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【结 构 式】

【分子编号】11818

【品名】Phenyl hydrazine; 1-Phenylhydrazine

【CA登记号】100-63-0

【 分 子 式 】C6H8N2

【 分 子 量 】108.143

【元素组成】C 66.64% H 7.46% N 25.9%
与该中间体有关的原料药合成路线共 20 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1

该中间体在本合成路线中的序号：(II)

This compound can be obtained by several different ways: 1) By condensation of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylic acid (I) with phenylhydrazine (II) by means of N,N-dimethylaniline in DMSO. 2) By a coupling reaction between 6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylic acid (III) with phenyldiazonium chloride (IV) (prepared with aniline (V), NaNO2 and HCl). 3) The coupling reaction of (IV) with ethyl 6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine 3-carboxylate (VI) gives ethyl 6-methyl-4-oxo-9-(phenylhydrazono)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (VII), which is hydrolyzed with NaOH in water. 4) By reaction of ethyl 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylate (VIII) with (II) in refluxing ethanol, giving (VII), already obtained. 5) By condensation of ethyl 9-hydroxy-6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylate (IX) with (II) in refluxing ethanol yielding (VII), already obtained.

参考文献 中间体
合成目标
【1】 Vasvari-Debreczy, L.; Horvath, A.; Dessy, F.; Hermecz, I.; De Vos, C.; Meszaros, Z.; Rodriguez, L.; Breining, T.; 18. New antiallergic 4H-pyridol[1,2-a]pyrimidin-4-ones. J Med Chem 1982, 25, 10, 1140-45.
【2】 Bitter, I.; Breining, T.; Mandi, A.; Szucs, T.; Horvath, A.; Meszaros, Z.; Virag, S.; Hermecz, I.; Vasvari, L.; Nagy, G.; Sebestyen, G. (Chinoin Pharmaceutical and Chemical Works Co., Ltd.); Condensed pyrimidine derivs., their preparation and pharmaceutical compsns. containing them. GB 2011898 .
【3】 Vasvari, L.; Horvath, A.; Hermecz, I.; Kokosi, J.; Breining, T. (Chinoin Pharmaceutical and Chemical Works Co., Ltd.); 9-Hydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidine-4-one derivs., their preparation and pharmaceutical compsns. containing them. GB 2051783 .
【4】 Castaner, J.; Serradell, M.N.; Sneddon, J.M.; Blancafort, P.; UCB-L-140. Drugs Fut 1983, 8, 7, 612.
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) 36163 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid C10H10Br2N2O3 详情 详情
(II) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(III) 36162 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid C10H12N2O3 详情 详情
(IV) 25897 benzenediazonium chloride C6H5ClN2 详情 详情
(V) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(VI) 36161 ethyl 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate C12H16N2O3 详情 详情
(VII) 36160 ethyl 6-methyl-4-oxo-9-[(Z)-2-phenylhydrazono]-7,8-dihydro-4H-pyrido[1,2-a]pyrimidine-3(6H)-carboxylate C18H20N4O3 详情 详情
(VIII) 36158 ethyl 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate C12H15BrN2O3 详情 详情
(IX) 36159 ethyl 9-hydroxy-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate C12H16N2O4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

The phenylhydrazone of benzaldehyde (I) is obtained in the usual way, phenylhydrazine (A) with benzaldehyde (B), which by reaction with benzoyl chloride (II) gives (C) and further treatment with HCl in an organic solvent results in the substituted hydrazine hydrochloride (III). Finally, this compound is condensed with levulinic acid (IV) at high temperature.

参考文献 中间体
合成目标
【1】 Francia, E.; Marin, A. (Uriach & Cia S.A.); Procedimiento de obtencion del acido 1-benzoil-2-metilindol-3-acetico. ES 471436 .
【2】 Francia, E.; Garcia Rafanell, J.; Delmetacin. Drugs Fut 1983, 8, 9, 764.
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) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(I) 36167 benzaldehyde N-phenylhydrazone 588-64-7 C13H12N2 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 36169 N-phenylbenzohydrazide C13H12N2O 详情 详情
(IV) 36170 4-oxopentanoic acid 123-76-2 C5H8O3 详情 详情
(C) 36168 N-phenyl-N'-[(E)-benzylidene]benzohydrazide C20H16N2O 详情 详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The condensation of aniline (I) with diethyl ethoxymethylenemalonate (II) by heating at 90 C gives diethyl anilinomethylenemalonate (III), which is cyclized to ethyl 4-hydroxyquinoline-3-carboxylate (IV) by heating at 240 C in diphenyl ether-biphenyl. The reaction of (IV) with hot POCl3 affords ethyl 4-chloro-quinoline-3-carboxylate (V), which is finally cyclized with phenylhydrazine (VI) by heating at 105 C in xylene. (VI) is prepared in the usual way starting from aniline (I) by diazotation with NaNO2-HCl to phenyldiazonium chloride (VII), and reduction with SnCl2-HCl.

