Carbonic acid--N,N-diethylethanamine (1/2) → HCID 68052028, compound

HRID 1428254Notes

Reaction equation

HRID 1428254 reaction equation
Br.[N:2]1([C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]2[CH:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>O>[N:2]1([C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]2[CH:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1

Participants

4

Reactant 2

HCID 15264167Carbonic acid--N,N-diethylethanamine (1/2)HCID 86694432HCID 86694432, compound

Product 1

HCID 68052028HCID 68052028, compound

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To the product of Step 1 (7.56 g, 18.7 mmol) was added water (100 mL). The solution was then sonicated and gently warmed to ensure complete dissolution of the starting material. To the light brown solution was added Biotage MP-carbonate resin (30 g, 3.34 mmol/g). The solution was swirled gently for 16 hours before being filtered through a thin pad of Celite which was rinsed with acetonitrile and water successively. The filtrate was concentrated in vacuo, azeotroped with toluene (twice), then azeotroped with methanol (twice). The resulting light brown solid was dissolved in methanol (40 mL) and separated by preparative SFC using a ChiralPak IA column (50×250 mm) with 35% modifier solution comprised of methanol with 0.2% diethylamine at 250 mL/min (enantiomer retention times=3.4 minutes {enantiomer 1}& 4.7 minutes {enantiomer 2}). Concentration of the separated enantiomer solutions gave 98.2% ee material for enantiomer 1 (retention time=3.4 minutes) and 94.6% ee for enantiomer 2 (retention time=4.7 minutes). LRMS calc'd for C13H18N5 [M+H]+, 244; found 244. 1H NMR (500 MHz, CD3OD) δ 8.05 (s, 1H), 7.06 (d, J=3.6Hz, 1H), 6.58 (d, J=3.5 Hz, 1H), 4.27 (m, 1H), 3.96 (m, 1H), 3.80 (m, 1H), 3.56 (m, 1H), 2.82-2.73 (m, 2H), 2.36 (m, 1H), 2.25 (m, 1H), 2.00 (m, 1H), 1.63-1.46 (m, 3H). Enantiomer 1 Jak1 activity: +; Enantiomer 2 Jak1 activity: +.

Workup

  1. customThe solution was then sonicated
  2. temperaturegently warmed
  3. dissolutiondissolution of the starting material
  4. filtrationbefore being filtered through a thin pad of Celite which
  5. washwas rinsed with acetonitrile and water successively
  6. concentrationThe filtrate was concentrated in vacuo
  7. customazeotroped with toluene (twice),
  8. customthen azeotroped with methanol (twice)
  9. dissolutionThe resulting light brown solid was dissolved in methanol (40 mL)
  10. customseparated by preparative SFC
  11. customcomprised of methanol with 0.2% diethylamine at 250 mL/min (enantiomer retention times=3.4 minutes {enantiomer 1}& 4.7 minutes {enantiomer 2})
  12. customConcentration of the separated enantiomer solutions gave 98.2% ee material for enantiomer 1 (retention time=3.4 minutes) and 94.6% ee for enantiomer 2 (retention time=4.7 minutes)

Sources & evidence

ORD record
ord-4c3ddfe1542342e7b3dfabc8125002a9
Source dataset
uspto-grants-2015_01
Patent number
US08937077B2

Reaction notes

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