Potassium Carbonate → 3-tert-butoxycarbonyl-7-chloro-6-(2,5'-difluoro-2'-methoxy-biphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 911516Notes

Reaction equation

HRID 911516 reaction equation
Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C:8]2[C:18]3[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[Cl:26])=[CH:4][C:3]=1[F:29].[F:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][C:18]2[C:8]([S:7][CH2:6][C:5]3[CH:27]=[CH:28][C:2]([C:33]4[CH:32]=[C:31]([F:30])[CH:36]=[CH:35][C:34]=4[O:40][CH3:41])=[C:3]([F:29])[CH:4]=3)=[C:9]([Cl:26])[CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 11776TriphenylphosphineHCID 27826735-Fluoro-2-methoxyphenylboronic acidHCID 576562686-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Product 1

HCID 667067973-tert-butoxycarbonyl-7-chloro-6-(2,5'-difluoro-2'-methoxy-biphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 93.3%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Degas a stirred mixture of 6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (212 mg, 0.424 mmol), 5-fluoro-2-methoxybenzene boronic acid (108 mg, 0.636 mmol), potassium carbonate (292 mg, 2.12 mmol), triphenylphosphine (11 mg, 0.0424 mmol) and bis(triphenylphosphine)-palladium(II) chloride (15 mg, 0.0212 mmol) in dioxane (3 mL) and water (1 mL). Purge with dry nitrogen and heat at 100° C. for 5 h. Cool to ambient temperature, add water, extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(2,5′-difluoro-2′-methoxy-biphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as yellow oil (216 mg, 93%). Use a method similar to the General Procedure 1-4 to give the title compound as a yellow foam. MS (ES+) m/z: 446 (M+H)+.

Workup

  1. customDegas
  2. customPurge with dry nitrogen
  3. temperatureCool to ambient temperature
  4. additionadd water
  5. extractionextract three times with EtOAc
  6. dry with materialdry over anhydrous Na2SO4
  7. concentrationconcentrate in vacuo
  8. customPurify by chromatography on silica gel eluting with hexane/EtOAc (9:1)

Sources & evidence

ORD record
ord-a114d1448ca048ab836a5afb31255d2b
Source dataset
uspto-grants-2011_09
Patent number
US08022062B2

Reaction notes

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