参考文献 中间体
合成目标
【1】 Yokoyama, N.; EP 0022078 .
【2】 Yokoyama, N.; US 4312870 .
【3】 Ritter, B.; Yokoyama, N.; Neubert, A.D.; 2-Arylpyrazolo[4,3-c]quinolin-3-ones: A partial novel agonist and antagonist of benzodiazepines. J Med Chem 1982, 25, 4, 337-339.
【4】 Serradell, M.N.; Grau, M.; Castaner, J.; Blancafort, P.; CGS-8216 and CGS-9896. Drugs Fut 1983, 8, 2, 99.
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) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(II) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(III) 35953 diethyl 2-(anilinomethylene)malonate C14H17NO4 详情 详情
(IV) 35954 ethyl 4-hydroxy-3-quinolinecarboxylate C12H11NO3 详情 详情
(V) 35955 ethyl 4-chloro-3-quinolinecarboxylate C12H10ClNO2 详情 详情
(VI) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(VII) 25897 benzenediazonium chloride C6H5ClN2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

By direct cyclization of phenylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Graul, A.; Castaner, J.; Edaravone. Drugs Fut 1996, 21, 10, 1014.
【2】 Nishi, H.; Watanabe, T.; Yuki, S.; Morinaka, Y.; Iseki, K.; Sakurai, H. (Mitsubishi Chemical Corp.); Prophylactic and therapeutic agent for circulatory disorders. EP 0208874; JP 1987108814; US 4857542 .
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) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(II) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 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 synthesis of [14C]-labeled Bay-u-3405 by two closely related ways has been described: 1) [14C]-Labeled aniline (I) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (II), which is condensed with the monoketal of cyclohexane-1,4-dione (III) under Fisher's indole synthesis (ZnCl2) to afford the tetrahydrocarbazole (IV). The hydrolysis of (IV) with HCl in THF/water yields 1,2,3,4-tetrahydrocarbazol-3-one (V), which is submitted to a reductive condensation with (S)-1-phenylethylamine (VI) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (VII), which, after purification, is dealkylated with ammonium formate and Pd/C to afford 1,2,3,4-tetrahydrocarbazole-3(R)-amine (VIII). The acylation of (VIII) with 4-fluorophenylsulfonyl chloride (IX) gives the corresponding sulfonamide (X), which is condensed with acrylonitrile by means of NaH, yielding 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (XI). Finally, this compound is hydrolyzed in the usual way. 2) The condensation of the sulfonamide (X) with methyl acrylate by means of NaH as before gives 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (XII), which is finally hydrolyzed in the usual way.

参考文献 中间体
合成目标
【1】 Pleiss, U.; Radtke, M.; Rosentreter, U.; Boberg, M.; Synthesis of (+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-[5,6,7,8,12,13-u-C-14]carbazolepropanoic acid, [C-14]BAY u 3405. J Label Compd Radiopharm 1994, 34, 12, 1207.
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) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(I) 45117 　 C6H7N 详情 详情
(II) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(II) 45118 　 C6H8N2 详情 详情
(III) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(IV) 12297 1,2,3,4-Tetrahydrospiro[9H-carbazole-3,2'-1,3-dioxolane] C14H15NO2 详情 详情
(IV) 45119 　 C14H15NO2 详情 详情
(V) 12288 1,2,4,9-Tetrahydro-3H-carbazol-3-one C12H11NO 详情 详情
(V) 45120 　 C12H11NO 详情 详情
(VI) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VII) 12290 N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine C20H22N2 详情 详情
(VII) 45121 　 C20H22N2 详情 详情
(VIII) 12291 (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine C12H14N2 详情 详情
(VIII) 45122 　 C12H14N2 详情 详情
(IX) 12292 4-Fluorobenzenesulfonyl chloride 349-88-2 C6H4ClFO2S 详情 详情
(X) 12293 4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide C18H17FN2O2S 详情 详情
(X) 45123 　 C18H17FN2O2S 详情 详情
(XI) 12304 N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide C21H20FN3O2S 详情 详情
(XI) 45124 　 C21H20FN3O2S 详情 详情
(XII) 12305 methyl 3-((3R)-3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoate C22H23FN2O4S 详情 详情
(XII) 45125 　 C22H23FN2O4S 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

