Phosgene → tert-Butyl N-[6-({7-bromo-15,15-difluoro-4,17,20-trimethyl-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]-N-[(tert-butoxy)carbonyl]carbamate

HRID 708821Notes

Reaction equation

HRID 708821 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:53])=[C:6]([CH2:8][N:9]([CH3:52])[C:10]([CH:12]([NH:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:32][CH:31]=[CH:30]3)[C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]([F:24])([F:23])[CH2:21][OH:22])=[C:15]([CH3:25])[CH:14]=2)=[O:11])[CH:7]=1.[C:54](Cl)(Cl)=[O:55]>ClCCl.C(#N)C>[Br:53][C:5]1[CH:4]=[CH:3][C:2]2=[CH:7][C:6]=1[CH2:8][N:9]([CH3:52])[C:10](=[O:11])[CH:12]([NH:26][C:27]1[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=1)[C:33]([N:37]([C:38]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:44])[C:45](=[O:46])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:32][CH:31]=[CH:30]3)[C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([C:20]([F:23])([F:24])[CH2:21][O:22][C:54](=[O:55])[NH:1]2)=[C:17]([CH3:19])[CH:18]=1

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 118098688tert-Butyl N-{6-[({[(5-amino-2-bromophenyl)methyl](methyl)carbamoyl}[4-(1,1-difluoro-2-hydroxyethyl)-3,5-dimethylphenyl]methyl)amino]isoquinolin-1-yl}-N-[(tert-butoxy)carbonyl]carbamate

Product 1

HCID 118098689tert-Butyl N-[6-({7-bromo-15,15-difluoro-4,17,20-trimethyl-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]-N-[(tert-butoxy)carbonyl]carbamateYield 59.4%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 4A (289 mg, 0.362 mmol) in dichloromethane (5 mL) and acetonitrile (5.00 mL) at 0° C., was added phosgene (20% in toluene) (0.242 mL, 0.488 mmol). The reaction mixture was stirred at 0° C. for 15 min. Nitrogen was bubbled though the mixture for 0.5 h, then DMPU (˜0.4 mL) was added. The resulting solution was added dropwise via a syringe pump into a solution of TEA (0.353 mL, 2.53 mmol) in dichloromethane (90 mL) at rt over 4 h, stirred for an additional 15 min and then evaporated. The crude product was purified by flash chromatography to give 4B (177 mg, 0.215 mmol, 59.3% yield) as a white solid. MS and 1H NMR are consistent with the desired product.

Workup

  1. customNitrogen was bubbled though the mixture for 0.5 h
  2. additionDMPU (˜0.4 mL) was added
  3. stirringstirred for an additional 15 min
  4. customevaporated
  5. customThe crude product was purified by flash chromatography

Sources & evidence

ORD record
ord-10c1514a7fa4439f8372f467f42b8d13
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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