OSI-7836, GS-7836, 4'-Thio-ara-C, -Drug Synthesis Database

【结构式】

【药物名称】OSI-7836, GS-7836, 4'-Thio-ara-C

【化学名称】4'-Thio-beta-D-arabinofuranosylcytosine
　　　　　　4-Amino-1-(4-thio-beta-D-arabinofuranosyl)-2(1H)-pyrimidinone
　　　　　　1-(4-Thio-beta-D-arabinofuranosyl)cytosine

【CA登记号】26599-17-7

【分子式】C₉H₁₃N₃O₄S

【分子量】259.28566

【开发单位】Southern Research Institute (Originator), Gilead (Licensee), OSI (Licensee)

【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Antimetabolites, Antimitotic Drugs

合成路线1 合成路线2 合成路线3

合成路线1

Methyl 4-thio-beta-D-arabinofuranoside (I) was converted to the tribenzoate ester (II) by means of benzoyl chloride and pyridine, and then treated with HBr in AcOH to give the arabinofuranosyl bromide (III). Displacement of bromide ion in (III) by bis(trimethylsilyl)-N-acetylcytosine (IV) at 130 C led to an anomeric mixture of nucleosides from which the required beta-anomer (V) was isolated by chromatography. Finally, deprotection of the benzoate esters and acetamido group of (V) was performed with methanolic ammonia at 0 C.

参考文献中间体

【1】 Whistler, R.L.; et al.; 4-Thio-D-arabinofuranosylpyrimidine nucleosides. J Org Chem 1971, 36, 1, 108.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	29614	(2R,3S,4S,5R)-2-(hydroxymethyl)-5-methoxytetrahydro-3,4-thiophenediol	C₆H₁₂O₄S	详情	详情
(II)	29615	[(2R,3S,4S,5R)-3,4-bis(benzoyloxy)-5-methoxytetrahydro-2-thiophenyl]methyl benzoate	C₂₇H₂₄O₇S	详情	详情
(III)	29616	[(2R,3S,4S,5S)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-thiophenyl]methyl benzoate	C₂₆H₂₁BrO₆S	详情	详情
(IV)	29617	N-(trimethylsilyl)-N-[2-[(trimethylsilyl)oxy]-4-pyrimidinyl]acetamide	C₁₂H₂₃N₃O₂Si₂	详情	详情
(V)	29618	[(2R,3S,4S,5R)-5-[4-(acetamido)-2-oxo-1(2H)-pyrimidinyl]-3,4-bis(benzoyloxy)tetrahydro-2-thiophenyl]methyl benzoate	C₃₂H₂₇N₃O₈S	详情	详情

合成路线2

In a related procedure, arabinofuranosyl bromide (III) was condensed with bis(trimethylsilyl)uracil (VI) to afford, after chromatographic separation, the beta-nucleoside (VII). Subsequent treatment of (VII) with P2S5 produced the 4-thiouridine analogue (VIII). Then, treatment of this derivative with methanolic ammonia at 110 C in a sealed tube yielded the title arabinofuranosyl citosine.

参考文献中间体

【1】 Whistler, R.L.; et al.; 4-Thio-D-arabinofuranosylpyrimidine nucleosides. J Org Chem 1971, 36, 1, 108.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	29616	[(2R,3S,4S,5S)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-thiophenyl]methyl benzoate	C₂₆H₂₁BrO₆S	详情	详情
(VI)	29619	2,4-bis[(trimethylsilyl)oxy]pyrimidine; trimethylsilyl 2-[(trimethylsilyl)oxy]-4-pyrimidinyl ether	C₁₀H₂₀N₂O₂Si₂	详情	详情
(VII)	29620	(2R,3S,4S,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-thiophenyl benzoate	C₃₀H₂₄N₂O₈S	详情	详情
(VIII)	29621	[(2R,3S,4S,5R)-3,4-bis(benzoyloxy)-5-[2-oxo-4-thioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-thiophenyl]methyl benzoate	C₃₀H₂₄N₂O₇S₂	详情	详情

合成路线3

An alternative procedure consisted in the condensation of tetraacetyl 4-thio-D-ribofuranose (IX) with silylated cytosine (IV) in the presence of SnCl4. After chromatographic separation of the major beta-nucleoside (X), deprotection of its acetyl groups with methanolic ammonia yielded the ribofuranoside (XI). In order to achieve the required epimerization of the 2'-hydroxyl group of (XI), cyclization between the 2 and 2' positions by means of POCl3 in DMF produced the cyclic derivative (XII). Finally, ring opening of (XII) by aqueous ammonia yielded the target arabinofuranosyl derivative.

参考文献中间体

【1】 Whistler, R.L.; Ototani, N.; Preparation and antitumor activity of 4'-thio analogs of 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine. J Med Chem 1974, 17, 5, 535.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	29617	N-(trimethylsilyl)-N-[2-[(trimethylsilyl)oxy]-4-pyrimidinyl]acetamide	C₁₂H₂₃N₃O₂Si₂	详情	详情
(IX)	29622	(2R,3R,4S,5R)-2,4-bis(acetoxy)-5-[(acetoxy)methyl]tetrahydro-3-thiophenyl acetate	C₁₃H₁₈O₈S	详情	详情
(X)	29623	(2R,3R,4S,5R)-2-[4-(acetamido)-2-oxo-1(2H)-pyrimidinyl]-4-(acetoxy)-5-[(acetoxy)methyl]tetrahydro-3-thiophenyl acetate	C₁₇H₂₁N₃O₈S	详情	详情
(XI)	29624	4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-thiophenyl]-2(1H)-pyrimidinone	C₉H₁₃N₃O₄S	详情	详情
(XII)	29625	(2R,3S,9aR)-2-(hydroxymethyl)-6-imino-2,3,3a,9a-tetrahydro-6H-thieno[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-3-ol	C₉H₁₁N₃O₃S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)