Trichloroacetonitrile → 6-(Difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline

HRID 40381

反応式

HRID 40381 の反応式
[F:1][C:2]1[C:3]([NH:14][NH2:15])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.[F:16][C:17]([F:32])([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[C:18](OC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C#N>C(Cl)Cl>[F:32][C:17]([F:16])([C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:7]=[C:2]([F:1])[C:3]2=[N:14][N:15]=1)[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2

参加物

7

反応物 5

HCID 11011TrichloroacetonitrileHCID 11776TriphenylphosphineHCID 81531DiisopropylethylamineHCID 58955252Methyl 2,2-difluoro-2-(quinolin-6-yl)acetateHCID 675032383-fluoro-2-hydrazinyl-5-(1-methyl-1H-pyrazol-4-yl)pyridine

生成物 1

HCID 441814606-(Difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

反応条件

温度
150 °C

実験手順

To a stirring suspension of 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (190 mg, 917 μmol), methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (218 mg, 917 μmol), triphenylphosphine polymer supported (241 mg, 917 μmol), DIEA (200 μl, 1146 μmol) in DCM (4 mL) was added 2,2,2-trichloroacetonitrile (92 μl, 917 μmol). The reaction vessel was then appropriately sealed and heated to 150° C. with microwaves for 15 min. The reaction was then concentrated onto dry silica under reduced pressure and product purified on silica (40 g) eluting with 1-4% of 2 M NH3 in MeOH/DCM. The product was then further purified by RP-HPLC eluting with water/ACN (0.1% TFA). Collected fractions concentrated under reduced pressure, dissolved in MeOH/DCM (5 mL) and stirred with Si-Carbonated (300 mg; 0.2 mmol) for 30 min at 23° C. Solids were then removed by filtration, and washed with MeOH (3×1 mL). The filtrate was then concentrated under reduced pressure, and product isolated as an off white solid. MS (ESI pos. ion) m/z: 395 (MH+). Calc'd exact mass for C20H13F3N6: 394.

後処理

  1. customThe reaction vessel was then appropriately sealed
  2. concentrationThe reaction was then concentrated onto dry silica under reduced pressure and product
  3. custompurified on silica (40 g)
  4. washeluting with 1-4% of 2 M NH3 in MeOH/DCM
  5. customThe product was then further purified by RP-HPLC
  6. washeluting with water/ACN (0.1% TFA)
  7. customCollected
  8. concentrationfractions concentrated under reduced pressure
  9. dissolutiondissolved in MeOH/DCM (5 mL)
  10. customSolids were then removed by filtration
  11. washwashed with MeOH (3×1 mL)
  12. concentrationThe filtrate was then concentrated under reduced pressure, and product
  13. customisolated as an off white solid

出典と根拠

ORDレコード
ord-a0e1136108024f5d99837d5053594de3
出典データセット
uspto-grants-2013_09
特許番号
US08524900B2

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