Pyrrolidine → HCID 71153171, compound

HRID 872246Notes

Reaction equation

HRID 872246 reaction equation
Br[C:2]1[C:3]([C:17]2[N:27]=[C:20]3[C:21]([CH3:26])=[N:22][CH:23]=[C:24]([CH3:25])[N:19]3[N:18]=2)=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:80]1[CH2:84][CH2:83][CH2:82][CH2:81]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][C:24]1[N:19]2[N:18]=[C:17]([C:3]3[C:2]([N:80]4[CH2:84][CH2:83][CH2:82][CH2:81]4)=[CH:7][N:6]4[CH:8]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=[C:5]4[CH:4]=3)[N:27]=[C:20]2[C:21]([CH3:26])=[N:22][CH:23]=1

Participants

7

Reactant 4

HCID 31268PyrrolidineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 71153141HCID 71153141, compound

Product 1

HCID 71153171HCID 71153171, compoundYield 10.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A 2.0-5.0 mL microwave vial was charged with 2-(6-bromo-2-phenylimidazo[1,2-a]pyridin-7-yl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (45 mg, 0.107 mmol) and dissolved in toluene (1073 μL). To that stirring solution was added sodium tert-butoxide (36.1 mg, 0.376 mmol), BINAP (6.68 mg, 10.73 μmol), pyrrolidine (22.90 mg, 0.322 mmol), and palladium(II) acetate (2.410 mg, 10.73 μmol). The vial was sealed and degassed using ultra pure argon under sonication for 1 minute. Once purged, the vial was placed in a reaction block preheated to 110° C. The reaction was let stir overnight. After 19 hours at 110° C. the reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The contents of the vial were filtered through a pad of diatomaceous earth (Celite®) and the layers were separated. The organic layer was concentrated under reduced pressure to remove excess pyrrolidine and then rediluted with ethyl acetate and transferred into a separatory funnel. The organic was washed with brine (×2), dried with magnesium sulfate, concentrated under reduced pressure, and purified by prepHPLC: Column: Waters XBridge C18 100×30 mm 5 μm, Solvents: water/acetonitrile/TFA, % B gradient (time): 0% (2 min), 0-100% (12 min), 100% (1 min), Flow Rate: 42 mL/min, 3 injections (1 mL DMSO). The desired fractions were collected and neutralized using a saturated solution of sodium bicarbonate and then diluted with ethyl acetate. The layers were separated and the organic was concentrated under reduced pressure and then diluted with methanol and passed through a Phenomenex STRATA-XC 1 g cartridge and was with several volumes of methanol. The product was eluted with 25 mL of 2.0M ammonia in methanol to give 5,8-dimethyl-2-(2-phenyl-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyridin-7-yl)-[1,2,4]triazolo[1,5-a]pyrazine (4.7 mg, 0.01079 mmol, 10% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.97 (d, J=7.0 Hz, 2H), 7.87 (s, 1H), 7.46 (t, J=7.5 Hz, 2H), 7.38-7.30 (m, 1H), 2.98-2.87 (m, 4H), 2.85 (s, 3H), 2.74 (s, 3H), 1.84-1.78 (m, 4H). Mass found 410 [M+H]+.

Workup

  1. customThe vial was sealed
  2. customdegassed
  3. customunder sonication for 1 minute
  4. customOnce purged
  5. custompreheated to 110° C
  6. additiondiluted with ethyl acetate and water
  7. filtrationThe contents of the vial were filtered through a pad of diatomaceous earth (Celite®)
  8. customthe layers were separated
  9. concentrationThe organic layer was concentrated under reduced pressure
  10. customto remove excess pyrrolidine
  11. additionrediluted with ethyl acetate
  12. customtransferred into a separatory funnel
  13. washThe organic was washed with brine (×2)
  14. dry with materialdried with magnesium sulfate
  15. concentrationconcentrated under reduced pressure
  16. custompurified by prepHPLC
  17. custom0% (2 min), 0-100% (12 min), 100% (1 min), Flow Rate: 42 mL/min, 3 injections (1 mL DMSO)
  18. customThe desired fractions were collected
  19. additiondiluted with ethyl acetate
  20. customThe layers were separated
  21. concentrationthe organic was concentrated under reduced pressure
  22. additiondiluted with methanol
  23. washThe product was eluted with 25 mL of 2.0M ammonia in methanol

Sources & evidence

ORD record
ord-57eb71d1aa75418ca61ea4c89aad3ec0
Source dataset
uspto-grants-2015_03
Patent number
US08975276B2

Reaction notes

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