Propionic Acid → HCID 59605714, compound

HRID 1946002Notes

Reaction equation

HRID 1946002 reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[N:16]2[CH3:19])=[C:12]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:11]=1.[C:37](O)(=O)[CH2:38][CH3:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(O)(=O)C>[CH2:38]([C:39]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([CH2:20][N:21]4[CH2:22][CH2:23][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:25][CH2:26]4)[N:16]3[CH3:19])=[C:12]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:11]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[N:1]=1)[CH3:37]

Participants

8

Reactant 4

HCID 1032Propionic Acid2×HCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 59606192HCID 59606192, compound

Product 1

HCID 59605714HCID 59605714, compoundYield 52%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-{1-[2-(2-amino-3-fluorophenylamino)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol (65 mg, 0.13 mmol), propionic acid (78 uL, 0.14 mmol) and DIPEA (49 uL, 0.29 mmol) in DMF (3 mL) was added HATU (59 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 18 hours. Propionic acid (78 uL, 0.14 mmol), DIPEA (49 uL, 0.29 mmol) and HATU (59 mg, 0.16 mmol) were added and the reaction mixture was stirred at room temperature for 2 days, then diluted with water and extracted with EtOAc. The organic layer was separated and washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated to give a red oil dissolved in acetic acid (2 mL). The mixture was stirred at 90° C. for 18 hours then concentrated under reduced pressure. The residue was azeotroped with toluene, then taken up in MeOH. The resulting solution was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed and the residue was subjected to flash chromatography (Si—PCC, 0-20% MeOH in EtOAc) to give 485 (36 mg, 52%). LCMS (Method I): RT 3.18 min; [M+H]+ 537. 1H NMR (400 MHz, CHCl3-d): δ 7.78-7.75 (m, 1 H); 7.21-7.12 (m, 1 H); 6.97 (dd, J=10.3, 8.0 Hz, 1 H); 4.34 (m, 4 H); 3.90-3.84 (m, 7 H); 3.73 (s, 2 H); 3.35 (q, 7.5 Hz, 2 H); 2.97 (d, J=11.4 Hz, 2 H); 2.12 (m, 2 H); 1.77 (m, 2 H); 1.44 (t, J=7.5 Hz, 3 H); 1.44-1.28 (m, 4 H); 1.24-1.15 (m, 6 H)

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 2 days
  2. extractionextracted with EtOAc
  3. customThe organic layer was separated
  4. washwashed with water
  5. dry with materiala saturated aqueous solution of sodium bicarbonate and brine, dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give a red oil
  9. stirringThe mixture was stirred at 90° C. for 18 hours
  10. concentrationthen concentrated under reduced pressure
  11. customThe residue was azeotroped with toluene
  12. washThe cartridge was washed with MeOH
  13. washthe desired product was eluted with 2M NH3 in MeOH
  14. customThe solvents were removed

Sources & evidence

ORD record
ord-fbf9bab9672a470f9ffcc0332f298299
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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