【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% |
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 |