3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester → 5-amino-2-(2,6-difluorophenyl)-N-[5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide

HRID 521945Notes

Reaction equation

HRID 521945 reaction equation
Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[S:14][C:15]=1[NH:16]C(=O)OC(C)(C)C)=[O:10].O.O.[F-].[K+].[O:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1>C1COCC1.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[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[NH2:16][C:15]1[S:14][C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:12][C:11]=1[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[C:39]1[CH2:40][CH2:41][O:36][CH2:37][CH:38]=1)=[O:10]

Participants

6

Reactant 3

HCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 23708904Potassium fluoride dihydrateHCID 86713771tert-butyl 4-(5-chloro-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate

Product 1

HCID 734384615-amino-2-(2,6-difluorophenyl)-N-[5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamideYield 17.7%

Reagents, catalysts & solvents 2

HCID 71310864Tris(dibenzylideneacetone)dipalladium tri-tert-butyl phosphonium tetrafluoroborateCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of tert-butyl (4-((5-chloro-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (234 mg, 0.5 mmol), potassium fluoride dihydrate (155 mg, 1.65 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (210 mg, 1.0 mmol) in THF (5 mL) was degassed by bubbling nitrogen through it for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2, 60 mg, 0.05 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 110° C. for 8 hr. Water (10 mL) was added and the mixture extracted with EtOAc (3×5 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel chromatography (isohexane then 0-5% MeOH/EtOAc). The resulting intermediate was dissolved in MeOH (5 mL) and treated with a solution of HCl in dioxane (4 M, 5 mL). The mixture was stirred at room temperature for 16 hr and the solvent removed under reduced pressure. Purification via preparative HPLC gave 101 as a brown solid (37 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.05 (s, 1H), 7.38-7.26 (m, 1H), 7.06-6.97 (m, 2H), 6.13 (s, 2H), 6.03-6.00 (m, 1H), 4.41 (d, J=2.8 Hz, 1H), 4.39 (d, J=2.8 Hz, 1H), 3.96 (t, J=5.3 Hz, 2H), 3.83 (s, 3H), 2.45-2.41 (m, 2H). LCMS (ES+) m/z 418 (M+1).

Workup

  1. customwas degassed
  2. customby bubbling nitrogen through it for 15 min
  3. customthe mixture degassed for a further 10 min
  4. additionWater (10 mL) was added
  5. extractionthe mixture extracted with EtOAc (3×5 mL)
  6. customThe combined organic layers were passed through a phase separation cartridge
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified via silica gel chromatography (isohexane
  9. dissolutionThe resulting intermediate was dissolved in MeOH (5 mL)
  10. additiontreated with a solution of HCl in dioxane (4 M, 5 mL)
  11. customthe solvent removed under reduced pressure
  12. customPurification via preparative HPLC

Sources & evidence

ORD record
ord-6a44804d1f0f4bcca097197121bff99e
Source dataset
uspto-grants-2016_05
Patent number
US09328106B2

Reaction notes

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