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【结 构 式】

【分子编号】18941

【品名】p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride

【CA登记号】122-04-3

【 分 子 式 】C7H4ClNO3

【 分 子 量 】185.5664

【元素组成】C 45.31% H 2.17% Cl 19.11% N 7.55% O 25.87%

与该中间体有关的原料药合成路线共 34 条

合成路线1

该中间体在本合成路线中的序号:(IV)

 

1 Shan FU,Fang G,Wu&2001. Improvement on synthesis of balsalazide disodium中国药物化学杂志.11(2): 110~111
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) 30566 N-(4-aminobenzoyl)-beta-alanine 7377-08-4 C10H12N2O3 详情 详情
(III) 15240 2-Hydroxybenzoic acid; Salicylic acid 69-72-7 C7H6O3 详情 详情
(IV) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(V) 66154 3-(4-nitrobenzamido)propanoic acid   C10H10N2O5 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 synthesis of RFCNU from 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide (III) has been described, as well as the preparation of 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide from 2,3-O-isopropylidene-D-ribosyl-furanose (I). Briefly, the synthesis is as follows: A cold solution of 2,3-O-isopropylidene-D-ribofuranose (I) in dry pyridine is stirred and treated with p-nitrobenzoyl chloride (A). Workup gives 2,3-O-isopropylene-1,5-di-O-p-nitrobenzoyl-D-ribofuranose (II), which is crystallized from methylene chloride/ether. (II) is added in portions to a dry solution of methylene chloride saturated with HBr at 0 C and stirred for 0.5 h. It is warmed to room temperature, the precipitated p-nitrobenzoic acid removed by filtration (under argon) and the filtrate concentrated. Addition of petroleum ether/diethyl ether and partial concentration by vacuum gives crystals of 2,3-isopropylidene-5-O-p-nitrobenzoyl-beta-ribosyl bromide (III). (III), dissolved in toluene, is reacted with silver isocyanate and refluxed under nitrogen. Silver bromide is filtered off and the filtrate concentrated by evaporation, yielding an oil. Dissolution of the oil in acetonitrile and cooling to -40 C yields crystals of isocyanato-1-O-isopropylidene-2,3-O-p-nitrobenzoyl-5-D-ribofuranose (IV). (IV) is reacted with an aqueous solution of 2-chloroethylamine (B) and the solution extracted with benzene. The organic base is separated, dried and refrigerated. Warming gives a yellow oil, which is treated with ethanol to give crystalline (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-urea (V). (V) is dissolved in methylene chloride, cooled to -40 C and an excess of liquid nitrosyl chloride (NOCl) is added with stirring. Addition of a mixture of chloroform and petroleum ether gives crystals of (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-nitrosourea (RFCNU). The synthesis may be modified to yield either the alpha or beta anomer. Both anomeric forms have shown the same antitumor activity.

1 Weigele, M.; De Bernado, S.; A synthesis of pyrazomycins. J Org Chem 1976, 41, 287-290.
2 Imbach, J.L.; Montero, J.L.; Rodriguez, M.; Sur une nouvelle voie de synthese de la R.F.C.N.U. Eur J Med Chem - Chim Ther 1977, 12, 408-412.
3 Eastland, G.; Bofumustine. Drugs Fut 1984, 9, 9, 641.
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) 16170 1,2-dichloroethane 107-06-2 C2H4Cl2 详情 详情
(A) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(I) 17718 (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol C8H14O5 详情 详情
(II) 34287 [(3aR,4R,6aR)-2,2-dimethyl-6-[(4-nitrobenzoyl)oxy]tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate C22H20N2O11 详情 详情
(III) 34288 [(3aS,4R,6aR)-6-bromo-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate C15H16BrNO7 详情 详情
(IV) 34289 [(3aR,4R,6aR)-6-isocyanato-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate C16H16N2O8 详情 详情
(V) 34290 [(3aR,4R,6aR)-6-([[(2-chloroethyl)amino]carbonyl]amino)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate C18H22ClN3O8 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

The condensation of 4-nitrobenzoyl chloride (I) with piperazine (II) in water by means of KOH gives 4-nitrobenzoylpiperazine (III), which is reduced with H2 over Pd/C in methanol yielding 4-aminobenzoyl piperazine (IV). The condensation of (IV) with 4-chloro-7-trifluoromethylquinoline (V) by means of HCl in refluxing ethanol affords 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (VI), which is finally acylated with 4-fluorobenzenesulfonyl chloride (VII) by means of triethylamine in THF.

1 McCall, J.M. (Pharmacia Corp.); Aminoquinolines. GB 2021567 .
2 Castaner, J.; Serradell, M.N.; U-54669-F. Drugs Fut 1984, 9, 1, 36.
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 20011 (4-nitrophenyl)(1-piperazinyl)methanone C11H13N3O3 详情 详情
(IV) 20014 (4-aminophenyl)(1-piperazinyl)methanone C11H15N3O 详情 详情
(V) 20003 4-chloro-7-(trifluoromethyl)quinoline 346-55-4 C10H5ClF3N 详情 详情
(VI) 20008 1-piperazinyl(4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl)methanone C21H19F3N4O 详情 详情
(VII) 12292 4-Fluorobenzenesulfonyl chloride 349-88-2 C6H4ClFO2S 详情 详情

合成路线4

该中间体在本合成路线中的序号:(II)

The condensation of methyl 5-methoxy-2-methylindole-3-acetate (I) with p-nitrobenzoyl chloride (II) by means of NaH in toluene gives methyl 1-(p-nItrobenzoyl)-5-methoxy-2-methylindole-3-acetate (III), which is hydrolyzed with p-toluenesulfonic acid in refluxing acetic acid yielding the corresponding free acid (IV). The reduction of (IV) with H2 over Pd/C in methanol affords 1-(p-aminobenzoyl)-5-methoxy-2-methyl indole-3-acetic acid (V) , which is finally treated with NaNO2 and HCl in acetic acid, and with NaN3 in water.

1 Tricerri, S.; et al.; Synthesis and preliminary pharmacological data on zidometacin, a new anti-inflammatory compound. Eur J Med Chem 1979, 14, 181-183.
2 Blancafort, P.; Serradell, M.N.; de Angelis, L.; Castaner, J.; Zidometacin. Drugs Fut 1979, 4, 11, 839.
3 Tricerri, S.; Bianchetti, A.; DE 2722399 .
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) 39636 methyl 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetate C13H15NO3 详情 详情
(II) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(III) 39637 methyl 2-[5-methoxy-2-methyl-1-(4-nitrobenzoyl)-1H-indol-3-yl]acetate C20H18N2O6 详情 详情
(IV) 39638 2-[5-methoxy-2-methyl-1-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid C19H16N2O6 详情 详情
(V) 39639 2-[1-(4-aminobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H18N2O4 详情 详情

合成路线5

该中间体在本合成路线中的序号:(C)

Epoxidation of trans-cinnamyl alcohol (A) gives compound (I), which in turn is reacted with sodium 2-ethoxyphenate (B) to give the diol (II). The primary alcoholic group of (II) is reacted with p-nitrobenzoyl chloride to obtain (III), and (IV) is prepared by treatment of (III) with methanesulfonyl chloride. By treatment of (IV) with sodium hydroxide in an aqueous/dioxane solution the epoxide (V) is obtained in high yield, and this reaction causes inversion of configuration at C-2 carbon atom. Treatment of (V) with aqueous methanolic ammonia gives (VI), which in turn is acylated to (VII) with chloroacetyl chloride and cyclized to morpholone (VIII) with potassium tert-butoxide. The reduction to the final compound FCE-20124 is performed with [sodium bis(2-methoxyethoxy)aluminum hydride] (RED-AL) in toluene.

