Phosgene → tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-{[(2R,15R)-7-(cyclopropanesulfonyl)-18-fluoro-20-methoxy-4,15-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}-7-fluoroisoquinolin-1-yl)carbamate

HRID 708892Notes

Reaction equation

HRID 708892 reaction equation
[C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:58]([CH:61]2[CH2:63][CH2:62]2)(=[O:60])=[O:59])=[C:10]([CH2:12][N:13]([CH3:57])[C:14]([CH:16]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][C:40]=2[F:41])[C:37]([N:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:36][CH:35]=[CH:34]3)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([C@@H:25]([CH3:28])[CH2:26][OH:27])=[CH:19][C:18]=2[F:29])=[O:15])[CH:11]=1>C(#N)C.C(Cl)Cl>[C:45]([O:44][C:43]([N:42]([C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][C@H:16]3[C:14](=[O:15])[N:13]([CH3:57])[CH2:12][C:10]4[CH:11]=[C:6]([CH:7]=[CH:8][C:9]=4[S:58]([CH:61]4[CH2:62][CH2:63]4)(=[O:59])=[O:60])[NH:5][C:1](=[O:2])[O:27][CH2:26][C@H:25]([CH3:28])[C:20]4[C:21]([O:23][CH3:24])=[CH:22][C:17]3=[C:18]([F:29])[CH:19]=4)=[C:40]([F:41])[CH:39]=2)[CH:34]=[CH:35][N:36]=1)[C:50](=[O:51])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:49])([CH3:47])([CH3:48])[CH3:46]

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 118101244tert-Butyl N-(6-{[({[5-amino-2-(cyclopropanesulfonyl)phenyl]methyl}(methyl)carbamoyl)({2-fluoro-4-[(2R)-1-hydroxypropan-2-yl]-5-methoxyphenyl})methyl]amino}-7-fluoroisoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamate

Product 1

HCID 118101213tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-{[(2R,15R)-7-(cyclopropanesulfonyl)-18-fluoro-20-methoxy-4,15-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}-7-fluoroisoquinolin-1-yl)carbamateYield 13.11%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Procedure

Phosgene (87 mg, 0.176 mmol) was added dropwise to a solution of 25D (148 mg, 0.176 mmol) in acetonitrile (2.5 mL)/CH2Cl2 (2.5 mL) at 0° C. The mixture was stirred at rt for 30 min. Ar was bubbled though the solution (10 min) to remove excess phosgene, and then the mixture was added to a solution of TEA (0.123 mL, 0.881 mmol) in CH2Cl2 (25 mL) at 40° C. over 5 h. The reaction was stirred at rt overnight, quenched with H2O (1 mL) and MeOH (5 mL) and then concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% ethyl acetate in hexane over 15 min using a 12 g silica gel cartridge). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 25E (20 mg, 0.023 mmol, 13.11% yield).

Workup

  1. customAr was bubbled though the solution (10 min)
  2. customto remove excess phosgene
  3. stirringThe reaction was stirred at rt overnight
  4. customquenched with H2O (1 mL) and MeOH (5 mL)
  5. concentrationconcentrated
  6. customThe crude product was purified by flash chromatography (loading in chloroform
  7. wait0% to 100% ethyl acetate in hexane over 15 min using
  8. customThe diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm)

Sources & evidence

ORD record
ord-6cdb233632cf4b9c8d8e87f465f52981
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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