E.; Mantlo, N.B. (Merck & Co., Inc.); Substd. aryl pyrroles, compsns. containing such cp. WO 9716441 .
【3】 De Laszlo, S.E.; Mantlo, N.B.; Ponticello, G.S.; Selnick, H.G.; Liverton, N.J. (Merck & Co., Inc.); 2,5-Substd. aryl pyrroles, comspns. containing suc. EP 0871444; JP 1999510511; WO 9705878 .
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) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(II) 23842 1-[4-(methylsulfinyl)phenyl]-1-ethanone C9H10O2S 详情 详情
(III) 23844 (E)-1-[4-(methylsulfinyl)phenyl]-3-(4-pyridinyl)-2-propen-1-one C15H13NO2S 详情 详情
(IV) 12317 3-[(Z)-1-Naphthylmethylidene]-2,5(4H)-furandione C15H10O3 详情 详情
(V) 23845 1-(4-fluorophenyl)-4-[4-(methylsulfinyl)phenyl]-2-(4-pyridinyl)-1,4-butanedione C22H18FNO3S 详情 详情
(VI) 23846 2-methyl-5-phenyl-1H-pyrrole C11H11N 详情 详情

合成路线11

该中间体在本合成路线中的序号：(IV)

Aldol condensation of 5-bromo-2-propoxybenzaldehyde (I) with 4'-chloroacetophenone in the presence of NaOH produced chalcone (III) (1), which was condensed with pyridine-4-carbaldehyde (IV) using NaCN as the catalyst to yield diketone (V). Finally, the target pyrrole was constructed by Paal-Knorr synthesis using diketone (V) and ammonium acetate in boiling AcOH.

参考文献 中间体
合成目标
【1】 Li, B.; Kim, D.; MacCoss, M.; de Laszlo, S.E.; Koch, G.E.; hacker, C.; Mantlo, N.; Pivinichny, J.V.; Cascieri, M.A.; Hagmann, W.K.; The development of 2-pyridyl-3,5-diaryl-pyrroles a. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.232.
【2】 Li, B.; Hacker, C.; De Laszlo, S.E.; et al.; Potent, orally absorbed glucagon receptor antagonists. Bioorg Med Chem Lett 1999, 9, 5, 641.
【3】 de Laszlo, S.E.; Kim, D.; Chang, L.L.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. US 5776954 .
【4】 De Laszlo, S.E.; Chang, L.L.; Kim, D.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. EP 0859771; JP 1999514651; WO 9716442 .
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) 23277 5-bromo-2-propoxybenzaldehyde C10H11BrO2 详情 详情
(II) 12685 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone 99-91-2 C8H7ClO 详情 详情
(III) 23279 (E)-3-(5-bromo-2-propoxyphenyl)-1-(4-chlorophenyl)-2-propen-1-one C18H16BrClO2 详情 详情
(IV) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(V) 23281 2-(5-bromo-2-propoxyphenyl)-4-(4-chlorophenyl)-1-(4-pyridinyl)-1,4-butanedione C24H21BrClNO3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine affords the phthalazinone (V), which is finally condensed with 4-chloroaniline (VI) by means of P2O5 and TEA at 170 C to provide the target phthalazine.

参考文献 中间体
合成目标
【1】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80.
【2】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73.
【3】 Andersen, L.; Pedersen, E.B.; Synthesis of 4-arylamino-1H-pyrazolo[3,4-d]pyrimidines. Acta Chem Scand Ser b 1988, B42, 492-3.
【4】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43.
【5】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310.
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) 12576 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one 87-41-2 C8H6O2 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 49917 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one C14H9NO2 详情 详情
(IV) 49918 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one C14H9NO2 详情 详情
(V) 49919 4-(4-pyridinylmethyl)-1(2H)-phthalazinone C14H11N3O 详情 详情
(VI) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情

合成路线13

该中间体在本合成路线中的序号：(V)