1 Lazzari, E.; Meroni, M.; Mazzini, G.; Melloni, P.; Della Torre, A.; Configurantional studies on 2[gamma-(2-ethoxyphenoxy)benzyl]morpholine FCE-20124. Tetrahedron 1985, 41, 7, 1393.
2 Torre, A.D.; Carniel, G.; Rossi, A.; Melloni, P. (Pharmacia Corp.); Substituted morpholine derivatives and compositions. DE 2901032; FR 2430412; FR 2442839; GB 2014981; JP 54148739; US 4229449 .
3 Riva, F.; FCE-20124. Drugs Fut 1985, 10, 11, 905.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(A) 13951 (E)-3-Phenyl-2-propen-1-ol 104-54-1 C9H10O 详情 详情
(B) 29768 sodium 2-ethoxybenzenolate C8H9NaO2 详情 详情
(I) 29767 [(2R,3S)-3-phenyloxiranyl]methanol C9H10O2 详情 详情
(II) 29769 (2S,3S)-3-(2-ethoxyphenoxy)-3-phenyl-1,2-propanediol C17H20O4 详情 详情
(III) 29770 (1S,2S)-1-(2-ethoxyphenoxy)-4-(4-nitrophenyl)-1-phenyl-2-butanol C24H25NO5 详情 详情
(IV) 29771 2-ethoxyphenyl (1S,2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-(4-nitrobenzyloxy)-1-phenylbutyl ether; [[(1S)-1-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]-3-(4-nitrobenzyloxy)propyl]oxy](methyl)dimethylene-lambda(6)-sulfane C27H31NO6S 详情 详情
(V) 29772 2-ethoxyphenyl (S)-2-oxiranyl(phenyl)methyl ether; 2-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]oxirane C17H18O3 详情 详情
(VI) 29773 (1S,2S)-3-amino-1-(2-ethoxyphenoxy)-1-phenyl-2-propanol C17H21NO3 详情 详情
(VII) 29774 1-[3-[(chlorocarbonyl)amino]-2-hydroxy-1-phenylpropoxy]-2-ethoxybenzene C18H20ClNO4 详情 详情
(VIII) 29775 (6R)-6-[(2-ethoxyphenoxy)(phenyl)methyl]-3-morpholinone C19H21NO4 详情 详情
(C) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情

合成路线6

该中间体在本合成路线中的序号:(B)

The sulfonation of methyl N-trifluoroacetyldaunosaminide (I) with mesyl chloride or with 4-bromophenylsulfonyl chloride in pyridine gives the corresponding 4-O-mesyl derivative (II) or 4-O-(4-bromophenylsulfonyl) derivative (IIa); both compounds by reaction with NaI in refluxing butanone yield the 4-iodo compound (III). The hydrogenation of (III) with H2 over Pd/C in methanol, followed by hydrolysis with hot acetic acid yields 4-deoxy-N-trifluoroacetyldaunosaminide (IV), which is esterified with p-nitrobenzoyl chloride in pyridine affording the corresponding p-nitrobenzoyl ester (V). The reaction of (V) with dry HCl in methylene chloride gives 1,4-dideoxy-N-trifluoroacetyldanosaminide (VI), which is condensed with daunomycinone (VII) by means of silver trifluoromethylsulfonate in methylene chloride and hydrolyzed with NaOH to afford 4'-deoxy-daunomycine (VIII). The bromination of (VIII) with Br2 in methanol-dioxane gives 4'-deoxy-14-bromodaunomycine (IX), which is finally hydrolyzed with aqueous sodium formate.

1 Penco, S.; Arcamone, F.; Di Marco, A.; Novel antitumor glycosides of the anthracycline series and process for their preparation. FR 2325659 .
2 Arcamone, F.; Penco, S.; Redaelli, S.; Hanessian, S.; Synthesis and antitumor activity of 4'-deoxydaunorubicin and 4'-deoxyadriamycin. J Med Chem 1976, 19, 1424-25.
3 Robinson, C.P.; Prous, J.; Castaner, J.; ESORUBICIN HYDROCHLORIDE < Rec INNM; USAN >. Drugs Fut 1990, 15, 10, 986.
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(A) 18964 4-bromobenzenesulfonyl chloride 98-58-8 C6H4BrClO2S 详情 详情
(IIa) 31180 (2S,3S,4S,6R)-6-methoxy-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl 4-bromobenzenesulfonate C15H17BrF3NO6S 详情 详情
(I) 30693 2,2,2-trifluoro-N-[(2S,3S,4S,6R)-3-hydroxy-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl]acetamide C9H14F3NO4 详情 详情
(II) 31179 (2S,3S,4S,6R)-6-methoxy-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl methanesulfonate C10H16F3NO6S 详情 详情
(III) 31181 2,2,2-trifluoro-N-[(2S,3R,4S,6R)-3-iodo-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl]acetamide C9H13F3INO3 详情 详情
(IV) 31182 2,2,2-trifluoro-N-[(2R,4R,6S)-2-hydroxy-6-methyltetrahydro-2H-pyran-4-yl]acetamide C8H12F3NO3 详情 详情
(V) 31183 (2S,4R,6S)-6-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl 4-nitrobenzoate C15H15F3N2O6 详情 详情
(VI) 31184 N-[(2S,4R,6S)-2-chloro-6-methyltetrahydro-2H-pyran-4-yl]-2,2,2-trifluoroacetamide C8H11ClF3NO2 详情 详情
(VII) 16223 (8S,10S)-8-acetyl-6,8,10,11-tetrahydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione 21794-55-8 C21H18O8 详情 详情
(VIII) 31185 (8S,10S)-8-acetyl-10-[[(2S,4R,6S)-4-amino-6-methyltetrahydro-2H-pyran-2-yl]oxy]-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione C27H29NO9 详情 详情
(IX) 31186 (8S,10S)-10-[[(2S,4R,6S)-4-amino-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-(2-bromoacetyl)-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione C27H28BrNO9 详情 详情

合成路线7

该中间体在本合成路线中的序号:(I)

Condensation of 4-nitrobenzoyl chloride (I) with 2-nitrobenzenamine (II) in boiling dioxane yields N-(2-nitrophenyl)-4-nitrobenzamide (III), which is catalytically reduced by H2 over Pd/C in dimethylfomamide.

1 Herrmann, M.; Satzinger, G.; Fritschi, E.; Weierhausen, U. (Godecke AG); N-Phenylbenzamide derivs.. EP 0116967; US 4816485 .
2 Satzinger, G.; Weiershausen, U.; Dinaline. Drugs Fut 1986, 11, 10, 833.
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 11608 o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine 88-74-4 C6H6N2O2 详情 详情
(III) 23926 4-nitro-N-(2-nitrophenyl)benzamide C13H9N3O5 详情 详情

合成路线8

该中间体在本合成路线中的序号:(I)

4-Nitrobenzoylchloride (I) is condensed with 2,6-dimethylaniline (II) in the presence of base (potassium carbonate or triethylamine) to provide the 4-nitrobenzamide (III). Reduction of the aromatic nitro group in (III) using catalytic hydrogenation produces the corresponding 4-aminobenzamide, ameltolide.

1 Clark, C.R.; Robertson, D.W.; Leander, J.D.; AMELTOLIDE. Drugs Fut 1990, 15, 10, 983.
2 Clark, C.R.; Sansom, R.T.; Lin, C.-M.; Norris, G.N.; Anticonvulsant activity of some 4-aminobenzanilides. J Med Chem 1985, 28, 9, 1259.
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(III) 31178 N-(2,6-dimethylphenyl)-4-nitrobenzamide C15H14N2O3 详情 详情

合成路线9

该中间体在本合成路线中的序号:(III)

1. The nitration of isosorbide (I) with fuming HNO3 in acetic acid/acetic anhydride gives the dinitrate (II), which is selectively monoreduced by means of diisopropyltitanium tetrahydroborate (obtained by reaction of disopropyltitanium dichloride with benzyltriethylammonium borohydride) in dichloromethane to afford the isosorbide 5-nitrate. 2. The reduction of dinitrate (II) can also be performed with benzyl triethyl ammonium tetrathiomolibdate in DMF. 3. The reduction of dinitrate (II) can also be performed with H2 over PtO2/C in methanol. 4. The reduction of dinitrate (II) can also be performed with cobalt phthalocyanine and NaBH4 in methanol. 5. The reduction of dinitrate (II) can also be performed with Zn and HOAc in ethanol/water. 6. The reduction of dinitrate (II) can also be performed with H2 over Pd/C and NiCl2 in ethanol/water. 7. The reaction of isosorbide (I) with 4-nitrobenzoyl chloride (III) and pyridine in dichloromethane gives the isosorbide 2-O-(4-nitrobenzoate (IV), which is nitrated with HNO3 in acetic acid/acetic anhydride to yield the isosorbide 5-O-nitrate-2-O-(4-nitrobenzoate) (V). Finally, this compound is selectively hydrolyzed with KOH in methanol/dichloromethane.

