Trifluoroacetic acid → ethyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate

HRID 921706Notes

Reaction equation

HRID 921706 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:24])=[C:10]([NH:16]C(=O)OC(C)(C)C)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:25].CCN(C(C)C)C(C)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(O)(C(F)(F)F)=O>CO.ClCCCl>[NH2:16][C:10]1[C:9]([Cl:24])=[C:8]([N:5]2[CH2:6][CH2:7][C@@H:2]([NH:1][C:36](=[O:37])[O:38][CH2:39][CH3:40])[C@H:3]([OH:25])[CH2:4]2)[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10928Ethyl chloroformateHCID 81531DiisopropylethylamineHCID 89919946tert-butyl (3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate

Product 1

HCID 131732395ethyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamateYield 39.7%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Procedure

A solution of tert-butyl (3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (Example 173A) (300 mg, 0.818 mmol) and DIPEA (0.428 mL, 2.453 mmol) in MeOH (15 mL) at 0° C. (ice bath) was treated with ethyl chloroformate (0.078 mL, 0.818 mmol). The reaction was stirred for 1 hour, and then the mixture was concentrated in vacuo. To the residue was added EtOAc (50 ml) and the mixture washed with 0.5M citric acid, sat. NaHCO3, water and brine. The solution was dried over Na2SO4 and solvents removed. To the crude material was added. DCE (5 mL) and TFA (2 mL, 26.0 mmol); the reaction stirred 2 h at 25° C. and solvents removed. The material was diluted with DCM and washed with sat. NaHCO3 and water. The organics dried over Na2SO4 and removed solvent. The material was purified on silica gel 25% EtOAc-DCM to afford ethyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate (110 mg).

Workup

  1. concentrationthe mixture was concentrated in vacuo
  2. additionTo the residue was added EtOAc (50 ml)
  3. washthe mixture washed with 0.5M citric acid, sat. NaHCO3, water and brine
  4. dry with materialThe solution was dried over Na2SO4 and solvents
  5. customremoved
  6. additionTo the crude material was added
  7. stirringthe reaction stirred 2 h at 25° C.
  8. customsolvents removed
  9. additionThe material was diluted with DCM
  10. washwashed with sat. NaHCO3 and water
  11. dry with materialThe organics dried over Na2SO4
  12. customremoved solvent
  13. customThe material was purified on silica gel 25% EtOAc-DCM

Sources & evidence

ORD record
ord-df31c8e03afc4af8ac7fe07039ad1e84
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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