Etoposide phosphate disodium salt, BMY-40481(free acid), BMY-40481-30, Etopophos, -Drug Synthesis Database

【结构式】

【药物名称】Etoposide phosphate disodium salt, BMY-40481(free acid), BMY-40481-30, Etopophos

【化学名称】Etoposide 4'-phosphate disodium salt
　　　　　　[5R-[5alpha,5abeta,8aalpha,9beta(R*)]]-5-[3,5-Dimethoxy-4-(phosphonooxy)phenyl]-9-[(4,6-O-ethylidene-beta-D-gluocopyranosyl)oxy]-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one disodium salt

【CA登记号】122405-33-8, 117091-64-2 (free acid), 122332-48-3 (free acid, former CAS), 138067-47-7 (free acid, former CAS)

【分子式】C₂₉H₃₁Na₂O₁₆P

【分子量】712.51422

【开发单位】Bristol-Myers Squibb (Originator), Sparta (Licensee)

【药理作用】Kaposi's Sarcoma Therapy, Leukemia Therapy, Lung Cancer Therapy, Lymphoma Therapy, Myeloid Leukemia Therapy, Non-Hodgkin's Lymphoma Therapy, Oncolytic Drugs, Solid Tumors Therapy, DNA Topoisomerase II Inhibitors, Epipodophyllotoxins

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

By reaction of etoposide (I) with POCl3 and diisopropylethylamine in acetonitrile, followed by hydrolysis with aqueous NaHCO3.

参考文献中间体

【1】 Saulnier, M.G.; Senter, P.D.; Kadow, J.F. (Bristol-Myers Squibb Co.); Epipodophyllotoxinglucoside-4'phosphate derivs. AU 8820306; BE 1002982; CH 676716; DE 3826562; FR 2622193; GB 2207674; US 4904768 .
【2】 Castaner, J.; Prous, J.; Etoposide Phosphate Disodium Salt. Drugs Fut 1992, 17, 9, 779.

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)	13041	Etoposide; (5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-Dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one	33419-42-0	C₂₉H₃₂O₁₃	详情	详情

合成路线2

Several new, related syntheses of etoposide phosphate disodium salt have been described: 1) The reaction of etoposide (I) with phosphoryl chloride by means of ethyl diisopropylamine gives the corresponding dichlorophosphoryl ester (II), which is then hydrolyzed with NaHCO3 in water. 2) The reaction of etoposide (I) with diphenyl chlorophosphate gives the diphenoxyphosphoryloxy derivative (III), which is hydrogenated with H2 over PtO2 to afford the free phosphoric acid (IV). Finally, this compound is treated with NaHCO3 as before.

参考文献中间体

【1】 Saulnier, M.G.; Tun, M.M.; Langley, D.R.; Knipe, J.O.; Doyle, T.W.; Senter, P.D.; Kadow, J.F.; Vyas, D.M.; Synthesis of etoposide phosphate, BMY-40481: A water-soluble clinically active prodrug of etoposide. Bioorg Med Chem Lett 1994, 4, 21, 2567.

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)	13041	Etoposide; (5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-Dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one	33419-42-0	C₂₉H₃₂O₁₃	详情	详情
(II)	13042	(5R,5aR,8aR,9S)-5-[4-(Dichlorophosphoryloxy)-3,5-dimethoxyphenyl]-9-(4-O,6-O-ethylidene-beta-D-glucopyranosyloxy)-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6-one		C₂₉H₃₁Cl₂O₁₄P	详情	详情
(III)	13043	4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl diphenyl phosphate		C₄₁H₄₁O₁₆P	详情	详情
(IV)	13044	4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dihydrogen phosphate		C₂₉H₃₃O₁₆P	详情	详情

合成路线3

3) The reaction of podophyllotoxin (V) with diphenyl chlorophosphate by means of ethyl diisopropylamine and dimethylaminopyridine (DMAP) gives the diphenylphosphoryloxy derivative (VI), which is glycosylated with 4,6-O-ethylidene-2,3-O-bis(2,2,2-trichloroethoxycarbonyl)-beta-D-glycopyranose (VII) by means of BF3/ethyl ether, yielding the protected etoposide derivative (VIII). The cleavage of the protecting groups of the carbohydrate moiety with Zn/acetic acid affords the free etoposide phosphate diphenyl ester (IX), already obtained (compound (III) of scheme 14675903a). The reductive cleavage of (IX) as before gives the free acid (X) (compound (IV) of scheme 14675903a), which is finally treated with NaHCO3. 4) The preceding reaction pathway carried out with dibenzyl chlorophosphate instead of diphenyl chlorophosphate yields compounds (XI), (XII), and finally (XIII), which by hydrogenolysis with H2 over Pd/C affords the free acid (X), already obtained.

参考文献中间体

【1】 Saulnier, M.G.; Tun, M.M.; Langley, D.R.; Knipe, J.O.; Doyle, T.W.; Senter, P.D.; Kadow, J.F.; Vyas, D.M.; Synthesis of etoposide phosphate, BMY-40481: A water-soluble clinically active prodrug of etoposide. Bioorg Med Chem Lett 1994, 4, 21, 2567.

