Trifluoroacetic acid → tert-Butyl 4-[(2-aminopyridin-3-yl)amino]piperidine-1-carboxylate

HRID 528026Notes

Reaction equation

HRID 528026 reaction equation
O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH2:22].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[NH2:22][C:16]1[C:17]([NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:19]=[CH:20][N:15]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 99562,3-DiaminopyridineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 22293217tert-Butyl 4-[(2-aminopyridin-3-yl)amino]piperidine-1-carboxylateYield 883.8%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A 50 mL 3-necked round bottom flask fitted with a thermometer and an overhead stirrer was charged with tert-butyl 4-oxopiperidine-1-carboxylate (3.00 g, 15.1 mmol) and acetonitrile (25 mL, HPLC grade). The reaction mixture was stirred at room temperature for 10 minutes to ensure complete dissolution of all solid material. Pyridine-2,3-diamine (1.50 g, 13.7 mmol) was added, the slurry was stirred for an additional 30 minutes, and resulted in the formation of a dark brown solution. The reaction mixture was cooled to 5° C. and trifluoroacetic acid (2 mL) was added over a period of 20 minutes. During the course of the addition, fuming was observed, accompanied by a slight temperature rise to 10-15° C. The reaction mixture was stirred for an additional 30 minutes at 5-10° C., and sodium triacetoxyborohydride (4.37 g, 20.6 mmol) was added over a period of 20 minutes. The ice bath was removed and the reaction mixture was stirred for an additional 30 minutes. The flask was placed back in an ice bath and aqueous 4M sodium hydroxide was added to the reaction in small portions to adjust the reaction mixture to pH 8. The solution was stirred for an additional 30 minutes, cooled to 5° C., and diluted with ice cold water (80 mL), and resulted in the formation of a brown precipitate. The resulting slurry was stirred overnight at room temperature. The solids were collected by vacuum filtration, washed with cold water (3×5 mL) and dried to constant weight to give 35.4 g (88% yield) of tert-butyl 4-(2-aminopyridin-3-ylamino)piperidine-1-carboxylate. This material was submitted to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (dd, 1H), 6.64 (d, 1H), 6.17 (dd, 1H), 5.43 (broad s, 2H), 4.48 (d, 1H), 3.88 (d, 2H), 3.38 (broad s, 1H), 2.87 (broad s, 2.87), 1.87 (d, 2H), 1.38 (s, 9H), 1.19 (m, 2H). MS (EI) for C15H24N4O2: 293 (MH+)

Workup

  1. customA 50 mL 3-necked round bottom flask fitted with a thermometer and an overhead stirrer
  2. dissolutiondissolution of all solid material
  3. stirringthe slurry was stirred for an additional 30 minutes
  4. customresulted in the formation of a dark brown solution
  5. temperatureThe reaction mixture was cooled to 5° C.
  6. additionDuring the course of the addition
  7. customaccompanied by a slight temperature rise to 10-15° C
  8. stirringThe reaction mixture was stirred for an additional 30 minutes at 5-10° C.
  9. customThe ice bath was removed
  10. stirringthe reaction mixture was stirred for an additional 30 minutes
  11. customThe flask was placed back in an ice bath
  12. additionaqueous 4M sodium hydroxide was added to the reaction in small portions
  13. stirringThe solution was stirred for an additional 30 minutes
  14. temperaturecooled to 5° C.
  15. additiondiluted with ice cold water (80 mL)
  16. customresulted in the formation of a brown precipitate
  17. stirringThe resulting slurry was stirred overnight at room temperature
  18. filtrationThe solids were collected by vacuum filtration
  19. washwashed with cold water (3×5 mL)
  20. customdried to constant weight

Sources & evidence

ORD record
ord-e3e4d0f33e0a439392eb7e2b97b40c35
Source dataset
uspto-grants-2016_05
Patent number
US09346807B2

Reaction notes

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