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2-Methyltetrahydrofuran → Azd-1656

HRID 418023
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HRID 418023 반응식
[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>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
참가 물질반응 조건실험 절차후처리출처 및 근거반응 노트

참가 물질

7

반응물 5

HCID 73012-Methyltetrahydrofuran2회HCID 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

생성물 1

HCID 16039797Azd-1656
수율 85%

시약·촉매·용매 1

HCID 962Water용매

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온도
5 °C

실험 절차

To a flask fitted with overhead stirrer, thermometer, condenser, and nitrogen line 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 (1.12 eq) and 2-methyltetrahydrofuran (4.4 vols) under a nitrogen atmosphere. The mixture was cooled to 5° C., and then N-methylmorpholine (5.0 eq) added drop-wise over at least 15 minutes maintaining the temperature at 5±5° C. 1-Propanephosphonic acid cyclic anhydride (T3P) (as 50% w/w solution in ethyl acetate) (2.5 eq) was added drop-wise over at least 15 minutes maintaining the temperature at 5±5° C. The mixture was heated to reflux for at least 16 hours then cooled to 22±5° C. Water (4.0 vols) was added to the reaction mixture, followed by 2-methyltetrahydrofuran (4.0 vols). After agitating for 30 minutes, the mixture was separated. The upper organic layer was retained and the aqueous layer treated with 2-methyltetrahydrofuran (4.0 vols). After agitating for 30 minutes, this mixture was separated. The organic layers were combined and further 2-methyltetrahydrofuran (6.0 vols) was then added. The mixture was agitated, and 1.0N hydrochloric acid (4.0 vols) was added. The mixture was agitated for at least 30 minutes at 22±5° C., and the layers were then separated. The organic layer was treated with 1.0N hydrochloric acid (4.0 vols) then the mixture was agitated for at least 30 minutes at 22±5° C., then the layers were separated. The organic layer was treated with 5% w/w sodium hydrogen carbonate (4.0 vols). The mixture was agitated for at least 30 minutes at 22±5° C., the layers were separated. The organic layer was treated again with 5% w/w sodium hydrogen carbonate (4.0 vols) following the same procedure, and then with water (4.0 vols) following the same procedure. The organic layer was then distilled at atmospheric pressure to a pot volume of 4.7 vols. Methyl iso-butylketone (10 vols) was added, and the batch distilled at atmospheric pressure to a pot volume of 4.68 vols. Methyl iso-butylketone (10 vols) was added, and the batch distilled at atmospheric pressure to a pot volume of 4.68 vols. The batch was cooled to 70° C., heptane (2.02 vols) was added slowly drop-wise over at least 30 minutes maintaining the reaction temperature at 70±5° C. The mixture was cooled to 60° C., and seeded with 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide Form 1, agitated at 60° C. for 1 hour, cooled to 50° C. at 0.1° C., agitated at 50° C. for 140 minutes, then cooled to 22° C. at 0.1° C./minute. The mixture was held at 22° C. for at least 12 hours. Heptane (5.06 vols) was then added—drop-wise over at least 120 minutes maintaining the batch temperature at a temperature at 22±5° C. The mixture was cooled to 0° C. at 0.1° C./minute then held at 0° C. for at least 12 hours and then filtered. The isolated solid was washed with a mixture of methyl iso-butylketone (1.0 vols) and heptane (3.0 vols) pre-chilled to 0° C. The solid was dried at 40° C. After drying in the vacuum oven at 40° C. overnight, the desired product was obtained as a solid (corrected yield 85%. 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), 7.56 (s, 1H), 7.46 (s, 1H), 7.12 (s, 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)

후처리

  1. customTo a flask fitted with overhead stirrer
  2. temperaturemaintaining the temperature at 5±5° C
  3. temperaturemaintaining the temperature at 5±5° C
  4. temperatureThe mixture was heated
  5. temperatureto reflux for at least 16 hours
  6. temperaturethen cooled to 22±5° C
  7. customthe mixture was separated
  8. additionthe aqueous layer treated with 2-methyltetrahydrofuran (4.0 vols)
  9. stirringAfter agitating for 30 minutes
  10. customthis mixture was separated
  11. additionfurther 2-methyltetrahydrofuran (6.0 vols) was then added
  12. stirringThe mixture was agitated
  13. addition1.0N hydrochloric acid (4.0 vols) was added
  14. stirringThe mixture was agitated for at least 30 minutes at 22±5° C.
  15. customthe layers were then separated
  16. additionThe organic layer was treated with 1.0N hydrochloric acid (4.0 vols)
  17. stirringthe mixture was agitated for at least 30 minutes at 22±5° C.
  18. customthe layers were separated
  19. additionThe organic layer was treated with 5% w/w sodium hydrogen carbonate (4.0 vols)
  20. stirringThe mixture was agitated for at least 30 minutes at 22±5° C.
  21. customthe layers were separated
  22. additionThe organic layer was treated again with 5% w/w sodium hydrogen carbonate (4.0 vols)
  23. distillationThe organic layer was then distilled at atmospheric pressure to a pot volume of 4.7 vols
  24. additionMethyl iso-butylketone (10 vols) was added
  25. distillationthe batch distilled at atmospheric pressure to a pot volume of 4.68 vols
  26. additionMethyl iso-butylketone (10 vols) was added
  27. distillationthe batch distilled at atmospheric pressure to a pot volume of 4.68 vols
  28. temperatureThe batch was cooled to 70° C.
  29. additionheptane (2.02 vols) was added slowly drop-wise over at least 30 minutes
  30. temperaturemaintaining the reaction temperature at 70±5° C
  31. temperatureThe mixture was cooled to 60° C.
  32. stirringagitated at 60° C. for 1 hour
  33. temperaturecooled to 50° C. at 0.1° C.
  34. stirringagitated at 50° C. for 140 minutes
  35. temperaturecooled to 22° C. at 0.1° C./minute
  36. waitThe mixture was held at 22° C. for at least 12 hours
  37. additionHeptane (5.06 vols) was then added—drop-wise over at least 120 minutes
  38. temperaturemaintaining the batch temperature at a temperature at 22±5° C
  39. temperatureThe mixture was cooled to 0° C. at 0.1° C./minute
  40. waitthen held at 0° C. for at least 12 hours
  41. filtrationfiltered
  42. washThe isolated solid was washed with a mixture of methyl iso-butylketone (1.0 vols) and heptane (3.0 vols)
  43. temperaturepre-chilled to 0° C
  44. customThe solid was dried at 40° C
  45. customAfter drying in the vacuum oven at 40° C. overnight

출처 및 근거

ORD 기록
ord-91e50f9ec1224ffc9af7d9dd2b6192f7
출처 데이터셋
uspto-grants-2012_01
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08093252B2

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