Potassium Carbonate → (3R,4R)-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 519169Notes

Reaction equation

HRID 519169 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 86727574(3R,4R)-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 86727573(3R,4R)-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 61.5%

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 (0.051 g, 0.365 mmol), (3R,4R)-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 (0.12 g, 0.243 mmol) and K2CO3 (0.067 g, 0.486 mmol) in dioxane (12 mL) and water (2 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.020 g, 0.024 mmol) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 3-30% EtOAc in petroleum ether) to give (3R,4R)-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 (0.076 g, 61%) as a colorless solid. 1H NMR (CDCl3, 400 MHz) δ 8.34 (brs, 1H), 7.44-7.32 (m, 1H), 7.24-7.11 (m, 3H), 6.85 (s, 1H), 6.73 (brs, 1H), 4.80 (brs, 1H), 4.70-4.53 (m, 2H), 4.43-4.17 (m, 1H), 3.90-3.60 (m, 1H), 2.89 (brs, 1H), 2.60 (brs, 2H), 1.56 (d, J=6.8 Hz, 3H), 1.46 (m, 10H), 0.72 (m, 3H). LC/MS (Table 1, Method 25), Rt=0.948 min.; MS m/z: 509 [M+H]+& 453 [M+H−56]+. SFC (Table 1, Method 46), Rt=6.21 min.

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. concentrationconcentrated in vacuo
  3. customthe residue was purified by column chromatography on silica gel (eluting with 3-30% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-57cd1e63e3994832a70395c50b7ae655
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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