Water → HCID 89456852, compound

HRID 577680Notes

Reaction equation

HRID 577680 reaction equation
[C:1]([C:3]1[C:11]2[C:10]([O:12][C@H:13]3[CH2:16][C@H:15]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:14]3)=[N:9][C:8]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[N:7][C:6]=2[N:5](COCC[Si](C)(C)C)[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:10]([O:12][CH:13]3[CH2:16][CH:15]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:14]3)=[N:9][C:8]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[N:7][C:6]=2[NH:5][CH:4]=1)#[N:2]

Participants

5

Reactant 3

HCID 962WaterHCID 6422Trifluoroacetic acidHCID 178460287HCID 178460287, compound

Product 1

HCID 89456852HCID 89456852, compoundYield 80%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of a 1:1 isomeric mixture of cis:trans N-{3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}prop-2-enamide in DCM (10 mL) was added TFA (1.9 mL). The solution was stirred at rt for 5 hrs and the solvents were removed. EtOH (20 mL), water (5 mL), and K2CO3 (424 mg) were added and the reaction mixture was stirred at rt for 30 min. The volatiles were removed to give a pale yellow solid. Water (20 mL) was added and the solid that precipitated out was collected by filtration, washed with water (5 mL) and dried to afford (185.6 mg, 80% yield) of N-[3-({5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)cyclobutyl]prop-2-enamide as a pale yellow solid (cis:trans mixture 1:1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66-9.47 (m, 1H) 8.58 (br. s., 1H) 7.84-8.08 (m, 1H) 7.74 (d, J=6.29 Hz, 1H) 7.48 (d, J=11.58 Hz, 1H) 5.99-6.34 (m, 2H) 5.40-5.71 (m, 2H) 4.06-5.20 (m, 2H) 3.71-3.90 (m, 3H) 2.90 (br. s., 1H) 2.12 (br. s., 1H). m/z (APCI+) for C18H18N8O2 379.1 (M+H)+. The cis/trans mixture (148 mg, 0.39 mmol) was subjected to further purification using supercritical fluid chromatography to separate the isomers: 64 mg of peak 1 and 60 mg of peak 2 was recovered from this separation. 1H NMR analysis of both peaks revealed that peak 1 corresponded to the cis isomer: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1H) 9.16 (s, 1H) 8.50 (d, J=7.81 Hz, 1H) 7.90 (s, 1H) 7.86 (s, 1H) 7.54 (s, 1H) 6.01-6.27 (m, 2H) 5.53-5.70 (m, 1H) 5.13 (quin, J=6.92 Hz, 1H) 4.13 (sxt, J=7.76 Hz, 1H) 3.82 (s, 3H) 2.82-2.99 (m, 2H) 2.04-2.21 (m, 2H). m/z (APCI+) for C18H18N8O2 379.1 (M+H)+.

Workup

  1. additionTo a solution of a 1:1 isomeric mixture of cis
  2. customthe solvents were removed
  3. additionEtOH (20 mL), water (5 mL), and K2CO3 (424 mg) were added
  4. stirringthe reaction mixture was stirred at rt for 30 min
  5. customThe volatiles were removed
  6. customto give a pale yellow solid
  7. customthe solid that precipitated out
  8. filtrationwas collected by filtration
  9. washwashed with water (5 mL)
  10. customdried

Sources & evidence

ORD record
ord-95284627b0984f9ab53cda2d6bacd2aa
Source dataset
uspto-grants-2015_05
Patent number
US09040547B2

Reaction notes

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