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【结 构 式】

【分子编号】25897

【品名】benzenediazonium chloride

【CA登记号】

【 分 子 式 】C6H5ClN2

【 分 子 量 】140.57188

【元素组成】C 51.27% H 3.59% Cl 25.22% N 19.93%

与该中间体有关的原料药合成路线共 5 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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.

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:(VII)

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.

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3

该中间体在本合成路线中的序号:(II)

[U-14C]-Aniline (I) is converted to [U-14C]phenyldiazonium chloride (II), which is condensed in situ with ethyl 2-(ethoxyalyl)propionate (III) to give [U-14C]phenylhydrazone of ethyl pyruvate (IV). Cyclization of (IV) by polyphosphoric acid in xylene affords ethyl [U-14C-phenyl]indole-2-carboxylic acid (V). Catalytic hydrogenation of compound (V) in the presence of platinum gives ethyl [U-14C-cyclohexyl]-(RS)-perhydroindole-2-carboxylic acid (VI), which is saponified to the corresponding acid (VIII). Compound (VI) can also be prepared by reduction of compound (V) with tin and hydrochloric acid to give compound (VII), and hydrogenation of the latter in the presence of palladium. Compound (VIII) is reesterified to the benzyl ester (IX), which is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine (X) in the presence of DCC and 1-hydroxy-1-benzotriazole. The resulting compound (X) is separated fom the mixture of isomers by silica gel column chromatography. Hydrogenolysis of the latter compound gives [U-14C-cyclohexyl]perindopril, which is isolated as the tert-bytylamine salt.

1 Pichat, L.; et al.; Syntheses du S-9490-3. J Label Compd Radiopharm 1988, 25, 5, 553.
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) 25897 benzenediazonium chloride C6H5ClN2 详情 详情
(III) 27781 diethyl 2-methyl-3-oxosuccinate 5965-53-7 C9H14O5 详情 详情
(IV) 27782 ethyl 2-[(E)-2-phenylhydrazono]propanoate C11H14N2O2 详情 详情
(V) 27783 Indole-2-carboxylic acid ethyl ester; 2-Carbethoxyindole; 1H-indole-2-carboxylic acid ethyl ester 3770-50-1 C11H11NO2 详情 详情
(VI) 27784 ethyl octahydro-1H-indole-2-carboxylate C11H19NO2 详情 详情
(VII) 27785 ethyl 2-indolinecarboxylate C11H13NO2 详情 详情
(VIII) 27789 octahydro-1H-indole-2-carboxylic acid C9H15NO2 详情 详情
(IX) 27790 benzyl octahydro-1H-indole-2-carboxylate C16H21NO2 详情 详情
(X) 27786 (2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propionic acid C10H19NO4 详情 详情
(XI) 27787 benzyl (2S,3aS,7aS)-1-((2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl)octahydro-1H-indole-2-carboxylate C26H38N2O5 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VII)

The sulfonation of D-tryptophan tert-butyl ester (I) with 4-vinylphenylsulfonyl chloride (II) and NMM in dichloromethane gives N2-(4-vinylphenylsulfonyl)-D-tryptophan tert-butyl ester (III), which is treated with ozone in dichloromethane to yield the benzaldehyde (IV). The condensation of (IV) with phenylsulfonyl hydrazide (V) in ethanol/THF affords the phenylsulfonyl hydrazone (VI), which is cyclized with phenyldiazonium chloride (VII) (aniline, NaNO2 and aq. HCl) in pyridine to provide the tetrazole derivative (VIII). Finally, the tert-butyl ester group of (VIII) is hydrolyzed with THF in dichloromethane to furnish the target D-tryptophan derivative.

1 Watanabe, F.; Tsuzuki, H.; Ohtani, M. (Shionogi & Co. Ltd.); Sulfonated amino acid derivs. and metalloproteinase inhibitors containing the same. EP 0950656; JP 2001316254; US 6207698; US 6235768; US 6441021; WO 9727174 .
2 Watanabe, F.; Kurihara, H.; Tamura, Y.; Sinosaki, T. (Shionogi & Co. Ltd.); Therapeutic or prophylactic agent for glomerulopathy. EP 1029541; US 6423729; WO 9904780 .
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) 55433 tert-butyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate C15H20N2O2 详情 详情
(II) 55434 4-Vinylbenzenesulfonyl chloride; p-Styrenesulfonyl chloride; p-Vinylbenzenesulfonyl chloride; 4-Styrenesulfonyl chloride 2633-67-2 C8H7ClO2S 详情 详情
(III) 55435 tert-butyl (2R)-3-(1H-indol-3-yl)-2-{[(4-vinylphenyl)sulfonyl]amino}propanoate C23H26N2O4S 详情 详情
(IV) 55436 tert-butyl (2R)-2-{[(4-formylphenyl)sulfonyl]amino}-3-(1H-indol-3-yl)propanoate C22H24N2O5S 详情 详情
(V) 55437 Benzenesulfonic acid hydrazide; Benzenesulfonyl hydrazide 80-17-1 C6H8N2O2S 详情 详情
(VI) 55438 tert-butyl (2R)-3-(1H-indol-3-yl)-2-{[(4-{[(E)-2-(phenylsulfonyl)hydrazono]methyl}phenyl)sulfonyl]amino}propanoate C28H30N4O6S2 详情 详情
(VII) 25897 benzenediazonium chloride C6H5ClN2 详情 详情
(VIII) 55439 tert-butyl (2R)-3-(1H-indol-3-yl)-2-({[4-(2-phenyl-2H-1,2,3,4-tetraazol-5-yl)phenyl]sulfonyl}amino)propanoate C28H28N6O4S 详情 详情

合成路线5

该中间体在本合成路线中的序号:(IV)

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.

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
Extended Information