1-Hydroxybenzotriazole → tert-Butyl 4-(4-((4-(2-(3-(2-amino-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

HRID 1485261Notes

Reaction equation

HRID 1485261 reaction equation
O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[N:57]=[C:56]([CH2:58][CH2:59][C:60]4[C:65]([CH2:66][C:67]([O-])=[O:68])=[CH:64][CH:63]=[CH:62][N:61]=4)[C:55]([C:70]([F:73])([F:72])[F:71])=[CH:54][N:53]=3)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:2][C:67](=[O:68])[CH2:66][C:65]1[C:60]([CH2:59][CH2:58][C:56]2[C:55]([C:70]([F:72])([F:73])[F:71])=[CH:54][N:53]=[C:52]([NH:51][C:48]3[CH:47]=[CH:46][C:45]([CH:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[N:57]=2)=[N:61][CH:62]=[CH:63][CH:64]=1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 517111Ammonium CarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 71209298Lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetate

Product 1

HCID 71209188tert-Butyl 4-(4-((4-(2-(3-(2-amino-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

1-Hydroxybenzotriazole (20.4 mg, 0.151 mmol), EDCl (29.0 mg, 0.151 mmol) and N,N-diisopropylethylamine (0.192 mL, 1.10 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetate (I123) (81.3 mg, 0.137 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (106 mg, 1.10 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left to stir at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow oil. The crude material was purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I124) (66.3 mg, 83%) as a white semi-solid; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=0.4 Hz, 1H), 8.49 (dd, J=4.8, 1.7 Hz, 1H), 7.62 (s, 1H), 7.54 (dd, J=7.7, 1.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.19-7.13 (m, 3H), 5.40-5.35 (m, 2H), 4.23 (s, 2H), 3.68 (s, 2H), 3.41-3.35 (m, 2H), 3.32-3.24 (m, 2H), 2.80 (t, J=12.6 Hz, 2H), 2.63 (tt, J=12.0, 3.4 Hz, 1H), 1.81 (d, J=12.5 Hz, 2H), 1.65-1.57 (m, peaks obscured by solvent), 1.48 (s, 9H). LCMS Method C: rt 5.25 min; m/z 607 [M+Na]+, 585 [M+H]+, 529 [M-tButyl+2H]+.

Workup

  1. waitThe reaction was left
  2. customThe volatiles were removed in vacuo
  3. additionthe residue was diluted with EtOAc (50 mL)
  4. washwashed with saturated NaHCO3 (50 mL)
  5. extractionThe aqueous layer was extracted with EtOAc (2×50 mL)
  6. washThe combined organic layers were washed with brine (50 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationAfter filtration the solvent
  9. customwas removed in vacuo
  10. customto afford a pale yellow oil
  11. customThe crude material was purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-c408b0b6ccfd41ac87b70d497b890273
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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