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【结 构 式】

【分子编号】26556

【品名】5,5-dibromo-2,4,6(1H,3H,5H)-pyrimidinetrione

【CA登记号】511-67-1

【 分 子 式 】C4H2Br2N2O3

【 分 子 量 】285.87956

【元素组成】C 16.81% H 0.71% Br 55.9% N 9.8% O 16.79%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XV)

Alternatively, reaction of 6-chloronicotinic acid (XIII) with methyllithium-lithium bromide complex gave methyl ketone (XIV). This was brominated by means of dibromobarbituric acid (XV) to produce bromoketone (XVI). Asymmetric reduction of (XVI) with (-)-B-chlorodiisopinocampheylborane provided the (R)-bromohydrin (XVII), which was converted to epoxide (XVIII) with NaOH in aqueous THF. Epoxide (XVIII) opening with 4-nitrophenethylamine (XIX) produced amino alcohol (XX), which by further protection with Boc2O gave carbamate (XXI). Concomitant dechlorination and nitro group reduction in (XXI) by hydrogenation using Raney Nickel as catalyst provided amine (XI). This was finally converted to the target compound by means of sulfonylation and deprotection as above.

1 Naylor, E.M.; Colandrea, V.J.; Candelore, M.R.; Cascieri, M.A.; Colwell, L.F. Jr; Deng, L.; Feeney, W.P.; Forrest, M.J.; Hom, G.J.; MacIntyre, D.E.; Strader, C.D.; Tota, L.; Wang, P.R.; Wyvratt, M.J.; Fisher, M.H.; Weber, A.E.; 3-Pyridylethanolamines: Potent and selective human beta3 adrenergic receptor agonists. Bioorg Med Chem Lett 1998, 8, 21, 3087.
2 Fisher, M.H.; Naylor, E.M.; Ok, D.; Weber, A.E.; Shih, T.; Ok, H. (Merck & Co., Inc.); Substd. sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0757674; JP 1997512275; US 5541197; US 5561142; WO 9529159 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 26548 4-[[(hexylamino)carbonyl]amino]benzenesulfonyl chloride C13H19ClN2O3S 详情 详情
(XI) 26553 tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate C20H27N3O3 详情 详情
(XIII) 12996 6-Chloronicotinic acid 5326-23-8 C6H4ClNO2 详情 详情
(XIV) 26555 1-(6-chloro-3-pyridinyl)-1-ethanone C7H6ClNO 详情 详情
(XV) 26556 5,5-dibromo-2,4,6(1H,3H,5H)-pyrimidinetrione 511-67-1 C4H2Br2N2O3 详情 详情
(XVI) 26557 2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanone C7H5BrClNO 详情 详情
(XVII) 26558 (1R)-2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanol C7H7BrClNO 详情 详情
(XVIII) 26559 2-chloro-5-[(2R)oxiranyl]pyridine C7H6ClNO 详情 详情
(XIX) 26560 4-nitrophenethylamine 24954-67-4 C8H10N2O2 详情 详情
(XX) 26561 (1R)-1-(6-chloro-3-pyridinyl)-2-[(4-nitrophenethyl)amino]-1-ethanol C15H16ClN3O3 详情 详情
(XXI) 26562 tert-butyl (2R)-2-(6-chloro-3-pyridinyl)-2-hydroxyethyl(4-nitrophenethyl)carbamate C20H24ClN3O5 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

Reaction of 6-chloronicotinic acid (I) with methyllithium lithium bromide complex gives methyl ketone (II), which is treated with dibromobarbituric acid (III) in refluxing THF to afford bromoketone (IV). Asymmetric reduction of (IV) with (-)-DIP-chloride [(-)-B-chlorodiisopinocampheylborane] provides bromohydrin (V), which is converted into epoxide (VI) by treatment with NaOH in THF/H2O. Opening of the epoxide moiety of (VI) with p-nitrophenethylamine hydrochloride (VII) in MeOH in the presence of Et3N followed by N-protection with Boc2O in THF yields ethanolamine (VIII), which is then hydrogenated over Ni-Raney in EtOH/NaOH to furnish dechlorinated aniline (IX). Condensation of (IX) with 1,1-bis(methylsulfanyl)-2-nitroethylene (X) in isopropanol gives compound (XI), which is then subjected to reaction with aniline (XII) in isopropanol to afford nitroethylenediamine (XIII). Finally, the desired product is obtained by Boc removal of (XIII) by treatment with TFA in CH2Cl2.

1 Wyvratt, M.J.; Cascieri, M.A.; Liu, Y.; Parmee, E.R.; Tota, L.; Brockunier, L.L.; Candelore, M.R.; Fisher, M.H.; Weber, A.E.; Human beta3 adrenergic receptor agonists containing cyanoguanidine and nitroethylenediamide moieties. Bioorg Med Chem Lett 2001, 11, 3, 379.
2 Naylor, E.M.; Colandrea, V.J.; Candelore, M.R.; Cascieri, M.A.; Colwell, L.F. Jr; Deng, L.; Feeney, W.P.; Forrest, M.J.; Hom, G.J.; MacIntyre, D.E.; Strader, C.D.; Tota, L.; Wang, P.R.; Wyvratt, M.J.; Fisher, M.H.; Weber, A.E.; 3-Pyridylethanolamines: Potent and selective human beta3 adrenergic receptor agonists. Bioorg Med Chem Lett 1998, 8, 21, 3087.
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) 12996 6-Chloronicotinic acid 5326-23-8 C6H4ClNO2 详情 详情
(II) 26555 1-(6-chloro-3-pyridinyl)-1-ethanone C7H6ClNO 详情 详情
(III) 26556 5,5-dibromo-2,4,6(1H,3H,5H)-pyrimidinetrione 511-67-1 C4H2Br2N2O3 详情 详情
(IV) 26557 2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanone C7H5BrClNO 详情 详情
(V) 26558 (1R)-2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanol C7H7BrClNO 详情 详情
(VI) 26559 2-chloro-5-[(2R)oxiranyl]pyridine C7H6ClNO 详情 详情
(VII) 26560 4-nitrophenethylamine 24954-67-4 C8H10N2O2 详情 详情
(VIII) 26562 tert-butyl (2R)-2-(6-chloro-3-pyridinyl)-2-hydroxyethyl(4-nitrophenethyl)carbamate C20H24ClN3O5 详情 详情
(IX) 26553 tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate C20H27N3O3 详情 详情
(X) 13853 Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene 13623-94-4 C4H7NO2S2 详情 详情
(XI) 48294 tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl(4-[[(Z)-1-(methylsulfanyl)-2-nitroethenyl]amino]phenethyl)carbamate C23H30N4O5S 详情 详情
(XII) 48295 3-aminobenzamide 3544-24-9 C7H8N2O 详情 详情
(XIII) 48296 tert-butyl 4-([(Z)-1-[3-(aminocarbonyl)anilino]-2-nitroethenyl]amino)phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate C29H34N6O6 详情 详情
Extended Information