Hydrogen Peroxide → 5-(((1R,2R)-2-amino-3,3-difluorocyclohexyl)amino)-3-(pyrazolo[1,5-a]pyridin-3-ylamino)pyrazine-2-carboxamide

HRID 2200521노트

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HRID 2200521 반응식
[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.Cl.Cl.[N:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]2=[C:24]([NH2:31])[CH:23]=1.C(=O)([O-])[O-:33].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[K+].OO>O1CCOCC1.CO.CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:31][C:24]2[CH:23]=[N:22][N:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=23)[C:14]([C:17]([NH2:18])=[O:33])=[N:15][CH:16]=1

참가 물질

11

반응물 6

HCID 784Hydrogen PeroxideHCID 10796Cesium carbonateHCID 14797Potassium HydroxideHCID 634876Binap, (A+-)-HCID 74889838Pyrazolo[1,5-a]pyridin-3-amine dihydrochlorideHCID 866855565-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile

생성물 1

HCID 895721845-(((1R,2R)-2-amino-3,3-difluorocyclohexyl)amino)-3-(pyrazolo[1,5-a]pyridin-3-ylamino)pyrazine-2-carboxamide수율 14.3%

시약·촉매·용매 4

HCID 167845palladium(II) acetate촉매HCID 679Dimethyl Sulfoxide용매HCID 887Methanol용매HCID 312751,4-Dioxane용매

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온도
115 °C

실험 절차

The mixture of 5-(((1R,2R)-2-amino-3,3-difluorocyclohexyl)amino)-3-chloropyrazine-2-carbonitrile (115 mg, 0.40 mmol), pyrazolo[1,5-a]pyridin-3-amine dihydrochloride (247 mg, 1.20 mmol), powder cesium carbonate (1.04 g, 3.20 mmol), BINAP (50 mg, 0.08 mmol), Pd(OAc)2 (18 mg, 0.08 mmol) in 20 mL dioxane was degassed with argon stream. It was stirred in argon atmosphere at 115° C. for overnight. The mixture was cooled, diluted with 100 mL EtOAc, vigorously stirred, and filtered through celite. The filtrate was concentrated and subjected to silica flash column with 0-9% MeOH in DCM to isolate the coupling product. It was dissolved in 10 mL MeOH and 2 mL DMSO. To the solution were added KOH (100 mg) and then 1 mL of H2O2 (50%). The mixture was stirred at RT for 30 m, quenched with acetonitrile and then TFA, concentrated in vacuo and subjected to reverse phase preparative HPLC to isolate the title compound (23 mg). MS found for C18H20F2N80 as (M+H)+403.6. UV: λ=289, 355 nm. 1H NMR: (CD3OD) δ 8.45 (1H, d, J=7.6 Hz), 8.23 (1H, s), 7.53 (1H, d, J=8.8 Hz), 7.47 (1H, s), 7.21 (1H, m), 6.89 (1H, t, J=6.8 Hz), 4.47 (1H, m), 3.93 (1H, m), 2.07-1.69 (6H, m) ppm.

후처리

  1. customwas degassed with argon stream
  2. temperatureThe mixture was cooled
  3. additiondiluted with 100 mL EtOAc
  4. stirringvigorously stirred
  5. filtrationfiltered through celite
  6. concentrationThe filtrate was concentrated
  7. customto isolate the coupling product
  8. stirringThe mixture was stirred at RT for 30 m
  9. customquenched with acetonitrile
  10. concentrationTFA, concentrated in vacuo

출처 및 근거

ORD 기록
ord-dd55dcdb9b2c45a2a00dbc76e91125d5
출처 데이터셋
uspto-grants-2016_06
특허 번호
US09359308B2

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