FA-FdUMP[10], -Drug Synthesis Database

【结构式】

【药物名称】FA-FdUMP[10]

【化学名称】2'-Deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylyl-(3'-5')-2'-deoxy-5-fluorocytidylic acid 2-[4-[4-(2-amino-4-oxo-3,4-dihydropteridin-6-ylmethylamino)benzamido]-5-(2-hydroxyethylamino)-5-oxopentanamido]ethyl ester

【CA登记号】

【分子式】C₁₁₃H₁₂₉F₁₀N₂₉O₇₆P₁₀

【分子量】3609.15878

【开发单位】University of Nebraska Medical Center (Originator)

【药理作用】ONCOLYTIC DRUGS

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

Esterification of ethanolamine hydrochloride (I) by means of acetyl chloride in HOAc yields 2-aminoethyl acetate (II). The carboxyl groups of folic acid (III) are protected by coupling with amino ester (II) in the presence of EDC, to produce diamide (IV). Subsequent condensation of (IV)with dimethylformamide diethylacetal (DMF-DEA) gives formamidine (V). The 4-carbonyl group of (V) is then protected as the phenethyl ether (VII) by treatment with 4-nitrophenethyl alcohol (VI) under Mitsunobu coupling conditions.

参考文献中间体

【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 .
【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 .

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)	10259	Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol	141-43-5	C₂H₇NO	详情	详情
(II)	59032	2-aminoethyl acetate		C₄H₉NO₂	详情	详情
(III)	59033	N-(4-{[(2-amino-4-oxo-3,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)glutamic acid		C₁₉H₁₉N₇O₆	详情	详情
(IV)	59034	2-({5-{[2-(acetyloxy)ethyl]amino}-2-[(4-{[(2-amino-4-oxo-3,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]-5-oxopentanoyl}amino)ethyl acetate		C₂₇H₃₃N₉O₈	详情	详情
(V)	59035	2-({5-{[2-(acetyloxy)ethyl]amino}-2-[(4-{[(2-{[(E)-(dimethylamino)methylidene]amino}-4-oxo-3,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]-5-oxopentanoyl}amino)ethyl acetate		C₃₀H₃₈N₁₀O₈	详情	详情
(VI)	32472	2-(4-nitrophenyl)-1-ethanol	100-27-6	C₈H₉NO₃	详情	详情
(VII)	59036	2-{[5-{[2-(acetyloxy)ethyl]amino}-2-({4-[({2-{[(E)-(dimethylamino)methylidene]amino}-4-[(4-nitrophenethyl)oxy]-6-pteridinyl}methyl)amino]benzoyl}amino)-5-oxopentanoyl]amino}ethyl acetate		C₃₈H₄₅N₁₁O₁₀	详情	详情

合成路线2

Partial hydrolysis of diacetate (VII) by means of ethanolamine, followed by reprotection with DMF-DEA, affords the desired mono-hydrolyzed compound (VIII), along with other by-products that are separated by column chromatography. Phosphitylation of alcohol (VIII) with cyanoethyl N,N-diisopropylphosphonamidic chloride furnishes the activated phosphoramidite (IX).

参考文献中间体

【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 .
【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	59036	2-{[5-{[2-(acetyloxy)ethyl]amino}-2-({4-[({2-{[(E)-(dimethylamino)methylidene]amino}-4-[(4-nitrophenethyl)oxy]-6-pteridinyl}methyl)amino]benzoyl}amino)-5-oxopentanoyl]amino}ethyl acetate	C₃₈H₄₅N₁₁O₁₀	详情	详情
(VIII)	59037	2-({2-({4-[({2-{[(E)-(dimethylamino)methylidene]amino}-4-[(4-nitrophenethyl)oxy]-6-pteridinyl}methyl)amino]benzoyl}amino)-5-[(2-hydroxyethyl)amino]-5-oxopentanoyl}amino)ethyl acetate	C₃₆H₄₃N₁₁O₉	详情	详情
(IX)	59038	16-cyano-13-(diisopropylamino)-5-({4-[({2-{[(E)-(dimethylamino)methylidene]amino}-4-[(4-nitrophenethyl)oxy]-6-pteridinyl}methyl)amino]benzoyl}amino)-4,8-dioxo-12,14-dioxa-3,9-diaza-13-phosphahexadec-1-yl acetate	C₄₅H₆₀N₁₃O₁₀P	详情	详情

合成路线3

Coupling of the deca-nucleotide of 5-fluoro-2'-deoxyuridine-5'-O-monophosphate (FdUMP[10]), attached to a solid support, with phosphoramidite (IX) produces the support-bound phosphite adduct (X). After oxidation of (X) to the corresponding phosphate with I2 in aqueous THF, the product is cleaved from the solid support with ammonium hydroxide to furnish (XI).

参考文献中间体

【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 .
【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	59038	16-cyano-13-(diisopropylamino)-5-({4-[({2-{[(E)-(dimethylamino)methylidene]amino}-4-[(4-nitrophenethyl)oxy]-6-pteridinyl}methyl)amino]benzoyl}amino)-4,8-dioxo-12,14-dioxa-3,9-diaza-13-phosphahexadec-1-yl acetate	C₄₅H₆₀N₁₃O₁₀P	详情	详情
(X)	59039		C₁₂₉H₁₄₆F₁₀N₃₂O₇₈P₁₀	详情	详情
(XI)	59040		C₁₂₆H₁₄₃F₁₀N₃₁O₇₉P₁₀	详情	详情

合成路线4

The p-nitrophenethyl protecting group of (XI) is finally removed by incubation with a DMF solution of DBU, to provide the title compound.

参考文献中间体

【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 .
【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	59040			C₁₂₆H₁₄₃F₁₀N₃₁O₇₉P₁₀	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)