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Trifluoroacetic acid → (1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine

HRID 1526653
Notes
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Reaction equation

HRID 1526653 reaction equation
C(OC(=O)[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH:24][C@H:25]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=4)[C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:20][C:19]=3[F:37])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)(C)(C)C.C(OC(=O)[NH:45][C:46]1[O:47][C@H:48]2[C@@H:50]([C@:51]([C:56]3[CH:61]=[C:60]([NH:62][C@@H:63]([C:68]4[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][N:69]=4)[C:64]([F:67])([F:66])[F:65])[CH:59]=[CH:58][C:57]=3[F:75])([CH:53]([F:55])[F:54])[N:52]=1)[CH2:49]2)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:25]([NH:24][C:22]2[CH:21]=[CH:20][C:19]([F:37])=[C:18]([C@:13]3([CH:15]([F:16])[F:17])[C@@H:12]4[C@@H:10]([CH2:11]4)[O:9][C:8]([NH2:7])=[N:14]3)[CH:23]=2)[C:26]([F:27])([F:28])[F:29])=[N:31][CH:32]=1.[Cl:74][C:71]1[CH:72]=[CH:73][C:68]([C@H:63]([NH:62][C:60]2[CH:59]=[CH:58][C:57]([F:75])=[C:56]([C@:51]3([CH:53]([F:54])[F:55])[C@@H:50]4[C@@H:48]([CH2:49]4)[O:47][C:46]([NH2:45])=[N:52]3)[CH:61]=2)[C:64]([F:65])([F:66])[F:67])=[N:69][CH:70]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 131733177tert-butyl ((1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)-carbamateHCID 131733178tert-butyl ((1R,5S,6R)-5-(5-(((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate

Product 2

HCID 90401361
(1R,5S,6R)-5-(5-(((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine
HCID 90401362(1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amineYield 97%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl((1R,5S,6R)-5-(5-(((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate and tert-butyl((1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (1:1 mixture of diastereomers, 0.070 g, 0.12 mmol) in DCM (2 mL) at room temperature was added trifluoroacetic acid (2.00 mL, 0.124 mmol). The reaction mixture was stirred at room temperature for 30 min and concentrated. The concentrate was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was discarded. The organic phase was washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (12 g, 20% to 60% EtOAc in heptane) to give (1R,5S,6R)-5-(5-(((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine and (1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (1:1 mixture of diastereomers, 0.056 g, 0.120 mmol, 97% yield) as a white solid. MS m/z=465.0 [M+H]+. Calculated for C19H15ClF6N4O 464.1. 1H NMR (400 MHz, CDCl3) δ 0.86-0.95 (m, 1H), 1.32-1.41 (m, 1H), 1.73-1.85 (m, 1H), 3.83-3.90 (m, 1H), 4.50 (br s, 2H), 4.87-4.97 (m, 1H), 5.33 (dd, J=11.93, 7.63 Hz, 1H), 6.02-6.34 (m, 1H), 6.60-6.66 (m, 1H), 6.87-6.96 (m, 2H) 7.27-7.35 (m, 1H), 7.65-7.70 (m, 1H), 8.57-8.59 (m, 1H).

Workup

  1. concentrationconcentrated
  2. customThe concentrate was partitioned between saturated NaHCO3 and EtOAc
  3. washThe organic phase was washed with brine
  4. dry with materialdried over MgSO4
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe residue was purified by flash column chromatography on silica gel (12 g, 20% to 60% EtOAc in heptane)

Sources & evidence

ORD record
ord-399f29b3fa3a46fcbe073825df1e01da
Source dataset
uspto-grants-2015_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09085576B2

Reaction notes

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