Phosgene → tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-{[(2R,15R)-7-(cyclopropanesulfonyl)-15-(fluoromethyl)-4,17-dimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaen-2-yl]amino}isoquinolin-1-yl)carbamate

HRID 708888Notes

Reaction equation

HRID 708888 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:31][CH:30]=[CH:29]3)[C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([CH2:22][OH:23])[CH2:20][F:21])=[C:15]([CH3:24])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:32]1[C:33]2[C:28](=[CH:27][C:26]([NH:25][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:53])=[O:54])[NH:1][C:58](=[O:59])[O:23][CH2:22][C@H:19]([CH2:20][F:21])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:24])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:41])[CH3:40]

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 118098757tert-Butyl N-(6-{[({[5-amino-2-(cyclopropanesulfonyl)phenyl]methyl}(methyl)carbamoyl)({4-[(2R)-1-fluoro-3-hydroxypropan-2-yl]-3-methylphenyl})methyl]amino}isoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamate

Product 1

HCID 118098758tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-{[(2R,15R)-7-(cyclopropanesulfonyl)-15-(fluoromethyl)-4,17-dimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaen-2-yl]amino}isoquinolin-1-yl)carbamateYield 76%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 24E (0.1 g, 0.124 mmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) at 0° C., was added phosgene solution (20% in toluene, 0.072 mL, 0.136 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was then added dropwise via syringe pump into a solution of TEA (0.138 mL, 0.993 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. Solvent was removed, and the crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give a mixture of diastereoisomers (0.1 g, 0.120 mmol, 97% yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 24F (38 mg, 76% yield). MS (ESI) (m/z): 831.9 (M+H)+.

Workup

  1. customExtra phosgene was removed
  2. customby bubbling Ar for 20 min
  3. stirringThe solution was stirred at rt over night
  4. customSolvent was removed
  5. customthe crude product was purified by flash chromatography (0-80% EtOAc/hexanes)
  6. customto give
  7. additiona mixture of diastereoisomers (0.1 g, 0.120 mmol, 97% yield)
  8. customThe diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm)

Sources & evidence

ORD record
ord-090dd84bae6443b9b0bb2620905ffbf9
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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