Tenofovir disoproxil fumarate, GS-4331-05, Bis(POC)PMPA, Viread, -Drug Synthesis Database

【结构式】

【药物名称】Tenofovir disoproxil fumarate, GS-4331-05, Bis(POC)PMPA, Viread

【化学名称】(R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid bis(isopropoxycarbonyloxymethyl) ester fumarate
　　　　　　2-(Adenin-9-yl)-1(R)-methylethoxymethylphosphonic acid bis(isopropoxycarbonyloxymethyl) ester fumarate

【CA登记号】202138-50-9, 201341-05-1 (free base)

【分子式】C₂₃H₃₄N₅O₁₄P

【分子量】635.52633

【开发单位】Japan Tobacco (Orphan Drug), Gilead (Originator), Japan Tobacco (Licensee)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors

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6

合成路线1

参考文献中间体

【1】 Parthasaradhi Reddy B, Rathnakar Reddy K. Raji Reddy R,et aL. 2007. Process for the prrparation of acyclic phosphonate nucleotide analogs. W0 2007013085

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)	19252	[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid		C₉H₁₄N₅O₄P	详情	详情
(II)	66828	(R,Z)-(((1-(6-(((dimethylamino)methylene)amino)-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid		C₁₂H₁₉N₆O₄P	详情	详情

合成路线2

参考文献中间体

【1】 Schultze LM, Chapman HH, Dubree NJ，et aL. 1998．Practical synthesis of the anti-HIV drug, PMPA. Tetrahedron Lett.,39(14):1853 ～1856

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)	19241	(2S)oxiranylmethanol	60456-23-7	C₃H₆O₂	详情	详情
(II)	66829	(R)-propane-1,2-diol	4254-14-2	C₃H₈O₂	详情	详情
(III)	19244	(4S)-4-methyl-1,3-dioxolan-2-one		C₄H₆O₃	详情	详情
(IV)	19232	(2S)-1-(6-amino-9H-purin-9-yl)-2-propanol		C₈H₁₁N₅O	详情	详情
(V)	19246	diethyl [[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate		C₁₃H₂₂N₅O₄P	详情	详情

合成路线3

参考文献中间体

【1】 Holy A, Dvorakovs H, Declercq ED, et al. Preparation of antiretroviral enantiomeric nucleotide analogs. WO 9403467

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)	66830	(S)-ethyl 2-hydroxypropanoate		C₅H₁₀O₃	详情	详情
(II)	66831	(2S)-ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate	73208-70-5	C₁₀H₁₈O₄	详情	详情
(III)	19228	(2S)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol	76946-21-9	C₈H₁₆O₃	详情	详情
(IV)	19229	(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methylbenzenesulfonate		C₁₅H₂₂O₅S	详情	详情
(V)	10343	9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine	73-24-5	C₅H₅N₅	详情	详情
(VI)	19231	9-[(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]-9H-purin-6-amine; 9-[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]-9H-purin-6-ylamine		C₁₃H₁₉N₅O₂	详情	详情
(VII)	19232	(2S)-1-(6-amino-9H-purin-9-yl)-2-propanol		C₈H₁₁N₅O	详情	详情
(VIII)	19233	N-[9-[(2S)-2-hydroxypropyl]-9H-purin-6-yl]benzamide		C₁₅H₁₅N₅O₂	详情	详情
(IX)	19234	(diisopropoxyphosphoryl)methyl 4-methylbenzenesulfonate		C₁₄H₂₃O₆PS	详情	详情
(X)	19246	diethyl [[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate		C₁₃H₂₂N₅O₄P	详情	详情

合成路线4

参考文献中间体

【1】 Holy A, Dvorakovs H, Declercq ED, et al. Preparation of antiretroviral enantiomeric nucleotide analogs. WO 9403467

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)	19228	(2S)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol	76946-21-9	C₈H₁₆O₃	详情	详情
(II)	19230	2-(((S)-1-(benzyloxy)propan-2-yl)oxy)tetrahydro-2H-pyran		C₁₅H₂₂O₃	详情	详情
(III)	66832	(S)-((2-(chloromethoxy)propoxy)methyl)benzene		C₁₁H₁₅ClO₂	详情	详情
(IV)	19238	diisopropyl [[(1S)-2-(benzyloxy)-1-methylethyl]oxy]methylphosphonate		C₁₇H₂₉O₅P	详情	详情
(V)	19239	diisopropyl [[(1S)-2-hydroxy-1-methylethyl]oxy]methylphosphonate		C₁₀H₂₃O₅P	详情	详情
(VI)	19240	(2S)-2-[(diisopropoxyphosphoryl)methoxy]propyl 4-methylbenzenesulfonate		C₁₇H₂₉O₇PS	详情	详情
(VII)	10343	9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine	73-24-5	C₅H₅N₅	详情	详情
(VIII)	19246	diethyl [[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate		C₁₃H₂₂N₅O₄P	详情	详情

合成路线5

参考文献中间体

【1】李卓荣，汤雁波，羽宗英等．2005．一组非环棱苷酸类似铀及其合成方法和在抗病毒中的应用．发明专利申请公开说明书，CN 1634943

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)	19233	N-[9-[(2S)-2-hydroxypropyl]-9H-purin-6-yl]benzamide		C₁₅H₁₅N₅O₂	详情	详情
(II)	12702	(diethoxyphosphoryl)methyl 4-methylbenzenesulfonate	31618-90-3	C₁₂H₁₉O₆PS	详情	详情
(III)	66833	(S)-diethyl (((1-(6-benzamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate		C₂₀H₂₆N₅O₅P	详情	详情
(IV)	19246	diethyl [[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate		C₁₃H₂₂N₅O₄P	详情	详情

合成路线6

The reaction of chloromethyl chloroformate (I) with isopropyl alcohol (II) by means of pyridine or triethylamine in ether gives the mixed carbonate (III), which is then condensed with (R)-PMPA (IV) by means of diisopropyl ethyl-amine in DMF.

参考文献中间体

【1】 Oliyai, R.; Dougherty, J.; Bischofberger, N.; Kim, C.U.; Mulato, A.; Shaw, J.P.; Cundy, K.C.; Arimilli, M.N.; Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs. Antivir Chem Chemother 1997, 8, 6, 557.
【2】 Sorbera, L.A.; Castañer, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279.
【3】 Arimilli, M.N.; Cundy, K.C.; Dougherty, J.P.; Kim, C.U.; Oliyai, R.; Stella, V.J. (Gilead Sciences Inc.); Nucleotide analogs. US 5922695; WO 9804569 .

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)	19249	Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane	22128-62-7	C₂H₂Cl₂O₂	详情	详情
(II)	19250	2-propanol	67-63-0	C₃H₈O	详情	详情
(III)	19251	chloromethyl isopropyl carbonate		C₅H₉ClO₃	详情	详情
(IV)	19252	[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid		C₉H₁₄N₅O₄P	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)