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【结 构 式】

【药物名称】DASABUvIR

【化学名称】N-[6-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl]naphthalen-2-yl]methanesulfonamide

【CA登记号】946414-94-4

【 分 子 式 】C26H27N3O5S

【 分 子 量 】493.575

【开发单位】 

【药理作用】Treatment of hepatitis C virus infection

合成路线1

Iodination of 2-tert-butylphenol (I) with excess NaI and NaOCl in the presence of NaOH in MeOH gives 2-tert-butyl-4,6-diiodophenol (II), which is O-alkylated with Me2SO4 and K2CO3 or with MeI and NaOH in refluxing acetone to yield 1-tert-butyl-3,5-diiodo-2-methoxybenzene (III). goldberg reaction of aryl iodide (III) with uracil (Iv) by means of CuI, K3PO4 and N-(2-cyanophenyl)picolinamide in DMSO at 60 °C affords 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)uracil (v) (1-4), which by Suzuki coupling with 6-hydroxy-2-naphthylboronic acid (vI) in the presence of Pd2dba3, K3PO4 and meCgPPh (1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.113,7]decane) in THF provides adduct (vII). Condensation of naphthol (vII) with perfluoro-butanesulfonyl fluoride (vIII) and K2CO3 in acetonitrile/DMF produces sulfonate (IX), which is finally condensed with methanesulfonamide (X) using Pd2dba3, K3PO4 and t-BuBrettPhos in t-amyl alcohol at 60 °C, THF, 2-MeTHF or EtOAc .
In a related procedure, dasabuvir is obtained by Suzuki coupling of aryl iodide (v) with pinacol 6-(methylsulfonamido)-2-naphth-ylboronate (XI) using K3PO4, Pd2dba3 and meCgPPh in THF/H2O at 50 °C .

1 Pratt, J.K., Betebenner, D., Flentge, C. et al. Aryl 1-uracil inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase: Uracil ring replacements. 244th ACS Natl Meet (August 19-23, Philadelphia) 2012, Abst MEDI 146.
3 Flentge, C.A., Hutchinson, D.K., Betebenner, D.A. et al. (Abbott Laboratories). Anti-infective pyrimidines and uses thereof. CN 101842360, CN 102746240, EP 2203431, EP 2368882, EP 2639226, JP 2010539187, US 8188104, US 2012244119, US 8501238, WO 2009039134.
4 Shekhar, S., Franczyk, T.S., Barnes, D.M., Dunn, T.B., Haight, A.R., Chan, v.S. (Abbvie, Inc.) Process for preparing antiviral compounds. CN 103097360, EP 2593439, JP 2013532636, KR 2013043195, US 2012014913, WO 2012009699.
2 Wagner, R., Tufano, M.D., Stewart, K.D. et al. (Abbvie Bahamas Ltd.). Uracil or thymine derivative for treating hepatitis C. CN 101801935, CN 102746239, EP 2222646, JP 2010539186, US 2012213733, WO 2009039127.
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) 67678 2-tert-butylphenol;o-t-Butylphenol;o-tert-Butylphenol;2-tert-Butyl-1-hydroxybenzene;2-(1,1-Dimethylethyl)phenol 88-18-6 C10H14O 详情 详情
(II) 67679 2-tert-butyl-4,6-diiodophenol   C10H12I2O 详情 详情
(III) 67680 1-tert-butyl-3,5-diiodo-2-methoxybenzene   C11H14I2O 详情 详情
(IV) 30921 2,4(1H,3H)-pyrimidinedione; Uracil 66-22-8 C4H4N2O2 详情 详情
(V) 67681 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)uracil   C15H17IN2O3 详情 详情
(VI) 67682 6-hydroxy-2-naphthylboronic acid 173194-95-1 C10H9BO3 详情 详情
(VII) 67683 1-(3-(tert-butyl)-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione   C25H24N2O4 详情 详情
(VIII) 67684 perfluoro-butanesulfonyl fluoride 375-72-4 C4F10O2S 详情 详情
(IX) 67685 6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate   C29H23F9N2O6S 详情 详情
(X) 39701 methanesulfonamide 3144-09-0 CH5NO2S 详情 详情
(XI) 67686 N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide   C17H22BNO4S 详情 详情

合成路线2

The boronate intermediate (XI) is prepared by hydrolysis of methyl 6-bromo-2-naphthoate (XII) with LiOH in H2O/THF to give 6-bromo-2-naphthoic acid (XIII), which by Curtius rearrangement with DPPA and Et3N in DMF at 100 °C yields 6-bromo-2-naphthylamine (XIv). Sulfonylation of amine (XIv) with mesyl chloride (Xv) in pyridine provides the sulfonamido naphthalene (XvI), which finally undergoes borylation with bis(pinacolato)diboron in the presence of KOAc and combiPhos-Pd6 catalyst in refluxing toluene .

1 Pratt, J.K., Betebenner, D., Flentge, C. et al. Aryl 1-uracil inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase: Uracil ring replacements. 244th ACS Natl Meet (August 19-23, Philadelphia) 2012, Abst MEDI 146.
2 Wagner, R., Tufano, M.D., Stewart, K.D. et al. (Abbvie Bahamas Ltd.). Uracil or thymine derivative for treating hepatitis C. CN 101801935, CN 102746239, EP 2222646, JP 2010539186, US 2012213733, WO 2009039127.
3 Flentge, C.A., Hutchinson, D.K., Betebenner, D.A. et al. (Abbott Laboratories). Anti-infective pyrimidines and uses thereof. CN 101842360, CN 102746240, EP 2203431, EP 2368882, EP 2639226, JP 2010539187, US 8188104, US 2012244119, US 8501238, WO 2009039134.
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) 67686 N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide   C17H22BNO4S 详情 详情
(XII) 59539 6-Bromo-2-naphthoic acid methyl ester; Methyl 6-bromo-2-naphthoate 33626-98-1 C12H9BrO2 详情 详情
(XIII) 42564 6-Bromo-2-naphthoic acid;(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid 5773-80-8 C11H7BrO2 详情 详情
(XIV) 55631 6-bromo-2-naphthalenamine; 6-bromo-2-naphthylamine 7499-66-3 C10H8BrN 详情 详情
(XV) 13467 Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride 124-63-0 CH3ClO2S 详情 详情
(XVI) 67687 N-(5-bromonaphthalen-1-yl)methanesulfonamide   C11H10BrNO2S 详情 详情
Extended Information