Hydrochloric Acid → tert-Butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

HRID 592365Notes

Reaction equation

HRID 592365 reaction equation
C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:67]4([C:70]([OH:72])=O)[CH2:69][CH2:68]4)[C:56]([C:73]([F:76])([F:75])[F:74])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[C:70]([C:67]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[CH2:60][CH2:59][C:57]2[C:56]([C:73]([F:75])([F:74])[F:76])=[CH:55][N:54]=[C:53]([NH:52][C:49]3[CH:48]=[CH:47][C:46]([CH:43]4[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[CH2:41][CH2:42]4)=[CH:51][CH:50]=3)[N:58]=2)[CH2:68][CH2:69]1)(=[O:72])[NH2:7]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 517111Ammonium CarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 867122861-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxylic acid

Product 1

HCID 86712287tert-Butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylateYield 44.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

HOBt (99 mg, 0.73 mmol), EDCl.HCl (140 mg, 0.73 mmol) and DIPEA (0.42 mL, 2.43 mmol) were added to a stirred solution of 1-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxylic acid (A5) (297 mg, 0.486 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (234 mg, 2.43 mmol) was added in one portion and the resulting solution was stirred at 40° C. for 72 hours. The volatiles were removed in vacuo and EtOAc (50 mL) and saturated NaHCO3 (50 mL) were added to the residue. After separating the organic layer, the aqueous phase was extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with brine and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.) to give the title compound A6 as a yellow solid (131 mg, 44%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.67 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.32 (dd, J=13.9, 5.0 Hz, 3H), 7.26-7.14 (m, 3H), 6.98 (s, 1H), 5.99 (s, 1H), 4.05 (dd, J=15.7, 8.8 Hz, 2H), 3.13 (dd, J=25.3, 9.9 Hz, 4H), 2.93-2.70 (m, 2H), 2.63 (t, J=12.2 Hz, 1H), 1.74 (d, J=12.5 Hz, 2H), 1.41 (s, 13H), 0.97 (s, 2H). LCMS-A: rt 6.720 min; m/z 610 [M+H]+.

Workup

  1. customThe volatiles were removed in vacuo and EtOAc (50 mL) and saturated NaHCO3 (50 mL)
  2. additionwere added to the residue
  3. customAfter separating the organic layer
  4. extractionthe aqueous phase was extracted with EtOAc (2×50 mL)
  5. washwashed with brine
  6. dry with materialdried over MgSO4
  7. customThe volatiles were removed under reduced pressure
  8. customthe residue was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-33e8891e342840e4bdfe0a9ed458287c
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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