Condensation between p-fluorobenzaldehyde (I), p-toluenesulfinic acid (II) and formamide in the presence of camphorsulfonic acid afforded 4-fluorophenyltosylmethyl formamide (III). Subsequent dehydration of (III) by means of POCl3 and Et3N produced isonitrile (IV). Imine (VII) was prepared by condensation of pyridine-4-carboxaldehyde (V) with 1-Boc-4-aminopiperidine (VI) using MgSO4 as the dehydrating reagent. Dipolar cycloaddition of this imine with the anion of tosyl isonitrile (IV) generated the trisubstituted imidazole (VIII). Finally, acid cleavage of the Boc protecting group furnished the title compound.

参考文献 中间体
合成目标
【1】 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 .
【2】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16598 Formamide 75-12-7 CH3NO 详情 详情
(I) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 25593 4-methylbenzenesulfinic acid C7H8O2S 详情 详情
(III) 25594 (4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide C15H14FNO3S 详情 详情
(IV) 25595 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide C15H12FNO2S 详情 详情
(V) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(VI) 28414 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine 87120-72-7 C10H20N2O2 详情 详情
(VII) 34886 tert-butyl 4-[[(Z)-4-pyridinylmethylidene]amino]-1-piperidinecarboxylate C16H23N3O2 详情 详情
(VIII) 34887 tert-butyl 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]-1-piperidinecarboxylate C24H27FN4O2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XI)

Heating p-fluorobenzaldehyde (I) with propionic anhydride (II) in the presence of sodium propionate affords methyl cinnamic acid derivative (III), which is then hydrogenated over Pd/C in EtOH to provide methyl hydrocinnamic acid derivative (IV). Ring closure of (IV) is then performed by heating with polyphosphoric acid to yield methylindanone derivative (V). Condensation of (V) with cyanoacetic acid (VI) by means of ammonium acetate and HOAc in refluxing toluene followed by treatment with KOH in refluxing EtOH provides acetic acid derivative (VII), which is then converted into acetyl chloride compound (VIII) by reaction with oxalyl chloride in refluxing THF. Coupling of (VIII) with benzylamine (IX) in refluxing CH2Cl2 gives indenylacetamide derivative (X), which is finally condensed with 4-pyridinecarboxaldehyde (XI) by means of NaOMe in MeOH to furnish the desired compound.

参考文献 中间体
合成目标
【1】 Piazza, G.; Gross, P.; Brendel, K.; Sperl, G.; Pamukcu, R. (Cell Pathways, Inc.; University of Arizona); N-Benzyl-3-indenylacetamides derivs. for treating neoplasia. EP 1044187; US 5948779; US 6066634; WO 9931065 .
【2】 Mayle, M.J.; Menander, K.B. (Cell Pathways, Inc.); A method for treating patients with acne by administering a cyclic GMP PDE inhibitor. WO 0044372 .
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) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 48870 (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid C10H9FO2 详情 详情
(IV) 48871 3-(4-fluorophenyl)-2-methylpropionic acid C10H11FO2 详情 详情
(V) 48872 6-Fluoro-2-methylindanone C10H9FO 详情 详情
(VI) 48873 2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile C3H3NO 详情 详情
(VII) 48874 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid C12H11FO2 详情 详情
(VIII) 48878 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetyl chloride C12H10ClFO 详情 详情
(IX) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(X) 48877 N-benzyl-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide C19H18FNO 详情 详情
(XI) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IX)

