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

HRID 1525867Notes

Reaction equation

HRID 1525867 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:24][CH2:23][C:13]3([O:18][CH2:17][C:16](=[O:19])[N:15]([CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)[CH2:12][CH2:11]2)[CH3:9])=[C:4]([F:25])[CH:3]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](B(O)O)[CH:34]=2)[CH:29]=[CH:28][CH:27]=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:20]1([N:15]2[CH2:14][C:13]3([CH2:23][CH2:24][N:10]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:33]5[CH:34]=[C:35]6[C:30]([CH:29]=[CH:28][CH:27]=[N:26]6)=[CH:31][CH:32]=5)=[CH:3][C:4]=4[F:25])[CH3:9])[CH2:11][CH2:12]3)[O:18][CH2:17][C:16]2=[O:19])[CH2:22][CH2:21]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 21886457Quinoline-7-boronic acidHCID 712707719-(1-(4-Bromo-2-fluorophenyl)ethyl)-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

Product 1

HCID 71275838(+)-4-Cyclopropyl-9-(1-(2-fluoro-4-(quinolin-7-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-oneYield 24.8%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

A solution of 9-(1-(4-bromo-2-fluorophenyl)ethyl)-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (0.438 mmol) in 1,4-dioxane (2 mL) was treated with quinolin-7-ylboronic acid (0.481 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.022 mmol), and 2M aq potassium carbonate (1.313 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 130° C. for 20 min. The resulting black mixture was diluted with water (50 mL) and extracted three times with dichloromethane. The aqueous layer was further diluted with brine (50 mL) and was then extracted with tetrahydrofuran. The organic layers were combined and were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (4-10% methanol/dichloromethane) followed by resolution of the product by chiral HPLC (Lux Cellulose-2 column, acetonitrile:methanol 85:15) afforded the title compound as a white solid (50 mg, 23%). MS(ES)+ m/e 460.2 [M+H]+, >99% ee, αD=+38 deg (c=0.02, acetonitrile:methano185:15).

Workup

  1. customThe reaction vessel was purged with nitrogen
  2. customsealed
  3. customthe mixture was irradiated in a Biotage Initiator Microwave at 130° C. for 20 min
  4. additionThe resulting black mixture was diluted with water (50 mL)
  5. extractionextracted three times with dichloromethane
  6. additionThe aqueous layer was further diluted with brine (50 mL)
  7. extractionwas then extracted with tetrahydrofuran
  8. additionwere treated with Silicycle Si-thiol (50 mg)
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customPurification of the residue by silica gel chromatography (4-10% methanol/dichloromethane)

Sources & evidence

ORD record
ord-a41796e6dd754116b6d304ce25d064af
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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