Sodium Hydroxide → Ethyl (2R,6S,12Z,13aS,14aR,16aS)-6-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)-2-[(6-methoxy-7-vinylisoquinolin-1-yl)oxy]-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate

HRID 389219Notes

Reaction equation

HRID 389219 reaction equation
[CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:4].CCN(C(C)C)C(C)C.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[NH2:31][C@@H:32]1[C:46](=[O:47])[N:45]2[CH2:48][C@H:49]([O:51][C:52]3[C:61]4[C:56](=[CH:57][C:58]([O:64][CH3:65])=[C:59]([CH:62]=[CH2:63])[CH:60]=4)[CH:55]=[CH:54][N:53]=3)[CH2:50][C@H:44]2[C:43](=[O:66])[NH:42][C@:41]2([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH2:67][C@H:40]2[CH:39]=[CH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[OH-].[Na+]>O1CCOCC1.C([O-])(O)=O.[Na+]>[CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][O:4][C:19]([NH:31][C@@H:32]1[C:46](=[O:47])[N:45]2[CH2:48][C@H:49]([O:51][C:52]3[C:61]4[C:56](=[CH:57][C:58]([O:64][CH3:65])=[C:59]([CH:62]=[CH2:63])[CH:60]=4)[CH:55]=[CH:54][N:53]=3)[CH2:50][C@H:44]2[C:43](=[O:66])[NH:42][C@:41]2([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH2:67][C@H:40]2[CH:39]=[CH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:21]

Participants

8

Reactant 5

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 107491582,2-Dimethylpent-4-en-1-olHCID 86647504Ethyl (2R,6S,12Z,13aS,14aR,16aS)-6-amino-2-[(6-methoxy-7-vinylisoquinolin-1-yl)oxy]-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate hydrochloride

Product 1

HCID 59571174Ethyl (2R,6S,12Z,13aS,14aR,16aS)-6-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)-2-[(6-methoxy-7-vinylisoquinolin-1-yl)oxy]-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylateYield 85.9%

Reagents, catalysts & solvents 2

HCID 312751,4-DioxaneSolvent2×HCID 516892Sodium BicarbonateSolvent

Procedure

To a stirred solution of 2,2-dimethylpent-4-en-1-ol (66.3 mg, 0.581 mmol) and DIPEA (0.101 mL, 0.581 mmol) in anhydrous 1,4-dioxane (10 mL), at 10° C., under nitrogen, was added a solution of triphosgene (60.3 mg, 0.203 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at RT for 1 hour. The product from Step 6 (178 mg, 0.290 mmol) and 1 M NaOH (0.871 mL) were then added and the reaction mixture was stirred at 50° C. for 15 hours. The reaction mixture was cooled to RT, diluted with aqueous saturated NaHCO3 (20 mL) and extracted with EtOAc (3×30 mL). The combined EtOAc layers were washed with water (30 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 5% to 75% EtOAc in hexane, to give the title product (125 mg). LRMS (ESI) m/z 717.5 [(M+H)+; calcd for C40H53N4O8: 717.4].

Workup

  1. stirringthe reaction mixture was stirred at 50° C. for 15 hours
  2. temperatureThe reaction mixture was cooled to RT
  3. extractionextracted with EtOAc (3×30 mL)
  4. washThe combined EtOAc layers were washed with water (30 mL), brine (20 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was chromatographed on silica gel
  9. washeluting with 5% to 75% EtOAc in hexane

Sources & evidence

ORD record
ord-6ba04cd58b0349b88b7eeea3af1bf5ff
Source dataset
uspto-grants-2013_02
Patent number
US08377874B2

Reaction notes

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