Acetone → HCID 71005136, compound

HRID 338865Notes

Reaction equation

HRID 338865 reaction equation
Cl.Cl.[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]5)[C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1.CCN(C(C)C)[CH:41]([CH3:43])[CH3:42].C(OC)(OC)OC.CC(C)=O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH:37][CH:41]([CH3:43])[CH3:42])[CH2:33]5)[C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1

Participants

8

Reactant 6

HCID 180AcetoneHCID 9005Trimethyl orthoformateHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 4311764Sodium borohydrideHCID 71468405HCID 71468405, compound

Product 1

HCID 71005136HCID 71005136, compoundYield 346%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of (3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine (Example 5; 0.15 g, 0.27 mmol), DIEA (0.14 mL, 0.81 mmol) and trimethyl orthoformate (0.59 mL, 5.40 mmol) in methanol (6 mL) was added acetone (0.30 mL, 0.41 mmol) and the mixture stirred at ambient temperature for 18 hours. The solution was cooled to 0° C. on an ice-bath and sodium borohydride (0.02 g, 0.54 mmol) was added and the mixture stirred at ambient temperature for 1 hour, then poured in a saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (MgSO4) filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M; 10-70% CH3CN/water gradient). The residue was stirred in methanol (0.20 mL) and treated with 2N HCl in diethyl ether (2 mL) and stirred for 30 minutes and the solvents removed under reduced pressure. The residue was dissolved in methanol (0.50 mL) and treated with dichloromethane (0.50 mL) and hexanes (0.50 mL) and concentrated under reduced pressure to afford (3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-N-isopropylpyrrolidin-3-amine (0.49 g, 30%). LCMS APCI (+) m/z 525 (M+H).

Workup

  1. temperatureThe solution was cooled to 0° C. on an ice-bath
  2. stirringthe mixture stirred at ambient temperature for 1 hour
  3. extractionextracted with ethyl acetate (20 mL)
  4. washThe organic layer was washed with brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by reverse phase chromatography (Biotage SP4
  9. stirringThe residue was stirred in methanol (0.20 mL)
  10. additiontreated with 2N HCl in diethyl ether (2 mL)
  11. stirringstirred for 30 minutes
  12. customthe solvents removed under reduced pressure
  13. dissolutionThe residue was dissolved in methanol (0.50 mL)
  14. additiontreated with dichloromethane (0.50 mL) and hexanes (0.50 mL)
  15. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-bce8decdc079449da59da5a4fe5d38cd
Source dataset
uspto-grants-2014_11
Patent number
US08889704B2

Reaction notes

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