Methyl iodide → HCID 66562353, compound

HRID 331502Notes

Reaction equation

HRID 331502 reaction equation
IC.[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[CH:22]=2)=[N:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1.[CH2:35](N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][N:29]([CH3:35])[CH2:28]3)[CH:22]=2)=[N:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1

Participants

5

Reactant 3

HCID 6328Methyl iodide2×HCID 8471TriethylamineHCID 66563582HCID 66563582, compound

Product 1

HCID 66562353HCID 66562353, compound

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

Iodomethane (17.09 mg, 7.496 μL, 0.1204 mmol) w as added to a stirred solution of 3-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]piperidine-3-carbonitrile (51 mg, 0.1204 mmol) and triethyl amine (30.46 mg, 41.96 μL, 0.3010 mmol) in chloroform (1 mL) and the reaction stirred at ambient temperature for 23 hours. A further portion of iodomethane (213.6 mg, 93.68 μL, 1.505 mmol) was added and the reaction stirred at ambient temperature for a further 5.5 hours. The solvent was removed in vacuo and the residue re-dissolved in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 0%-100% B (solvent A: 10 mM ammonium formate in water; solvent B: 10 mM ammonium formate in 1:1 MeOH:CH3CN) over 14 minutes at 25 mL/min]. The relevant fractions were concentrated in vacuo and partitioned between dichloromethane/saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer extracted with dichloromethane (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was freeze-dried to give 3-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]-1-methyl-piperidine-3-carbonitrile Compound I-37 as a yellow solid (14.1 mg, 27% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.96-1.71 (m, 4H), 2.20 (s, 3H), 2.21-2.19 (m, 1H), 2.68 (br d, 1H), 2.75 (br d, 1H), 3.22-3.20 (m, 1H), 7.21 (br s, 2H), 7.51-7.44 (m, 3H), 7.68 (s, 1H), 7.94-7.91 (m, 2H), 8.00 (dd, 1H), 8.12 (s, 1H), 8.59 (d, 1H) and 8.93 (s, 1H) ppm LC/MS m/z 438.2 [M+H]+.

Workup

  1. stirringthe reaction stirred at ambient temperature for a further 5.5 hours
  2. customThe solvent was removed in vacuo
  3. dissolutionthe residue re-dissolved in dichloromethane
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo
  6. customthe residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 0%-100% B (solvent A: 10 mM ammonium formate in water; solvent B: 10 mM ammonium formate in 1:1 MeOH:CH3CN) over 14 minutes at 25 mL/min]
  7. concentrationThe relevant fractions were concentrated in vacuo
  8. custompartitioned between dichloromethane/saturated aqueous sodium bicarbonate
  9. customThe layers were separated
  10. extractionthe aqueous layer extracted with dichloromethane (×3)
  11. dry with materialThe combined organic extracts were dried (MgSO4)
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customThe residue was freeze-dried

Sources & evidence

ORD record
ord-456dc120aa244cb295713934b23d7400
Source dataset
uspto-grants-2014_11
Patent number
US08877759B2

Reaction notes

Loading…