Sodium Hydroxide → N-(2-(Methyloxy)-5-{4-[5-(6-oxa-9-azaspiro[4.5]dec-9-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide

HRID 38879

반응식

HRID 38879 반응식
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][N:26]3[CH2:35][C:30]4([CH2:34][CH2:33][CH2:32][CH2:31]4)[O:29][CH2:28][CH2:27]3)=[N:22][N:21]=2)[CH:3]=1.[CH3:36][O:37][C:38]1[C:43]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][N:39]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.[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]>[CH3:36][O:37][C:38]1[C:43]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:42][C:41]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[C:4]([C:20]3[O:24][C:23]([CH2:25][N:26]4[CH2:35][C:30]5([CH2:31][CH2:32][CH2:33][CH2:34]5)[O:29][CH2:28][CH2:27]4)=[N:22][N:21]=3)[CH:3]=2)=[CH:40][N:39]=1

참가 물질

8

반응물 4

HCID 14798Sodium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 59564698N-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamideHCID 666921539-({5-[6-Bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)-6-oxa-9-azaspiro[4.5]decane

생성물 1

HCID 66695895N-(2-(Methyloxy)-5-{4-[5-(6-oxa-9-azaspiro[4.5]dec-9-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide수율 99.6%

시약·촉매·용매 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 962Water용매HCID 312751,4-Dioxane용매

반응 조건

온도
100 °C

실험 절차

To a solution of 9-({5-[6-bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)-6-oxa-9-azaspiro[4.5]decane (74 mg, 0.133 mmol) in 1,4 dioxane (2.5 ml) and water (1 ml) was added N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (47.8 mg, 0.146 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (19.39 mg, 0.027 mmol) and potassium phosphate tribasic (84 mg, 0.398 mmol). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The mixture was 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 with 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, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (1 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a white solid (71.5 mg).

후처리

  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 with 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. customThe mixture was evaporated to dryness under a stream of nitrogen
  8. customThe residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml)
  9. customseparated with a hydrophilic frit
  10. customThe solvent was removed under a stream of nitrogen
  11. dissolutionthe crude residue was dissolved in DMSO (1 ml)
  12. custompurified by Mass Directed Automated Preparative HPLC

출처 및 근거

ORD 기록
ord-8fc92e640a714f0fbffc8708afbfdb07
출처 데이터셋
uspto-grants-2013_09
특허 번호
US08524751B2

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