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)	13053	(5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one	6559-91-7	C₂₁H₂₀O₈	详情	详情
(VI)	13045	4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl diphenyl phosphate		C₃₃H₂₉O₁₁P	详情	详情
(VII)	13046	(2R,4aR,6R,7R,8S,8aR)-6-hydroxy-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate		C₁₄H₁₆Cl₆O₁₀	详情	详情
(VIII)	13047	(2R,4aR,6R,7R,8S,8aR)-6-[((5S,5aR,8aR,9R)-9-[4-[(diphenoxyphosphoryl)oxy]-3,5-dimethoxyphenyl]-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)oxy]-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate		C₄₇H₄₃Cl₆O₂₀P	详情	详情
(IX)	13043	4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl diphenyl phosphate		C₄₁H₄₁O₁₆P	详情	详情
(X)	13044	4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dihydrogen phosphate		C₂₉H₃₃O₁₆P	详情	详情
(XI)	13050	4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl dibenzyl phosphate		C₃₅H₃₃O₁₁P	详情	详情
(XII)	13051	(2R,4aR,6R,7R,8S,8aR)-6-[[(5S,5aR,8aR,9R)-9-(4-[[bis(benzyloxy)phosphoryl]oxy]-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]oxy]-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate		C₄₉H₄₇Cl₆O₂₀P	详情	详情
(XIII)	13052	4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dibenzyl phosphate		C₄₃H₄₅O₁₆P	详情	详情

合成路线4

A new synthesis for etoposide phosphate disodium salt has been reported: The reaction of 4'-demethylepipodophpyllotoxin (I) with dibenzyl phosphite and diisopropylethylamine (DIEA) in acetonitrile gives the corresponding 4'-dibenzyl phosphate ester (II), which is condensed with 2,3-di-O-benzyl-4,6-O-ethylidene-alpha,beta-D-glucose (alpha:beta ratio = 85:15) by means of boron trifluoride ethearate in acetonitrile to afford the tetrabenzylated compound (IV). Finally, this compound is deprotected by hydrogenolysis with H2 over Pd/C in methanol/THF.

参考文献中间体

【1】 Silverberg, L.J.; Vemishetti, P.; Dillon, J.L. Jr.; Usher, J.J. (Bristol-Myers Squibb Co.); Process of preparing etoposide phosphate and etoposide. EP 0652226; JP 1995196680; JP 1998152499; US 5459248 .

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)	13053	(5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one	6559-91-7	C₂₁H₂₀O₈	详情	详情
(II)	13050	4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl dibenzyl phosphate		C₃₅H₃₃O₁₁P	详情	详情
(III)	13055	(2R,4aR,6S,7R,8R,8aS)-7,8-Bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-ol		C₂₂H₂₆O₆	详情	详情
(IV)	13056	4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dibenzyl phosphate		C₅₇H₅₇O₁₆P	详情	详情

合成路线5

The reaction of D-glucopyranose (A) with allyl alcohol (B) by means of HCl gives glucoside (C), which is treated with acetaldehyde diethylacetal (D) and TsOH in dichloromethane to yield the 4,6-O-ethylideneglucoside (E). Reaction of (E) with benzyl bromide (F), by means of NaH in DMF, affords the 2,3-di-O-benzyl-4,6-O-ethylideneglucoside (G), which is treated with potassium tert-butoxide and with HgO, HgCl2 to give the fully protected sugar (III).

参考文献中间体

【1】 Vemishetti, P.; Sleezer, P.D.; Dillon, J.L.; Discordia, R.P.; Hartung, K.B.; Silverberg, L.J.; Efficient synthesis of the anticancer drug etoposide 4'-phosphate: Use of benzylic ether-protecting groups on the carbohydrate segment. Org Process Res Dev 2000, 4, 1, 34.

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)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(F)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(A)	23276	5-(hydroxymethyl)-1,2,3,4-cyclohexanetetrol		C₆H₁₂O₆	详情	详情
(E)	40484	(2R,4aR,7R,8R,8aS)-6-(allyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol		C₁₁H₁₈O₆	详情	详情
(G)	40485	(2R,4aR,7R,8R,8aS)-6-(allyloxy)-7,8-bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxine; (2R,4aR,7R,8R,8aS)-6-(allyloxy)-7-(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl benzyl ether		C₂₅H₃₀O₆	详情	详情
(D)	40486	1-ethoxyethyl ethyl ether; 1,1-diethoxyethane	105-57-7	C₆H₁₄O₂	详情	详情
(III)	13055	(2R,4aR,6S,7R,8R,8aS)-7,8-Bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-ol		C₂₂H₂₆O₆	详情	详情
(C)	40483	(3R,4S,5S,6R)-2-(allyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol		C₉H₁₆O₆	详情	详情

Extended Information