A new synthesis of FK-1052 has been described: The cyclization of 2-methylcyclohexane-1,3-dione (I) with phenylhydrazine (II) by means of sulfuric acid in toluene gives 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (III), which is condensed with 5-methyl-1-(triphenylmethyl)imidazole-4-carbaldehyde (IV) by means of lithium diisopropylamide (LDA) in THF to yield 7-[hydroxy[5-methyl-1-(triphenylmethyl)imidazol-4-yl]methyl]-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (V). The acylation of (V) with acetic anhydride in pyridine affords the corresponding acetate (VI), which by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is converted to the methylene derivative (VII). Finally, this compound is hydrogenated and deprotected by hydrogenolysis with H2 over Pd/C in acetic acid. In order to obtain the (+)-enantiomer, the racemic mixture is treated with (+)-di-p-toluoyl-D-tartaric acid, and the mixture of diastereomeric salts is separated by fractional crystallization. The (+)-enantiomer is obtained by treatment of the corresponding tartrate salt with 2N NaOH. Finally, the (+)-free base is converted to the hydrochloride by treatment with HCl in EtOH and recrystallization from MeOH/ether.

参考文献 中间体
合成目标
【1】 Ito, K.; Kato, M.; Yamakuni, H.; Nishino, S.; Takasugi, H.; New 5-HT3 (serotonin-3) receptor antagonists. I. Synthesis and structure-activity relationships of pyrido[1,2-a]indoles. Chem Pharm Bull 1994, 42, 12, 2546.
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) 15504 2-methyl-1,3-cyclohexanedione 1193-55-1 C7H10O2 详情 详情
(II) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(III) 15498 10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C13H13NO 详情 详情
(IV) 15499 5-methyl-1-trityl-1H-imidazole-4-carbaldehyde C24H20N2O 详情 详情
(V) 15508 7-[hydroxy(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C37H33N3O2 详情 详情
(VI) 15501 (10-methyl-6-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indol-7-yl)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl acetate C39H35N3O3 详情 详情
(VII) 15502 10-methyl-7-[(E)-(5-methyl-1-trityl-1H-imidazol-4-yl)methylidene]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C37H31N3O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The title indolomorphinan derivative was synthesized by Fisher indole synthesis from the known 14-O-ethyl-5-methylnaltrexone (I) and phenylhydrazine hydrochloride (II) in refluxing acetic acid, followed by conversion to the corresponding hydrochloride salt.

参考文献 中间体
合成目标
【1】 Helv Chim Acta 1993, 76, 476.
【2】 Schmidhammer, H. (AstraZeneca plc); New antagonist cpds.. EP 0759922; JP 1998500131; US 6136817; WO 9531463 .
【3】 Monory, K.; Daurer, D.; Schmidhammer, H.; Borsodi, A.; Wieser, M.; Traynor, J.R.; Elliott, J.; Synthesis and biological evaluation of 14-alkoxymorphinans. 14. 14-Ethoxy-5-methyl substituted indolomorphinans with delta opioid receptor selectivity. Bioorg Med Chem Lett 1997, 7, 2, 151.
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) 42229 (1R,5R,13R,17S)-4-(cyclopropylmethyl)-17-ethoxy-10-hydroxy-13-methyl-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one C23H29NO4 详情 详情
(II) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IV)

The intermediate amino pyrazole (I) was prepared as follows. Acylation of malononitrile (IV) with acetyl chloride (V) in the presence of Et3N afforded (1-hydroxyethyliden)malononitrile (VI). Subsequent methylation of the hydroxyl group with dimethyl sulfate gave enol ether (VII). Alternatively, malononitrile (IV) was converted to the ethyl enol ether (VIII) by condensation with triethyl orthoacetate in the presence of Ac2O. Cyclization of either (VII) or (VIII) with phenylhydrazine (IX) furnished 5-amino-4-cyano-1-phenylpyrazole (I).

参考文献 中间体
合成目标
【1】 Hasegawa, H.; et al.; Synthesis of endothelin converting enzyme inhibitors and their structure activity relationships. 21st Symp Med Chem (Nov 28 2001, Kyoto) 2001, Abst 1P-21.
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) 49117 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile C11H10N4 详情 详情
(IV) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(IV) 12061 Malononitrile 109-77-3 C3H2N2 详情 详情
(V) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(VI) 56569 2-(1-hydroxyethylidene)malononitrile C5H4N2O 详情 详情
(VII) 56570 2-(1-methoxyethylidene)malononitrile C6H6N2O 详情 详情
(VIII) 56571 2-(1-ethoxyethylidene)malononitrile C7H8N2O 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

The reaction of phenylhydrazine (I) with propionaldehyde (II) gives the corresponding hydrazone (III), which is condensed with phenyldiazoninum chloride (IV) to yield the formazan (V). The cyclization of (V) by means of BF3 in hot acetic acid affords 3-ethyl-1,2,4-benzotriazine (VI), which is finally oxidized to the target dioxide by means of H2O2 and trifluoroacetic anhydride in dichloromethane.

