Ammonia → HCID 58993548, compound

HRID 391438Notes

Reaction equation

HRID 391438 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:10]=1)[C:5](O)=[O:6].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N.CO.C([N:49](CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[C:5]([C:4]1[CH:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[CH:10]=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)[CH:3]=1)(=[O:6])[NH2:49]

Participants

10

Reactant 6

HCID 222AmmoniaHCID 887MethanolHCID 81531DiisopropylethylamineHCID 2856454-Fluorophenylboronic acidHCID 2724699PyBOPHCID 58993646HCID 58993646, compound

Product 1

HCID 58993548HCID 58993548, compound

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

3-Bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methoxy)methyl)benzoic acid (0.66 g, 1.31 mmol), 4-fluorophenylboronic acid (0.55 g, 3.93 mmol), and tetrakis(triphenylphosphine) palladium(0) (82 mg, 0.05 mmol) were combined in dry tetrahydrofuran (10 mL) in a microwave tube and sealed. After flushing with nitrogen, 5.5 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in dimethylformamide (6 mL) and cooled to 0° C. The reaction mixture was sequentially treated with methylene chloride (2 mL), 7 N ammonia in methanol (0.33 mL, 2.3 mmol), N,N-diisopropylethylamine (0.51 mL, 2.9 mmol), and PyBop® (0.72 g, 1.4 mmol). The ice bath was removed and the solution stirred for 1.5 h and concentrated. The product was purified by column chromatography (50% ethyl acetate/hexanes) to give 0.4 g (66%). 1H-NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.43-7.46 (m, 2H), 7.41 (s, 1H), 7.37 (s, 1H), 7.28-7.31 (m, 4H), 7.15-7.18 9 (m, 1H), 7.07-7.10 (m, 2H), 4.40 (s, 2H), 3.67-3.69 (m, 2H), 3.40 (s, 2H), 2.96-3.00 (m, 2H), 2.14-2.16 (m, 2H), 1.80-1.86 (m, 2H), 1.37 (s, 9H). Mass spec.: 519.39 (MH)+.

Workup

  1. customsealed
  2. customAfter flushing with nitrogen, 5.5 mL of a 1 N potassium hydroxide aqueous solution
  3. additionwas introduced
  4. temperatureAfter cooling to room temperature
  5. concentrationthe reaction mixture was concentrated
  6. dissolutiondissolved in dimethylformamide (6 mL)
  7. temperaturecooled to 0° C
  8. customThe ice bath was removed
  9. concentrationconcentrated
  10. customThe product was purified by column chromatography (50% ethyl acetate/hexanes)
  11. customto give 0.4 g (66%)

Sources & evidence

ORD record
ord-25cd1c99b9ff4c02b354a573f76163a6
Source dataset
uspto-grants-2013_02
Patent number
US08383821B2

Reaction notes

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