Hydrochloric Acid → HCID 86712676, compound

HRID 1779025Notes

Reaction equation

HRID 1779025 reaction equation
C[O:2][C:3](=O)[CH2:4][C:5]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)N=1.O[Li].[OH2:50].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[NH4+:87].[NH4+:88]>CO.O.C1COCC1.CCOC(C)=O>[NH2:87][C:3](=[O:2])[CH2:4][C:5]1[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:50])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:88]=1

Participants

12

Reactant 7

HCID 313Hydrochloric Acid2×HCID 757711-Hydroxybenzotriazole2×HCID 81531Diisopropylethylamine2×HCID 168937Lithium hydroxide, monohydrate2×HCID 517111Ammonium Carbonate2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 86712675HCID 86712675, compound2×

Product 1

HCID 86712676HCID 86712676, compound

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent2×HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

A suspension of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A61) (0.100 g, 0.150 mmol) and LiOH.H2O (0.051 g, 1.21 mmol) in MeOH (2 mL), water (2 mL) and THF (2 mL) was heated at 40° C. for 16 hours. In a separate flask, a suspension of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A61) (0.070 g, 0.105 mmol) and LiOH.H2O (0.036 g, 0.858 mmol) in MeOH (2 mL), water (2 mL) and THF (2 mL) was heated at 40° C. for 16 hours. The resulting mixtures were combined and the volatiles were removed under reduced pressure. The resulting solid was dissolved in dry DMF (5 mL) and dry THF (5 mL) and HOBt (0.053 g, 0.398 mmol), EDCl.HCl (0.061 g, 0.398 mmol), DIPEA (0.260 mL, 1.53 mmol) and ammonium carbonate (0.144 g, 1.53 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours then HOBt (0.053 g, 0.398 mmol), EDCl.HCl (0.061 g, 0.398 mmol), DIPEA (0.260 mL, 1.53 mmol) and ammonium carbonate (0.144 g, 1.53 mmol) were added and stirring was continued overnight. The resulting mixture was diluted with EtOAc, then washed with 10% aqueous NaHCO3. The organic layer was dried (MgSO4) and the volatiles were removed in vacuo. The resulting solid was adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A62 as a yellow solid (0.086 g, 43%); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.55-7.47 (m, 5H), 7.38 (d, J=8.3 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.48-5.28 (m, 2H), 4.39-4.15 (m, 2H), 3.74 (s, 2H), 3.22-3.13 (m, 2H), 3.12-3.05 (m, 2H), 2.88-2.73 (m, 2H), 2.70-2.56 (m, 1H), 1.85-1.80 (m, 2H), 1.70-1.61 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 6.646 min; m/z 652 [M+H]+.

Workup

  1. temperaturewas heated at 40° C. for 16 hours
  2. customthe volatiles were removed under reduced pressure
  3. dissolutionThe resulting solid was dissolved in dry DMF (5 mL)
  4. stirringstirring
  5. waitwas continued overnight
  6. washwashed with 10% aqueous NaHCO3
  7. dry with materialThe organic layer was dried (MgSO4)
  8. customthe volatiles were removed in vacuo
  9. customthen purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-c227c1108b114fb4a8b37cead6be6395
Source dataset
uspto-grants-2016_02
Patent number
US09266864B2

Reaction notes

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