Potassium Carbonate → (+)-Methyl 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-methoxyquinolin-7-yl)phenyl)acetate

HRID 1525911Notes

Reaction equation

HRID 1525911 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:27][CH2:26][C:16]3([O:21][CH2:20][C:19](=[O:22])[N:18]([CH:23]4[CH2:25][CH2:24]4)[CH2:17]3)[CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:28])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:53]1[CH:62]=[C:61]2[C:56]([CH:57]=[C:58]([O:63][CH3:64])[CH:59]=[N:60]2)=[CH:55][CH:54]=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:23]1([N:18]2[CH2:17][C:16]3([CH2:26][CH2:27][N:13]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:53]5[CH:62]=[C:61]6[C:56]([CH:57]=[C:58]([O:63][CH3:64])[CH:59]=[N:60]6)=[CH:55][CH:54]=5)=[CH:3][C:4]=4[F:28])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][CH2:15]3)[O:21][CH2:20][C:19]2=[O:22])[CH2:25][CH2:24]1

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 533932397-Bromo-3-methoxyquinolineHCID 71270944Methyl 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate

Product 1

HCID 71270822(+)-Methyl 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-methoxyquinolin-7-yl)phenyl)acetateYield 28.1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
80 °C

Procedure

A solution of methyl 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (0.626 mmol) in 1,4-dioxane (2.5 mL) was treated with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.751 mmol), potassium acetate (0.939 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.031 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an oil bath at 80° C. overnight. The reaction mixture was cooled to room temperature and was treated with 7-bromo-3-methoxyquinoline (0.626 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.031 mmol), and 2M aq potassium carbonate (1.878 mmol). The solution was degassed with a stream of nitrogen for 3 min, at which point 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 was extracted three times with chloroform. The combined organic layers were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chiralpak IA column, methanol:acetonitrile-1:1) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid (94 mg, 26%). MS(ES)+ m/e 534.2 [M+H]+, >99% ee, αD=+58 deg (c=0.05, methanol:acetonitrile 1:1).

Workup

  1. customThe reaction vessel was purged with nitrogen
  2. customsealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. customThe solution was degassed with a stream of nitrogen for 3 min, at which
  5. customwas 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)
  9. extractionwas extracted three times with chloroform
  10. additionThe combined organic layers were treated with Silicycle Si-thiol (50 mg)
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-34a76907c5c14423b491e35346580a4a
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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