Potassium Carbonate → 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl ester

HRID 1891365Notes

Reaction equation

HRID 1891365 reaction equation
[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](C2OC(C)(C)C(C)(C)O2)=[CH:13][C:12]=1[S:27]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2[CH:37]=[CH:38][CH:39]=[CH:40][C:31]1=2)(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].Br[C:43]1[C:48]([C:49]#[N:50])=[CH:47][C:46]([C:51]([F:54])([F:53])[F:52])=[N:45][CH:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:43]2[CH:44]=[N:45][C:46]([C:51]([F:54])([F:53])[F:52])=[CH:47][C:48]=2[C:49]#[N:50])=[CH:13][C:12]=1[S:27]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2[CH:37]=[CH:38][CH:39]=[CH:40][C:31]1=2)(=[O:29])=[O:28])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 569733155-Bromo-2-(trifluoromethyl)isonicotinonitrileHCID 684728354-[5-Chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-butyric acid tert-butyl ester

Product 1

HCID 594102404-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl esterYield 85.5%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

4-[5-Chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-butyric acid tert-butyl ester (60.0 mg, 0.1 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (23 mg, 0.09 mmol), Pd(Ph3P)4 (12 mg, 0.01 mmol) and K2CO3 (56 mg, 0.4 mmol) in a mixture of dioxane (1.5 mL) and water (0.15 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and heated at 100° C. for 16 hrs. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated, washed with brine (2×5 mL), dried over MgSO4, filtered, concentrated and purified by TLC plates eluting with ethyl acetate in hexanes (1/3) to give 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl ester 6-1 as a white foam (50 mg). MS: 593.9 (M+H-tBu)*; tR=6.98 min (method 4). NMR (CDCl3), δ, 8.791 (1H, s), 7.738-8.101 (2H, m), 7.060-7.272 (4H, m), 6.774-6.828 (1H, m), 4.213 (2H, m), 3.780 (2H, m), 2.833 (2H, m), 2.404 (2H, t), 1.912-2.029 (4H, m), 1.591-1.657 (2H, m), 1.448 (9H, s).

Workup

  1. customwas degassed with N2 for 5 min
  2. customThe reaction vessel was sealed
  3. additionEthyl acetate (5 mL) and water (5 mL) were added
  4. customThe organic layer was separated
  5. washwashed with brine (2×5 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. custompurified by TLC plates
  10. washeluting with ethyl acetate in hexanes (1/3)

Sources & evidence

ORD record
ord-c05e6f9a2f634edfbb9c57722e622d0d
Source dataset
uspto-grants-2013_08
Patent number
US08507536B2

Reaction notes

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