1,4-Dioxane → N-[5-{4-[5-({[2-Hydroxy-3-(4-morpholinyl)propyl]amino}methyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-2-(methyloxy)-3-pyridinyl]methanesulfonamide

HRID 38888Notes

Reaction equation

HRID 38888 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:24][C:23]([CH2:25][NH:26][CH2:27][CH:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:22][N:21]=2)[CH:3]=1.[CH3:37][O:38][C:39]1[C:44]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[OH:36][CH:28]([CH2:29][N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)[CH2:27][NH:26][CH2:25][C:23]1[O:24][C:20]([C:4]2[CH:3]=[C:2]([C:42]3[CH:43]=[C:44]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[C:39]([O:38][CH3:37])=[N:40][CH:41]=3)[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][NH:8]3)=[N:21][N:22]=1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 59564698N-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamideHCID 666939741-[({5-[6-Bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)amino]-3-(4-morpholinyl)-2-propanol

Product 1

HCID 66691647N-[5-{4-[5-({[2-Hydroxy-3-(4-morpholinyl)propyl]amino}methyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-2-(methyloxy)-3-pyridinyl]methanesulfonamide

Reagents, catalysts & solvents 2

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

Conditions

Temperature
80 °C

Procedure

1-[({5-[6-Bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)amino]-3-(4-morpholinyl)-2-propanol (100 mg, 0.346 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (81 mg, 0.247 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (25.35 mg, 0.0345 mmol) and potassium phosphate tribasic (110.5 mg, 0.5195 mmol) were added to a mixture of 1,4-dioxane (2.5 ml) and water (0.25 ml). The reaction mixture was heated under microwave irradiation at 80° C. for 30 mins and then 100° C. for 10 mins. The mixture was then passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated by a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml) and stirred at room temperature for 1 h. The mixture was neutralised with addition of 2M HCl, dissolved in DMSO, filtered through a filter tube and purified by high pH MDAP (Method E). The appropriate fractions and waste were evaporated to dryness in vacuo. The residue was dissolved in 1:1 DMSO/water and purified by preparative HPLC using the following method:

Workup

  1. washwashing with MeOH
  2. customThe solvent was removed under a stream of nitrogen
  3. customthe residue was partitioned between DCM (10 ml) and water (10 ml)
  4. customseparated by a hydrophobic frit
  5. customthe solvent again removed under a stream of nitrogen
  6. dissolutionThe protected compound was dissolved in 1,4-dioxane (1 ml)
  7. additionThe mixture was neutralised with addition of 2M HCl
  8. dissolutiondissolved in DMSO
  9. filtrationfiltered through a filter tube
  10. custompurified by high pH MDAP (Method E)
  11. customThe appropriate fractions and waste were evaporated to dryness in vacuo
  12. dissolutionThe residue was dissolved in 1:1 DMSO/water
  13. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-e8b29213b0d74728a2c1852d123b5014
Source dataset
uspto-grants-2013_09
Patent number
US08524751B2

Reaction notes

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