Methyl isobutyrate → 2-[6-[(4-tert-Butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]-2-methylpropanoic acid methyl ester

HRID 1691445Notes

Reaction equation

HRID 1691445 reaction equation
[C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:19]1[CH:20]=[CH:21][C:22]2[NH:28][C:27]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:26]=3[CH2:25][N:24]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:23]=2[CH:50]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.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]>[CH3:7][O:6][C:1](=[O:5])[C:2]([C:19]1[CH:20]=[CH:21][C:22]2[NH:28][C:27]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:26]=3[CH2:25][N:24]([S:37]([C:40]3[CH:41]=[CH:42][C:43]([C:46]([CH3:48])([CH3:47])[CH3:49])=[CH:44][CH:45]=3)(=[O:39])=[O:38])[C:23]=2[CH:50]=1)([CH3:4])[CH3:3]

Participants

7

Reactant 4

HCID 11039Methyl isobutyrateHCID 2733832Lithium HexamethyldisilazideHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 596186368-bromo-6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine

Product 1

HCID 596187022-[6-[(4-tert-Butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]-2-methylpropanoic acid methyl ester

Reagents, catalysts & solvents 2

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 1140TolueneSolvent

Procedure

To methyl isobutyrate (128 mg, 1.25 mmol) in toluene (5 mL) was added 1.46 mL of LiHMDS (1.0 M in PhMe, 1.46 mmol) at 0° C. After stirring at rt for 10-15 min, the mixture was transferred via cannula to a mixture of intermediate 53 (225 mg, 0.416 mmol), Pd(dba)2 (24 mg, 0.042 mmol), and tri-t-butylphosphonium tetrafluoroborate (12 mg, 0.042 mmol). After stirring at rt for 48 hrs, the reaction was quenched with aqueous NH4Cl (20 mL) and the product was extracted with EtOAc (50 mL). The extracts were washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on silica gel column eluting with 5-30% EtOAc in hexanes to afford the title compound. LCMS: m/e 562.2 (M+H)+.

Workup

  1. stirringAfter stirring at rt for 48 hrs
  2. customthe reaction was quenched with aqueous NH4Cl (20 mL)
  3. extractionthe product was extracted with EtOAc (50 mL)
  4. washThe extracts were washed with water (30 mL) and brine (30 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified on silica gel column
  9. washeluting with 5-30% EtOAc in hexanes

Sources & evidence

ORD record
ord-8f21da8eedde4cd0b0722064304045bf
Source dataset
uspto-grants-2012_04
Patent number
US08153626B2

Reaction notes

Loading…