Ammonium Chloride → HCID 178461204, compound

HRID 81255Notes

Reaction equation

HRID 81255 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:25])([F:24])[F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:24])([F:23])[F:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1

Participants

5

Reactant 3

HCID 25517Ammonium ChlorideHCID 33557Sodium AzideHCID 178461206HCID 178461206, compound

Product 1

HCID 178461204HCID 178461204, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A vial equipped with a stir bar was charged with 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.3, Step 1) (67 mg, 0.133 mmol), sodium azide (87 mg, 1.332 mmol), and ammonium chloride (72.0 mg, 1.345 mmol). DMF (1.3 mL) was added, and the mixture was degassed with N2. The vial was then sealed and heated at 120° C. for 16 hours. The reaction was then cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by mass triggered reverse phase HPLC(C-18), eluting with acetonitrile/water containing 0.1% TFA afforded 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine (TFA salt). MS ESI calc'd. for C25H27ClF3N9 [M+H]+ 546. found 546. 1H NMR (600 MHz, CD3OD) δ 8.86 (d, J=1.5, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.38 (t, J=2.1 Hz, 1H), 8.26 (s, 1H), 5.36-5.27 (m, 1H), 3.92 (dd, J=9.0, 14.7 Hz, 1H), 3.87-3.79 (m, 1H), 3.73-3.66 (m, 1H), 3.61 (dd, J=5.5, 14.7 Hz, 1H), 2.48-2.36 (m, 1H), 2.21-2.10 (m, 2H), 2.08-1.98 (m, 1H), 1.45 (dd, J=1.4, 11.7 Hz, 2H), 1.23-1.13 (m, 1H), 1.13-1.04 (m, 1H), 1.02-0.94 (m, 1H), 0.72 (d, J=6.6 Hz, 3H), 0.71-0.56 (m, 3H), 0.57-0.46 (m, 2H).

Workup

  1. customA vial equipped with a stir bar
  2. customthe mixture was degassed with N2
  3. customThe vial was then sealed
  4. temperatureThe reaction was then cooled to room temperature
  5. additiondiluted with EtOAc
  6. washwashed with water and brine
  7. dry with materialThe organic layer was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification of the residue by mass triggered reverse phase HPLC(C-18)
  11. washeluting with acetonitrile/water containing 0.1% TFA

Sources & evidence

ORD record
ord-0b96802255e547d79daf76d991f0a32d
Source dataset
uspto-grants-2014_09
Patent number
US08846657B2

Reaction notes

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