SB-596168, TAS-106, ECyd, -Drug Synthesis Database

【结构式】

【药物名称】SB-596168, TAS-106, ECyd

【化学名称】3'-Ethynylcytidine
　　　　　　1-(3-C-Ethynyl-beta-D-ribofuranosyl)cytosine

【CA登记号】180300-43-0

【分子式】C₁₁H₁₃N₃O₅

【分子量】267.24336

【开发单位】Taiho (Originator), GlaxoSmithKline (Licensee)

【药理作用】ONCOLYTIC DRUGS, Solid Tumors Therapy, Apoptosis Inducers, DNA-Directed RNA Polymerase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

The selective protection of 1,2-O-isopropylidene-D-xylofuranose (I) with Tbdms-Cl and pyridine gives the silyl ether (II), which is oxidized with CrO3, pyridine and Ac2O in dichloromethane to yield the ketone (III). Stereoselective addition of trimethylsilylacetylene (IV) to the ketone (III) by means of BuLi in THF affords the beta-adduct (V), which is desilylated by means of TBAF in THF to provide 3-C-ethynyl-2,3-o-isopropylidene-alpha-D-ribofuranose (VI). The selective monobenzoylation of (VI) with benzoyl chloride and pyridine gives the monobenzoate (VII), which is treated with HCl in methanol to cleave the isopropylidene protecting group and yield (VIII). The exhaustive benzoylation of (VIII) with benzoyl chloride and DMAP in pyridine at 100 C affords the tribenzoate (IX), which is treated with H2SO4 and Ac2O to provide the monoacetate (X). The condensation of (X) with cytosine (XI) by means of SnCl4 in acetonitrile gives the cytidine derivative (XII), which is finally debenzoylated by means of NH3 in methanol to yield the target ethynyl-cytidine derivative.

参考文献中间体

【1】 Nomura, M.; Sato, T.; Masato, W.; Tanaka, M.; Asao, T.; Shuto, S.; Matsuda, A.; Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbruggen glycosylation . Tetrahedron 2002, 58, 7, 1279.
【3】 Hattori, H.; et al.; Nucleosides and nucleotides. 158. 1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil, and their nucleobase analogues as new potential multifunctional antitumor nucleosides with a broad spectrum of activity. J Med Chem 1996, 39, 25, 5005.
【2】 Nozawa, E.; Hattori, H.; Shuto, S.; Tanaka, M.; Sasaki, T.; Matsuda, A.; Synthesis and antitumor activity of 1-(3-C-ethynyl-beta-D-ribo-pentfuranosyl)cytosine, -uracil and their sugar modified derivatives. Nucleic Acids Symp Ser 1996, 35, 31.
【4】 Matsuda, A.; Sasaki, T. (Taiho Pharmaceutical Co., Ltd.); 3'-Substd. nucleoside derivs.. EP 0747389; WO 9618636 .

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)	41907	(3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol	20031-21-4	C₈H₁₄O₅	详情	详情
(II)	54394	(3aR,5R,6S,6aR)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol		C₁₄H₂₈O₅Si	详情	详情
(III)	54395	(3aR,5R,6aS)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(5H)-one		C₁₄H₂₆O₅Si	详情	详情
(IV)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(V)	54396	(3aR,5R,6R,6aR)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]tetrahydrofuro[2,3-d][1,3]dioxol-6-ol		C₁₉H₃₆O₅Si₂	详情	详情
(VI)	54397	(3aR,5R,6R,6aR)-6-ethynyl-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol		C₁₀H₁₄O₅	详情	详情
(VII)	54398	[(3aR,5R,6R,6aR)-6-ethynyl-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate		C₁₇H₁₈O₆	详情	详情
(VIII)	54399	[(2R,3S,4R,5S)-3-ethynyl-3,4-dihydroxy-5-methoxytetrahydro-2-furanyl]methyl benzoate		C₁₅H₁₆O₆	详情	详情
(IX)	54400	[(2R,3R,4R,5S)-3,4-bis(benzoyloxy)-3-ethynyl-5-methoxytetrahydro-2-furanyl]methyl benzoate		C₂₉H₂₄O₈	详情	详情
(X)	54401	[(2R,3R,4R,5R)-5-(acetyloxy)-3,4-bis(benzoyloxy)-3-ethynyltetrahydro-2-furanyl]methyl benzoate		C₃₀H₂₄O₉	详情	详情
(XI)	12706	Cytosine; 4-Amino-2(1H)-pyrimidinone	71-30-7	C₄H₅N₃O	详情	详情
(XII)	54402	[(2R,3R,4R,5R)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-3,4-bis(benzoyloxy)-3-ethynyltetrahydro-2-furanyl]methyl benzoate		C₃₂H₂₅N₃O₈	详情	详情

合成路线2

The reaction of 1,2-O-isopropylidene-D-xylofuranose (I) with 4-chlorobenzoyl chloride (II) and TEA gives the 5-O-(4-chlorobenzoate) (III), which is oxidized with TEMPO and NaClO to yield the 3-oxo derivative (IV). The ethynylation of (IV) by means of trimethylsilylethynyl magnesium bromide (V) affords the 3-C-trimethylsilylethynyl derivative (VI), which is hydrolyzed by means of refluxing aqueous HCOOH to provide the 3-C-ethynylated sugar (VII). The acylation of (VII) by means of 4-chlorobenzoyl chloride (II), TEA and DMAP gives the tetrabenzoate sugar (VIII), which is used for the glycosylation of bis trimethylsilyl cytosine (IX) by means of SnCl4 to yield the protected precursor (X). Finally, this compound is desilylated and debenzoylated by means of DBU in hot methanol to afford the target nucleoside.

