4-Methylmorpholine → Asciminib

HRID 73747

反応式

HRID 73747 の反応式
[Cl:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.CN1CCOCC1.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[OH:43][C@@H:44]1[CH2:48][CH2:47][N:46]([C:49]2[C:57]([C:58]3[N:62](C4CCCCO4)[N:61]=[CH:60][CH:59]=3)=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][N:50]=2)[CH2:45]1>C1COCC1.O>[Cl:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:53](=[O:54])[C:52]2[CH:56]=[C:57]([C:58]3[NH:62][N:61]=[CH:60][CH:59]=3)[C:49]([N:46]3[CH2:47][CH2:48][C@@H:44]([OH:43])[CH2:45]3)=[N:50][CH:51]=2)=[CH:6][CH:5]=1

参加物

8

反応物 5

HCID 79724-MethylmorpholineHCID 5727934-(Chlorodifluoromethoxy)anilineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2 回HCID 725460876-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acidHCID 178526939HCID 178526939、化合物

生成物 1

HCID 72165228Asciminib

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
25 °C

実験手順

Alternatively, Stage 9.1 was prepared by adding 4-(chlorodifluoromethoxy)aniline (16.6 g, 84.9 mmol), NMM (21.7 g, 212.1 mmol), hydroxybenzotriazole hydrate (HOBt.H2O, 11.9 g, 77.77 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 20.9 g, 109.0 mmol) to a solution of 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid (Stage 9.4, 29.83 g, 70.7 mmol) in THF (271 mL). The mixture was stirred for 1.5 h at 25° C. and then at 65° C. for 16 h. After cooling the RM to 35° C., further EDCI.HCl (13.3 g, 69.4 mmol) was added and the RM was stirred for 1.5 h at 35° C. then again at 65° C. for 16 h. After cooling the RM to 35° C., water (150 mL) was added, the THF was removed under reduced pressure, EtOAc (180 mL) was added and the mixture was stirred for at 35° C. for 1 h. The two layers were separated and the aq. phase was then extracted with EtOAc (60 mL). The combined organic layers were washed with water (90 mL), brine (90 mL). The solvent was evaporated off under reduced pressure to give a brown solid which was purified by column chromatography (Silica gel, DCM/MeOH 40:1 to 20:1) to afford the title compound as a yellow solid.

後処理

  1. customAlternatively, Stage 9.1 was prepared
  2. waitat 65° C. for 16 h
  3. temperatureAfter cooling the RM to 35° C.
  4. stirringthe RM was stirred for 1.5 h at 35° C.
  5. waitagain at 65° C. for 16 h
  6. temperatureAfter cooling the RM to 35° C.
  7. customthe THF was removed under reduced pressure, EtOAc (180 mL)
  8. additionwas added
  9. stirringthe mixture was stirred for at 35° C. for 1 h
  10. customThe two layers were separated
  11. extractionthe aq. phase was then extracted with EtOAc (60 mL)
  12. washThe combined organic layers were washed with water (90 mL), brine (90 mL)
  13. customThe solvent was evaporated off under reduced pressure
  14. customto give a brown solid which
  15. customwas purified by column chromatography (Silica gel, DCM/MeOH 40:1 to 20:1)

出典と根拠

ORDレコード
ord-7ddc1e2b8fbc4223b35ba5678f072ea8
出典データセット
uspto-grants-2014_09
特許番号
US08829195B2

関連ノート

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