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

HRID 1525860Notes

Reaction equation

HRID 1525860 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]=[C:57]([CH3:62])[CH:58]=[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]=[C:57]([CH3:62])[CH:58]=[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 189422807-Bromo-3-methylquinolineHCID 71271075HCID 71271075, compound

Product 1

HCID 71270860(+)-2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-methylquinolin-7-yl)phenyl)acetamideYield 31%

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 (0.223 mmol) in dry 1,4-dioxane (1.5 mL) was treated with bis(pinacolato)diboron (0.268 mmol), potassium acetate (0.499 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.011 mmol). The solution was degassed with nitrogen, sealed, and stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and was treated with 7-bromo-3-methylquinoline (0.223 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.011 mmol) and 2M aq potassium carbonate (0.669 mmol). The reaction vessel was purged with nitrogen gas, sealed, and irradiated in a Biotage Initiator Microwave at 120° C. for 15 minutes. The resulting black mixture was diluted with water (50 mL) and extracted with dichloromethane three times. The combined organic layer was treated with Silicycle Si-thiol (30 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-10% methanol/dichloromethane followed by 30% methanol/dichloromethane) and resolution by chiral HPLC (Chromegachiral CC4, methanol) afforded the title compound in >99% ee (31% yield). MS(ES)+ m/e 503.2 [M+H]+. αD=+ 38 deg (c=0.03, methanol).

Workup

  1. customThe solution was degassed with nitrogen
  2. customsealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. customThe reaction vessel was purged with nitrogen gas
  5. customsealed
  6. customirradiated in a Biotage Initiator Microwave at 120° C. for 15 minutes
  7. additionThe resulting black mixture was diluted with water (50 mL)
  8. extractionextracted with dichloromethane three times
  9. additionThe combined organic layer was treated with Silicycle Si-thiol (30 mg)
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customPurification of the residue by silica gel chromatography (0-10% methanol/dichloromethane followed by 30% methanol/dichloromethane) and resolution by chiral HPLC (Chromegachiral CC4, methanol)

Sources & evidence

ORD record
ord-1a7636a19b0c4101b7a2a24795c5a918
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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