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

HRID 1525926Notes

Reaction equation

HRID 1525926 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.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:61]=[C:60]2[C:55]([CH:56]=[C:57]([F: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]([F: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 690851037-Bromo-3-fluoroquinolineHCID 71271075HCID 71271075, compound

Product 1

HCID 71270902(+)-2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-fluoroquinolin-7-yl)phenyl)acetamide

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (110 mg, 0.25 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (63 mg, 0.25 mmol), and potassium acetate (49 mg, 0.5 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (20.4 mg, 0.025 mmol). The reaction mixture was purged with nitrogen and then was heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromo-3-fluoroquinoline (56.5 mg, 0.25 mmol) and 2M aq K2CO3 (0.27 mL, 0.55 mmol) were added. The reaction mixture was purged with nitrogen and was heated with stirring at 100° C. for one hour. The reaction mixture was diluted with dichloromethane (60 mL), and salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate. The filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min and was then filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) followed by chiral HPLC (Chromegachiral CC4, methanol) afforded the title product in >98% ee (34 mg, 27%). αD=+37 deg (c=0.04, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.60-0.69 (m, 2 H) 0.77-0.86 (m, 2 H) 1.64-1.77 (m, 2 H) 1.85-1.97 (m, 2 H) 2.26-2.38 (m, 1 H) 2.57 (d, J=14.40 Hz, 1 H) 2.66-2.76 (m, 2 H) 2.79 (d, J=10.86 Hz, 1 H) 3.15 (s, 2 H) 4.00 (d, J=1.77 Hz, 2 H) 4.53 (s, 1 H) 5.63 (br. s., 1 H) 7.26 (d, J=3.79 Hz, 1 H) 7.46 (t, J=7.71 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.62 (dd, J=7.96, 1.89 Hz, 1 H) 7.84-7.93 (m, 2 H) 7.93-8.00 (m, 1 H) 8.38 (s, 1 H) 8.88 (d, J=2.78 Hz, 1 H).

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. temperatureThe reaction mixture was cooled
  3. customThe reaction mixture was purged with nitrogen
  4. temperaturewas heated
  5. additionThe reaction mixture was diluted with dichloromethane (60 mL), and salts
  6. filtrationwere filtered away
  7. filtrationThe organic mixture was filtered through a plug of celite and sodium sulfate
  8. additionThe filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min
  9. filtrationwas then filtered
  10. concentrationconcentrated in vacuo
  11. customPurification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-aa12bdcfd1694a95803c8edc0a71feda
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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