Potassium Carbonate → HCID 71270866, compound

HRID 1525929Notes

Reaction equation

HRID 1525929 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.[Cl:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34](B1OC(C)(C)C(C)(C)O1)[CH:33]=2.B(O)O.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>[Cl:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]3[CH2:26][CH2:25][C:15]4([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]5[CH2:24][CH2:23]5)[CH2:16]4)[CH2:14][CH2:13]3)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1)[CH:33]=2

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 71271075HCID 71271075, compoundHCID 178431018HCID 178431018, compound

Product 1

HCID 71270866HCID 71270866, compoundYield 4%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

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 (137 mg, 0.31 mmol), crude 3-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline/boronic acid mixture (45.0 mg), and 2M aq potassium carbonate (0.17 mL, 0.342 mmol) in 1,4-dioxane (0.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (10.2 mg, 0.012 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 to dryness. Purification of the residue by reverse phase HPLC (5-45% acetonitrile+0.1% TFA:water+0.1% TFA) followed by resolution of the racemate by chiral HPLC (Chromegachiral CC4, methanol) afforded the title product in >98% ee (9 mg, 4% yield over the two steps). αD=+41 deg (c=0.02, methanol); MS(ES)+ m/e 523.5 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.65 (br. s., 2 H) 0.82 (d, J=5.81 Hz, 2 H) 1.59 (br. s., 4 H) 1.92 (br. s., 1 H) 2.72 (br. s., 3 H) 3.16 (br. s., 3 H) 4.01 (br. s., 2 H) 4.53 (br. s., 1 H) 5.58 (s, 1 H) 7.27 (br. s., 1 H) 7.63 (br. s., 1 H) 7.92 (d, J=7.07 Hz, 2 H) 8.25 (d, J=2.02 Hz, 1 H) 8.35 (s, 1 H) 8.89 (d, J=2.27 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 to dryness
  10. customPurification of the residue by reverse phase HPLC (5-45% acetonitrile+0.1% TFA:water+0.1% TFA)

Sources & evidence

ORD record
ord-20aa24658e24453a927d7e9779d44549
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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