Potassium Carbonate → 2-(4-(3-Cyanoquinolin-7-yl)-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

HRID 1525937Notes

Reaction equation

HRID 1525937 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[C:56]([C:61]#[N:62])[CH:57]=[N:58]2)=[CH:53][CH:52]=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>[C:61]([C:56]1[CH:57]=[N:58][C:59]2[C:54]([CH:55]=1)=[CH:53][CH:52]=[C:51]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]3[CH2:25][CH2:24][C:15]4([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]4)[CH2:14][CH2:13]3)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1)[CH:60]=2)#[N:62]

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 690822957-Bromoquinoline-3-carbonitrileHCID 712709392-(4-Bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

Product 1

HCID 712708502-(4-(3-Cyanoquinolin-7-yl)-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamideYield 58.5%

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-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (202 mg, 0.47 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (120 mg, 0.47 mmol), and potassium acetate (93 mg, 0.94 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (38.5 mg, 0.05 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromoquinoline-3-carbonitrile (110 mg, 0.47 mmol) and 2M aq K2CO3 (0.52 mL, 1.04 mmol) were added. The reaction mixture was purged with nitrogen and heated with stirring at 100° C. for 1 h. The reaction mixture was diluted with dichloromethane (60 mL) and any salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate and the filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) afforded the title product (138 mg, 55% yield). MS(ES)+ m/e 502 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.13 (t, J=7.20 Hz, 3 H) 1.65-1.84 (m, 2 H) 1.86-2.04 (m, 2 H) 2.25-2.40 (m, 1 H) 2.55-2.74 (m, 2 H) 2.75-2.87 (m, 1 H) 3.18 (s, 2 H) 3.41 (q, J=7.07 Hz, 2 H) 3.92-4.11 (m, 2 H) 4.56 (s, 1 H) 5.62 (d, J=3.54 Hz, 1 H) 7.28 (d, J=4.29 Hz, 1 H) 7.49 (t, J=7.71 Hz, 1 H) 7.58 (dd, J=11.12, 1.77 Hz, 1 H) 7.65 (dd, J=8.08, 1.77 Hz, 1 H) 8.00 (dd, J=8.59, 1.77 Hz, 1 H) 8.06 (d, J=8.34 Hz, 1 H) 8.43 (s, 1 H) 8.63 (d, J=2.02 Hz, 1 H) 9.10 (d, J=2.02 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. temperatureheated
  5. additionThe reaction mixture was diluted with dichloromethane (60 mL)
  6. filtrationany salts were 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. filtrationThe mixture was 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-fda36c9f84444b708e199f936e458c19
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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