Water → HCID 178480015, compound

HRID 629308Notes

Reaction equation

HRID 629308 reaction equation
BrC1C([O:17][C:18]2C=CC(F)=C[C:19]=2[F:25])=CC2N=CN(C3CCCCO3)C=2C=1.Br[C:27]1[C:41]([O:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[F:50])=[CH:40][C:30]2[N:31](C3CCCCO3)[CH:32]=[N:33][C:29]=2[CH:28]=1.[F-:51].[Cs+].[CH3:53][N:54]1[CH:59]=[C:58](B2OC(C)(C)C(C)(C)O2)[C:57]2[CH:69]=[N:70][N:71](COCC[Si](C)(C)C)[C:56]=2[C:55]1=[O:80].[OH2:81]>C(O)CCC.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.Cl[Pd]Cl>[F:51][C:19]([F:25])([F:49])[C:18]([OH:17])=[O:81].[F:50][C:44]1[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=1[O:42][C:41]1[C:27]([C:58]2[C:57]3[CH:69]=[N:70][NH:71][C:56]=3[C:55](=[O:80])[N:54]([CH3:53])[CH:59]=2)=[CH:28][C:29]2[N:33]=[CH:32][NH:31][C:30]=2[CH:40]=1

Participants

8

Reactant 5

HCID 962WaterHCID 25953Cesium fluorideHCID 1180936316-bromo-5-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzimidazoleHCID 1180936675-bromo-6-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzimidazoleHCID 1233662896-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

Product 1

HCID 178480015HCID 178480015, compoundYield 63%

Reagents, catalysts & solvents 2

HCID 86647055di-tert-butyl(4-dimethylaminophenylphosphine) dichloropalladium(II)CatalystHCID 2631-ButanolSolvent

Conditions

Temperature
100 °C

Procedure

A suspension of 6-bromo-5-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzimidazole and 5-bromo-6-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzimidazole (0.0350 g, 0.0855 mmol) (mixture of isomers from step 6), cesium fluoride (0.0455 g, 0.299 mmol), and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.0381 g, 0.0941 mmol) in 1-butanol (0.39 mL) and water (0.091 mL) was degassed with nitrogen for 5 min, treated with 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1) (0.908 mg, 0.00128 mmol), degassed with nitrogen for 5 min, and heated at 100° C. for 2 h. The reaction mixture was poured into ethyl acetate (35 mL), washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude oil. Purification by flash column chromatography (100% hexanes to 30% ethyl acetate [containing 5% MeOH]70% hexanes over 1 min and then 30% ethyl acetate [containing 5% MeOH]70% hexanes to 100% ethyl acetate [containing 5% MeOH] over 30 min) gave the desired product (33 mg, 63%) as a mixture of isomers. LCMS calculated for C31H36F2N5O4Si (M+H)+: m/z=608.2. found: 608.2.

Workup

  1. customwas degassed with nitrogen for 5 min
  2. customdegassed with nitrogen for 5 min
  3. additionThe reaction mixture was poured into ethyl acetate (35 mL)
  4. washwashed with water and brine
  5. dry with materialdried with sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to a crude oil
  8. customPurification by flash column chromatography (100% hexanes to 30% ethyl acetate [containing 5% MeOH]70% hexanes over 1 min

Sources & evidence

ORD record
ord-780dc868c31145c68ff4b9b965d9b510
Source dataset
uspto-grants-2016_04
Patent number
US09315501B2

Reaction notes

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