2-Methyltetrahydrofuran → Azd-1656

HRID 658423Notes

Reaction equation

HRID 658423 reaction equation
[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=3)[C:17]([OH:19])=O)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.CC1CCCO1.CN1CCOCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=3)[C:17]([NH:36][C:33]3[CH:32]=[N:31][C:30]([CH3:29])=[CH:35][N:34]=3)=[O:19])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1

Participants

6

Reactant 5

HCID 73012-MethyltetrahydrofuranHCID 79724-MethylmorpholineHCID 111923Propylphosphonic anhydrideHCID 3132155-Methylpyrazin-2-amineHCID 591271113-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid

Product 1

HCID 16039797Azd-1656Yield 62%

Conditions

Temperature
0 °C

Procedure

To a flask was added 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid (1.0 eq), 5-methylpyrazin-2-amine (1.0 eq) and 2-methyltetrahydrofuran (3.5 vols) under a nitrogen atmosphere. The mixture was cooled to 0° C. N-methylmorpholine (5.0 eq) was added at 0° C., then 1-propanephosphonic acid cyclic anhydride (T3P) (supplied as 50% w/w in ethyl acetate) (2.5 eq) was added in one portion via addition funnel over 45 minutes maintaining the reaction temperature at 0-5° C. The addition funnel was washed with 2-methyltetrahydrofuran (0.5 vols), then the reaction mixture was boiled under reflux under nitrogen for at least 14 hours, before being cooled to 22° C. Water (4.0 vols) was added to the reaction mixture in one portion, followed by 2-methyltetrahydrofuran (4.0 vols). After agitating for 30 minutes, the layers were separated. The upper organic layer was retained and the aqueous layer returned to the flask. 2-Methyltetrahydrofuran (4.0 vols) was added to the flask, the mixture was agitated for 30 minutes, then the layers were separated. The organic layers were combined in the flask and further 2-methyltetrahydrofuran (6.0 vols) was then added. The mixture was agitated, and 1.0N hydrochloric acid (4.0 vols) was then added. The mixture was agitated for at least 30 minutes at 22±5° C., and the layers were then separated. 1.0N Hydrochloric acid (4.0 vols) was added to the organic layer. The mixture was agitated for at least 30 minutes at 22±5° C. the mixture was separated 5% w/w Sodium hydrogen carbonate (4.0 vols) solution was added the organic layer. The mixture was agitated for at least 30 minutes at 22±5° C. then the mixture was separated. This process was repeated. Water (4.0 vols) was added to the organic layer, the mixture was agitated for at least 30 minutes at 22±5° C. then the layers were separated. The organic layer was distilled under vacuum at 35° C. collecting 19 vols of distillates. 2-Methyltetrahydrofuran (4 vols) was added, and the distillation was continued under vacuum at 35° C. collecting 6 vols distillates. Further 2-methyltetrahydrofuran (4 vols) was added and the reaction mixture sampled for water content. Further 2-methyltetrahydrofuran (4 vols) was added, and the reaction mixture was filtered through a CUNO™ filter then distilled until the pot volume was approximately 7 vols, then methyl iso-butylketone (11 vols) was added and the mixture vacuum distilled at 35° C. to a pot volume of approximately 7 vols. Methyl iso-butylketone (11 vols) was added and the mixture vacuum distilled at 35° C. to a pot volume of approximately 6 vols. N-Heptane (0.5 vols) was added to the mixture, and the temperature adjusted to 60° C., the mixture was cooled to 46° C., seeded, then cooled to 22° C. and agitated for at least 12 hours. The mixture was filtered. The solid was washed with a mixture of methyl iso-butylketone (1.5 vols)/heptane (0.16 vols). The solid was washed with heptane (˜1.5 vols). The isolated solid was dried at 22° C. under vacuum to afford the title compound as an off white solid. Corrected yield was 62%. 1H NMR δ (400 MHz DMSO) 11.04 (s, 1H), 9.26 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.57 (bs, 1H), 7.47 (bs, 1H), 7.13 (bs, 1H), 4.81-4.77 (m, 1H), 4.58-4.54 (t, 2H), 4.11-4.07 (t, 2H), 3.55-3.47 (m, 2H), 3.3 (s, 3H), 2.48 (s, 3H), 2.34-2.26 (m, 2H), 1.26-1.25 (d, 3H)

Workup

  1. temperaturemaintaining the reaction temperature at 0-5° C
  2. washThe addition funnel was washed with 2-methyltetrahydrofuran (0.5 vols)
  3. temperatureunder reflux under nitrogen for at least 14 hours
  4. temperaturebefore being cooled to 22° C
  5. additionWater (4.0 vols) was added to the reaction mixture in one portion
  6. customthe layers were separated
  7. addition2-Methyltetrahydrofuran (4.0 vols) was added to the flask
  8. stirringthe mixture was agitated for 30 minutes
  9. customthe layers were separated
  10. additionwas then added
  11. stirringThe mixture was agitated
  12. addition1.0N hydrochloric acid (4.0 vols) was then added
  13. stirringThe mixture was agitated for at least 30 minutes at 22±5° C.
  14. customthe layers were then separated
  15. addition1.0N Hydrochloric acid (4.0 vols) was added to the organic layer
  16. stirringThe mixture was agitated for at least 30 minutes at 22±5° C. the mixture
  17. customwas separated 5% w/w Sodium hydrogen carbonate (4.0 vols) solution
  18. additionwas added the organic layer
  19. stirringThe mixture was agitated for at least 30 minutes at 22±5° C.
  20. customthe mixture was separated
  21. additionWater (4.0 vols) was added to the organic layer
  22. stirringthe mixture was agitated for at least 30 minutes at 22±5° C.
  23. customthe layers were separated
  24. distillationThe organic layer was distilled under vacuum at 35° C.
  25. distillationcollecting 19 vols of distillates
  26. addition2-Methyltetrahydrofuran (4 vols) was added
  27. distillationthe distillation
  28. customwas continued under vacuum at 35° C.
  29. distillationcollecting 6 vols distillates
  30. additionFurther 2-methyltetrahydrofuran (4 vols) was added
  31. aliquotthe reaction mixture sampled for water content
  32. additionFurther 2-methyltetrahydrofuran (4 vols) was added
  33. filtrationthe reaction mixture was filtered through a CUNO™
  34. filtrationfilter
  35. distillationthen distilled until the pot volume
  36. additionmethyl iso-butylketone (11 vols) was added
  37. distillationthe mixture vacuum distilled at 35° C. to a pot volume of approximately 7 vols
  38. additionMethyl iso-butylketone (11 vols) was added
  39. distillationthe mixture vacuum distilled at 35° C. to a pot volume of approximately 6 vols
  40. additionN-Heptane (0.5 vols) was added to the mixture
  41. customadjusted to 60° C.
  42. temperaturethe mixture was cooled to 46° C.
  43. temperaturecooled to 22° C.
  44. stirringagitated for at least 12 hours
  45. filtrationThe mixture was filtered
  46. washThe solid was washed with a mixture of methyl iso-butylketone (1.5 vols)/heptane (0.16 vols)
  47. washThe solid was washed with heptane (˜1.5 vols)
  48. customThe isolated solid was dried at 22° C. under vacuum

Sources & evidence

ORD record
ord-20e5f3643ad145e2ada35fe2d7235f23
Source dataset
uspto-grants-2011_12
Patent number
US08076481B2

Reaction notes

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