Sodium Carbonate → n-{4-[3-Amino-7-(4-morpholinylmethyl)-1h-indazol-4-yl]phenyl}-n'-[3-(trifluoromethyl)phenyl]urea

HRID 239870Notes

Reaction equation

HRID 239870 reaction equation
I[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]2[C:3]=1[C:4]([NH2:18])=[N:5][NH:6]2.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:35])=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:4]1[C:3]2[C:7](=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:2]=2[C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=3)=[O:35])=[CH:31][CH:32]=2)[NH:6][N:5]=1

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 161251031-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)ureaHCID 161255114-Iodo-7-(4-morpholinylmethyl)-1h-indazol-3-amine

Product 1

HCID 11341195n-{4-[3-Amino-7-(4-morpholinylmethyl)-1h-indazol-4-yl]phenyl}-n'-[3-(trifluoromethyl)phenyl]ureaYield 49%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
145 °C

Procedure

A solution of Example 15F (80 mg, 0.22 mmol) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea (108 mg, 0.268 mmol) in toluene (2 mL) and ethanol (1.5 mL) was treated with a solution of Na2CO3 (58 mg) in water (1 mL), degassed with nitrogen for 2 minutes, treated with Pd(PPh3)4 (13 mg, 0.011 mmol), and degassed with nitrogen for another 2 minutes. The vial was capped and heated to 140-150° C. for 8-10 minutes with stirring in a Smith Synthesizer microwave oven (at 300 W). The reaction was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by HPLC using the conditions in Example 15H to provide 55 mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 3.10-4.08 (m, 8H), 4.55 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.38-7.47 (m, 3H), 7.53 (t, J=7.80 Hz, 1H), 7.58-7.69 (m, 3H), 8.06 (s, 1H), 9.17 (s, 1H), 9.30 (s, 1H); MS (ESI(+)) m/e 511 (M+H)+.

Workup

  1. customdegassed with nitrogen for 2 minutes
  2. customdegassed with nitrogen for another 2 minutes
  3. customThe vial was capped
  4. additionThe reaction was poured into water
  5. extractionextracted three times with ethyl acetate
  6. washThe combined extracts were washed with water and brine
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe concentrate was purified by HPLC

Sources & evidence

ORD record
ord-7808a13adee742128d01154fb899f7ed
Source dataset
uspto-grants-2014_02
Patent number
US08642776B2

Reaction notes

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