1 Bhar, D.; Chandrasekaran, S.; A highly chemoselective reduction of isosorbide-2,5-dinitrate mediated by tetrathiomolybdate. Indian J Chem 1997, 36B, 9, 793.
2 Ravikumar, K.S.; Chandrasekaran, S.; Highly chemoselective reduction of 2,5-dinitro-1,4:3,6-dianhydro-D-glucitol with titanium(III) tetrahydroborates: Efficient synthesis of isomerically pure 2- and 5-nitro-1,4:3,6-dianhydro-D-glucitols. Synthesis (Stuttgart) 1994, 10, 1032.
3 Brown, C.; et al.; New preparative routes to isosorbide 5-mononitrate. J Chem Soc - Perkins Trans I 2000, 12, 1809.
4 Camera, E.; Filipuzzi, F.; De Lucchi, O.; Modena, G. (Consiglio Nazionale delle Ricerche); Process for the preparation of isosorbide-5-mononitrate. EP 0201067; US 4713466 .
5 Gallardo Carrera, A. (Fordonal SL); Process for the preparation of isosorbide-5-nitrate. ES 8402305 .
6 Roberts, S.M.; Marston, R.W.; Quigley, P.F.; Brown, C.M.; Cross, S.J.; Synthesis of isosorbide mononitrate. EP 1248788; WO 0149692 .
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) 59337 (1R,3aS,4S,6aS)octahydro-1,4-pentalenediol C8H14O2 详情 详情
(II) 59338 (1R,3aS,4S,6aS)-1,4-bis(nitrooxy)octahydropentalene C8H12N2O6 详情 详情
(III) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(IV) 59340 (1R,3aR,4R,6aR)-1,3a,6a-trimethyl-4-[2-(4-methylphenyl)-2-propenyl]octahydropentalene C21H30 详情 详情
(V) 59339 (1S,3aS,4R,6aS)-4-(nitrooxy)octahydro-1-pentalenyl 4-nitrobenzoate C15H16N2O7 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 synthesis of CMDA (VII) was accomplished using a modified version of the published procedures: The di-tert-butyl 4-nitrobenzoyl-L-glutamate (II) was reduced to di-tert-butyl 4-aminobenzoyl-L-glutamate (III) using transfer hydrogenation. The reductive amination of (III) with chloroethanal yielded the monofunctional di-tert-butyl 4-[(2-chloroethyl)amino]benzoyl-L-glutamate (IV), which was N-alkylated with ethylene oxide to give di-tert-butyl 4-[(2-chloroethyl)(2-hydroxyethyl)amino]benzoyl-L-glutamate (V). Reaction of (V) with methanesulfonyl chloride at 5 C yielded di-tert-butyl 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamate (VI). Treatment of (VI) with formic acid followed by lyophilization gave the diacid, 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid (VII).

1 Springer, C.J.; Mann, J.; Bagshawe, K.D.; Haase-Held, M.; Synthesis of an N-mustard prodrug. Tetrahedron 1990, 46, 5377-82.
2 Antoniw, P.; Bisset, G.M.F.; Springer, C.J.; Searle, F.; Jarman, M.; Bagshawe, K.D.; Novel prodrugs which are activated to cytotoxic alkylating agents by carboxypeptidase G2. J Med Chem 1990, 33, 2, 677-81.
3 Springer, C.J.; CMDA. Drugs Fut 1993, 18, 3, 212.
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 13674 di(tert-butyl) (2S)-2-[(4-nitrobenzoyl)amino]pentanedioate C20H28N2O7 详情 详情
(III) 13675 di(tert-butyl) (2S)-2-[(4-aminobenzoyl)amino]pentanedioate C20H30N2O5 详情 详情
(IV) 13676 di(tert-butyl) (2S)-2-([4-[(2-chloroethyl)amino]benzoyl]amino)pentanedioate C22H33ClN2O5 详情 详情
(V) 13677 di(tert-butyl) (2S)-2-([4-[(2-chloroethyl)(2-hydroxyethyl)amino]benzoyl]amino)pentanedioate C24H37ClN2O6 详情 详情
(VI) 13678 di(tert-butyl) (2S)-2-[[4-((2-chloroethyl)[2-[(methylsulfonyl)oxy]ethyl]amino)benzoyl]amino]pentanedioate C25H39ClN2O8S 详情 详情
(VII) 13679 (2S)-2-[[4-((2-Chloroethyl)[2-[(methylsulfonyl)oxy]ethyl]amino)benzoyl]amino]pentanedioic acid C17H23ClN2O8S 详情 详情
(VIII) 13680 4-((2-Chloroethyl)[2-[(methylsulfonyl)oxy]ethyl]amino)benzoic acid C12H16ClNO5S 详情 详情

合成路线11

该中间体在本合成路线中的序号:(VII)

3-Chloropropionyl chloride (II) was condensed with 4-aminoveratrole (I) in the presence of triethylamine to give the chloropropionamide (III). Further alkylation of N-methyl-2-(3,4-dimethoxyphenyl)ethylamine (IV) with (III) in refluxing acetonitrile afforded the aminopropionamide (V), which was subsequently reduced to diamine (VI) with LiAlH4 in boiling THF. Finally, acylation of (VI) with 4-nitrobenzoyl chloride (VII) gave the target amide.

1 Nadler, G.; Faivre, J.F.; Forest, M.C.; Cheval, B.; Martin, M.; Souchet, M.; Gout, B.; Bril, A.; Synthesis, electrophysiological properties and analysis of structural requirements of a novel class of antiarrhythmic agents with potassium and calcium channel blocking properties. Bioorg Med Chem 1998, 6, 11, 1993.
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) 18935 3,4-dimethoxyphenylamine; 3,4-dimethoxyaniline 6315-89-5 C8H11NO2 详情 详情
(II) 18936 3-chloropropanoyl chloride 625-36-5 C3H4Cl2O 详情 详情
(III) 18937 3-chloro-N-(3,4-dimethoxyphenyl)propanamide C11H14ClNO3 详情 详情
(IV) 18938 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine 3490-06-0 C11H17NO2 详情 详情
(V) 18939 3-[(3,4-dimethoxyphenethyl)(methyl)amino]-N-(3,4-dimethoxyphenyl)propanamide C22H30N2O5 详情 详情
(VI) 18940 N(1)-(3,4-dimethoxyphenethyl)-N(3)-(3,4-dimethoxyphenyl)-N(1)-methyl-1,3-propanediamine; N-[3-(3,4-dimethoxyanilino)propyl]-N-(3,4-dimethoxyphenethyl)-N-methylamine C22H32N2O4 详情 详情
(VII) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情

合成路线12

该中间体在本合成路线中的序号:(V)

A new synthesis of OPC-31260 has been published: The reductocondensation of 1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-one (I) with methylamine and NaBH4 gives N-(1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N-methylamine (II), which is methylated with formaldehyde and sodium cyanoborohydride to yield N-(1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N,N-dimethylamine (III). The hydrolysis of (III) with polyphosphoric acid affords N-(2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N,N-dimethylamine (IV), which is acylated with 4-nitrobenzoyl chloride to the expected benzoyl derivative (VI). The reduction of the nitro group of (VI) with H2 over Pd/C affords the corresponding 4-aminobenzoyl derivative (VII), which is finally acylated with 2-methylbenzoyl chloride by means of triethylamine in dichloromethane.

