1,1'-Carbonyldiimidazole → 1-[(1S,3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone

HRID 1854562Notes

Reaction equation

HRID 1854562 reaction equation
C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][C:22]([OH:24])=O.[Si:25]([O:32][CH2:33][C@H:34]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:44][CH2:45][C:46]([CH3:49])([OH:48])[CH3:47])[C@H:36]([CH3:50])[NH:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O1CCCC1>[Si:25]([O:32][CH2:33][C@H:34]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:44][CH2:45][C:46]([OH:48])([CH3:49])[CH3:47])[C@H:36]([CH3:50])[N:35]1[C:22](=[O:24])[CH2:21][C:15]1[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 810582,6-Dichlorophenylacetic acidHCID 1236252274-((1S,3R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbutan-2-ol

Product 1

HCID 1234269101-[(1S,3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanoneYield 97.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
25 °C

Procedure

Add 1,1′-carbonyldiimidazole (112.9 g, 682.36 mmol) to a mixture of 2,6-dichlorophenylacetic acid (173.09 g, 818.83 mmol) in tetrahydrofuran (1.63 L) in an appropriate vessel and stir at 25° C. After 1 hour add a solution of 4-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (217 g, 545.89 mmol) in tetrahydrofuran (1.63 L) to the mixture, heat the mixture to 45° C. and stir. After 24 hours, cool the mixture to 20° C., remove 2 L of tetrahydrofuran by concentrating under reduced pressure and dilute the residues with ethyl acetate (2.5 L). Wash the ethyl acetate solution with saturated aqueous ammonium chloride (1.5 L), 1M aqueous sodium hydroxide (1 L), water (1 L) and brine (1.5 L). Dry the organics over anhydrous sodium sulfate and concentrate under reduced pressure to give the title compound (376 g, 532.70 mmol). MS (m/z): 564.2 (M+1 (35C1)), 566.2 (M+1 (37Cl)).

Workup

  1. temperatureheat the mixture to 45° C.
  2. stirringstir
  3. temperaturecool the mixture to 20° C.
  4. customremove 2 L of tetrahydrofuran
  5. concentrationby concentrating under reduced pressure
  6. additiondilute the residues with ethyl acetate (2.5 L)
  7. washWash the ethyl acetate solution with saturated aqueous ammonium chloride (1.5 L), 1M aqueous sodium hydroxide (1 L), water (1 L) and brine (1.5 L)
  8. dry with materialDry the organics over anhydrous sodium sulfate
  9. concentrationconcentrate under reduced pressure

Sources & evidence

ORD record
ord-4a916082130246008a28a527cc70ce72
Source dataset
uspto-grants-2015_02
Patent number
US08962654B2

Reaction notes

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