Sodium Bicarbonate → (R)-4-(2-methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)-6-(trifluoromethyl)-1H-indazole

HRID 58119

Reaction equation

HRID 58119 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:15])[CH2:10]2)=[N:6][C:7]=1[CH3:8].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[C:20](B(O)O)[CH:19]=1.[C:32]([O-:35])(O)=[O:33].[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:32]([OH:35])([C:17]([F:31])([F:30])[F:16])=[O:33].[CH3:8][C:7]1[C:2]([C:20]2[CH:19]=[C:18]([C:17]([F:31])([F:30])[F:16])[CH:26]=[C:25]3[C:21]=2[CH:22]=[N:23][NH:24]3)=[CH:3][CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:15])[CH2:10]2)[N:6]=1

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 89783507HCID 89783507, compoundHCID 89794907(R)-1-(5-bromo-6-methylpyridin-2-yl)-3-methylpiperazine

Product 2

HCID 6422Trifluoroacetic acidHCID 89794891(R)-4-(2-methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)-6-(trifluoromethyl)-1H-indazoleYield 29.2%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
145 °C

Procedure

In a 10 mL microwave vial were mixed (R)-1-(5-bromo-6-methylpyridin-2-yl)-3-methylpiperazine (120 mg, 0.444 mmol), (6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (133 mg, 0.577 mmol), PdCl2(dppf) (32.5 mg, 0.044 mmol), and aqueous NaHCO3 (0.950 mL, 1.777 mmol) in dioxane (10 mL) to give an orange suspension. The vial was sealed and heated in a microwave reactor to 145° C. for 45 minutes. The reaction mixture was then filtered and the product was purified by preparative HPLC, eluting with a gradient of 15-40% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The pure fractions were lyophilized to give a TFA salt of the title compound as a white solid (31.6 mg, 14.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (d, J=6.57 Hz, 3H), 2.27 (s, 3H), 2.95 (dd, J=14.02, 10.48 Hz, 1H), 3.05-3.21 (m, 2H), 3.36 (d, J=7.33 Hz, 1H), 3.44 (d, J=11.62 Hz, 1H), 4.44 (d, J=13.14 Hz, 2H), 6.94 (d, J=8.59 Hz, 1H), 7.24 (d, J=1.52 Hz, 1H), 7.64 (d, J=8.59 Hz, 1H), 7.92-7.94 (m, 1H), 7.95 (d, J=1.01 Hz, 1H), 8.77 (d, J=8.59 Hz, 1H), 9.10 (d, J=8.34 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C19H20F3N5, 376.2. found 376.4.

Workup

  1. customto give an orange suspension
  2. customThe vial was sealed
  3. filtrationThe reaction mixture was then filtered
  4. customthe product was purified by preparative HPLC
  5. washeluting with a gradient of 15-40% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA)

Sources & evidence

ORD record
ord-3b6739e8385a46cda3900b530fb52374
Source dataset
uspto-grants-2016_09
Patent number
US09434743B2

Linked notes

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