1 Ogawa, H.; Yamashita, H.; Kondo, K.; et al.; Orally active, nonpeptide vasopressin V2 receptor antagonists: A novel series of 1-[4-(benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepines and related compounds. J Med Chem 1996, 39, 18, 3574.
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) 14763 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H17NO3S 详情 详情
(II) 14764 N-methyl-1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N-methyl-N-[1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]amine C18H22N2O2S 详情 详情
(III) 14765 N,N-dimethyl-1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N,N-dimethyl-N-[1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]amine C19H24N2O2S 详情 详情
(IV) 14762 N,N-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N,N-dimethyl-N-(2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)amine C12H18N2 详情 详情
(V) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(VI) 14768 [5-(dimethylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl](4-nitrophenyl)methanone C19H21N3O3 详情 详情
(VII) 14769 (4-aminophenyl)[5-(dimethylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]methanone C19H23N3O 详情 详情
(VIII) 14770 2-methylbenzoyl chloride; o-Toluoyl chloride 933-88-0 C8H7ClO 详情 详情

合成路线13

该中间体在本合成路线中的序号:(IV)

Acylation of 3,4,6-tri-O-benzyl-D-glucosamine (I) by means of pentachlorophenyl dichloroacetate (II) yielded the dichloroacetamide (III). Acylation of glucosamine (III) with acid chloride (IV) in pyridine/CH2Cl2 provided the 1-O-p-nitrobenzoyl derivative (V), which was treated with hydrogen bromide in CH2Cl2 to furnish glycosyl bromide (VI). Coupling of bromide (VI) with the glucosamine cyclic carbamate (VII) was performed in the presence of mercury(II) cyanide to afford the disaccharide (VIII). Alkaline hydrolysis of the dichloroacetamide and cyclic carbamate functions of (VIII) gave diamine (IX), which was subsequently acetylated to diamide (X) by means of acetic anhydride in pyridine.

1 Kusumoto, S.; et al.; Chemical synthesis and biological activities of two disaccharide dipeptides corresponding to the repeating units of bacterial peptidoglycan. Bull Chem Soc Jpn 1986, 59, 5, 1411.
2 Kusumoto, S.; et al.; Synthesis of N-acetyl-beta-D-glucosaminyl-(1-4)-N-acetylmuramyl-L-alanyl-D-isoglutamine. Tetrahedron Lett 1978, 45, 4407.
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) 56323 (3R,4R,5S,6R)-3-amino-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-ol C27H31NO5 详情 详情
(II) 56324 Pentachlorophenyl dichloroacetate 19745-69-8 C8HCl7O2 详情 详情
(III) 56325 N-{(3R,4R,5S,6R)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]-2-hydroxytetrahydro-2H-pyran-3-yl}-2,2-dichloroacetamide C29H31Cl2NO6 详情 详情
(IV) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(V) 56326 (3R,4R,5S,6R)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]-3-[(2,2-dichloroacetyl)amino]tetrahydro-2H-pyran-2-yl 4-nitrobenzoate C36H34Cl2N2O9 详情 详情
(VI) 56327 N-{(3R,4R,5S,6R)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl}-2,2-dichloroacetamide C29H30BrCl2NO5 详情 详情
(VII) 56328 (4R,5R)-4-(diethoxymethyl)-5-[(R)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](hydroxy)methyl]-1,3-oxazolidin-2-one C43H54Cl2N2O12 详情 详情
(VIII) 56329 N-[(2S,3R,4R,5S,6R)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]-2-({(R)-[(4R,5R)-4-(diethoxymethyl)-2-oxo-1,3-oxazolidin-5-yl][(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}oxy)tetrahydro-2H-pyran-3-yl]-2,2-dichloroacetamide C43H54Cl2N2O12 详情 详情
(IX) 56330 (1S,2R,3R)-3-amino-1-({(2S,3R,4R,5S,6R)-3-amino-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4,4-diethoxy-2-butanol C40H56N2O10 详情 详情
(X) 56331 N-{(1R,2R,3S)-3-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-1-(diethoxymethyl)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxypropyl}acetamide C44H60N2O12 详情 详情

合成路线14

该中间体在本合成路线中的序号:

A new synthesis of nelfinavir has been described: The protection of the amino group of the dioxolane derivative (I) with benzyl chloroformate and K2CO3 in toluene gives the carbamate (II), which is mesylated with MsCl and triethylamine in toluene yielding the mesylate (III). Reaction of compound (III) with thiophenol (IV) by means of tetrabutylammonium bromide and NaOH in toluene/water affords the thioether (V), which is treated with HCl in methanol/water to provide diol (VI). Protection of the primary OH group of (VI) with p-nitrobenzoyl chloride and 2-picoline yields the p-nitrobenzoate (VII), which is mesylated as before to afford the protected compound (VIII). The reaction of (VIII) with KOH in dioxane gives epoxide (IX), which is condensed with N-tert-butylperhydroisoquinoline-3-carboxamide (X) in refluxing methanol to yield the addition product (XI). This compound (XI) can also be obtained by direct condensation of compound (VIII) with isoquinoline (X) by means of K2CO3 in methanol/water. Removal of the benzyloxycarbonyl group of (XI) with KOH in hot isopropanol affords compound (XII), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (XIII) by means of NaHCO3 in ethyl acetate to give the corresponding amide (XIV). Finally, this compound is deacetylated with ammonia in methanol.

1 Schaus, S.E.; et al.; Practical synthesis of enantiopure cyclic 1,2-amino alcohols via catalytic asymmetric ring opening of meso epoxides. J Org Chem 1997, 62, 12, 4197.
2 Busse, J.K.; Borer, B.C.; Zook, S.E.; A concise synthesis of the HIV-protease inhibitor nelfinavir via an unusual tetrahydrofuran rearrangement. Tetrahedron Lett 2000, 41, 36, 7017.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(I) 46589 (2S)-2-amino-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol C7H15NO3 详情 详情
(II) 46590 benzyl (1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylcarbamate C15H21NO5 详情 详情
(III) 46591 (2S)-2-[[(benzyloxy)carbonyl]amino]-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl methanesulfonate C16H23NO7S 详情 详情
(IV) 12951 Benzenethiol; Phenylmercaptan; Phenylhydrosulfide 108-98-5 C6H6S 详情 详情
(V) 46592 benzyl (1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethylcarbamate C21H25NO4S 详情 详情
(VI) 46593 benzyl (1R,2R)-2,3-dihydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate C18H21NO4S 详情 详情
(VII) 46594 (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-(phenylsulfanyl)butyl 4-nitrobenzoate C25H24N2O7S 详情 详情
(VIII) 46595 (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(methylsulfonyl)oxy]-4-(phenylsulfanyl)butyl 4-nitrobenzoate C26H26N2O9S2 详情 详情
(IX) 16755 benzyl N-[(1R)-1-[(2S)oxiranyl]-2-(phenylsulfanyl)ethyl]carbamate C18H19NO3S 详情 详情
(X) 13955 (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide C14H26N2O 详情 详情
(XI) 16757 benzyl (1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate C32H45N3O4S 详情 详情
(XII) 16758 (3S,4aS,8aS)-2-[(2R,3R)-3-amino-2-hydroxy-4-(phenylsulfanyl)butyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide C24H39N3O2S 详情 详情
(XIII) 46596 3-(chlorocarbonyl)-2-methylphenyl acetate C10H9ClO3 详情 详情
(XIV) 46597 3-[([(1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propyl]amino)carbonyl]-2-methylphenyl acetate C34H47N3O5S 详情 详情

合成路线15

该中间体在本合成路线中的序号:(V)

Condensation of benzodiazepinone (IV) with 4-nitrobenzoyl chloride (V) afforded amide (VI), which was alkylated with ethyl bromoacetate in the presence of NaH to give (VII). The nitro group of (VII) was reduced to aniline (VIII) using Fe and AcOH. Subsequent coupling of (VIII) with the acid chloride generated from biphenyl carboxylic acid (III) and oxalyl chloride produced the corresponding amide (IX). The ester group of (IX) was then hydrolyzed with NaOH, and the resulting carboxylic acid (X) was finally condensed with N-methylpiperazine (XI) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole as the coupling reagents.

