Trifluoroacetic acid → Itacitinib

HRID 1617344Notes

Reaction equation

HRID 1617344 reaction equation
[F:1][C:2]1[C:44]([C:45]([F:48])([F:47])[F:46])=[N:43][CH:42]=[CH:41][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][C:14]([CH2:38][C:39]#[N:40])([N:16]3[CH:20]=[C:19]([C:21]4[C:22]5[CH:29]=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=5[N:24]=[CH:25][N:26]=4)[CH:18]=[N:17]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:44]([C:45]([F:48])([F:46])[F:47])=[N:43][CH:42]=[CH:41][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[CH2:13][C:14]([CH2:38][C:39]#[N:40])([N:16]3[CH:20]=[C:19]([C:21]4[C:22]5[CH:29]=[CH:28][NH:27][C:23]=5[N:24]=[CH:25][N:26]=4)[CH:18]=[N:17]3)[CH2:15]2)[CH2:10][CH2:11]1)=[O:5]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 58431381{1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

Product 1

HCID 53380437Itacitinib

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Into a solution of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours. After removing the solvents in vacuum, the residue was dissolved in a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the solution was purified by HPLC (method B) to give the title compound. LC-MS: 554.3 (M+H)+; 1H NMR (400 MHz, CDCl3): 9.71 (s, 1H), 8.82 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.52 (t, J=4.6 Hz, 1H), 7.39 (dd, J1=3.4 Hz, J2=1.5 Hz, 1H), 6.77 (dd, J1=3.6 Hz, J2=0.7 Hz, 1H), 4.18 (m, 1H), 3.75 (m, 2H), 3.63 (dd, J1=7.8 Hz, J2=3.7 Hz, 2H), 3.45 (m, 2H), 3.38 (s, 2H), 3.11 (m, 1H), 2.57 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H).

Workup

  1. customAfter removing the solvents in vacuum
  2. dissolutionthe residue was dissolved in a methanol solution
  3. additioncontaining 20% ethylenediamine
  4. stirringAfter being stirred at room temperature for 1 hour
  5. customthe solution was purified by HPLC (method B)

Sources & evidence

ORD record
ord-13f9b33f843e455abf4395426574ba6b
Source dataset
uspto-grants-2014_07
Patent number
US08765734B2

Reaction notes

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