1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione -Drug Synthesis Database

【结构式】

【分子编号】31160

【品名】1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione

【CA登记号】

【分子式】C₃₅H₃₂N₂O₅

【分子量】560.64956

【元素组成】C 74.98% H 5.75% N 5% O 14.27%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XI)

The benzoylation of 2'-deoxy-5-iodouridine (I) with benzoyl chloride by means of pyridine in dichloromethane gives 5'-O-benzoyl-2'-deoxy-5-iodouridine (II), which is treated with benzyl trichloroacetimidate (III) and trifluoromethanesulfonic acid in dichloromethane - THF to afford the 3'-O-benzyl derivative (IV). The hydrolysis of (IV) with sodium ethoxide in ethanol yields 3'-O-benzyl-2'-deoxy-5-iodouridine (V), which is finally trifluoromethylated with bromotrifluoromethane and copper in pyridine-DMF by means of dimethylaminopyridine. The tritylation of 2'-deoxyuridine (IX) with trityl chloride in hot pyridine gives 2'-deoxy-5'-O-trityluridine (X), which is benzylated with benzyl chloride and NaH in THF yielding 3'-O-benzyl-2'-deoxy-5'-O-trityluridine (XI). The photochemical trifluoromethylation of (XI) with N-nitroso-N-(trifluoromethyl)trifluoromethanesulfonamide and biacetyl in acetonitrile irradiated with a high-pressure Hg lamp in a glass tube at room temperature affords 3'-O-benzyl-2'-deoxy-5-(trifluoromethyl-5'-O-trityluridine (XII), which is finally deprotected with HCl in methanol.

参考文献中间体

合成目标

【1】 Fujii, S.; Yamashita, J.; Matsumoto, H.; Takeda, S.; Terada, T.; Yasumoto, M.; Unemi, N. (Taiho Pharmaceutical Co., Ltd.); Novel 2'-deoxy-5-substd. uridine derivs., processes for preparing the same and antitumor agent containing the same. EP 0129984; ES 8606381; ES 8606382; ES 8607982; ES 8706715; JP 1984216899; JP 1985061591 .
【2】 Yasumoto, M.; Matsumoto, H.; Tada, Y.; Kobayashi, K.; Noguchi, K. (Taiho Pharmaceutical Co., Ltd.); Method for the preparation of 3'-O-benzyl-2'-deoxy-beta-uridines. JP 1987187484 .
【3】 Yamashita, J.-I.; Takeda, S.; Matsumoto, H.; Unemi, N.; Yasumoto, M.; Studies on antitumor agents. 8. Antitumor activities of O-alkyl derivatives of 2'-deoxy-5-(trifluoromethyl)uridine and 2'-deoxy-5-fluorouridine. J Med Chem 1989, 32, 1, 136-139.
【4】 Hoshi, A.; Prous, J.; Castaner, J.; FTC-092. Drugs Fut 1990, 15, 8, 790.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
	19171	1-(Chloromethyl)benzene; Benzyl chloride	100-44-7	C₇H₇Cl	详情	详情
(I)	31154	1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione	54-42-2	C₉H₁₁IN₂O₅	详情	详情
(II)	31155	[(2R,3S,5R)-3-hydroxy-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₁₆H₁₅IN₂O₆	详情	详情
(III)	31156	benzyl 2,2,2-trichloroethanimidoate	81927-55-1	C₉H₈Cl₃NO	详情	详情
(IV)	31157	[(2R,3S,5R)-3-(benzyloxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₁IN₂O₆	详情	详情
(V)	31158	1-[(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione		C₁₆H₁₇IN₂O₅	详情	详情
(IX)	11875	1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine	951-78-0	C₉H₁₂N₂O₅	详情	详情
(X)	31159	1-[(2R,4S,5R)-4-hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione		C₂₈H₂₆N₂O₅	详情	详情
(XI)	31160	1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione		C₃₅H₃₂N₂O₅	详情	详情
(XII)	31161	1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione		C₃₆H₃₁F₃N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The condensation of azetidinone (I) with carbonate (II) by means of TiCl4 and tributylamine in toluene gives the addition product (III), which is desilylated with HCl in aqueous acetonitrile and resilylated again with Tes-Cl and imidazole in toluene/acetonitrile yielding the silyl ether (IV). The condensation of (IV) with the oxalyl derivative (V) by means of pyridine in toluene affords the addition compound (VI), which is cyclized by means of P(OEt)3 in hot heptane giving the carbapenem compound (VII). The condensation of (VII) with naphthosultam (VIII) by means of palladium acetate and P(OBu)3 affords the protected target compound (IX), which is finally desilylated with aqueous Tf-OH, debenzylated with H2 over Pd/C, and treated with sodium benzenesulfonate to obtain the sulfonate salt of the target compound.

参考文献中间体

合成目标

【1】 Humphrey, G.R.; et al.; Efficient and practical synthesis of a potent anti-MRSA beta-methylcarbapenem containing a releasable side chain. J Am Chem Soc 1999, 121, 49, 11261.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate	C₁₃H₂₅NO₄Si	详情	详情
(II)	31601	tert-butyl 2-oxobutyl carbonate	C₉H₁₆O₄	详情	详情
(III)	31602	tert-butyl (3R)-3-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxobutyl carbonate	C₂₀H₃₇NO₆Si	详情	详情
(IV)	31603	tert-butyl (3R)-2-oxo-3-((2R,3S)-4-oxo-3-[(1R)-1-[(triethylsilyl)oxy]ethyl]azetidinyl)butyl carbonate	C₂₀H₃₇NO₆Si	详情	详情
(V)	31604	3-(4-nitrobenzyloxy)-2-oxopropanoyl chloride	C₉H₆ClNO₅	详情	详情
(VI)	31605	tert-butyl (3R)-3-((2R,3S)-1-[3-(4-nitrobenzyloxy)-2-oxopropanoyl]-4-oxo-3-[(1R)-1-[(triethylsilyl)oxy]ethyl]azetidinyl)-2-oxobutyl carbonate	C₂₉H₄₂N₂O₁₁Si	详情	详情
(VII)	31606	tert-butyl ((4S,5R,6S)-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl)methyl carbonate	C₂₉H₄₂N₂O₉Si	详情	详情
(VIII)	31607	1-(2-amino-2-oxoethyl)-4-[2-(1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)ethyl]-1,4-diazoniabicyclo[2.2.2]octane di(trifluoromethanesulfonate)	C₂₂H₂₆F₆N₄O₉S₃	详情	详情
(IX)	31160	1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione	C₃₅H₃₂N₂O₅	详情	详情

Extended Information