Oxazole → 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(3-oxazol-2-yl-pyrazolo[3,4-b]pyridin-1-yl)-ethanone

HRID 930561Notes

Reaction equation

HRID 930561 reaction equation
[O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]3[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[C:30](I)=[N:29]3)[C@@H:22]([CH3:39])[CH2:21]2)=[C:14]([F:40])[CH:13]=1>O1CCCC1.C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]3[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[C:30]([C:2]4[O:1][CH:5]=[CH:4][N:3]=4)=[N:29]3)[C@@H:22]([CH3:39])[CH2:21]2)=[C:14]([F:40])[CH:13]=1

Participants

8

Reactant 3

HCID 9255OxazoleHCID 160060321-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanoneHCID 178418339Butyllithium

Product 1

HCID 160054501-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(3-oxazol-2-yl-pyrazolo[3,4-b]pyridin-1-yl)-ethanoneYield 44.1%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of oxazole (40 μL, 0.54 mmol, 3 equiv) in tetrahydrofuran (1 mL) under nitrogen atmosphere, was added dropwise n-butyl lithium (2.5 M in Hexane, 220 μL, 0.54 mmol, 3 equiv.). The resultant mixture was stirred at −78° C. for an additional 30 min followed by the addition of ZnCl2 (0.5M in THF, 1.5 mL, 0.72 mmol, 4 equiv.). The reaction solution was allowed to warm to 0° C. and stirred 1 hr followed by the addition of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (100.2 mg, 0.18 mmol, 1 equiv) and palladium tetrakis(triphenylphosphine) (22.3 mg, 0.018, 0.1 equiv). The reaction mixture was then heated to reflux for 48 hr, cooled to room temperature and diluted with ethyl acetate (150 mL). The reaction mixture was washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to provide the crude product. Purification by preparative HPLC provided the desired product 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(3-oxazol-2-yl-pyrazolo[3,4-b]pyridin-1-yl)-ethanone as a white powder (38.5 mg): LCMS (ES) M+H 485.5, Rf 2.56 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).

Workup

  1. temperatureThe reaction mixture was then heated
  2. temperatureto reflux for 48 hr
  3. temperaturecooled to room temperature
  4. washThe reaction mixture was washed with water (20 mL), brine (20 mL)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customto provide the crude product
  8. customPurification by preparative HPLC

Sources & evidence

ORD record
ord-bd4a24e25780412690b891f24591d984
Source dataset
uspto-grants-2016_03
Patent number
US09296740B2

Reaction notes

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