Formic Acid → (R)-1-(2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

HRID 713311Notes

Reaction equation

HRID 713311 reaction equation
C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@H:19]([F:40])[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:27]=[C:28]3[CH2:39][CH2:38][NH:37][CH2:36][C:29]3=[N:30][C:31]=2[NH:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1.CO>C1COCC1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@H:19]([F:40])[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:27]=[C:28]3[CH2:39][CH2:38][N:37]([C:5](=[O:7])[CH3:6])[CH2:36][C:29]3=[N:30][C:31]=2[NH:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1

Participants

6

Reactant 4

HCID 284Formic AcidHCID 887MethanolHCID 7918Acetic AnhydrideHCID 118159121(R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

Product 1

HCID 118159318(R)-1-(2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Acetic anhydride (14.1 μL, 0.149 mmol) and formic acid (38.1 μL, 0.994 mmol) were combined in THF (99 μL) and stirred at room temperature for 10 min. This solution was cooled to 0° C. and was added to a stirring solution of (R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (41.7 mg, 0.099 mmol) in THF (895 μL) at 0° C. After 10 min, UPLC-MS showed conversion not to the formylated product, but to the acetylated product. The reaction mixture was treated with MeOH, concentrated under reduced pressure, taken up in MeOH, filtered, and purified by HPLC Method B to give the title compound, as a TFA salt, as a pale yellow solid (17.5 mg, 30.6%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.28 (m, 6H), 1.45 (d, J=12.7 Hz, 1H), 1.65 (m, 2H), 2.01 (m, 1H), 2.09 (m, 1H), 2.18 (s, 1.1H), 2.20 (s, 1.9H), 2.76 (m, 4H), 3.49 (m, 2H), 3.81 (t, J=6.1 Hz, 1.3H), 3.85 (t, J=5.9 Hz, 0.7H), 4.13 (m, 1H), 4.57 (s, 0.7H), 4.61 (s, 1.3H), 5.52 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H); ESI-MS m/z [M+H]+ 462.4.

Workup

  1. temperatureThis solution was cooled to 0° C.
  2. waitAfter 10 min
  3. concentrationconcentrated under reduced pressure
  4. filtrationfiltered
  5. custompurified by HPLC Method B

Sources & evidence

ORD record
ord-9743192153e34dc9a81cbdf60d7af270
Source dataset
uspto-grants-2015_11
Patent number
US09181249B2

Reaction notes

Loading…