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

HRID 1525923Notes

Reaction equation

HRID 1525923 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([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=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>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:44]=[C:43]5[C:38]([CH:39]=[CH:40][CH:41]=[N:42]5)=[CH:37][CH:36]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 592961167-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)QuinolineHCID 712709392-(4-Bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

Product 1

HCID 71270890(+)-2-(4-Ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetamide

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

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 (214 mg, 0.5 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (127 mg, 0.5 mmol) and 2M aq K2CO3 (0.55 mL, 1.1 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 the vessel was sealed and irradiated in the microwave at 110° C. for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HCl. The organic phase was then washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (5-65% acetonitrile:water with 0.1% NH4OH) afforded the title product as a racemate, which was resolved by chiral HPLC (Chromegachiral CC4, methanol) to yield the title product in >98% ee (31 mg, 13%). αD=+21 deg (c=0.06, methanol); MS(ES)+ m/e 477 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.13 (t, J=7.20 Hz, 3 H) 1.65-1.74 (m, 1 H) 1.75-1.80 (m, 1 H) 1.89-2.01 (m, 2 H) 2.31-2.41 (m, 1 H) 2.58-2.70 (m, 2 H) 2.78 (br. s., 1 H) 3.19 (s, 2 H) 3.41 (q, J=7.33 Hz, 2 H) 3.97-4.08 (m, 2 H) 4.54 (s, 1 H) 5.65 (br. s., 1 H) 7.27 (br. s., 1 H) 7.43-7.48 (m, 2 H) 7.55 (d, J=1.77 Hz, 1 H) 7.64 (dd, J=7.96, 1.89 Hz, 1 H) 7.87 (dd, J=8.59, 2.02 Hz, 1 H) 7.98 (d, J=8.59 Hz, 1 H) 8.25 (dd, J=8.34, 1.01 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 8.97 (dd, J=4.04, 1.77 Hz, 1 H).

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. customthe vessel was sealed
  3. customirradiated in the microwave at 110° C. for 25 min, at which
  4. additionThe reaction mixture was diluted with ethyl acetate (25 mL)
  5. washwashed with 5 mL of 1M aq HCl
  6. washThe organic phase was then washed with brine (5 mL)
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered through a pad of celite
  9. concentrationconcentrated in vacuo
  10. customPurification of the residue by reverse phase HPLC (5-65% acetonitrile:water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-edf59a69189840aba634628b178fc257
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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