参考文献 中间体
合成目标
【1】 Kelson, A.B.; et al.; 1,2,4-Benzotriazine 1,4-dioxides. An important class of hypoxic cytotoxins with antitumor activity. Anti-Cancer Drug Des 1998, 13, 6, 575.
【2】 Brown, M.J. (Leland Stanford Junior University); Method of tumor treatment. EP 0649658 .
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) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(II) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(III) 25896 propanal N-phenylhydrazone C9H12N2 详情 详情
(IV) 25897 benzenediazonium chloride C6H5ClN2 详情 详情
(V) 25898 1-[(E)-2-phenyldiazenyl]-1-propanone N-phenylhydrazone C15H16N4 详情 详情
(VI) 25899 3-ethyl-1,2,4-benzotriazine C9H9N3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(III)

The reduction of 3,5-dimethoxybenzoic acid (I) first with Li in liquid NH3 and methanol, and then with LiAlH4 in THF gives 3,5-dimethoxy-1,4-dihydrobenzyl alcohol (II), which is cyclized with phenylhydrazine (III) in refluxing 4% sulfuric acid yielding 2-(hydroxymethyl)-1,2,3,4-tetrahydrocarbazol-4-one (IV). The reaction of (IV) with tosyl chloride in pyridine affords the corresponding tosylate (V), which is finally condensed with 4-(4-fluorobenzoyl)piperidine (VI) in N-methyl-2-pyrrolidone.

参考文献 中间体
合成目标
【1】 Masaguer, C.F.; Formoso, E.; Raviña, E.; Tristán, H.; Loza, M.I.; Rivas, E.; Fontenla, J.A.; Butyrophenone analogues in the carbazole series: Synthesis and determination of affinities at D2 and 5-HT2A receptors. Bioorg Med Chem Lett 1998, 8, 24, 3571.
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) 22761 3,5-dimethoxybenzoic acid 1132-21-4 C9H10O4 详情 详情
(II) 25566 (3,5-dimethoxy-2,5-cyclohexadien-1-yl)methanol C9H14O3 详情 详情
(III) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(IV) 25567 2-(hydroxymethyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one C13H13NO2 详情 详情
(V) 25568 (4-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)methyl 4-methylbenzenesulfonate C20H19NO4S 详情 详情
(VI) 21497 (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine 56346-57-7 C12H14FNO 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VI)

The condensation of 3,5-dimethoxybenzoic acid (I) with 4-(4-fluorobenzoyl)piperidine (II) by means of DCC and HOBT in DMF gives the piperidide (III), which is reduced with LiAlH4 in THF to yield 1-(3,5-dimethoxybenzyl)-4-(4-fluorobenzoyl)piperidine (IV). The reduction of (IV) with Li in liquid ammonia affords the 1,4-dihydro derivative (V), which is finally cyclized with phenylhydrazine (VI) in refluxing aqueous sulfuric acid to provide the target tetrahydrocarbazolone.

参考文献 中间体
合成目标
【1】 Masaguer, C.F.; Loza, M.I.; Fontenla, J.A.; Brea, J.; Raviña, E.; Tristan, H.; Butyrophenone analogues in the carbazole series as potential atypical antipsychotics: Synthesis and determination of affinities at D2, 5-HT2A, 5-HT2B and 5-HT2C receptors. Eur J Med Chem 2000, 35, 1, 83.
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) 22761 3,5-dimethoxybenzoic acid 1132-21-4 C9H10O4 详情 详情
(II) 21497 (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine 56346-57-7 C12H14FNO 详情 详情
(III) 51415 (3,5-dimethoxyphenyl)[4-(4-fluorobenzoyl)-1-piperidinyl]methanone C21H22FNO4 详情 详情
(IV) 51416 [1-(3,5-dimethoxybenzyl)-4-piperidinyl](4-fluorophenyl)methanone C21H24FNO3 详情 详情
(V) 51417 [1-[(3,5-dimethoxy-2,5-cyclohexadien-1-yl)methyl]-4-piperidinyl](4-fluorophenyl)methanone C21H26FNO3 详情 详情
(VI) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(III)

The reduction of 3,5-dimethoxybenzoic acid (I) first with Li in liquid NH3 and methanol, and then with LiAlH4 in THF gives 3,5-dimethoxy-1,4-dihydrobenzyl alcohol (II), which is cyclized with phenylhydrazine (III) in refluxing 4% sulfuric acid yielding 2-(hydroxymethyl)-1,2,3,4-tetrahydrocarbazol-4-one (IV). The reaction of (IV) with tosyl chloride in pyridine affords the corresponding tosylate (V), which is finally condensed with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (VI) in N-methyl-2-pyrrolidone.

