Dichloromethane → {2-Fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-carbamic acid tert-butyl ester

HRID 516643Notes

Reaction equation

HRID 516643 reaction equation
[C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[F:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:27]2[N:23]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[N:24]=[CH:25][CH:26]=2)[C:10]=1[F:16])([CH3:7])([CH3:6])[CH3:5]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole2×HCID 66729642HCID 66729642, compound

Product 1

HCID 66729612{2-Fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-carbamic acid tert-butyl esterYield 152.5%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 18180031Water 1,2-dimethoxyethaneSolvent

Procedure

In a microwave tube N-Boc-3-bromo-2-fluoro-aniline (300 mg, 1.034 mmol) was dissolved in a 9:1 DME/H2O mixture (12 mL) and argon was bubbled through the solution for 10 minutes. 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (prepared as described in WO2010/010154) (576 mg, 2.071 mmol, 2 eq) was then added, followed by cesium carbonate (1.0 g, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (84 mg, 14.6 mmol, 0.1 eq) and the reaction mixture was irradiated at 100° C. for 30 minutes. A further addition of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq) was made and a second microwave cycle was performed at 100° C. for 30 min. The mixture was then filtered over a Celite pad, which was washed with AcOEt. The filtrate was washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on silica gel (Hex/AcOEt 8:2) to give 570 mg of {2-Fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-carbamic acid tert-butyl ester contaminated by N-tetrahydropyranyl-pyrazole (NMR title about 57%). HPLC (254 nm): Rt: 6.82 min; 1H NMR (DMSO-d6) Shift: 9.09 (s, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.22-7.29 (m, 1H), 7.16-7.22 (m, 1H), 6.42-6.45 (m, 1H), 5.09-5.15 (m, 1H), 3.86-3.95 (m, 1H), 3.35-3.46 (m, 1H), 1.51-1.73 (many m, 6H), 1.48 (s, 9H); HRMS (ESI) calcd for C19H25FN3O3 [M+H]+ 362.1875. found 362.1874.

Workup

  1. customwas bubbled through the solution for 10 minutes
  2. filtrationThe mixture was then filtered over a Celite pad, which
  3. washwas washed with AcOEt
  4. washThe filtrate was washed with water and brine
  5. dry with materialdried over Na2SO4
  6. customevaporated to dryness
  7. customThe crude was purified by chromatography on silica gel (Hex/AcOEt 8:2)

Sources & evidence

ORD record
ord-7e4f0ed775c94693879cf64129d7a719
Source dataset
uspto-grants-2015_08
Patent number
US09114137B2

Reaction notes

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