1 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 16915 4'-methyl[1,1'-biphenyl]-2-carboxylic acid 7148-03-0 C14H12O2 详情 详情
(IV) 18498 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one C9H10N2O 详情 详情
(V) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(VI) 27975 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one C16H13N3O4 详情 详情
(VII) 27976 ethyl 2-[5-(4-nitrobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C20H19N3O6 详情 详情
(VIII) 27977 ethyl 2-[5-(4-aminobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C20H21N3O4 详情 详情
(IX) 27978 ethyl 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C34H31N3O5 详情 详情
(X) 27979 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetic acid C32H27N3O5 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线16

该中间体在本合成路线中的序号:(V)

Alkylation of benzodiazepinone (I) with 3-(chloromethyl)- pyridine (II) in the presence of NaH gave the 1-substituted benzodiazepinone (III). Reduction of the amide group of (III) with borane in THF afforded benzodiazepine (IV). Subsequent condensation with 4-nitrobenzoyl chloride (V) gave nitrobenzamide (VI), which was reduced to amine (VII) by hydrogenation in the presence of Pd/C. This compound was coupled with acid chloride (IX) (prepared by treatment of 2-phenylbenzoic acid (VIII) with oxalyl chloride) to yield the title compound.

1 Matsuhisa, A.; Koshio, H.; Sakamoto, K.; Taniguchi, N.; Yatsu, T.; Tanaka, A.; Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: Synthesis and pharmacological properties of 2-phenyl-4'-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carbonyl)benzanilide derivatives. Chem Pharm Bull 1998, 46, 10, 1566.
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) 18498 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one C9H10N2O 详情 详情
(II) 15793 3-(Chloromethyl)pyridine 3099-31-8 C6H6ClN 详情 详情
(III) 18500 1-(3-pyridinylmethyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one C15H15N3O 详情 详情
(IV) 18501 1-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine C15H17N3 详情 详情
(V) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(VI) 18503 (4-nitrophenyl)[5-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]methanone C22H20N4O3 详情 详情
(VII) 18504 (4-aminophenyl)[5-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]methanone C22H22N4O 详情 详情
(VIII) 18505 [1,1'-biphenyl]-2-carboxylic acid 947-84-2 C13H10O2 详情 详情
(IX) 18506 [1,1'-biphenyl]-2-carbonyl chloride C13H9ClO 详情 详情

合成路线17

该中间体在本合成路线中的序号:

Nibentan is obtained as illustrated in Scheme 22645801a: Phenylacetonitrile (I) is condensed with diethyl carbonate by means of sodium ethylate in toluene to give sodium (ethoxycarbonyl)cyanophenylmethanate (II). Subsequent alkylation of (II) with 1,4-dibromobutane provides 5-bromo-1-(ethoxycarbonyl)-1-cyano-1-phenylpentane (III). Treatment of (III) with diethylamine gives 1-(ethoxycarbonyl)-1-cyano-5-(diethylamino)-1-phenylpentane (IV), which is decarboxylated with aqueous KOH in the presence of triethylbenzylammonium chloride to 1-cyano-5-(diethylamino)-1-phenylpentane (V). The reaction of (V) with H2O2 in dimethylsulfoxide gives 1-carbamoyl-5-(diethylamino)-1-phenylpentane (VI), which is rearranged to 1-(methoxycarbonylamino)-5-(diethylamino)-1-phenylpentane (VII) according to Hoffman reaction by means of bromine and sodium methylate in methanol. Hydrolysis of (VII) with NaOH in ethanol provides amine (VIII). Subsequent coupling of (VIII) with 4-nitrobenzoyl chloride in acetonitrile yields nibentan.

1 Glushkov, R.G, Mashkovski, M.C.; Yuzhakov, S.D.; Nibentan. Drugs Fut 1997, 22, 1, 30.
2 L'vov, A.I.; Davydova, N.K.; Sizova, O.S.; Glushov, R.G.; Mashkovskiy, M.D.; Vinogradova, S.M.; Yurhakov, S.D.; Synthesis and antifibrillatory activity of nibentan and its analogues. Eur J Med Chem 2000, 35, 2, 205.
3 Glushkov, R.G.; Lvov, A.I.; Davidova, N.K.; Sizova, O.S.; Sanzarova, G.M.; Polakova, M.J.; Skachilova, S.J.; Zeltuchin, N.K.; Cherkasova, E.M.; The method of preparation of hydrochloride 1-phenyl-1-p-nitrobenzoylamino-5-N,N-diethylaminopentane and 1-phenyl-1-amino-5-N,N-diethylaminopentane. SU 2059612 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(I) 17046 Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide 140-29-4 C8H7N 详情 详情
(II) 17047 ethyl 2-cyano-2-phenylacetate 4553-07-5 C11H11NO2 详情 详情
(III) 17048 ethyl 6-bromo-2-cyano-2-phenylhexanoate C15H18BrNO2 详情 详情
(IV) 17049 ethyl 2-cyano-6-(diethylamino)-2-phenylhexanoate C19H28N2O2 详情 详情
(V) 17050 6-(diethylamino)-2-phenylhexanenitrile C16H24N2 详情 详情
(VI) 17051 6-(diethylamino)-2-phenylhexanamide C16H26N2O 详情 详情
(VII) 17052 methyl N-[5-(diethylamino)-1-phenylpentyl]carbamate C17H28N2O2 详情 详情
(VIII) 17053 N-(5-amino-5-phenylpentyl)-N,N-diethylamine; N(5),N(5)-diethyl-1-phenyl-1,5-pentanediamine C15H26N2 详情 详情

合成路线18

该中间体在本合成路线中的序号:(II)

Acylation of 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (I) with 4-nitrobenzoyl chloride (II) by means of TEA in CH2Cl2 gives 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (III), which is hydrogenated with H2 over Raney-Ni in MeOH, yielding the corresponding amine derivative (IV). Acylation of (IV) with biphenyl-2-carboxylic acid (V) by means of oxalyl chloride in CH2Cl2 affords the expected amide (VI) which is brominated with either Br2 or CuBr2, providing the alpha-bromo ketone (VII). This ketone (VII) is cyclized with acetamidine hydrochloride (VIII) by means of K2CO3 in MeCN, furnishing a mixture of conivaptan and oxazolo[4,5-d][1]benzodiazepine compound. Finally, conivaptan is separated by column chromatography over silica gel and is treated with 4N HCl to provide the desired hydrochloride.

1 Castañer, R.M.; Norman, P.; Rabasseda, X.; Leeson, P.A.; Castañer, J.; Conivaptan Hydrochloride. Drugs Fut 2000, 25, 11, 1121.
2 Tanaka, A.; Koshio, H.; Taniguchi, N.; Matsuhisa, A.; Sakamoto, K.; Yamazaki, A.; Yatsu, T. (Yamanouchi Pharmaceutical Co., Ltd.); Fused benzazepine deriv. and pharmaceutical compsn. containing the same. EP 0709386; JP 1995505056; US 5723606; WO 9503305 .
3 Koshio, H.; Taniguchi, N.; Tanaka, A.; Yatsu, T.; Matsuhisa, A.; Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: Synthesis and pharmacological properties of 4'-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanilide derivatives and 4'-(5,6-dihydro-4H-thiazolo[5,4-d][1]benzoaze. Chem Pharm Bull 2000, 48, 1, 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) 41810 1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C10H11NO 详情 详情
(II) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(III) 41811 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H14N2O4 详情 详情
(IV) 41812 1-(4-aminobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H16N2O2 详情 详情
(V) 18505 [1,1'-biphenyl]-2-carboxylic acid 947-84-2 C13H10O2 详情 详情
(VI) 41813 N-[4-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]phenyl][1,1'-biphenyl]-2-carboxamide C30H24N2O3 详情 详情
(VII) 41814 N-[4-[(4-bromo-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]phenyl][1,1'-biphenyl]-2-carboxamide C30H23BrN2O3 详情 详情
(VIII) 15866 ethanimidamide C2H6N2 详情 详情

合成路线19

该中间体在本合成路线中的序号:(I)

The reaction of 4-nitrobenzoyl chloride (I) with 3-chloropropylamine (II) by menas of triethylamine in dichloromethane gives the corresponding amide (III), which is then condensed with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of triethylamine in refluxing dichloromethane.