参考文献 中间体
合成目标
【1】 Masaguer, C.F.; Formoso, E.; Raviña, E.; Tristán, H.; Loza, M.I.; Rivas, E.; Fontenla, J.A.; Butyrophenone analogues in the carbazole series: Synthesis and determination of affinities at D2 and 5-HT2A receptors. Bioorg Med Chem Lett 1998, 8, 24, 3571.
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) 22761 3,5-dimethoxybenzoic acid 1132-21-4 C9H10O4 详情 详情
(II) 25566 (3,5-dimethoxy-2,5-cyclohexadien-1-yl)methanol C9H14O3 详情 详情
(III) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(IV) 25567 2-(hydroxymethyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one C13H13NO2 详情 详情
(V) 25568 (4-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)methyl 4-methylbenzenesulfonate C20H19NO4S 详情 详情
(VI) 17910 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole C12H13FN2O 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VI)

The condensation of 3,5-dimethoxybenzoic acid (I) with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (II) by means of DCC and HOBT in DMF gives the piperidide (III), which is reduced with LiAlH4 in THF to yield 1-(3,5-dimethoxybenzyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (IV). The reduction of (IV) with Li in liquid ammonia affords the 1,4-dihydro derivative (V), which is finally cyclized with phenylhydrazine (VI) in refluxing aqueous sulfuric acid to provide the target tetrahydrocarbazolone.

参考文献 中间体
合成目标
【1】 Masaguer, C.F.; Loza, M.I.; Fontenla, J.A.; Brea, J.; Raviña, E.; Tristan, H.; Butyrophenone analogues in the carbazole series as potential atypical antipsychotics: Synthesis and determination of affinities at D2, 5-HT2A, 5-HT2B and 5-HT2C receptors. Eur J Med Chem 2000, 35, 1, 83.
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) 22761 3,5-dimethoxybenzoic acid 1132-21-4 C9H10O4 详情 详情
(II) 17910 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole C12H13FN2O 详情 详情
(III) 51420 (3,5-dimethoxyphenyl)[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methanone C21H21FN2O4 详情 详情
(IV) 51418 3-[1-(3,5-dimethoxybenzyl)-4-piperidinyl]-6-fluoro-1,2-benzisoxazole; 3-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl]-5-methoxyphenyl methyl ether C21H23FN2O3 详情 详情
(V) 51419 3-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl]-5-methoxy-1,4-cyclohexadien-1-yl methyl ether; 3-[1-[(3,5-dimethoxy-2,5-cyclohexadien-1-yl)methyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole C21H25FN2O3 详情 详情
(VI) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(IV)

