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

HRID 1525858Notes

Reaction equation

HRID 1525858 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([C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)O1.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:36]5[CH:45]=[C:44]6[C:39]([CH:40]=[CH:41][CH:42]=[N:43]6)=[CH:38][CH:37]=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

6

Reactant 3

HCID 11430Potassium CarbonateHCID 592961167-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)QuinolineHCID 71271075HCID 71271075, compound

Product 1

HCID 712707212-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetamideYield 91%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Argon was bubbled through a suspension of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)acetamide (4.61 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (5.76 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.138 mmol), and 2.0 M aqueous potassium carbonate (18.44 mmol) in 1,4-dioxane (36.9 mL) for 10 minutes then the reaction was heated at 100° C. for 2 hours. The reaction was cooled, treated with silica powder (˜10 g) then evaporated under reduced pressure to dryness. Purification of the residue on silica gel by flash chromatography (ethyl acetate, then 10% methanol/ethyl acetate) followed by combination of the product fractions and concentration to a residue that was taken into dichloromethane, filtered through celite, and concentrated in vacuo afforded the title product racemate (2.27 g, 91% yield) as a light tan solid. MS(ES)+ m/e 489.5 [M+H]+. Chiral resolution of the racemate by chiral HPLC (Chromegachiral CC4, methanol) gave the title product as a light yellow foam (1.0 g, 45%). This solid was triturated with hot 3,3-dimethyl-2-butanone (10 mL) with ultrasonification for 5 minutes. The suspension was cooled to room temperature and the solids were filtered then vacuum dried to afford the title compound as an off white solid in 100% ee (770 mg, 34%). MS(ES)+ m/e 489.4 [M+H]+. αD=+43 deg (c=0.2, methanol).

Workup

  1. temperatureThe reaction was cooled
  2. additiontreated with silica powder (˜10 g)
  3. customthen evaporated under reduced pressure to dryness
  4. customPurification of the residue on silica gel by flash chromatography (ethyl acetate
  5. concentration10% methanol/ethyl acetate) followed by combination of the product fractions and concentration to a residue that
  6. filtrationfiltered through celite
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-87ab42195a434a8b9dd89eeb2bbe70aa
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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