1 Nadler, G.M.M.G.; Martin, M.J.R. (SmithKline Beecham plc); Nitro-benzamides useful as anti-arrhythmic agents. EP 0788474; FR 2726267; JP 1998508013; US 5977179; WO 9613479 .
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 20781 3-chloro-1-propanamine; 3-chloropropylamine 14753-26-5 C3H8ClN 详情 详情
(III) 20782 N-(3-chloropropyl)-4-nitrobenzamide C10H11ClN2O3 详情 详情
(IV) 10098 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine 120-20-7 C10H15NO2 详情 详情

合成路线20

该中间体在本合成路线中的序号:(IV)

Thiocolchicine (II) was prepared from colchicine (I) by treatment with sodium methylthiolate. Then, hydrolysis of acetamide group with methanolic HCl afforded deacetyl thiocolchicine (III). Subsequent acylation with p-nitrobenzoyl chloride (IV) in the presence of pyridine provided amide (V), which was demethylated with excess BBr3 to give the corresponding triphenol (VI). Finally, esterification with acetyl chloride in the presence of pyridine and 4-(dimethylamino)pyridine furnished the target triacetate.

1 Guan, J.; et al.; Antitumor agents. 185. Synthesis and biological evaluation of tridemethylthiocolchicine analogues as novel topoisomerase II inhibitors. J Med Chem 1998, 41, 11, 1956.
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) 18479 N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide 64-86-8 C22H25NO6 详情 详情
(II) 18480 N-[(7S)-1,2,3-trimethoxy-10-(methylsulfanyl)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide C22H25NO5S 详情 详情
(III) 18481 (7S)-7-amino-1,2,3-trimethoxy-10-(methylsulfanyl)-6,7-dihydrobenzo[a]heptalen-9(5H)-one C20H23NO4S 详情 详情
(IV) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(V) 18483 4-nitro-N-[(7S)-1,2,3-trimethoxy-10-(methylsulfanyl)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]benzamide C27H26N2O7S 详情 详情
(VI) 18484 4-nitro-N-[(7S)-1,2,3-trihydroxy-10-(methylsulfanyl)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]benzamide C24H20N2O7S 详情 详情

合成路线21

该中间体在本合成路线中的序号:(IV)

Thiocolchicine (II) was prepared from colchicine (I) by treatment with sodium methylthiolate. Then, hydrolysis of acetamide group with methanolic HCl afforded deacetyl thiocolchicine (III). Subsequent acylation with p-nitrobenzoyl chloride (IV) in the presence of pyridine provided amide (V), which was demethylated with excess BBr3 to give the corresponding triphenol.

1 Guan, J.; et al.; Antitumor agents. 185. Synthesis and biological evaluation of tridemethylthiocolchicine analogues as novel topoisomerase II inhibitors. J Med Chem 1998, 41, 11, 1956.
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) 18479 N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide 64-86-8 C22H25NO6 详情 详情
(II) 18480 N-[(7S)-1,2,3-trimethoxy-10-(methylsulfanyl)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide C22H25NO5S 详情 详情
(III) 18481 (7S)-7-amino-1,2,3-trimethoxy-10-(methylsulfanyl)-6,7-dihydrobenzo[a]heptalen-9(5H)-one C20H23NO4S 详情 详情
(IV) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(V) 18483 4-nitro-N-[(7S)-1,2,3-trimethoxy-10-(methylsulfanyl)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]benzamide C27H26N2O7S 详情 详情

合成路线22

该中间体在本合成路线中的序号:(XII)

The bromination of styrene (II) with N-bromosuccinimide in the presence of cyanamide (I) provided 2-bromo-1-phenylethylcyanamide (III). Further addition of MeOH to (III) in the presence of HCl, followed by Na2CO3-promoted cyclization, produced the methoxyimidazoline (IV). Acylation of indoline (V) with trifluoroacetic anhydride and pyridine gave amide (VI) and subsequent chlorosulfonation yielded sulfonyl cloride (VII). This acid chloride was coupled to imidazoline (IV) in the presence of NaHCO3 in aqueous acetone to furnish a mixture of sulfonyl imidazolines (VIII) and (IX). The major isomer (IX) was isolated by column chromatography, and then, hydrolysis with HCl in MeOH at r.t. provided imidazolidinone (X). The trifluoroacetamide group of (X) was further hydrolyzed by treatment with NaOH in aqueous MeOH to give (XI). Subsequent condensation of (XI) with 4-nitrobenzoyl chloride (XII) in the presence of pyridine yielded 4-nitrobenzamide (XIII), which was finally reduced to the aminobenzamide by hydrogenation using Raney-nickel as the catalyst.

1 Jung, S.-H.; Lee, H.S.; Song, J.S.; Kim, H.M.; Han, S.B.; Lee, C.W.; Lee, M.; Choi, D.R.; Lee, J.A.; Chung, Y.H.; Yoon, S.J.; Moon, E.Y.; Hwang, H.S.; Seong, S.K.; Lee, D.K.; Synthesis and antitumor activity of 4-phenyl-1-arylsulfonyl imidazolidinones. Bioorg Med Chem Lett 1998, 8, 12, 1547.
2 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 .
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) 19648 Cyanamide 420-04-2 CH2N2 详情 详情
(II) 19649 1-vinylbenzene 100-42-5 C8H8 详情 详情
(III) 19650 2-bromo-1-phenylethylcyanamide C9H9BrN2 详情 详情
(IV) 19651 methyl 5-phenyl-4,5-dihydro-1H-imidazol-2-yl ether; 2-methoxy-5-phenyl-4,5-dihydro-1H-imidazole C10H12N2O 详情 详情
(V) 19652 indoline 496-15-1 C8H9N 详情 详情
(VI) 19653 1-(2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoro-1-ethanone C10H8F3NO 详情 详情
(VII) 19654 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride C10H7ClF3NO3S 详情 详情
(VIII) 19655 2,2,2-trifluoro-1-[5-[(2-methoxy-5-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone C20H18F3N3O4S 详情 详情
(IX) 19656 2,2,2-trifluoro-1-[5-[(2-methoxy-4-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone C20H18F3N3O4S 详情 详情
(X) 19657 4-phenyl-1-[[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-2-imidazolidinone C19H16F3N3O4S 详情 详情
(XI) 19658 1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone C17H17N3O3S 详情 详情
(XII) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(XIII) 19660 1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone C24H20N4O6S 详情 详情

合成路线23

该中间体在本合成路线中的序号:(XII)

A synthesis of the (S)-enantiomer of the target compound has also been reported, starting from (S)-1-phenylethanolamine (XIV). Treatment with phenyl chloroformate (XV) and NaHCO3 yielded carbamate (XVI). Subsequent reaction of (XVI) with methanesulfonyl chloride and Et3N provided mesylate (XVII). The sulfonamide (XVIII) was prepared from sulfonyl chloride (VII) by treatment with ammonia gas in CH2Cl2. Condensation of this sulfonamide with mesylate (XVII) in the presence of NaH produced the chiral imidazolidinone (XIX). Finally, the target compound was obtained by condensation with 4-nitrobenzoyl chloride (XII), followed by reduction with H2 in the presence of Raney-Ni.

1 Jung, S.-H.; Lee, H.S.; Song, J.S.; Kim, H.M.; Han, S.B.; Lee, C.W.; Lee, M.; Choi, D.R.; Lee, J.A.; Chung, Y.H.; Yoon, S.J.; Moon, E.Y.; Hwang, H.S.; Seong, S.K.; Lee, D.K.; Synthesis and antitumor activity of 4-phenyl-1-arylsulfonyl imidazolidinones. Bioorg Med Chem Lett 1998, 8, 12, 1547.
2 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 19654 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride C10H7ClF3NO3S 详情 详情
(XII) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(XIV) 10973 (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol 20989-17-7 C8H11NO 详情 详情
(XV) 13580 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate 1885-14-9 C7H5ClO2 详情 详情
(XVI) 19663 phenyl (1S)-2-hydroxy-1-phenylethylcarbamate C15H15NO3 详情 详情
(XVII) 19664 (2S)-2-[(phenoxycarbonyl)amino]-2-phenylethyl methanesulfonate C16H17NO5S 详情 详情
(XVIII) 19665 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonamide C10H9F3N2O3S 详情 详情
(XIX) 19666 (4S)-1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone C17H17N3O3S 详情 详情
(XX) 19667 (4S)-1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone C24H20N4O6S 详情 详情

合成路线24

该中间体在本合成路线中的序号:(IX)

Protection of indoline (I) using trifluoroacetic anhydride provided N-trifluoroacetylindoline (II), which was sulfonated with chlorosulfonic acid to give sulfonyl chloride (III). Further treatment with ammonia in CH2Cl2 produced sulfonamide (IV). Phenylglycinol (V) was condensed with phenyl chloroformate to afford carbamate (VI). Subsequent reaction of (VI) with metanesulfonyl chloride and triethylamine yielded mesylate (VII). The condensation of sulfonamide (IV) with mesylate (VII), with concomitant cyclization of carbamate group and trifluoroacetyl deprotection, furnished imidazolone (VIII). This was further condensed with 4-nitrobenzoyl chloride (IX), and the resulting 4-nitrobenzamide (X) was finally reduced to the target aminobenzamide by hydrogenation over Raney Nickel.

