Edelfosine, Ro-14-5243, (?-ET-18-OMe, (?-ET-18-OCH3, -Drug Synthesis Database

【结构式】

【药物名称】Edelfosine, Ro-14-5243, (?-ET-18-OMe, (?-ET-18-OCH3

【化学名称】(±)-1-O-Octadecyl-2-O-methyl-rac-glycero-3-phosphocholine
　　　　　　(±)-4-Hydroxy-7-methoxy-N,N,N-trimethyl-3,5,9-trioxa-4-phosphaheptacosan-1-aminium hydroxide inner salt, 4-oxide

【CA登记号】70641-51-9

【分子式】C₂₇H₅₈NO₆P

【分子量】523.74021

【开发单位】Max-Planck-Gesellschaft (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Antileishmanials, Oncolytic Drugs, Treatment of Protozoal Diseases, CoA-Independent Transacyclase (CoA-IT) Inhibitors

合成路线1 合成路线2

合成路线1

Two different routes have been described for the preparation of Et-18-OCH3: 1) The methylation of 1,3-benzylideneglycerol (I) with methyl iodide and KOH gives 1,3-benzytidene-2-O-methylglycerol (II), which is hydrolyzed with HCl to 2-O-methylglycerol (III). The condensation of (III) with octadecyl bromide (IV) and KOH in DMSO/THF yields 1-O-octadecyl-2-O-methyl-(rac)-glycerol (V), which by reaction with phosphorodichloric acid 2-bromoethyl ester (VI) and pyridine is converted to 3-octadecyloxy-2-methoxypropyl bromoethyl phosphate (VII). Finally, this compound is converted to Et-18-OCH3 with trimethylamine (VIII) in toluene and treated with silver carbonate to remove traces of bromide. 2) The reaction of 1,2-isopropylidene-sn-glycerol (IX) with benzyl bromide (X) and NaNH2 in benzene gives 1,2-isopropylidene-3-O-benzyl-sn-glycerol (XI), which is hydrolyzed with acetic acid to 3-O-benzyl-sn-glycerol (XII). The etherification of (XII) with (IV) as before or with NaNH2 gives 1-O-octadecyl-3-O-benzyl-sn-glycerol (XIII), which is methylated with methyl iodide and NaNH2 in dioxane to give 1-O-octadecyl-2-O-methyl-3-O-benzyl-sn-glycerol (XIV). Finally, this compound is debenzytaled by hydrogenolysis with H2 over Pd/C in petroleum ether to form (V), an intermediate previously described above.

参考文献中间体

【1】 Tsutsumi, H.; Kamata, T.; Nakajima, K.; Katagi, M.; Tsuchihashi, H.; Nishioka, H.; Nishikawa, M.; Miki, A.; Tatsuno, M.; Chem Phys Lipids 1982, 30, 9, 389-392.
【2】 Fast, L.D.; et al.; Chem Pharm Bull 1982, 30, 9, 3260-3270.
【3】 Castaner, R.M.; Castaner, J.; Serradell, M.N.; ET-18-OCH3. Drugs Fut 1987, 12, 4, 341.

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)	28795	2-phenyl-1,3-dioxan-5-ol	1708-40-3	C₁₀H₁₂O₃	详情	详情
(II)	28796	5-methoxy-2-phenyl-1,3-dioxane		C₁₁H₁₄O₃	详情	详情
(III)	13579	2-Methoxy-1,3-propanediol		C₄H₁₀O₃	详情	详情
(IV)	28797	1-bromooctadecane	112-89-0	C₁₈H₃₇Br	详情	详情
(V)	28798	2-methoxy-3-(octadecyloxy)-1-propanol		C₂₂H₄₆O₃	详情	详情
(VI)	13033	Dichlorophosphoric acid 2-bromoethyl ester		C₂H₄BrCl₂O₂P	详情	详情
(VII)	28799	2-bromoethyl 2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate		C₂₄H₅₀BrO₆P	详情	详情
(IX)	16476	2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane; (2,2-dimethyl-1,3-dioxolan-4-yl)methanol; 2,3-o-Isopropylideneglycerol	100-79-8	C₆H₁₂O₃	详情	详情
(X)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(XI)	28800	benzyl 2,2-dimethyl-1,3-dioxolan-4-yl ether		C₁₂H₁₆O₃	详情	详情
(XII)	28801	1-(benzyloxy)-1,2-ethanediol		C₉H₁₂O₃	详情	详情
(XIII)	28802	1-(benzyloxy)-2-(octadecyloxy)-1-ethanol		C₂₇H₄₈O₃	详情	详情
(XIV)	28803	1-[[1-methoxy-2-(octadecyloxy)ethoxy]methyl]benzene		C₂₈H₅₀O₃	详情	详情

合成路线2

The reaction of (R)-O-benzylglycidol (I) with octadecanol (II) by means of NaH in hot DMF gives (R)-1-(benzyloxy)-3-(octadecyloxy)-2-propanol (III), which is methylated with methyl iodide and NaH in DMF yielding the corresponding methyl ether (IV). The debenzylation of (IV) with H2 over Pd/C in THF affords the primary alcohol (V), which is finally treated with POCl3/pyridine in CHCl3 and condensed with choline tosylate (VI) to furnish the target phosphorylcholine derivative.

参考文献中间体

【1】 Bittman, R.; Lohmeyer, M.; Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19, 11, 1021.
【2】 Barner, R.; Hirth, G.; Synthese von Glyceryätherphosphatiden. Herstellung von 1-O-octadecyl-2-O-acetyl-sn-glyceryl-3-phosphorylchloline (`Platelet Activating Factor'), des Enantiomeren sowie einiger analoger Verbindungen. Helv Chim Acta 1982, 65, 1059-84.

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)	12350	Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane	14618-80-5	C₁₀H₁₂O₂	详情	详情
(II)	21494	1-octadecanol	112-92-5	C₁₈H₃₈O	详情	详情
(III)	41263	(2R)-1-(benzyloxy)-3-(octadecyloxy)-2-propanol		C₂₈H₅₀O₃	详情	详情
(IV)	41264	1-([[(2R)-2-methoxy-3-(octadecyloxy)propyl]oxy]methyl)benzene; benzyl (2R)-2-methoxy-3-(octadecyloxy)propyl ether		C₂₉H₅₂O₃	详情	详情
(V)	40717	(2S)-2-methoxy-3-(octadecyloxy)-1-propanol		C₂₂H₄₆O₃	详情	详情
(VI)	41265	2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate		C₁₂H₂₁NO₄S	详情	详情

Extended Information