Sodium Carbonate → N-{3-methyl-5-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine

HRID 1040149Notes

Reaction equation

HRID 1040149 reaction equation
Br[C:2]1[S:3][C:4]([C:7]2[CH:8]=[C:9]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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(Cl)Cl.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].O1CCOCC1>[CH3:13][C:11]1[CH:10]=[C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:8]=[C:7]([C:4]2[S:3][C:2]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[N:6][CH:5]=2)[CH:12]=1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27740104-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 58456233N-[3-(2-bromo-1,3-thiazol-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine

Product 1

HCID 58456134N-{3-methyl-5-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amineYield 9%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a sealed tube was added INTERMEDIATE 9 (30.0 mg, 0.072 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16.8 mg, 0.087 mmol), Pd(dppf)Cl2—CH2Cl2 (13.2 mg, 0.018 mmol), dioxane (722 μL, 0.1 M), and aqueous Na2CO3 (90 μL, 2 M). The reaction vessel was purged with argon, sealed and heated to 110° C. for 8 hours. The completed reaction was cooled to 60° C. and to the vial was added silica bound Si-2,4,6-trimercaptotriazine (74.5 mg, 0.144 mmol, 1.94 mmol/g) as a Pd(dppf)Cl2 scavenger. The reaction was shaken for 4 hours at 60° C. The completed scavenging reaction was passed through a syringe filter and concentrated in vacuo. Purification by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v TFA modifier) afforded the title product (3M mg, 0.0065 mmol, 7.8%). MS ESI: [M+H]+ m/z 403.1. 1H NMR (500 MHz, DMSO) δ 10.27 (s, 1H), 8.83 (d, J=4.9, 1H), 8.37-8.07 (m, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.47 (s, 1H), 7.28 (d, J=4.9, 1H), 7.18 (s, 1H), 2.32 (s, 3H). rhSTK activity=+++

Workup

  1. customThe reaction vessel was purged with argon
  2. customsealed
  3. customThe completed reaction
  4. temperaturewas cooled to 60° C. and to the vial
  5. additionwas added silica
  6. customThe completed scavenging reaction
  7. customwas passed through a syringe
  8. filtrationfilter
  9. concentrationconcentrated in vacuo
  10. customPurification by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v TFA modifier)

Sources & evidence

ORD record
ord-61448dda71da4590bf44c5427d9e6ea7
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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