Triethylamine → tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate

HRID 705754Notes

Reaction equation

HRID 705754 reaction equation
Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]3)=[CH:16][C:15]=2[O:33][CH3:34])[N:7]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 57416157Tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate

Product 1

HCID 86675841tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylateYield 30%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 21868497Tert-butyl alcohol 1,2-dichloroethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

Zinc chloride (1.0 M in Et2O) (8.56 mL, 8.56 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.06 mL, 7.85 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under nitrogen. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (I26) (1.97 g, 7.13 mmol) in 1:1 DCE/tBuOH (30 mL) was added. A solution of triethylamine (600 μL, 0.432 mmol, 1.1 eq) in 1:1 DCE/t-BuOH (10 mL) was next added drop-wise at 0° C. The reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final addition and then at room temperature for 24 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-45% EtOAc in petroleum benzine 40-60° C.) to give a pale yellow oil which solidified upon standing. This was triturated sequentially with water, 1:1 water/MeOH and MeOH and the precipitate was filtered to afford a white solid. The solid was recrystallised from water to give the title compound (I34) (0.92 g, 30%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 6.86 (dd, J=8.4, 1.7 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.25 (s, 2H), 3.91 (s, 3H), 2.81 (t, J=11.8 Hz, 2H), 2.64 (tt, J=12.1, 3.6 Hz, 1H), 1.83 (d, J=13.5 Hz, 2H), 1.69-1.57 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 7.00 min; m/z=487.0 [M+H]+, 431.0 [M-tButyl+H]+, 485.0 [M−H]−.

Workup

  1. customat 0° C
  2. stirringThe reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final
  3. additionaddition
  4. waitat room temperature for 24 hours
  5. customThe solvent was removed in vacuo
  6. customto afford a brown oily residue which
  7. customwas purified by column chromatography on silica gel (0-45% EtOAc in petroleum benzine 40-60° C.)
  8. customto give a pale yellow oil which
  9. customThis was triturated sequentially with water, 1:1 water/MeOH and MeOH
  10. filtrationthe precipitate was filtered
  11. customto afford a white solid
  12. customThe solid was recrystallised from water

Sources & evidence

ORD record
ord-1b51f24e9ac74df0b2c28aed4df5625c
Source dataset
uspto-grants-2015_11
Patent number
US09174946B2

Reaction notes

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