Hydrochloric Acid → HCID 131727489, compound

HRID 1986099Notes

Reaction equation

HRID 1986099 reaction equation
[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[Cl:37][C:38]1[N:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])=[O:41].Cl.CN1C(=O)CCC1>O1CCOCC1>[ClH:37].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[F:50])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 13387N-methyl-2-pyrrolidoneHCID 162230054-(4-(1h-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride salt2×HCID 57721368HCID 57721368, compound

Product 1

HCID 131727489HCID 131727489, compound

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent2×

Procedure

4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (40 mg, 164 μmol, Compound C of Example 1) and 2-chloro-N-(2,4-difluorophenyl)-6-methylnicotinamide (51 mg, 181 μmol) were suspended in 1,4-dioxane (1 mL). 4M HCl in 1,4-dioxane (0.16 mL, 0.333 mmol) was added and the reaction was irradiated (CEM personal microwave, 300 W) to a temperature of 160° C. for 60 min. The reaction was cooled to ambient temperature and NMP (1 mL) was added. The reaction mixture was re-heated to 160° C. (microwave irradiation, 300 W) for an additional two hours. The 1,4-dioxane was removed by rotary evaporation and the residue was partitioned between 10% aq. NaHCO3 solution (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was extracted EtOAc (2×10 mL). The combined organic layers were washed with 10% LiCl (20 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative (RP) HPLC Chromatography (YMC S5 ODS, 20×100 mm, 10 minute gradient from 33% to 90% aqueous methanol with 0.1% TFA). The fractions containing the desired product were combined and concentrated. The purified material was dissolved in MeOH (1 mL), acidified with 4 N HCl in 1,4-dioxane (0.10 mL) and concentrated. The resulting salt was triturated with hot EtOAc and collected by filtration to afford a brown solid (4.4 mg, >97% HPLC purity). 1H NMR (DMSO-d6) δ 3.15 (s, 3H), 6.48 (s, 1H), 6.69 (d, 1H, J=6.10 Hz), 6.91 (d, 1H, J=7.63 Hz), 7.06-7.21 (m, 1H), 7.31-7.44 (m, 2H), 7.46-7.64 (m, 3H), 8.12-8.42 (m, 3H), 10.41 (s, 1H), 10.96 (s, 1H), 12.58 (s, 1H); MS(ESI+) m/z 490.2 (M+H)+.

Workup

  1. customthe reaction was irradiated (CEM personal microwave, 300 W) to a temperature of 160° C. for 60 min
  2. temperatureThe reaction mixture was re-heated to 160° C.
  3. custom(microwave irradiation, 300 W) for an additional two hours
  4. customThe 1,4-dioxane was removed by rotary evaporation
  5. customthe residue was partitioned between 10% aq. NaHCO3 solution (10 mL) and EtOAc (10 mL)
  6. customThe organic layer was separated
  7. extractionthe aqueous layer was extracted EtOAc (2×10 mL)
  8. washThe combined organic layers were washed with 10% LiCl (20 mL)
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated in vacuo
  11. customThe crude product was purified by preparative (RP) HPLC Chromatography (YMC S5 ODS, 20×100 mm, 10 minute gradient from 33% to 90% aqueous methanol with 0.1% TFA)
  12. additionThe fractions containing the desired product
  13. concentrationconcentrated
  14. dissolutionThe purified material was dissolved in MeOH (1 mL)
  15. concentrationconcentrated
  16. customThe resulting salt was triturated with hot EtOAc
  17. filtrationcollected by filtration
  18. customto afford a brown solid (4.4 mg, >97% HPLC purity)

Sources & evidence

ORD record
ord-c2018069cd5f4b358cfbd6f042e73c5b
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

Loading…