Chlorination of 1,4-benzodioxan (I) in AcOH afforded the 6,7-dichloro derivative (II). Subsequent Friedel-Crafts acylation of (II) with acetyl chloride and AlCl3 produced ketone (III), which was nitrated employing fuming nitric acid to give nitro compound (IV). Hydrogenation of the nitro group of (IV) with concomitant hydrogenolysis of the halogen atoms in the presence of Pd/C yielded amino ketone (V). After protection of the amino group of (V) as the corresponding acetamide (VI), chlorination by means of N-chlorosuccinimide provided (VII). Optionally, amide hydrolysis with NaOH afforded amine (VIII). Aldol condensation of (VIII) with pyridine-4-carboxaldehyde (IX) in ethanolic KOH gave rise to the unsaturated ketone (X). This compound was also obtained by condensation of the N-acetylated amino ketone (VII) with aldehyde (IX) in methanolic NaOH. In a related procedure, the aldol condensation of ketone (VIII) with aldehyde (IX) using LDA in cold THF produced hydroxy ketone (XI). This was further dehydrated to unsaturated ketone (X) by means of concentrated H2SO4. Hydrogenation of the olefinic double bond of (X) over Pd/C in THF generated the saturated ketone (XII). Further hydrogenation of the pyridine ring of (XII) using Rh/Al2O3 furnished the corresponding piperidine (XIII). Alternatively, (XIII) was obtained by direct hydrogenation of (X) over Rh/Al2O3.

参考文献 中间体
合成目标
【1】 Kowalczyk, B.A.; et al.; Process development of the synthetic route to sulamserod hydrochloride. Org Process Res Dev 2001, 5, 2, 116.
【2】 Wong, E.H.F.; Eglen, R.M.; Leung, E.; Johnson, L.G.; Langston, J.A.; Flippin, L.A.; Jahangir, A.; Bonhaus, D.W.; Clark, R.D.; RS-100235: A high affinity 5-HT4 receptor antagonist. Bioorg Med Chem Lett 1995, 5, 18, 2119.
【3】 Clark, R.D.; Eglen, R.; Jahangir, A.; Miller, A.B.; Gardner, J.O. (Syntex (USA), Inc.); Novel 1-phenylalkanone 5-HT4 receptor ligands. EP 0700383; JP 1996510743; WO 9427965 .
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) 35630 2,3-dihydro-1,4-benzodioxine 493-09-4 C8H8O2 详情 详情
(II) 35631 6,7-dichloro-2,3-dihydro-1,4-benzodioxine C8H6Cl2O2 详情 详情
(III) 35632 1-(6,7-dichloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-ethanone C10H8Cl2O3 详情 详情
(IV) 35634 1-(6,7-dichloro-8-nitro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-ethanone C10H7Cl2NO5 详情 详情
(V) 35633 1-(8-amino-2,3-dihydro-1,4-benzodioxin-5-yl)-1-ethanone C10H11NO3 详情 详情
(VI) 35635 N-(8-acetyl-2,3-dihydro-1,4-benzodioxin-5-yl)acetamide C12H13NO4 详情 详情
(VII) 35636 N-(8-acetyl-6-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)acetamide C12H12ClNO4 详情 详情
(VIII) 35637 1-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-ethanone C10H10ClNO3 详情 详情
(IX) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(X) 35638 (E)-1-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(4-pyridinyl)-2-propen-1-one C16H13ClN2O3 详情 详情
(XI) 35639 1-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-hydroxy-3-(4-pyridinyl)-1-propanone C16H15ClN2O4 详情 详情
(XII) 35640 1-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(4-pyridinyl)-1-propanone C16H15ClN2O3 详情 详情
(XIII) 35641 1-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(4-piperidinyl)-1-propanone C16H21ClN2O3 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The intermediate secondary amine (IV) was prepared by condensation of 3-aminopyridine (I) with isonicotinic aldehyde (II), followed by catalytic hydrogenation of the resulting imine (III).

参考文献 中间体
合成目标
【1】 Kubota, H.; Suzumura, K.; Suzuki, T.; Ohmizu, H.; Kashimura, Y.; Antioxidative property of T-0970, a new ureidophenol derivative. Free Radical Research 2000, 32, 3, 255.
【2】 Suzuki, T.; Ohmizu, H.; Hashimura, Y.; Kubota, H.; Tanaka, K. (Tanabe Seiyaku Co., Ltd.); Phenol-derivs. having pharmaceutical activity and process for preparing the same. EP 0790240; JP 1998195037; US 5849732 .
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) 33327 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine 462-08-8 C5H6N2 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 41431 N-[(Z)-4-pyridinylmethylidene]-3-pyridinamine; N-(3-pyridinyl)-N-[(Z)-4-pyridinylmethylidene]amine C11H9N3 详情 详情
(IV) 41432 N-(3-pyridinyl)-N-(4-pyridinylmethyl)amine; N-(4-pyridinylmethyl)-3-pyridinamine C11H11N3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(I)

