Sodium Carbonate → HCID 86727603, compound

HRID 519189Notes

Reaction equation

HRID 519189 reaction equation
[CH3:1][C@@H:2]1[C@H:7]([C:8]2[CH:9]=[C:10]3[C:19](=[CH:20][C:21]=2B2OC(C)(C)C(C)(C)O2)[O:18][CH2:17][C:16]2[N:11]3[C@H:12]([CH3:32])[C:13](=[O:31])[NH:14][N:15]=2)[CH2:6][CH2:5][N:4]([C:33]([OH:35])=[O:34])[CH2:3]1.Br[C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[F:44].C(=O)([O-])[O-].[Na+].[Na+]>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:2]([O:35][C:33]([N:4]1[CH2:5][CH2:6][C@@H:7]([C:8]2[CH:9]=[C:10]3[C:19](=[CH:20][C:21]=2[C:37]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=2[F:44])[O:18][CH2:17][C:16]2[N:11]3[C@H:12]([CH3:32])[C:13](=[O:31])[NH:14][N:15]=2)[C@@H:2]([CH3:1])[CH2:3]1)=[O:34])([CH3:7])([CH3:3])[CH3:1]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 1235571-Bromo-2,6-difluorobenzeneHCID 86727604HCID 86727604, compound

Product 1

HCID 86727603HCID 86727603, compoundYield 36.5%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
90 °C

Procedure

To a mixture of (3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperidine-1-carboxylic acid (0.028 g, 0.052 mmol), 2-bromo-1,3-difluoro-benzene (0.015 g, 0.078 mmol) and sodium carbonate (0.018 g, 0.130 mmol) in 1,4-dioxane (3.0 mL) and water (0.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.008 g, 0.010 mmol) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was partitioned between EtOAc (20 mL) and water (20 mL). The organic portion was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 36) to give (3R,4R)-4-[(R)-7-(2,6-difluoro-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 (0.005 g, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.41-7.51 (m, 1H), 7.08 (m, 2H), 6.95 (s, 1H), 6.82 (s, 1H), 4.57-4.65 (m, 5H), 4.25 (m, 1H), 3.83 (m, 1H), 2.80 (m, 1H), 2.43-2.74 (m, 2H), 2.15-2.30 (m, 1H), 1.40-1.51 (m, 12H), 1.29 (s, 3H). LC/MS (Table 1, Method 25) Rt=0.930 min; MS (ESI): m/z 527 [M+H]+.

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. filtrationfiltered
  3. customThe filtrate was partitioned between EtOAc (20 mL) and water (20 mL)
  4. customThe organic portion was separated
  5. extractionthe aqueous layer was extracted with EtOAc (3×50 mL)
  6. dry with materialThe combined organic phase was dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by preparative HPLC (Table 3, Method 36)

Sources & evidence

ORD record
ord-39cf722f777246e0a802db1f7b3b8200
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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