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Sodium 2-methylbutan-2-olate → N-(2,5-Difluoro-4-(morpholinomethyl)phenyl)-5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine

HRID 1924019
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HRID 1924019 반응식
[F:1][C:2]1[C:3]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12]([CH3:20])=[N:11][CH:10]=2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[C:34]([F:35])=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:24]([F:36])[CH:23]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[F:35][C:34]1[CH:33]=[C:25]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:24]([F:36])=[CH:23][C:22]=1[NH:8][C:5]1[N:4]=[C:3]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12]([CH3:20])=[N:11][CH:10]=2)[C:2]([F:1])=[CH:7][N:6]=1
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참가 물질

7

반응물 3

HCID 2733478Sodium 2-methylbutan-2-olateHCID 166654985-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amineHCID 595438614-(4-Bromo-2,5-difluorobenzyl)morpholine

생성물 1

HCID 49781787N-(2,5-Difluoro-4-(morpholinomethyl)phenyl)-5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine수율 64.3%

시약·촉매·용매 3

HCID 636044
1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)
촉매
HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매
HCID 1140Toluene용매

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온도
110 °C

실험 절차

5-Fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.876 g, 3.16 mmol), 4-(4-bromo-2,5-difluorobenzyl)morpholine (0.923 g, 3.16 mmol), Sodium tert-pentoxide (0.696 g, 6.32 mmol, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.026 g, 0.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.018 g, 0.03 mmol) in toluene (10 mL) were mixed and degassed. The mixture was stirred at 110° C. under a nitrogen atmosphere overnight. The mixture was concentrated. Dichloromethane and water was added and the phases were separated. The organic phase was concentrated and the crude was purified by prep HPLC. The pooled fractions were concentrated to about half volume and the residue was extracted with EtOAc (×2). The organic phases were concentrated and the residue was dried under vacuum at 40° C. over a weekend to give the title compound (0.992 g, 64%) as a solid.

후처리

  1. customdegassed
  2. concentrationThe mixture was concentrated
  3. additionDichloromethane and water was added
  4. customthe phases were separated
  5. concentrationThe organic phase was concentrated
  6. customthe crude was purified by prep HPLC
  7. concentrationThe pooled fractions were concentrated to about half volume
  8. extractionthe residue was extracted with EtOAc (×2)
  9. concentrationThe organic phases were concentrated
  10. customthe residue was dried under vacuum at 40° C. over a weekend

출처 및 근거

ORD 기록
ord-d6c389ecaf0240e7823f10878351043c
출처 데이터셋
uspto-grants-2012_05
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08178529B2

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