Sodium Bicarbonate → Trifluoroacetic acid

HRID 58093Notes

Reaction equation

HRID 58093 reaction equation
Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:15][O:16][C:17]([C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].[C:28]([O-:31])(O)=[O:29].[Na+]>O1CCOCC1.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:28]([OH:31])([C:11]([F:14])([F:13])[F:12])=[O:29].[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[N:5][NH:6]2)=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([C:17]([O:16][CH3:15])=[O:18])=[N:24][CH:23]=2)[CH:10]=1

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 247292324-Bromo-6-(trifluoromethyl)-1H-indazoleHCID 455881876-(Methoxycarbonyl)pyridine-3-boronic acid

Product 2

HCID 6422Trifluoroacetic acidHCID 89783491HCID 89783491, compound

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

A vial was charged with a mixture of 4-bromo-6-(trifluoromethyl)-1H-indazole (0.732 g, 2.76 mmol), (6-(methoxycarbonyl)pyridin-3-yl)boronic acid (0.5 g, 2.76 mmol) and PdCl2(dppf) (0.101 g, 0.138 mmol) in dioxane (10 mL) and aqueous saturated NaHCO3 (3 mL). The resulting light brown suspension was heated at 140° C. for 45 minutes in a microwave reactor. The reaction mixture was subsequently concentrated. The residue was diluted with DCM, washed with water, and the volatiles removed via rotary evaporation. The crude product was purified by CombiFlash® chromatography (0-30% MeOH in DCM over 180 minutes). The product-containing fractions were combined and concentrated by rotary evaporation to give product with some impurities (0.28 g). A portion of the product (20 mg) was re-purified by preparative HPLC, eluting with 40% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) over a period of 6.5 minutes to give a TFA salt of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H), 7.69 (s, 1H), 8.07 (s, 1H), 8.23 (dd, J=8.21, 0.63 Hz, 1H), 8.39-8.57 (m, 2H), 9.10-9.26 (m, 1H), 13.86 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H10F3N3O2, 322.1. found 322.11.

Workup

  1. concentrationThe reaction mixture was subsequently concentrated
  2. additionThe residue was diluted with DCM
  3. washwashed with water
  4. customthe volatiles removed via rotary evaporation
  5. customThe crude product was purified by CombiFlash® chromatography (0-30% MeOH in DCM over 180 minutes)
  6. concentrationconcentrated by rotary evaporation
  7. customto give product with some impurities (0.28 g)
  8. customA portion of the product (20 mg) was re-purified by preparative HPLC
  9. washeluting with 40% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) over a period of 6.5 minutes

Sources & evidence

ORD record
ord-190515e5695844aabd656cb1760f387c
Source dataset
uspto-grants-2016_09
Patent number
US09434743B2

Reaction notes

Loading…