Trifluoroacetic acid → (+/-)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-4-chlorobenzonitrile

HRID 1430859Notes

Reaction equation

HRID 1430859 reaction equation
[Si:1]([O:8][C@H:9]1[C@H:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:13][CH2:12][N:11]([C:21]2[C:22]([Cl:37])=[C:23]([NH:29]C(=O)OC(C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[CH:26]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:29][C:23]1[CH:24]=[C:25]([CH:26]=[C:21]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:10]2)[C:22]=1[Cl:37])[C:27]#[N:28]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 86708551(+/-)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate

Product 1

HCID 86708550(+/-)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-4-chlorobenzonitrileYield 94%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(+/−)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (138 mg, 0.250 mmol) was treated with TFA (25% in 1,2-dichloroethane, 3 mL, 9.73 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 5-40% ethyl acetate/hexanes). (+/−)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-4-chlorobenzonitrile (106 mg) was obtained as a yellow/brown solid.

Workup

  1. washwashed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10)
  2. customThe layers were separated
  3. extractionaqueous layer was extracted with dichloromethane two more times
  4. dry with materialThe combined organic layers were dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customthe crude product was purified by flash chromatography on silica gel using
  8. washan automated ISCO system (24 g column, eluting with 5-40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-dc4deb4536014d8ca3cd19c49d10fec8
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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