Sodium Carbonate → N-{6-[5-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 1695742Notes

Reaction equation

HRID 1695742 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([NH:21][C:22]([C:24]2[N:25]=[C:26]([CH2:29][N:30]3[CH2:35][C@H:34]([CH3:36])[O:33][C@H:32]([CH3:37])[CH2:31]3)[S:27][CH:28]=2)=[O:23])[CH:3]=1.[CH3:38][O:39][C:40]1[C:45]([NH2:46])=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][N:41]=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].C(Cl)Cl.O>[NH2:46][C:45]1[CH:44]=[C:43]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)(=[O:12])=[O:13])=[C:4]([NH:21][C:22]([C:24]3[N:25]=[C:26]([CH2:29][N:30]4[CH2:35][C@H:34]([CH3:36])[O:33][C@H:32]([CH3:37])[CH2:31]4)[S:27][CH:28]=3)=[O:23])[CH:3]=2)[CH:42]=[N:41][C:40]=1[O:39][CH3:38]

Participants

8

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 595579202-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine

Product 1

HCID 58255776N-{6-[5-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 44.3%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

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 (4 g), 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (1.8 g), sodium carbonate (2.8 g) and Pd(dppf)Cl2 (0.48 g) were weighed to a 500 ml round-bottomed flask and 1,4-dioxane (150 ml) and water (150 ml) were added. The reaction was heated to 80° C. for 2 hours. The reaction was cooled then passed through a 10 g silica cartridge, washing with DCM:methanol. The reaction was concentrated to leave only the aqueous phase. DCM was added and the product extracted. The DCM was passed through a hydrophobic frit, then evaporated to dryness. The residue was purified on silica chromatography eluting with 0-6% methanol in DCM over 30 mins. Product containing fractions were combined and evaporated to dryness. The residue was repurified by silica chromatography using a gradient of 1.5-5% methanol in DCM over 30 mins. Product containing fractions were combined and evaporated to dryness to give title compound (1.9 g).

Workup

  1. temperatureThe reaction was cooled
  2. washwashing with DCM
  3. concentrationThe reaction was concentrated
  4. customto leave only the aqueous phase
  5. extractionthe product extracted
  6. customevaporated to dryness
  7. customThe residue was purified on silica chromatography
  8. washeluting with 0-6% methanol in DCM over 30 mins
  9. additionProduct containing fractions
  10. customevaporated to dryness
  11. customThe residue was repurified by silica chromatography
  12. customover 30 mins
  13. additionProduct containing fractions
  14. customevaporated to dryness

Sources & evidence

ORD record
ord-c89d528c19224cc3993427c40993eb86
Source dataset
uspto-grants-2012_04
Patent number
US08163743B2

Reaction notes

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