Triethylamine → Itacitinib

HRID 877894Notes

Reaction equation

HRID 877894 reaction equation
Cl.Cl.[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[C:6]([C:12]2[CH:13]=[N:14][N:15]([C:17]3([CH2:21][C:22]#[N:23])[CH2:20][NH:19][CH2:18]3)[CH:16]=2)=[N:5][CH:4]=1.C(N(CC)CC)C.[F:31][C:32]1[C:46]([C:47]([F:50])([F:49])[F:48])=[N:45][CH:44]=[CH:43][C:33]=1[C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[C:6]([C:12]2[CH:13]=[N:14][N:15]([C:17]3([CH2:21][C:22]#[N:23])[CH2:20][N:19]([CH:39]4[CH2:40][CH2:41][N:36]([C:34](=[O:35])[C:33]5[CH:43]=[CH:44][N:45]=[C:46]([C:47]([F:50])([F:49])[F:48])[C:32]=5[F:31])[CH2:37][CH2:38]4)[CH2:18]3)[CH:16]=2)=[N:5][CH:4]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 584313981-(3-Fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-oneHCID 903867522-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitriledihydrochloride

Product 1

HCID 53380437Itacitinib

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (6, 20 g, 56.78 mmol), dichloromethane (200 mL) and triethylamine (TEA, 16.62 mL, 119.2 mmol, 2.1 equiv) at ambient temperature. The mixture was stirred at ambient temperature for 30 minutes before 1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-one (7, 17.15 g, 57.91 mmol, 1.02 equiv) was added to the mixture. The mixture was then treated with sodium triacetoxyborohydride (25.34 g, 113.6 mmol, 2.0 equiv) in 5 minutes at ambient temperature (below 26° C.). The resulting reaction mixture was stirred at ambient temperature for 2 hours. After the reaction was complete as monitored by HPLC, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL). The two phases were separated and the aqueous phase was extracted with methylene chloride (200 mL). The combined organic phase was washed with 4% brine (100 mL) followed by solvent switch of methylene chloride to acetone by distillation. The resulting solution of the desired crude product (8) in acetone was directly used for the subsequent adipate salt formation. A small portion of solution was purified by column chromatography (SiO2, 0-10% of MeOH in EtOAc gradient elution) to afford the analytically pure 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base) as an off-white solid. For 8: 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H).

Workup

  1. customTo a 0.5-L flask equipped with a nitrogen inlet
  2. additionwas added to the mixture
  3. customThe resulting reaction mixture
  4. customthe reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL)
  5. customThe two phases were separated
  6. extractionthe aqueous phase was extracted with methylene chloride (200 mL)
  7. washThe combined organic phase was washed with 4% brine (100 mL)
  8. distillationfollowed by solvent switch of methylene chloride to acetone by distillation
  9. customA small portion of solution was purified by column chromatography (SiO2, 0-10% of MeOH in EtOAc gradient elution)

Sources & evidence

ORD record
ord-a8d8f5c9215a4ccf83bd7bea9fa18ba7
Source dataset
uspto-grants-2015_03
Patent number
US08987443B2

Reaction notes

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