Tocladesine, Adenazole, ICN-1256, NSC-614491, 8-Cl-cAMP, -Drug Synthesis Database

【结构式】

【药物名称】Tocladesine, Adenazole, ICN-1256, NSC-614491, 8-Cl-cAMP

【化学名称】8-Chloroadenosine-3',5'-O-monophosphate

【CA登记号】41941-56-4

【分子式】C₁₀H₁₁ClN₅O₆P

【分子量】363.65587

【开发单位】Cancer Research UK (Originator), National Cancer Institute (Originator), Ribapharm (Originator)

【药理作用】Colorectal Cancer Therapy, Oncolytic Drugs

合成路线1 合成路线2

合成路线1

Direct chlorination of adenosine 3',5'-cyclic phosphate (I) was carried out by treatment with anhydrous HCl and m-chloroperbenzoic acid (m-CPBA) in DMF or with N-chlorosuccinimide and NaCl in aqueous HOAc. Chlorination of adenosine (II) was achieved by treatment with HCl in the presence of m-CPBA or in the absence of the oxidating reagent m-CPBA at a higher temperature and longer reaction times. The resultant 8-chloroadenosine (III) was converted to the monophosphate (IV) by means of POCl3, and this was further cyclized to the title compound using DCC. 8-Chloroadenosine monophosphate (IV) was also accessible by chlorination of adenosine monophosphate (V). Optionally, the chlorinated adenosine (III) was directly converted to the title cyclic phosphate by phosphorylation with POCl3 in the presence of NaOH in triethyl phosphate as the solvent.

参考文献中间体

【1】 Woo, N.-T.; et al.; The facile and efficient synthesis of 8-chloroadenosine 3',5'-cyclic monophosphate by phosphorylative cyclization of 8-chloroadenosine and its characterization by 1H and 13C NMR spectroscopy. Arch Pharmacal Res 1997, 20, 2, 176.
【2】 Robins, R.K.; Revankar, G.R.; Chang, Y. (Nucleic Acid Res. Inst., Costa Mesa); Treatment of malignant tumours with 8-chloroadenosine 3'-5'-cyclic phosphate, 8-aminoadenosine 3',5'-cyclic phosphate and preparation thereof. EP 0499291; WO 8905648 .

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)	28980	(4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-2,7-dihydroxytetrahydro-4H-2lambda(5)-furo[3,2-d][1,3,2]dioxaphosphinin-2-one	60-92-4	C₁₀H₁₂N₅O₆P	详情	详情
(II)	11988	Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol	58-61-7	C₁₀H₁₃N₅O₄	详情	详情
(III)	59293	(3R,4S,5R)-2-(6-amino-8-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol		C₁₀H₁₂ClN₅O₄	详情	详情
(IV)	59294	[(2R,3S,4R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl dihydrogen phosphate		C₁₀H₁₃ClN₅O₇P	详情	详情
(V)	59295	[(2R,3S,4R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl dihydrogen phosphate		C₁₀H₁₄N₅O₇P	详情	详情

合成路线2

The title chloro derivative was also obtained by halogen exchange of the previously reported 8-bromoadenosine cyclic phosphate (VI) with CaCl2 in hot DMF. Alternatively, the 8-thioadenosine derivative (VII) was converted into the target compound by treatment with elemental chlorine in methanolic HCl at -15 C.

参考文献中间体

【1】 Muneyama, K.; et al.; Synthesis and biological activity of 8-haloadenosine 3',5'-cyclic phosphates. J Carbohydr Nucleosides Nucleotides 1974, 1, 1, 55.
【2】 Robins, R.K.; Revankar, G.R.; Chang, Y. (Nucleic Acid Res. Inst., Costa Mesa); Treatment of malignant tumours with 8-chloroadenosine 3'-5'-cyclic phosphate, 8-aminoadenosine 3',5'-cyclic phosphate and preparation thereof. EP 0499291; WO 8905648 .

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)	59296	(4aR,7R,7aS)-6-(6-amino-8-bromo-9H-purin-9-yl)-2,7-dihydroxytetrahydro-4H-2lambda~5~-furo[3,2-d][1,3,2]dioxaphosphinin-2-one		C₁₀H₁₁BrN₅O₆P	详情	详情
(VII)	59297	(4aR,7R,7aS)-6-(6-amino-8-sulfanyl-9H-purin-9-yl)-2,7-dihydroxytetrahydro-4H-2lambda~5~-furo[3,2-d][1,3,2]dioxaphosphinin-2-one		C₁₀H₁₂N₅O₆PS	详情	详情

Extended Information