2,6-Lutidine → 1-((4S,5R)-5-(4-(6-(aminomethyl)pyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-3-yl)-2,2-difluoroethanone

HRID 525526Notes

Reaction equation

HRID 525526 reaction equation
[F:1][CH:2]([F:35])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25]C(=O)OC(C)(C)C)=[N:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:34])[CH3:33])=[O:4].N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.[NH4+].[Cl-].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[NH2:25][CH2:24][C:21]1[N:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C@H:8]3[O:7][C:6]([CH3:33])([CH3:34])[N:5]([C:3](=[O:4])[CH:2]([F:35])[F:1])[C@@H:9]3[CH2:10][F:11])=[CH:17][CH:16]=2)=[CH:19][CH:20]=1

Participants

7

Reactant 5

HCID 79372,6-Lutidine2×HCID 25517Ammonium Chloride2×HCID 123564tert-Butyldimethylsilyl trifluoromethanesulphonate2×HCID 2724141Tetrabutylammonium FluorideHCID 86695413tert-butyl (5-(4-((4S,5R)-3-(2,2-difluoroacetyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-5-yl)phenyl)pyridin-2-yl)methylcarbamate

Product 1

HCID 866954151-((4S,5R)-5-(4-(6-(aminomethyl)pyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-3-yl)-2,2-difluoroethanoneYield 6.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of tert-butyl (5-(4-((4S,5R)-3-(2,2-difluoroacetyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-5-yl)phenyl)pyridin-2-yl)methylcarbamate (970 mg, 4.5 mmol) in CH2Cl2 (25 mL) at 0° C. is added 2,6-lutidine (4604, 3.9 mmol) followed by t-butyldimethylsilyltrifluoromethanesulfonate (7004, 2.9 mmol). The reaction is stirred at room temperature for 18 hours. Additional lutidine (2304, 1.9 mmol) and t-butyldimethylsilyltrifluoromethanesulfonate (3504, 1.4 mmol) is added and contents heated to 35° C. for 1 hour. Saturated NH4Cl is added and the reaction is stirred for 15 minutes. Contents are diluted with CH2Cl2 and separated. The organic phase is washed with saturated NH4Cl, saturated NaHCO3, brine, dried (Na2SO4) and concentrated under vacuum. Crude silyl carbamate is dissolved in tetrahydrofuran (20 mL) and tetrabutylammonium fluoride (0.6 mL, 2.0 mmol) is added and stirred for 20 minutes. Saturated NH4Cl is added and contents are extracted with ethylacetate. The organic phase is washed successively with saturated sodium hydrogen carbonate, brine, dried with Na2SO4 and concentrated under vacuum to afford the title compound (123 mg): m/z (Cl) M+H 394.

Workup

  1. temperaturecontents heated to 35° C. for 1 hour
  2. stirringthe reaction is stirred for 15 minutes
  3. customseparated
  4. washThe organic phase is washed with saturated NH4Cl, saturated NaHCO3, brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated under vacuum
  7. dissolutionCrude silyl carbamate is dissolved in tetrahydrofuran (20 mL)
  8. stirringstirred for 20 minutes
  9. extractioncontents are extracted with ethylacetate
  10. washThe organic phase is washed successively with saturated sodium hydrogen carbonate, brine
  11. dry with materialdried with Na2SO4
  12. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-0612d9eb7da74fb880b2e831ce8bb311
Source dataset
uspto-grants-2016_05
Patent number
US09340564B2

Reaction notes

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