Sodium Carbonate → N-{6-[5-{[(2,4-Difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide

HRID 1695739Notes

Reaction equation

HRID 1695739 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:28][CH3:29])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)(=[O:11])=[O:10].Br[C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][N:37]2[S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])=[C:33]([NH:50][C:51]([C:53]2[N:54]=[C:55]([CH2:58][N:59]3[CH2:64][C@H:63]([CH3:65])[O:62][C@H:61]([CH3:66])[CH2:60]3)[S:56][CH:57]=2)=[O:52])[CH:32]=1.C(=O)([O-])[O-].[Na+].[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].O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[C:17]([C:31]2[CH:39]=[C:38]3[C:34]([CH:35]=[N:36][N:37]3[S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])=[C:33]([NH:50][C:51]([C:53]3[N:54]=[C:55]([CH2:58][N:59]4[CH2:64][C@H:63]([CH3:65])[O:62][C@H:61]([CH3:66])[CH2:60]4)[S:56][CH:57]=3)=[O:52])[CH:32]=2)[CH:16]=[N:15][C:14]=1[O:28][CH3:29])(=[O:10])=[O:11]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 58255797N-{6-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamideHCID 595647052,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide

Product 1

HCID 58255764N-{6-[5-{[(2,4-Difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamideYield 51.4%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

2,4-Difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (116 mg), N-{6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (150 mg), Pd(dppf)Cl2 (18 mg), sodium carbonate (79 mg), 1,4-dioxane (5 ml) and water (5 ml) were combined and heated at 80° C. for 3 hours. The cooled reaction mixture was filtered through a 1 g silica cartridge, washing with methanol, then evaporated to dryness. The residue was dissolved in DCM and washed with water. The DCM was passed through a hydrophobic frit and evaporated to dryness. The residue was purified by ISCO companion, 12 g Silica cartridge using 0-5% MeOH in DCM over 16 mins. Pure fractions were combined and evaporated to give title compound, (105 mg).

Workup

  1. customThe cooled reaction mixture
  2. filtrationwas filtered through a 1 g silica cartridge
  3. washwashing with methanol
  4. customevaporated to dryness
  5. dissolutionThe residue was dissolved in DCM
  6. washwashed with water
  7. customevaporated to dryness
  8. customThe residue was purified by ISCO companion, 12 g Silica cartridge
  9. customover 16 mins
  10. customevaporated

Sources & evidence

ORD record
ord-2ec28384a3ae4b8d8a37c3617cbda0eb
Source dataset
uspto-grants-2012_04
Patent number
US08163743B2

Reaction notes

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