Hydrochloric Acid → US9777003, Example 156

HRID 628372Notes

Reaction equation

HRID 628372 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH:38]1[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]1)(=O)=O.Cl.O1CCOCC1>CN(C=O)C.O>[NH:40]1[CH2:41][CH:38]([N:22]2[CH:21]=[CH:20][C:19]([C:7]3[N:6]([CH2:5][C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=4)[C:10]4[CH:11]=[CH:12][C:13]5[N:14]([C:15]([CH3:18])=[N:16][N:17]=5)[C:9]=4[CH:8]=3)=[N:23]2)[CH2:39]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 10753243Tert-butyl 3-(methanesulfonyloxy)azetidine-1-carboxylateHCID 118159473US9777003, Example 155

Product 1

HCID 118159435US9777003, Example 156Yield 46%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in DMF (1.5 mL) was treated with Cs2CO3 (34 mg, 0.10 mmol, Aldrich) and tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (26 mg, 0.10 mmol, prepared as in WO 2012004703). The mixture was heated at 70° C. for 14 hours. After cooling to room temperature, the mixture was diluted with water and extracted with three portions of EtOAc. The combined extracts were washed twice with brine, then were dried over sodium sulfate, filtered, and concentrated. The residue, dissolved in acetonitrile (1.0 mL) was treated with 4.0 M HCl in dioxane (0.40 mL, 1.6 mmol). After 20 minutes, the solvent and excess HCl were removed in vacuo. The residue was re-dissolved in methanol and pH was made basic by the addition of a few drops of NH4OH solution. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded clean product (13.2 mg, 46%).

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionextracted with three portions of EtOAc
  3. washThe combined extracts were washed twice with brine
  4. dry with materialwere dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe residue, dissolved in acetonitrile (1.0 mL)
  8. customthe solvent and excess HCl were removed in vacuo
  9. dissolutionThe residue was re-dissolved in methanol
  10. additionpH was made basic by the addition of a few drops of NH4OH solution
  11. customPurification via preparative HPLC-MS (C18
  12. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH)

Sources & evidence

ORD record
ord-99cd378e90a341a482f33f7a90bee66b
Source dataset
uspto-grants-2016_04
Patent number
US09309246B2

Reaction notes

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