Potassium Carbonate → (3S,4S)-4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester

HRID 519173Notes

Reaction equation

HRID 519173 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[CH:25]=[C:26]3[C:35](=[CH:36][C:37]=2Br)[O:34][CH2:33][C:32]2[N:27]3[C@H:28]([CH3:40])[C:29](=[O:39])[NH:30][N:31]=2)[C@H:20]([CH3:41])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[CH:25]=[C:26]3[C:35](=[CH:36][C:37]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:34][CH2:33][C:32]2[N:27]3[C@H:28]([CH3:40])[C:29](=[O:39])[NH:30][N:31]=2)[C@H:20]([CH3:41])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 27343542-Fluorophenylboronic acidHCID 86727581(3S,4S)-4-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3-methyl-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 86727580(3S,4S)-4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl esterYield 78%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a mixture of (2-fluorophenyl)boronic acid (0.019 g, 0.137 mmol), (3S,4S)-4-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.045 g, 0.091 mmol) and K2CO3 (0.025 g, 0.182 mmol) in dioxane (12 mL) and water (2 mL) was added PdCl2(dppf)-CH2Cl2 adduct (7.45 mg, 9.12 μmol) and the reaction mixture was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep-TLC (eluting with 55% EtOAc in petroleum ether) to give (3S,4S)-4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.036 g, 78%) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.48-7.37 (m, 1H), 7.29-7.14 (m, 3H), 6.91 (s, 1H), 6.81 (s, 1H), 4.93 (m, 1H), 4.63-4.58 (m, 2H), 4.23 (m, 1H), 3.81 (m, 1H), 3.03-2.86 (m, 1H), 2.79-2.42 (m, 3H), 2.34-2.11 (m, 2H), 1.50-1.41 (m, 14H), 0.75 (m, 3H). LC/MS (Table 1, Method 4) Rt=2.830 min.; MS m/z: 531 [M+Na]+& 453 [M+H−56]+. SFC (Table 1, Method 46), Rt=6.84 min.

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. concentrationconcentrated in vacuo
  3. customThe residue was purified by prep-TLC (eluting with 55% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-bd3483b55ac2407ca9df70ee134cf5ab
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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