Reductive amination of pyridine-4-carbaldehyde (I) with isopropylamine (II) in the presence of NaBH4 furnished the secondary amine (III). This was then acylated with the indoleacetic acid (IV) using PyBOP as the coupling reagent to yield the target amide.

参考文献 中间体
合成目标
【1】 Lumma, W.C.; Quigley, A.G.; Sisko, J.T.; et al.; 2-Arylindole-3-acetamides as FPP-competitive inhibitors of farnesyltransferase. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 154.
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) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(II) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
(III) 50896 N-isopropyl-N-(4-pyridinylmethyl)amine; N-(4-pyridinylmethyl)-2-propanamine C9H14N2 详情 详情
(IV) 50897 2-(1-methyl-2-phenyl-1H-indol-3-yl)acetic acid C17H15NO2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3,4-bis(trifluoromethyl)aniline (VII) in ethanol to afford the 1-anilino-phthalazine.

参考文献 中间体
合成目标
【1】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73.
【2】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80.
【3】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43.
【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310.
【5】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 .
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) 12576 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one 87-41-2 C8H6O2 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 49917 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one C14H9NO2 详情 详情
(IV) 49918 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one C14H9NO2 详情 详情
(V) 49919 4-(4-pyridinylmethyl)-1(2H)-phthalazinone C14H11N3O 详情 详情
(VI) 41367 1-chloro-4-(4-pyridinylmethyl)phthalazine C14H10ClN3 详情 详情
(VII) 51495 3,4-bis(trifluoromethyl)phenylamine; 3,4-bis(trifluoromethyl)aniline C8H5F6N 详情 详情

合成路线19

该中间体在本合成路线中的序号：(II)

The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3-bromo-4-methylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.

参考文献 中间体
合成目标
【1】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43.
【2】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80.
【3】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73.
【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310.
【5】 Altmann, K.-H.; Mett, H.; Wood, J.; Stover, D.R.; Frei, J.; Bold, G.; Traxler, P. (Novartis AG); Phthalazines with angiogenesis inhibiting activity. EP 0970070; WO 9835958 .
【6】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 .
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) 12576 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one 87-41-2 C8H6O2 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 49917 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one C14H9NO2 详情 详情
(IV) 49918 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one C14H9NO2 详情 详情
(V) 49919 4-(4-pyridinylmethyl)-1(2H)-phthalazinone C14H11N3O 详情 详情
(VI) 41367 1-chloro-4-(4-pyridinylmethyl)phthalazine C14H10ClN3 详情 详情
(VII) 49517 3-Bromo-p-toluidine; 4-Amino-2-bromotoluene; 3-Bromo-4-methylaniline 7745-91-7 C7H8BrN 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3-bromo-5-trifluoromethylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.

参考文献 中间体
合成目标
【1】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43.
【2】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73.
【3】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80.
【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310.
【5】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 .
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) 12576 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one 87-41-2 C8H6O2 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 49917 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one C14H9NO2 详情 详情
(IV) 49918 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one C14H9NO2 详情 详情
(V) 49919 4-(4-pyridinylmethyl)-1(2H)-phthalazinone C14H11N3O 详情 详情
(VI) 41367 1-chloro-4-(4-pyridinylmethyl)phthalazine C14H10ClN3 详情 详情
(VII) 51493 3-Amino-5-bromobenzotrifluoride 54962-75-3 C7H5BrF3N 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3-chloro-5-trifluoromethylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.

