Potassium Carbonate → (+)-2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(2-methylquinolin-7-yl)phenyl)acetamide

HRID 1525896Notes

Reaction equation

HRID 1525896 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:61]=[C:60]2[C:55]([CH:56]=[CH:57][C:58]([CH3:62])=[N:59]2)=[CH:54][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:52]5[CH:61]=[C:60]6[C:55]([CH:56]=[CH:57][C:58]([CH3:62])=[N:59]6)=[CH:54][CH:53]=5)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 123328967-Bromo-2-methylquinolineHCID 71271075HCID 71271075, compound

Product 1

HCID 71270826(+)-2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(2-methylquinolin-7-yl)phenyl)acetamideYield 21%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.341 mmol) in dry 1,4-dioxane (1.5 mL) was treated with bis(pinacolato)diboron (0.409 mmol), potassium acetate (0.499 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.017 mmol). The solution was degassed with a stream of nitrogen for three minutes, at which point the reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an oil bath at 100° C. overnight. At this point the reaction was cooled to room temperature and 7-bromo-2-methylquinoline (0.341 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.017 mmol), and 2M aq potassium carbonate (1.022 mmol) were added. The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (100 mL) and brine (30 mL) and was extracted with ethyl acetate three times. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-9% methanol/dichloromethane) followed by chiral HPLC (Chromegachiral CC4, methanol) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid in >98% ee (38 mg, 21% yield). MS(ES)+ m/e 503.0 [M+H]+. αD=+48 deg (c=0.04, methanol).

Workup

  1. customThe solution was degassed with a stream of nitrogen for three minutes, at which
  2. customwas purged with nitrogen
  3. customsealed
  4. temperatureAt this point the reaction was cooled to room temperature
  5. customThe reaction vessel was purged with nitrogen
  6. customsealed
  7. customthe mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min
  8. additionThe resulting black mixture was diluted with water (100 mL) and brine (30 mL)
  9. extractionwas extracted with ethyl acetate three times
  10. additionThe combined organic layers were treated with Silicycle Si-thiol (20 mg)
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification of the residue by silica gel chromatography (0-9% methanol/dichloromethane)

Sources & evidence

ORD record
ord-5e604e0feb454ae390f13163c6bcd6bb
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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