1 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13580 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate 1885-14-9 C7H5ClO2 详情 详情
(I) 19652 indoline 496-15-1 C8H9N 详情 详情
(II) 19653 1-(2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoro-1-ethanone C10H8F3NO 详情 详情
(III) 19654 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride C10H7ClF3NO3S 详情 详情
(IV) 19665 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonamide C10H9F3N2O3S 详情 详情
(V) 10973 (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol 20989-17-7 C8H11NO 详情 详情
(VI) 19663 phenyl (1S)-2-hydroxy-1-phenylethylcarbamate C15H15NO3 详情 详情
(VII) 19664 (2S)-2-[(phenoxycarbonyl)amino]-2-phenylethyl methanesulfonate C16H17NO5S 详情 详情
(VIII) 19666 (4S)-1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone C17H17N3O3S 详情 详情
(IX) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(X) 19667 (4S)-1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone C24H20N4O6S 详情 详情

合成路线25

该中间体在本合成路线中的序号:(II)

1-Adamantanol (I) was esterified with 4-nitrobenzoyl chloride (II) in the presence of pyridine, yielding adamantanyl 4-nitrobenzoate (III). After catalytic hydrogenation of the nitro group of (III), the resultant aniline (IV) was condensed with 2,5-dihydroxybenzaldehyde (V) to afford the corresponding Schiff base (VI). Subsequent hydrogenation of the imine double bond of (VI) over Pd/C gave rise to the target amine.

1 Narayanan, V.L.; Sausville, E.A.; Kaur, G.; Varma, R.K. (US Department of Health & Human Services); Disubstd. lavendustin A analogs and pharmaceutical compsns. comprising the analogs. EP 1060160; WO 9943636 .
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) 52642 1-Adamantanol; 1-Hydroxyadamantane; Tricyclo[3.3.1.1]decan-1-ol 768-95-6 C10H16O 详情 详情
(II) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(III) 52643 tricyclo[3.3.1.1~3,7~]dec-1-yl 4-nitrobenzoate C17H19NO4 详情 详情
(IV) 52644 tricyclo[3.3.1.1~3,7~]dec-1-yl 4-aminobenzoate C17H21NO2 详情 详情
(V) 52645 5-Hydroxysalicylaldehyde; Gentisinaldehyde; 2,5-Dihydroxybenzaldehyde 1194-98-5 C7H6O3 详情 详情
(VI) 52646 tricyclo[3.3.1.1~3,7~]dec-1-yl 4-{[(2,5-dihydroxyphenyl)methylidene]amino}benzoate C24H25NO4 详情 详情

合成路线26

该中间体在本合成路线中的序号:(II)

Treatment of substituted aminobenzoate (I) with 4-nitrobenzoyl chloride (II) affords amide (III), whose nitro group is converted into an amino group by hydrogenation over Pd/C, providing compound (IV). Finally, reaction of aniline (IV) with isocyanate (V) furnishes the target product.

1 Hayashi, H.; Goto, Y.; Isobe, Y.; Misawa, S.; Ogita, H.; Sekine, R.; Takaku, H.; Synthesis and structure-activity relationship of inhibitor on smooth muscle cell proliferation induced by PDGF. 19th Symp Med Chem (Nov 17 1999, Tokyo) 1999, Abst 1P-03.
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) 47630 ethyl 2-amino-4,5-dimethoxybenzoate C11H15NO4 详情 详情
(II) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(III) 47631 ethyl 4,5-dimethoxy-2-[(4-nitrobenzoyl)amino]benzoate C18H18N2O7 详情 详情
(IV) 47632 ethyl 2-[(4-aminobenzoyl)amino]-4,5-dimethoxybenzoate C18H20N2O5 详情 详情
(V) 47633 4-isocyanatoaniline; 4-isocyanatophenylamine C7H6N2O 详情 详情

合成路线27

该中间体在本合成路线中的序号:(I)

4-Nitrobenzoyl chloride (I) was condensed with tert-butyl amine to give amide (II). The nitro group of (II) was then reduced to aniline (III) by transfer hydrogenation with hydrazine and Pd/C. Finally, acylation of (III) with acetyl chloride provided the title acetamide.

1 Sorbera, L.A.; Castañer, J.; Leeson, P.A.; CPI-1189. Drugs Fut 2001, 26, 7, 647.
2 Flitter, W.D.; Irwin, I.; Garland, W.A. (Centaur Pharmaceuticals, Inc.); Benzamide therapeutics for the treatment of inflammatory bowel disease. WO 9959569 .
3 Garland, W.A.; Wilcox, A.L.; Paylor, R.E.; Flitter, W.D. (Centaur Pharmaceuticals, Inc.); Benzamides for neurodegenerative disorder treatment. US 5955506; WO 9631462 .
4 Garland, W. (Centaur Pharmaceuticals, Inc.); Benzamide treatment of dementia, associated with AIDS virus (HIV-1) infection. WO 9738684 .
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 38444 N-(tert-butyl)-4-nitrobenzamide C11H14N2O3 详情 详情
(III) 38445 4-amino-N-(tert-butyl)benzamide C11H16N2O 详情 详情

合成路线28

该中间体在本合成路线中的序号:(I)

The acylation of piperazine (II) with 4-nitrobenzoyl chloride (I) afforded a mixture of monoacylated (III) and diacylated (IV) products, which were separated by chromatography. Subsequent alkylation of monosubstituted piperazine (III) with 4-nitrophenethyl bromide (V) in the presence of K2CO3 and NaI yielded the title compound.

1 Kanojia, R.M.; Kauffman, J.; Salata, J.J.; Synthesis and class III type antiarrhythmic activity of 4-aroyl (and aryl)-1-aralkylpiperazines. Bioorg Med Chem Lett 2000, 10, 24, 2819.
2 Kanojia, R.M.; et al.; Synthesis and selective class III type antiarrhythmic activity of 4-aroyl (and aryl)-1-aralkylpiperazines. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 204.
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 20011 (4-nitrophenyl)(1-piperazinyl)methanone C11H13N3O3 详情 详情
(IV) 40947 [4-(4-nitrobenzoyl)-1-piperazinyl](4-nitrophenyl)methanone C18H16N4O6 详情 详情
(V) 19191 1-(2-bromoethyl)-4-nitrobenzene 5339-26-4 C8H8BrNO2 详情 详情

合成路线29

该中间体在本合成路线中的序号:(VI)

Coupling between 4-nitrobenzoyl chloride (VI) and 4-aminobenzoic acid (VII) afforded nitrobenzamide (VIII), which was further reduced to amine (IX) by catalytic hydrogenation over Pd/C. Acylation of (IX) with phthalimidoacetyl chloride (X) yielded diamide (XI). The carboxyl group of (XI) was then activated as the corresponding acid chloride (XII) by treatment with SOCl2. Then, condensation of the glycylamide derivative (XIII) with acid chloride (XII) furnished amide (XIV).

