Diisopropylethylamine → tert-butyl 6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

HRID 2202277Notes

Reaction equation

HRID 2202277 reaction equation
C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH2:37][CH3:38])[CH:32]=2)[CH:27]1[C:39]([OH:41])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[CH2:42]([O:44][CH2:45][C:46]([C:49]1[C:55]([F:56])=[CH:54][C:52]([NH2:53])=[CH:51][C:50]=1[F:57])([CH3:48])[CH3:47])[CH3:43].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH2:37]([O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]([C:39](=[O:41])[NH:53][C:52]1[CH:51]=[C:50]([F:57])[C:49]([C:46]([CH3:48])([CH3:47])[CH2:45][O:44][CH2:42][CH3:43])=[C:55]([F:56])[CH:54]=1)[N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:35][CH2:34]2)[CH3:38]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 1186226932-(Tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acidHCID 1186227684-(1-Ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline

Product 1

HCID 118622749tert-butyl 6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateYield 50.2%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

T3P (4.62 mL, 7.85 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (841 mg, 2.62 mmol), 4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (600 mg, 2.62 mmol), DIEA (2.285 mL, 13.09 mmol) and DMAP (320 mg, 2.62 mmol) in ethyl acetate (5 mL), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give tert-butyl 6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (700 mg, 1.314 mmol, 50.2%) as white crystals.

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washThe organic layer was washed with brine
  3. dry with materialdried over magnesium sulfate
  4. customthe solvent was evaporated under reduced pressure
  5. customThe obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane)
  6. customcrystallized from ethyl acetate/hexane

Sources & evidence

ORD record
ord-8bb9a0cc47094b7695dfba37ec0e359c
Source dataset
uspto-grants-2016_06
Patent number
US09365520B2

Reaction notes

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