Sodium Hydroxide → HCID 66743161, compound

HRID 1431073Notes

Reaction equation

HRID 1431073 reaction equation
[Si:1]([O:8][C@@H:9]([CH2:28][O:29][CH3:30])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]2[C:20](=[O:27])[N:21]([CH3:26])[N:22]=[C:23](Cl)[CH:24]=2)=[N:16][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O:34][CH2:35][C:36]1[C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=[CH:38][C:37]=1[N:51]1[N:60]=[CH:59][C:58]2[C:53](=[C:54]([F:65])[CH:55]=[C:56]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH:57]=2)[C:52]1=[O:66])(=O)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>C(O)CCC.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[C:61]([C:56]1[CH:57]=[C:58]2[C:53](=[C:54]([F:65])[CH:55]=1)[C:52](=[O:66])[N:51]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([C:23]3[CH:24]=[C:19]([NH:18][C:15]4[CH:14]=[CH:13][C:12]([O:11][CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:28][O:29][CH3:30])=[CH:17][N:16]=4)[C:20](=[O:27])[N:21]([CH3:26])[N:22]=3)[C:36]=1[CH2:35][OH:34])[N:60]=[CH:59]2)([CH3:64])([CH3:62])[CH3:63]

Participants

10

Reactant 5

HCID 14798Sodium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 594737692-(6-(tert-Butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetateHCID 66742217HCID 66742217, compound2×

Product 1

HCID 66743161HCID 66743161, compoundYield 75%

Reagents, catalysts & solvents 4

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 2631-ButanolSolventHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
110 °C

Procedure

In a 50 mL test tube, (S)-4-(5-(2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one (178 mg, 391 μmol) and 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (332 mg, 469 μmol) were combined in n-butanol (4 ml) to give a orange solution. 1 mL of water was added and the reaction mixture was purged with argon. X-PHOS (18.6 mg, 39.1 μmol) and potassium phosphate tribasic (166 mg, 782 μmol) were added. After argon was bubbled through the reaction mixture for 5 min. bis(dibenzylideneacetone)-palladium (0) (11.2 mg, 19.6 μmol) was added. The resulting suspension was heated in a oil bath at 110° C. for 1.5 hours. No (S)-4-(5-(2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one remained by LCMS. Two main products were observed by LCMS, acetylated and deacetylated product. The reaction mixture was allowed to cool to 25° C. overnight. The reaction mixture was concentrated to small volume, poured into 75 mL H2O and extracted with EtOAc (3×75 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 20% to 60% EtOAc in hexanes) to afford 2 product peaks. These were combined and conc. to give 290 mg of a 1:1 mixture of acetylated and deacetylated product. This mixture was taken up in 15 mL THF and treated with 2 mL of 1N NaOH. The reaction mixture was heated to 60° C. and stirred for 20 h. Mostly complete by tlc. The reaction mixture was poured into 100 mL H2O and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 70% EtOAc in hexanes) to afford 217 mg of the desired product (75% yield). (M+H)+=745 m/e.

Workup

  1. customto give a orange solution
  2. customthe reaction mixture was purged with argon
  3. additionwas added
  4. temperatureto cool to 25° C. overnight
  5. concentrationThe reaction mixture was concentrated to small volume
  6. additionpoured into 75 mL H2O
  7. extractionextracted with EtOAc (3×75 mL)
  8. dry with materialThe organic layers were dried over Na2SO4
  9. concentrationconcentrated in vacuo
  10. customThe crude material was purified by flash chromatography (silica gel, 24 g, 20% to 60% EtOAc in hexanes)
  11. customto afford 2 product peaks
  12. customconc. to give
  13. addition290 mg of a 1:1 mixture of acetylated and deacetylated product
  14. temperatureThe reaction mixture was heated to 60° C.
  15. extractionextracted with EtOAc (3×50 mL)
  16. washThe combined organic extracts were washed with brine
  17. dry with materialdried over MgSO4
  18. concentrationconcentrated in vacuo
  19. customThe crude material was purified by flash chromatography (silica gel, 40 g, 20% to 70% EtOAc in hexanes)

Sources & evidence

ORD record
ord-05ab18f20bfa40c49e758cdb41e72bbd
Source dataset
uspto-grants-2015_01
Patent number
US08940741B2

Reaction notes

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