The asymetric Michael addition of malonic ester (II) to 2-cyclohexenone (I) catalyzed by (R)-ALB and t-BuOK in THF gives the (R)-enantiomer (III), which is cyclized with phenylhydrazine (IV) in hot acetic acid yielding the tetrahydrocarbazole (V). The protection of (V) with Boc2O, TEA and DMAP in dichloromethane gives protected (VI), which is condensed with acetaldehyde (VII) by means of LDA in THF affording crotonate (VIII). The reduction of the ester group of (VIII) with DIBAL, followed by oxidation with MnO2 gives the corresponding aldehyde (IX), which is reductocondensed with 2-aminoacetaldehyde dimethylacetal (XI) by means of titanium tetraisopropoxide and NaBH4 in toluene/methanol providing adduct (XI). The deprotection of (XI) with TFA and anisole gives the free tetrahydrocarbazole (XII), which is cyclized by means of DDQ in THF yielding the tetracyclic compound (XIII). The reduction of the exocyclic double bond of (XIII) with RhCl(PPh3)3 in benzene/isopropanol affords the (S)-ethyl derivative (XIV), which is treated with Et-SH and BF3/Et2O in dichloromethane to give the thioacetal (XV). Finally, this compound is cyclized with DMTSF, LiAlH4 and Raney-Ni in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Shimizu, S.; et al.; Catalytic asymmetric synthesis of tubifolidine. J Org Chem 1998, 63, 21, 7547.
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) 26253 2-cyclohexen-1-one；Cyclohex-2-enone；2-cyclohexenone 930-68-7 C6H8O 详情 详情
(II) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(III) 37225 dimethyl 2-[(1R)-3-oxocyclohexyl]malonate C11H16O5 详情 详情
(IV) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(V) 37226 methyl 2-[(2R)-2,3,4,9-tetrahydro-1H-carbazol-2-yl]acetate C15H17NO2 详情 详情
(VI) 37227 tert-butyl (2R)-2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate C20H25NO4 详情 详情
(VII) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(VIII) 37228 tert-butyl (2R)-2-[(E)-1-(methoxycarbonyl)-1-propenyl]-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate C22H27NO4 详情 详情
(IX) 37229 tert-butyl (2R)-2-[(E)-1-formyl-1-propenyl]-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate C21H25NO3 详情 详情
(X) 37158 ethyl 5-[3-(benzyloxy)-2-formylphenoxy]pentanoate C21H24O5 详情 详情
(XI) 37230 tert-butyl (2R)-2-((E)-1-[[(2,2-dimethoxyethyl)amino]methyl]-1-propenyl)-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate C25H36N2O4 详情 详情
(XII) 37231 (E)-N-(2,2-dimethoxyethyl)-2-[(2R)-2,3,4,9-tetrahydro-1H-carbazol-2-yl]-2-buten-1-amine; N-(2,2-dimethoxyethyl)-N-[(E)-2-[(2R)-2,3,4,9-tetrahydro-1H-carbazol-2-yl]-2-butenyl]amine C20H28N2O2 详情 详情
(XIII) 37232 2-[(1S,12R)-13-[(E)ethylidene]-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraen-15-yl]-1-methoxyethyl methyl ether; (1S,12R)-15-(2,2-dimethoxyethyl)-13-[(E)ethylidene]-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraene C20H26N2O2 详情 详情
(XIV) 37233 2-[(1S,12R,13S)-13-ethyl-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraen-15-yl]-1-methoxyethyl methyl ether; (1S,12R,13S)-15-(2,2-dimethoxyethyl)-13-ethyl-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraene C20H28N2O2 详情 详情
(XV) 37234 ethyl 2-[(1S,12R,13S)-13-ethyl-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraen-15-yl]-1-(ethylsulfanyl)ethyl sulfide; (1S,12R,13S)-15-[2,2-bis(ethylsulfanyl)ethyl]-13-ethyl-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraene C22H32N2S2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VII)

By condensation of substituted nicotinamide (VI) with the carbazolyoxymethyl-oxirane (XII) in hot methanol/water. The intermediates the nicotinamide (VI) and the oxirane (XII) have been obtained as follows: 1.- Nicotinamide (VI): The reaction of 4-hydroxybenzyl alcohol (I) with 2-nitropropane (II) by means of potassium tert-butoxide in hot diglyme gives 4-(2-methyl-2-nitropropyl)phenol (III), which is reduced to the corresponding amino derivative (IV) with H2 over Pd/C in methanol/ethanol/acetic acid. Finally, this compound is condensed with 6-chloronicotinamide (V) by means of K2CO3 in dimethylacetamide/isooctane. 2.- Oxirane (XII): The reaction of phenylhydrazine (VII) with cyclohexane-1,3-dione (VIII) by means of NaHCO3 in isopropanol/water gives the monohydrazone (IX), which is cyclized with hotpolyphosphoric acid yielding the 4-hydroxycarbazole (X). Finally, this compound is condensed with the glycidyl 3-nitrophenylsulfonate (XI) by means of K2CO3 in refluxing acetone.

参考文献 中间体
合成目标
【1】 Crowell, T.A.; Evrard, D.A.; Jones, C.D.; Muehl, B.S.; Rito, C.J.; Shuker, A.J.; Thorpe, A.J.; Thrasher, K.J. (Eli Lilly and Company); Carbazole analogues as selective B3 adrenergic agonists. EP 0827746; WO 9809625 .
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) 29474 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol 623-05-2 C7H8O2 详情 详情
(II) 21819 2-nitropropane 79-46-9 C3H7NO2 详情 详情
(III) 29475 4-(2-methyl-2-nitropropyl)phenol C10H13NO3 详情 详情
(IV) 29476 4-(2-amino-2-methylpropyl)phenol 51706-55-9 C10H15NO 详情 详情
(V) 29477 6-chloronicotinamide 6271-78-9 C6H5ClN2O 详情 详情
(VI) 29478 6-[4-(2-amino-2-methylpropyl)phenoxy]nicotinamide C16H19N3O2 详情 详情
(VII) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(VIII) 11244 1,3-Cyclohexanedione 504-02-9 C6H8O2 详情 详情
(IX) 29479 3-hydroxy-2-cyclohexen-1-one N-phenylhydrazone C12H14N2O 详情 详情
(X) 29480 4-Hydroxycarbazole; 9H-carbazol-4-ol 52602-39-8 C12H9NO 详情 详情
(XI) 16259 (2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate 115314-14-2 C9H9NO6S 详情 详情
(XII) 29481 9H-carbazol-4-yl (2S)oxiranylmethyl ether; 4-[(2S)oxiranylmethoxy]-9H-carbazole C15H13NO2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(I)

The condensation of phenyl hydrazine (I) with the cis N-methyl-perhydroisoindoletrione (II) gave hydrazone (III), which underwent Fischer indole synthesis upon treatment with methanolic H2SO4 to afford the pyrrolocarbazole (IV) as the major regioisomer (1). Reduction of the imide group of (IV) with aluminum hydride, generated from LiAlH4 and H2SO4, provided the corresponding amine as a racemic mixture. Separation of the desired (R,R)-enantiomer was then achieved by chiral HPLC on Chiralcel(R) OJ.

