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【结 构 式】 
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【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 |