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【结 构 式】

【分子编号】15649

【品名】2-amino-6-nitrobenzaldehyde

【CA登记号】

【 分 子 式 】C7H6N2O3

【 分 子 量 】166.13632

【元素组成】C 50.61% H 3.64% N 16.86% O 28.89%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XV)

9-Amino-20(RS)-camptothecin is obtained as follows: The cyclization of cyanoacetamide (I) with 2-ethoxy-4-oxo-2-pentenoic acid ethyl ester (II) by means of K2CO3 in hot DMF gives the intermediate pyridone (III), which without isolation is cyclized again with methyl acrylate (IV) in the same conditions affording the indolizinone (V). The treatment of (V) with concentrated HCl in refluxing acetic acid gives the indolizinedione (VI), which is treated with ethylene glycol and trimethylsilyl chloride in dichloromethane to yield the ethylene ketal (VII). The carboxylation of (VII) with diethyl carbonate and KH in refluxing toluene affords the acetic ester derivative (VIII), which is alkylated with ethyl iodide and potassium tert-butoxide in anhydrous DME to the corresponding butyric ester derivative (IX). The reductive acetylation of (IX) with H2 over RaNi in acetic anhydride gives the acetamide derivative (X), which is treated with NaNO2 in acetic acid to yield the corresponding N-nitroso compound (XI). Thermal degradation of (XI) in refluxing CCl4 affords the acetoxymethyl compound (XII), which is submitted to a oxidative cyclization with O2 in methanol/K2CO3 to give the tetracyclic ketal (XIII). Hydrolysis of the ketal group of (XIII) with 2N H2SO4 in hot DME yields the tricyclic triketone (XIV), which is further cyclized with 2-amino-6-nitrobenzaldehyde (XV) by heating at 160 C to afford 9-nitro-20(RS)-camptothecin (XVI). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol. The title product can also be obtained by direct cyclization of tricyclic triketone (XIV) with 2,6-diaminobenzaldehyde (XVII) in the same conditions.

1 Sinai, B.K.; Palmer, K.H.; McPhail, A.T.; Sim, G.A.; Topoisomerase inhibitors. A review of their therapeutic potential in cancer. Drugs 1995, 49, 11-19.
2 Wall, M.E.; Wani, M. (Research Triangle Institute); Camptothecin analogs as potent inhibitors of colorectal cancer. EP 0497910; JP 1993508619; US 5106742; WO 9105556 .
3 Wall, M.E.; Wani, M.C.; Nicholas, A.W.; Manikumar, G. (Research Triangle Institute); Synthesis of camptothecin and analogs thereof. WO 9003169 .
4 Wall, M.E.; Wani, M.C.; Nicholas, A.W.; Manikumar, G. (Res. Triangle Inst.); Camptothecin and analogues thereof and pharmaceutical compsns and method using them. US 5122526 .
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) 12122 Cyanoacetamide; 2-Cyanoacetamide 107-91-5 C3H4N2O 详情 详情
(II) 15636 ethyl (Z)-2-ethoxy-4-oxo-2-pentenoate C9H14O4 详情 详情
(III) 15637 ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydro-2-pyridinecarboxylate C10H10N2O3 详情 详情
(IV) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(V) 15639 methyl 6-cyano-1-hydroxy-7-methyl-5-oxo-3,5-dihydro-2-indolizinecarboxylate C12H10N2O4 详情 详情
(VI) 15640 7-methyl-1,5-dioxo-1,2,3,5-tetrahydro-6-indolizinecarbonitrile C10H8N2O2 详情 详情
(VII) 15641 7'-Methyl-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-6'-ylcarbonitrile C12H12N2O3 详情 详情
(VIII) 15642 2-[6'-Cyano-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]acetic acid ethyl ester C15H16N2O5 详情 详情
(IX) 15643 2-[6'-Cyano-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester C17H20N2O5 详情 详情
(X) 15644 2-[6'-(Acetamidomethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester C19H26N2O6 详情 详情
(XI) 15645 2-[6'-(N-Nitrosoacetamidomethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester C19H25N3O7 详情 详情
(XII) 15646 2-[6'-(Acetoxymethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester C19H25NO7 详情 详情
(XIII) 15647 4'-Ethyl-4'-hydroxy-3',4',6',7',8',10'-hexahydro-1'H-spiro[1,3-dioxole-2,6'-pyrano[3,4-f]indolizine]-3',10'-dione C15H17NO6 详情 详情
(XIV) 63309 (?-beta-methoxydiisopinocamphenylborane 85134-98-1 C13H13NO5 详情 详情
(XV) 15649 2-amino-6-nitrobenzaldehyde C7H6N2O3 详情 详情
(XVI) 15650 4-ethyl-4-hydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C20H15N3O6 详情 详情
(XVII) 15651 2,6-diaminobenzaldehyde C7H8N2O 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VI)

This compound can be obtained in two different ways: 1) By direct nitration of camptothecin (I) with nitric acid in sulfuric acid. 2) By direct nitration of camptothecin (I) with different inorganic nitrates (or mixtures of inorganic nitrates) in sulfuric acid. 3) The reaction of 2,6-dinitrobenzaldehyde (II) with ethylene glycol (III) and p-toluenesulfonic acid in refluxing toluene gives the corresponding ethylene ketal (IV), which is reduced with sodium sulfide in refluxing ehanol/water yielding 2-amino-6-nitrobenzaldehyde ethylene ketal (V). The hydrolysis of (V) with aqueous sulfuric acid affords 2-amino-6-nitrobenzaldehyde (VI), which is finally cyclized with the tricyclic ketone (VII) in refluxing acetic acid (the same cyclization can be performed with the ketal (V) and the ketone (VII).

1 Cao, Z.S.; et al.; Nitration of campothecin with various inorganic nitrate salts in concentrated sulfuric acid: A new preparation of anticancer drug 9-nitrocamptothecin. Synthesis 1998, 12, 1724.
2 Sawada, S.; Matsuoka, S.-I.; Nokata, K.-I.; Nagata, H.; Furuta, T.; Yokokura, T.; Miyasaka, T.; Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins. Chem Pharm Bull 1991, 39, 12, 3183.
3 Wani, M.C.; Nicholas, A.W.; Wall, M.E.; Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues. J Med Chem 1986, 29, 11, 2358.
4 Leitner, P.; Tele, C.; Truesdale, A.; Nicholas, A.W.; Moore, L.; Besterman, J.M.; Manikumar, G.; Wani, M.C.; Wall, M.E.; Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs. J Med Chem 1993, 36, 18, 2689.
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) 10816 Camptothecin; (4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-et-4-hydroxy-1,12-dihydro-4h-2-oxa-6,12a-diaza-dibenzo(b,h)fluorene-3,13-dione 7689-03-4 C20H16N2O4 详情 详情
(II) 39891 2,6-dinitrobenzaldehyde 606-31-5 C7H4N2O5 详情 详情
(III) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IV) 39892 2-(2,6-dinitrophenyl)-1,3-dioxolane C9H8N2O6 详情 详情
(V) 39893 2-(1,3-dioxolan-2-yl)-3-nitrophenylamine; 2-(1,3-dioxolan-2-yl)-3-nitroaniline C9H10N2O4 详情 详情
(VI) 15649 2-amino-6-nitrobenzaldehyde C7H6N2O3 详情 详情
(VII) 10841 (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione C13H13NO5 详情 详情
Extended Information