参考文献中间体

【1】 Nomura, M.; Sato, T.; Masato, W.; Tanaka, M.; Asao, T.; Shuto, S.; Matsuda, A.; Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbruggen glycosylation . Tetrahedron 2002, 58, 7, 1279.

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)	41907	(3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol	20031-21-4	C₈H₁₄O₅	详情	详情
(II)	10295	p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride	122-01-0	C₇H₄Cl₂O	详情	详情
(III)	61573	[(3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl 4-chlorobenzoate		C₁₅H₁₇ClO₆	详情	详情
(IV)	61574	[(3aR,5R,6aS)-2,2-dimethyl-6-oxotetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl 4-chlorobenzoate		C₁₅H₁₅ClO₆	详情	详情
(V)	34561	methyl 3-methyl-1-(2-methylphenyl)-2-(trimethylsilyl)-1H-pyrrolo[3,2-c]quinolin-6-yl ether; 6-methoxy-3-methyl-1-(2-methylphenyl)-2-(trimethylsilyl)-1H-pyrrolo[3,2-c]quinoline		C₂₃H₂₆N₂OSi	详情	详情
(VI)	61575	{(3aR,5R,6R,6aR)-6-hydroxy-2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]tetrahydrofuro[2,3-d][1,3]dioxol-5-yl}methyl 4-chlorobenzoate		C₂₀H₂₅ClO₆Si	详情	详情
(VII)	61576	{(2R,3S,4R)-3,4,5-trihydroxy-3-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl}methyl 4-chlorobenzoate		C₁₇H₂₁ClO₆Si	详情	详情
(VIII)	61577	(3R,4R,5R)-3,4-bis[(4-chlorobenzoyl)oxy]-5-{[(4-chlorobenzoyl)oxy]methyl}-4-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl 4-chlorobenzoate		C₃₈H₃₀Cl₄O₉Si	详情	详情
(IX)	61578	N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-(trimethylsilyl)-N-{2-[(trimethylsilyl)oxy]-4-pyrimidinyl}amine		C₁₀H₂₁N₃OSi₂	详情	详情
(X)	61579	(2R,3R,4R,5R)-4-[(4-chlorobenzoyl)oxy]-5-{[(4-chlorobenzoyl)oxy]methyl}-2-[2-oxo-4-[(trimethylsilyl)amino]-1(2H)-pyrimidinyl]-4-[2-(trimethylsilyl)ethynyl]tetrahydro-3-furanyl 4-chlorobenzoate		C₃₈H₃₈Cl₃N₃O₈Si₂	详情	详情

合成路线3

The reaction of cytidine (I) with benzoyl anhydride in dioxane gives N-benzoylcytidine (II), which is selectively monoprotected at the primary OH group by means of 4-methoxytrityl chloride and pyridine to yield N-benzoyl-5'O-(monomethoxytrityl)cytidine (III). The monosilylation of (III) by means of Tbdms-Cl and AgNO3 in pyridine/THF affords a mixture of the 3'-O-silyl (IV) and the desired 2'-O-silyl (V) derivative which is easily separated by flash chromatography. (The yield of the desired 2'-O-silyl isomer (V) can be improved by isomerization of the 3'-O-silyl isomer (IV) by means of pyridine in methanol at 70 C). The oxidation of (V) by means of CrO3 and Ac2O provides the 3'-oxonucleoside (VI), which is selectively deprotected by means of TsOH in chloroform/methanol to give compound (VII). The reaction of (VII) with trimethylsilylacetylene (VIII) by means of BuLi and CeCl3 in THF yields the protected ethynyl nucleoside (IX), which is debenzoylated by means of NH3 in methanol to afford the silylated nucleoside (X). Finally, this compound is treated with TBAF in THF to obtain the target ethynyl cytidine.

参考文献中间体

【1】 Ludwig, P.S.; Schwender, R.A.; Schott, H.; A new laboratory scale synthesis for the anticancer drug 3'-C.ethynylcytidine. Synthesis (Stuttgart) 2002, 16, 2387.

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)	27920	Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone	65-46-3	C₉H₁₃N₃O₅	详情	详情
(II)	61580	N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide	13089-48-0	C₁₆H₁₇N₃O₆	详情	详情
(III)	61581	N-[1-((2R,3R,4S,5R)-3,4-dihydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide		C₃₈H₃₇N₃O₉	详情	详情
(IV)	61582	N-[1-((2R,3R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide		C₄₄H₅₁N₃O₉Si	详情	详情
(V)	61583	N-[1-((2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide		C₄₄H₅₁N₃O₉Si	详情	详情
(VI)	61584	N-[1-((2R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide		C₄₄H₄₉N₃O₉Si	详情	详情
(VII)	61585	N-{1-[(2R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)-4-oxotetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide		C₂₂H₂₉N₃O₆Si	详情	详情
(VIII)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(IX)	61586	N-(1-{(2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-(hydroxymethyl)-4-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl}-2-oxo-1,2-dihydro-4-pyrimidinyl)benzamide		C₂₇H₃₉N₃O₆Si₂	详情	详情
(X)	61587	4-amino-1-{(2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-(hydroxymethyl)-4-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl}-2(1H)-pyrimidinone		C₂₀H₃₅N₃O₅Si₂	详情	详情

Extended Information