Potassium Phosphate, Tribasic → 4-(3-fluoroazetidin-1-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine

HRID 72706Notes

Reaction equation

HRID 72706 reaction equation
[F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[CH:10][N:9]=[C:8]3[N:12]([CH3:16])[N:13]=[C:14](I)[C:7]=23)[CH2:3]1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[CH:10][N:9]=[C:8]3[N:12]([CH3:16])[N:13]=[C:14]([C:21]4[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=4)[C:7]=23)[CH2:3]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 711144194-(3-fluoroazetidin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Product 1

HCID 710936304-(3-fluoroazetidin-1-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

4-(3-Fluoroazetidin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C10) (500 mg, 1.50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (910 mg, 2.63 mmol), tris(dibenzylideneacetone)dipalladium(0) (98%, 56 mg, 0.060 mmol), and tricyclohexylphosphine (96%, 35.1 mg, 0.120 mmol) were combined in 1,4-dioxane (10 mL). An aqueous solution of potassium phosphate (97%, 657 mg, 3.00 mmol) in water (5 mL) was added, and the reaction mixture was subjected to microwave irradiation at 150° C. and 200 W for 90 minutes. The reaction mixture was partitioned between ethyl acetate (20 mL) and aqueous phosphate buffer (20 mL), and the aqueous layer was extracted with ethyl acetate (2×20 mL) and dichloromethane (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography [Gradient: 35% to 100% (10% methanol in ethyl acetate) in heptane] afforded the product as a glass. Yield: 302.3 mg, 1.05 mmol, 70%. LCMS m/z 288.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 3.83-3.92 (m, 2H), 3.93 (s, 6H), 4.14-4.26 (m, 2H), 5.23-5.43 (m, 1H, JHF=58.0 Hz), 7.63 (d, J=0.6 Hz, 1H), 7.99 (br s, 1H), 8.35 (s, 1H).

Workup

  1. customirradiation at 150° C.
  2. customThe reaction mixture was partitioned between ethyl acetate (20 mL) and aqueous phosphate buffer (20 mL)
  3. extractionthe aqueous layer was extracted with ethyl acetate (2×20 mL) and dichloromethane (2×20 mL)
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification via silica gel chromatography [Gradient: 35% to 100% (10% methanol in ethyl acetate) in heptane]

Sources & evidence

ORD record
ord-f169910bdb134ae5a9820bf517bbf4cc
Source dataset
uspto-grants-2014_09
Patent number
US08829010B2

Reaction notes

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