参考文献 中间体
合成目标
【1】 Berman, B.; Kaufman, J.; Can J Chem 1982, 60, 4, 419-424.
【2】 Pitis, P.M.; Carmosin, R.J.; Carson, J.R. (Ortho-McNeil Pharmaceutical, Inc.); Octahydropyrrolo-[3,4-c]carbazoles useful as analgesic agents. US 6063803; WO 9965911 .
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) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(II) 31525 (3aS,7aR)-2-methyltetrahydro-1H-isoindole-1,3,5(2H,4H)-trione C9H11NO3 详情 详情
(III) 31526 (3aS,7aR)-2-methyltetrahydro-1H-isoindole-1,3,5(2H,4H)-trione 5-(N-phenylhydrazone) C15H17N3O2 详情 详情
(IV) 31527 (3aR,10cR)-2-methyl-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione C15H14N2O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(III)

Synthesis of [18F]FEtNTI: The intermediate 2-(N1-phenylhydrazino)acetic acid ethyl ester (II) has been obtained by two different ways: 1.- By nitrosation of N-phenylglycine ethyl ester (I) with NaNO2 followed by readuction with Zn/acetic acid (low yields). 2.- By condensation of phenylhydrazine (III) with ethyl bromoacetate (IV) by means of an excess of triethylamine. The cyclization of intermediate (II) with naltrexone (V) by mans of HCl in methanol gives the indolomorphinanylacetic ester (VI), which is benzyl protected at the OH group by means of benzyl bromide and K2CO3 in DMF yielding the benzyl ether (VII). The reduction of the ester group of (VII) with LiAlH4 in THF/toluene afords the indolomorphinanylethanol (VIII), which is treated with tosyl chloride and potassium trimethylsilanolate in toluene to provide the corresponding tosylate (IX). The reaction of (IX) with potassium [18F]fluoride, K2CO3 and Kryptpfix [2.2.2] in hot DMF gives the 18F labeled intermediate (X), which is finally debenzylated by hydrogenation with H2 over Pd/C in DMF/triethylamine.

参考文献 中间体
合成目标
【1】 Mathews, W.B.; et al.; Synthesis of N1´-([F-18]fluoroethyl)naltrindole ([F-18]FEtNTI): A radioligand for positron emission tomographic studies of delta opioid receptors. J Label Compd Radiopharm 1999, 42, 1, 43.
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) 25701 ethyl 2-anilinoacetate 2216-92-4 C10H13NO2 详情 详情
(II) 25702 ethyl 2-(1-phenylhydrazino)acetate C10H14N2O2 详情 详情
(III) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 25079 (1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one; Naltrexone 16590-41-3 C20H23NO4 详情 详情
(VI) 25704 ethyl 2-[(1S,2S,13S,21R)-22-(cyclopropylmethyl)-2,16-dihydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate C31H33NO5 详情 详情
(VII) 25705 ethyl 2-[(1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-2-hydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate C38H39NO5 详情 详情
(VIII) 25706 (1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-hydroxyethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol C36H37NO4 详情 详情
(IX) 25707 2-[(1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-2-hydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]ethyl 4-methylbenzenesulfonate C43H43NO6S 详情 详情
(X) 25708 (1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-fluoroethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol C36H36FNO3 详情 详情
(X) 45358 (1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-fluoroethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol C36H36FNO3 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

Noroxymorphindole (III) was prepared by Fischer indole synthesis from noroxymorphone (I) and phenylhydrazine (II) under acidic conditions. Alkylation of (III) with 2-methyl-2-propenyl bromide (IV) in the presence of NaHCO3 in DMF afforded the title compound.