1 Rousseaux, O.; Simonot, C. (Guerbet SA); Gadolinium complex tetramides and use in medical imaging. EP 1178975; FR 2793795; WO 0071526 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(VII) 20004 p-aminobenzoic acid; 4-aminobenzoic acid 150-13-0 C7H7NO2 详情 详情
(VIII) 56045 4-[(4-nitrobenzoyl)amino]benzoic acid C14H10N2O5 详情 详情
(IX) 56046 4-[(4-aminobenzoyl)amino]benzoic acid C14H12N2O3 详情 详情
(X) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(XI) 56047 4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoic acid C24H17N3O6 详情 详情
(XII) 56048 4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoyl chloride C24H16ClN3O5 详情 详情
(XIII) 56049 5-[(2-aminoacetyl)amino]-2,4,6-tribromo-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide C34H57Br3N4O23 详情 详情
(XIV) 56050 2,4,6-tribromo-5-{[2-({4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoyl}amino)acetyl]amino}-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide C58H72Br3N7O28 详情 详情

合成路线30

该中间体在本合成路线中的序号:(II)

Acylation of the anilino ester (I) with 4-nitrobenzoyl chloride (II) affords amide (III). After reduction of the 4-nitrobenzamide (III) by catalytic hydrogenation, the resultant amine (IV) is condensed with (2-ethyl-1-imidazolyl)benzoyl chloride (V) to furnish diamide (VI). Subsequent ester group saponification in (VI) gives acid (VII). This is finally coupled with N-methylpiperazine (VIII) in the presence of EDC and HOBt to produce the title compound.

1 Kakefuda, A.; Kusayama, T.; Tahara, A.; Tsukamoto, S.-I.; Tsukada, J.; N-Methylbenzanilide derivatives as a novel class of selective V1A receptor antagonists. Bioorg Med Chem Lett 2002, 12, 2, 229.
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) 57789 ethyl 6-[5-methyl-2-(methylamino)phenoxy]hexanoate C16H25NO3 详情 详情
(II) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(III) 57790 ethyl 6-{5-methyl-2-[methyl(4-nitrobenzoyl)amino]phenoxy}hexanoate C23H28N2O6 详情 详情
(IV) 57791 ethyl 6-{2-[(4-aminobenzoyl)(methyl)amino]-5-methylphenoxy}hexanoate C23H30N2O4 详情 详情
(V) 57792 2-(2-ethyl-1H-imidazol-1-yl)benzoyl chloride C12H11ClN2O 详情 详情
(VI) 57793 ethyl 6-{2-[(4-{[2-(2-ethyl-1H-imidazol-1-yl)benzoyl]amino}benzoyl)(methyl)amino]-5-methylphenoxy}hexanoate C35H40N4O5 详情 详情
(VII) 57794 6-{2-[(4-{[2-(2-ethyl-1H-imidazol-1-yl)benzoyl]amino}benzoyl)(methyl)amino]-5-methylphenoxy}hexanoic acid C33H36N4O5 详情 详情
(VIII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线31

该中间体在本合成路线中的序号:(II)

Condensation of 2-aminothiophenol (I) with 4-nitrobenzoyl chloride (II) produces the benzothiazole (III). Reduction of the nitro group of (III) by means of SnCl2 in refluxing EtOH yields aniline (IV). Then, alkylation of (IV) with 11C-labeled iodomethane gives rise to the target 11C-methylated aniline.

1 Mathis, C.A.; et al.; A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett 2002, 12, 3, 295.
2 Wang, Y.; Klunk, W.E.; Mathis, C.A. Jr. (University of Pittsburgh); Thioflavin derivs. for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition. WO 0216333 .
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) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(II) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(III) 58508 2-(4-nitrophenyl)-1,3-benzothiazole C13H8N2O2S 详情 详情
(IV) 58509 4-(1,3-benzothiazol-2-yl)aniline; 4-(1,3-benzothiazol-2-yl)phenylamine C13H10N2S 详情 详情

合成路线32

该中间体在本合成路线中的序号:(X)

The cyclization of 2-oxoacetic acid ethyl ester (I), 1-phenylethylamine (II) and cyclopentadiene (III) by means of BF3 and TFA in dichloromethane gives the 2-azabicyclo[2.2.1]heptene (IV), which is debenzylated with H2 over Pd/C in ethanol to yield 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylic acid ethyl ester (V) The acylation of (V) with 5-chloro-2-nitrobenzoyl chloride (VI) and TEA in dichloromethane affords the bicyclic amide (VII), which is submitted to a reductive cyclization with Fe in refluxing acetic acid to afford the polycyclic benzodiazepinedione (VIII). The reduction of the carbonyl groups of (VIII) by means of LiAlH4 in THF provides the benzodiazepine (IX), which is acylated with 4-nitrobenzoyl chloride (X) and TEA in dichloromethane to give the polycyclic amide (XI). The reduction of the nitro group of (XI) with Zn and NH4Cl in refluxing methanol yields the corresponding amino derivative (XII), which is finally acylated with 4'-methylbiphenyl-2-carbonyl chloride (XIII) and TEA in dichloromethane to furnish the target polycyclic benzodiazepine.

1 Dyatkin, A.B.; Demarest, K.; Look, R.; Maryanoff, B.E.; Hoekstra, W.J.; Gunnet, J.; Andrade-Gordon, P.; DeGaravilla, L.; Hlasta, D.J.; Structurally novel V2-selective and dual V1A/V2 vasopressin receptor antagonists. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 35.
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) 48591 Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester 924-44-7 C4H6O3 详情 详情
(II) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(III) 15148 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine 618-36-0 C8H11N 详情 详情
(IV) 54051 ethyl 2-(1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate n/a C17H21NO2 详情 详情
(V) 54052 ethyl 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate n/a C9H13NO2 详情 详情
(VI) 44133 5-chloro-2-nitrobenzoyl chloride C7H3Cl2NO3 详情 详情
(VII) 54053 ethyl 2-(5-chloro-2-nitrobenzoyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate n/a C16H15ClN2O5 详情 详情
(VIII) 54054 6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraene-3,11-dione n/a C14H11ClN2O2 详情 详情
(IX) 54055 6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraene n/a C14H15ClN2 详情 详情
(X) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(XI) 54056 (6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraen-10-yl)(4-nitrophenyl)methanone n/a C21H18ClN3O3 详情 详情
(XII) 54057 (4-aminophenyl)(6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraen-10-yl)methanone n/a C21H20ClN3O 详情 详情
(XIII) 54058 4'-methyl[1,1'-biphenyl]-2-carbonyl chloride n/a C14H11ClO 详情 详情

合成路线33

该中间体在本合成路线中的序号:(IV)

 

1 Shi ZH, DingJ,Ning Q,et al.2003.Synthesis of balsalazide sodium中国医药工业杂志,34r 537~538
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(V) 66154 3-(4-nitrobenzamido)propanoic acid   C10H10N2O5 详情 详情
(VI) 17022 beta-Alanine; 3-aminopropionic acid 107-95-9 C3H7NO2 详情 详情
(VII) 30566 N-(4-aminobenzoyl)-beta-alanine 7377-08-4 C10H12N2O3 详情 详情

合成路线34

该中间体在本合成路线中的序号:(XII)

 

1 Tsunoda T, Tanaka A, et al.2004.Anew synthetic route to YM087, an argirune asopressin antagonist.Heterocycles, 63: 1113---1122
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 14763 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H17NO3S 详情 详情
(I) 11161 methyl 2-aminobenzoate; Methyl anthranilate 134-20-3 C8H9NO2 详情 详情
(II) 66212 methyl 2-(4-methylphenylsulfonamido)benzoate   C15H15NO4S 详情 详情
(III) 66213 methyl 2-(N-(3-cyanopropyl)-4-methylphenylsulfonamido)benzoate   C19H20N2O4S 详情 详情
(IV) 66214 4-ethynyl-1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one   C19H17N2O3S 详情 详情
(VI) 41815 4-bromo-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H16BrNO3S 详情 详情
(VII) 41816 2-methyl-6-[(4-methylphenyl)sulfonyl]-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine C19H19N3O2S 详情 详情
(VIII) 41817 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine 318237-73-9 C12H13N3 详情 详情
(IX) 41818 [2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl](4-nitrophenyl)methanone C19H16N4O3 详情 详情
(X) 41819 (4-aminophenyl)[2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl]methanone C19H18N4O 详情 详情
(XII) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
Extended Information