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【结 构 式】

【药物名称】

【化学名称】[2R,4R,5S(E)]-1-[4,5-Bis(hydroxymethyl)tetrahydrothien-2-yl]-5-(2-bromovinyl)pyrimidine-2,4(1H,3H)-dione
      [2R,4R,5S(E)]-1-[4,5-Bis(hydroxymethyl)tetrahydrothien-2-yl]-5-(2-bromovinyl)uracil

【CA登记号】

【 分 子 式 】C12H15BrN2O4S

【 分 子 量 】363.23235

【开发单位】Nippon Kayaku (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs

合成路线1

Opening of the (S,S)-epoxide (I) with the silylmethyl Grignard reagent (II) in the presence of CuI, followed by oxidative cleavage of the silyl alcohol (III) with H2O2 gave diol (IV). Then, selective protection of the primary hydroxyl group of (IV) with tert-butyldimethylsilyl chloride, followed by condensation with methanesulfonyl chloride, afforded mesylate (V). Subsequent alkylation of the sodium salt of ethyl mercaptoacetate (VI) gave thioether (VII). Desilylation of (VII) with tetrabutylammonium fluoride, followed by mesylation provided sulfonate (VIII). Subsequent intramolecular ring closure of (VIII) using NaH in DMF produced the tetrahydrothiophene (IX) as a 2:3 mixture of stereoisomers. Hydrolysis of the ethyl ester of (IX) with LiOH gave carboxylic acid (X), which was submitted to a modified Hunsdiecker reaction with Pb(OAc)4 to furnish the 1-O-acetate (XI) as a 1:1 anomeric mixture.

1 Upcroft, P.; Campbell, R.W.; Benakli, K.; Upcroft, J.A.; Vanelle, P.; Efficacy of new 5-nitroimidazoles against metronidazole-susceptible and -resistant Giardia, Trichomonas, and Entamoeba spp. Antimicrob Agents Chemother 1999, 43, 1, 73.
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) 25266 benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane C18H20O3 详情 详情
(III) 25267 (2R,3R)-1,4-bis(benzyloxy)-3-[[isopropoxy(dimethyl)silyl]methyl]-2-butanol C24H36O4Si 详情 详情
(IV) 25268 (2R,3R)-4-(benzyloxy)-2-[(benzyloxy)methyl]-1,3-butanediol C19H24O4 详情 详情
(V) 25269 (1R,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)propyl methanesulfonate C26H40O6SSi 详情 详情
(VI) 23995 ethyl 2-sulfanylacetate 2713-34-0 C4H8O2S 详情 详情
(VII) 25270 ethyl 2-[[(1S,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)propyl]sulfanyl]acetate C29H44O5SSi 详情 详情
(VIII) 25271 ethyl 2-[((1S,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-[[(methylsulfonyl)oxy]methyl]propyl)sulfanyl]acetate C24H32O7S2 详情 详情
(IX) 25272 ethyl (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenecarboxylate C23H28O4S 详情 详情
(X) 25273 (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenecarboxylic acid C21H24O4S 详情 详情
(XI) 25274 (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenyl acetate C22H26O4S 详情 详情

合成路线2

Acetate (XI) was coupled with the bis-silylated uracil (XII) in the presence of trimethylsilyl triflate to give the 1:1 mixture of glycosylated products (XIII). The benzyl protecting groups of (XIII) were removed with BCl3, and the resulting mixture of diols was separated by preparative RP-HPLC. The desired isomer (XIV) was acetylated with Ac2O to give the diacetate ester (XV). After iodination of (XV) using LiI and ammonium cerium nitrate, the acetate groups were removed by treatment with methanolic NaOMe to afford 5-iodouracil (XVI). Subsequent Heck reaction of (XVI) with methyl acrylate (XVII) in the presence of Pd(OAc)2 and PPh3 produced ester (XVIII) together with some deiodinated product. Hydrolysis of the ester function of (XVIII) gave carboxylic acid (XIX), which was finally treated with N-bromosuccinimide and K2CO3 in DMF to yield the target bromovinyl compound.

1 Upcroft, P.; Campbell, R.W.; Benakli, K.; Upcroft, J.A.; Vanelle, P.; Efficacy of new 5-nitroimidazoles against metronidazole-susceptible and -resistant Giardia, Trichomonas, and Entamoeba spp. Antimicrob Agents Chemother 1999, 43, 1, 73.
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) 25274 (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenyl acetate C22H26O4S 详情 详情
(XII) 25275 1,3-bis(trimethylsilyl)-2,4(1H,3H)-pyrimidinedione C10H20N2O2Si2 详情 详情
(XIII) 25276 1-[(4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenyl]-2,4(1H,3H)-pyrimidinedione C24H26N2O4S 详情 详情
(XIV) 25277 1-[(2R,4R,5S)-4,5-bis(hydroxymethyl)tetrahydro-2-thiophenyl]-2,4(1H,3H)-pyrimidinedione C10H14N2O4S 详情 详情
(XV) 25278 [(2S,3R,5R)-2-[(acetoxy)methyl]-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-thiophenyl]methyl acetate C14H18N2O6S 详情 详情
(XVI) 25279 1-[(2R,4R,5S)-4,5-bis(hydroxymethyl)tetrahydro-2-thiophenyl]-5-iodo-2,4(1H,3H)-pyrimidinedione C10H13IN2O4S 详情 详情
(XVII) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(XVIII) 25280 methyl (E)-3-[1-[(2R,4R,5S)-4,5-bis(hydroxymethyl)tetrahydro-2-thiophenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]-2-propenoate C14H18N2O6S 详情 详情
(XIX) 25281 (E)-3-[1-[(2R,4R,5S)-4,5-bis(hydroxymethyl)tetrahydro-2-thiophenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]-2-propenoic acid C13H16N2O6S 详情 详情
Extended Information