Potassium Carbonate → (+)-2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2,6-difluoro-4-(quinolin-7-yl)phenyl)acetamide

HRID 1525936Notes

Reaction equation

HRID 1525936 reaction equation
Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:13]2[CH2:27][CH2:26][C:16]3([O:21][CH2:20][C:19](=[O:22])[N:18]([CH:23]4[CH2:25][CH2:24]4)[CH2:17]3)[CH2:15][CH2:14]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:28])[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][CH:43]=[N:44]3)=[CH:39][CH:38]=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:23]1([N:18]2[CH2:17][C:16]3([CH2:26][CH2:27][N:13]([CH:9]([C:5]4[C:6]([F:8])=[CH:7][C:2]([C:37]5[CH:46]=[C:45]6[C:40]([CH:41]=[CH:42][CH:43]=[N:44]6)=[CH:39][CH:38]=5)=[CH:3][C:4]=4[F:28])[C:10]([NH2:12])=[O:11])[CH2:14][CH2:15]3)[O:21][CH2:20][C:19]2=[O:22])[CH2:25][CH2:24]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 592961167-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)QuinolineHCID 712712402-(4-Bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

Product 1

HCID 71270886(+)-2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2,6-difluoro-4-(quinolin-7-yl)phenyl)acetamideYield 22%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (246 mg, 0.54 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (137 mg, 0.54 mmol) and 2M aq K2CO3 (0.59 mL, 1.18 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (21.9 mg, 0.03 mmol). The reaction mixture was purged with nitrogen, 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 washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. Purification of the residue with reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) followed by chiral HPLC (Lux Cell 4, methanol) afforded the title product in 99.9% ee (61 mg, 22% yield). αD=+30 deg (c=0.1, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.58-0.71 (m, 2 H) 0.76-0.87 (m, 2 H) 1.65 (dd, J=11.12, 4.29 Hz, 1 H) 1.71-1.81 (m, 1 H) 1.95 (s, 1 H) 1.92 (s, 1 H) 2.29-2.38 (m, 1 H) 2.64-2.75 (m, 2 H) 2.75-2.84 (m, 1 H) 2.84-2.96 (m, 1 H) 3.14 (s, 2 H) 3.98 (s, 2 H) 4.78 (s, 1 H) 5.68 (br. s., 1 H) 7.40-7.47 (m, 3 H) 7.49 (dd, J=8.21, 4.17 Hz, 1 H) 7.85 (dd, J=8.59, 2.02 Hz, 1 H) 8.00 (d, J=8.59 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.36 (s, 1 H) 8.99 (dd, J=4.29, 1.77 Hz, 1 H).

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. customsealed
  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 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 with reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-a2c84c523ef74d42a0d71c5f977df382
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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