Adipic Acid → Itacitinib adipate

HRID 877895Notes

Reaction equation

HRID 877895 reaction equation
[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[N:12][N:13]([C:15]3([CH2:38][C:39]#[N:40])[CH2:18][N:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](=[O:37])[C:26]5[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=5[F:36])[CH2:21][CH2:20]4)[CH2:16]3)[CH:14]=2)=[N:3][CH:2]=1.[C:41]([OH:50])(=[O:49])[CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47].CCCCCCC>CC(C)=O>[C:41]([OH:50])(=[O:49])[CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47].[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[N:12][N:13]([C:15]3([CH2:38][C:39]#[N:40])[CH2:18][N:17]([CH:19]4[CH2:20][CH2:21][N:22]([C:25](=[O:37])[C:26]5[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[C:27]=5[F:36])[CH2:23][CH2:24]4)[CH2:16]3)[CH:14]=2)=[N:3][CH:2]=1

Participants

5

Reactant 3

HCID 196Adipic AcidHCID 8900HeptaneHCID 53380437Itacitinib

Product 1

HCID 67390313Itacitinib adipateYield 85.7%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Procedure

To a 0.5-L flask equipped with a mechanical stirrer, a thermocouple, an addition funnel, and a nitrogen inlet was added a solution of crude 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, 31.38 g, 56.7 mmol) in acetone (220 mL) and adipic acid (8.7 g, 59.53 mmol, 1.05 equiv) at ambient temperature. The reaction mixture was then heated to reflux to give a solution. n-Heptane (220 mL) was gradually added to the reaction mixture at 40-50° C. in one hour. The resulting mixture was gradually cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 16 hours. The solids were collected by filtration, washed with n-heptane (2×60 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 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 adipate (9, 34.0 g, 39.7 g theoretical, 85.6% for two steps) as a white to off-white solid. 9: 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 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), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5 (MW 699.66; C26H23F4N9O for free base, MW, 553.51), LCMS (EI) m/e 554.0 (M++H).

Workup

  1. customTo a 0.5-L flask equipped with a mechanical stirrer
  2. temperatureThe reaction mixture was then heated
  3. temperatureto reflux
  4. customto give a solution
  5. filtrationThe solids were collected by filtration
  6. washwashed with n-heptane (2×60 mL)
  7. customdried under vacuum at 50° C. with nitrogen sweeping to constant weight

Sources & evidence

ORD record
ord-063f013eb512462a905d98fa3aa6a507
Source dataset
uspto-grants-2015_03
Patent number
US08987443B2

Reaction notes

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