参考文献 中间体
合成目标
【1】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80.
【2】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43.
【3】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73.
【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310.
【5】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 .
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) 12576 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one 87-41-2 C8H6O2 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 49917 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one C14H9NO2 详情 详情
(IV) 49918 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one C14H9NO2 详情 详情
(V) 49919 4-(4-pyridinylmethyl)-1(2H)-phthalazinone C14H11N3O 详情 详情
(VI) 41367 1-chloro-4-(4-pyridinylmethyl)phthalazine C14H10ClN3 详情 详情
(VII) 51492 3-chloro-5-(trifluoromethyl)phenylamine; 3-chloro-5-(trifluoromethyl)aniline C7H5ClF3N 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 4-chloro-3-trifluoromethylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.

参考文献 中间体
合成目标
【1】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73.
【2】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80.
【3】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43.
【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310.
【5】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 .
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) 12576 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one 87-41-2 C8H6O2 详情 详情
(II) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(III) 49917 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one C14H9NO2 详情 详情
(IV) 49918 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one C14H9NO2 详情 详情
(V) 49919 4-(4-pyridinylmethyl)-1(2H)-phthalazinone C14H11N3O 详情 详情
(VI) 41367 1-chloro-4-(4-pyridinylmethyl)phthalazine C14H10ClN3 详情 详情
(VII) 51494 4-Chloro-3-trifluoromethylaniline; 4-Chloro-alpha,alpha,alpha-trifluoro-m-toluidine; 5-Amino-2-chlorobenzotrifluoride; 2-Chloro-5-aminobenzotrifluoride; 2-Amino-5-chlorotrifluoromethylbenzene 320-51-4 C7H5ClF3N 详情 详情

合成路线23

该中间体在本合成路线中的序号：(VI)

The intermediate anthranilamide (IV) is prepared by two alternative methods. Acylation of 3-(trifluoromethyl)aniline (I) with 2-nitrobenzoyl chloride (II) yields benzamide (III). The nitro group of (III) is then reduced to the corresponding amine (IV) by catalytic hydrogenation over Pd/C (1). Alternatively, 3-(trifluoromethyl)aniline (I) is condensed with isatoic anhydride (V) to furnish directly anthranilamide (IV) (2). Finally, reductive alkylation of (IV) with pyridine-4-carbaldehyde (VI) employing NaBH3CN gives rise to the target pyridylmethyl amine.

参考文献 中间体
合成目标
【1】 Manley, P.W.; Furet, P.; Bold, G.; Bruggen, J.; Mestan, J.; Meyer, T.; Schnell, C.R.; Wood, J.; Anthranilic acid amides: A novel class of antiangiogenic VEGF receptor kinase inhibitors. J Med Chem 2002, 45, 26, 5687.
【2】 Seidelmann, D.; Huth, A.; Manley, P.W.; Thierauch, K.-H.; Krüger, M.; Bold, G.; Haberey, M.; Furet, P.; Altmann, K.-H.; Mestan, J.; Menrad, A.; Ferrari, S.; Wood, J.M.; Hofmann, F. (Novartis AG; Schering AG); N-Aryl(thio)anthranilic acid amide derivs., their preparation and their use as VEGF receptor tyrosine kinase inhibitors. EP 1129075; JP 2002529453; US 6448277; WO 0027820 .
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) 26347 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride 98-16-8 C7H6F3N 详情 详情
(II) 21099 o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride 610-14-0 C7H4ClNO3 详情 详情
(III) 64309 2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide C14H9F3N2O3 详情 详情
(IV) 64310 2-amino-N-[3-(trifluoromethyl)phenyl]benzamide C14H11F3N2O 详情 详情
(V) 29797 2H-3,1-benzoxazine-2,4(1H)-dione；Isatoic anhydride;4H-3,1-Benzoxazine-2,4(1H)-dione；1,2-Dihydro-4H-3,1-benzoxazine-2,4-dione;1H-benzo[d][1,3]oxazine-2,4-dione 118-48-9 C8H5NO3 详情 详情
(VI) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
Extended Information