参考文献 中间体
合成目标
【1】 McLamore, S.; et al.; Effect of N-alkyl and N-alkenyl substituents in noroxymorphindole, 17-substituted-6,7-dehydro-4,5alpha-epoxy-3,14-dihydroxy-6,7:2',3'-indolomorphinans on opioid receptor affinity, selectivity, and efficacy. J Med Chem 2001, 44, 9, 1471.
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) 33927 (1S,5R,13R,17S)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one C16H17NO4 详情 详情
(II) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(III) 50974 (1S,2S,13R,21R)-14-oxa-11,22-diazaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaene-2,16-diol C22H20N2O3 详情 详情
(IV) 40015 3-bromo-2-methyl-1-propene 1458-98-6 C4H7Br 详情 详情

合成路线19

该中间体在本合成路线中的序号：(V)

The methylation of 6-chloro-1H-indole-2-carboxylic acid ethyl ester (I) with NaH and Me-I in DMF gives the 1-methylindole derivative (II), which is condensed with 2-chloro-2-oxoacetic acid ethyl ester (III) by means of TiCl4 in dichloroethane to yield 6-chloro-2-[2-(ethoxycarbonyl)-1-methyl-1H-indol-3-yl]-2-oxoacetic acid ethyl ester (IV). The cyclization of (IV) with phenylhydrazine (V) in refluxing acetic acid affords the 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylic acid ethyl ester (VI). The reduction of the ester group of (VI) by means of NaBH4 in refluxing THF/methanol affords the hydroxymethyl derivative (VII), which is oxidized with MnO2 in refluxing dichloromethane to provide the corresponding carbaldehyde (VIII). The reaction of (VIII) with p-Toluenesulfonylmethyl isocyanide (TosMIC) and potassium tert-butoxide in dimethoxyethane gives the acetonitrile derivative (IX), which is hydrolyzed with HCl in refluxing methanol to yield the acetate ester derivative (X). Finally, this compound is treated with dimethylamine and trimethylaluminum in toluene to afford the target dimethylacetamide derivative.

参考文献 中间体
合成目标
【1】 Bartsch, R.; Sevrin, M.; Froissant, J.; Evanno, Y.; Dubois, L.; Marguet, F.; Gille, C. (Sanofi-Synthélabo); 4-Oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetamide derivs., their preparation and their application in therapy. EP 1000063; FR 2766823; JP 2001512122; US 6262045; WO 9906406 .
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) 55771 ethyl 6-chloro-1H-indole-2-carboxylate C11H10ClNO2 详情 详情
(II) 55772 ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate C12H12ClNO2 详情 详情
(III) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(IV) 55773 ethyl 6-chloro-3-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-indole-2-carboxylate C16H16ClNO5 详情 详情
(V) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(VI) 55774 ethyl 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate C20H16ClN3O3 详情 详情
(VII) 55775 7-chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one C18H14ClN3O2 详情 详情
(VIII) 55776 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carbaldehyde C18H12ClN3O2 详情 详情
(IX) 55777 2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)acetonitrile C19H13ClN4O 详情 详情
(X) 55778 methyl 2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)acetate C20H16ClN3O3 详情 详情
(XI) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情

合成路线20

该中间体在本合成路线中的序号：(I)

The cyclization of phenylhydrazine (I) with 3-[4-(methylsulfanyl)phenyl]acrylonitrile (II) by means of NaOEt in refluxing ethanol gives the aminopyrazoline (III), which is dehydrogenated by means of MnO2 in dichloromethane to yield the 3-aminopyrazole (IV). The diazotation of (IV) with NaNO2 and HCl in water, followed by a treatment with Cu2Cl2, affords the 3-chloropyrazole (V), which is finally oxidized to the target sulfone by means of MCPBA in dichloromethane.

参考文献 中间体
合成目标
【1】 Matsuo, M.; Okumura, K.; Ogino, T.; Nakamura, K.; Nishimura, H.; Harada, K.; Hotta, Y.; Tsuji, K. (Fujisawa Pharmaceutical Co., Ltd.); 1,3,5-Trisubstd. pyrazoles for treatment of inflammation. EP 0856000; JP 1999513403; WO 9713755 .
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) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(II) 52011 (E)-3-[4-(methylsulfanyl)phenyl]-2-propenenitrile C10H9NS 详情 详情
(III) 52012 5-[4-(methylsulfanyl)phenyl]-1-phenyl-4,5-dihydro-1H-pyrazol-3-amine; 5-[4-(methylsulfanyl)phenyl]-1-phenyl-4,5-dihydro-1H-pyrazol-3-ylamine C16H17N3S 详情 详情
(IV) 52013 5-[4-(methylsulfanyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine; 5-[4-(methylsulfanyl)phenyl]-1-phenyl-1H-pyrazol-3-amine C16H15N3S 详情 详情
(V) 52014 4-(3-chloro-1-phenyl-1H-pyrazol-5-yl)phenyl methyl sulfide; 3-chloro-5-[4-(methylsulfanyl)phenyl]-1-phenyl-1H-pyrazole C16H13ClN2S 详情 详情
Extended Information