Pyridine → 1-(3-Chloro-4-(trifluoromethyl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea

HRID 63516

Reaction equation

HRID 63516 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH2:5].N1C=CC=CC=1.CCN(C(C)C)C(C)C.[C:28](Cl)(Cl)=[O:29].CS([O-])(=O)=O.[O:37]=[C:38]1[CH:43]([N:44]2[CH2:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49]([CH2:53][NH3+:54])[CH:50]=3)[C:45]2=[O:55])[CH2:42][CH2:41][C:40](=[O:56])[NH:39]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:28]([NH:54][CH2:53][C:49]2[CH:50]=[C:51]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:55])[N:44]([CH:43]2[CH2:42][CH2:41][C:40](=[O:56])[NH:39][C:38]2=[O:37])[CH2:52]3)=[O:29])[CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]

Participants

7

Reactant 5

HCID 1049PyridineHCID 6371PhosgeneHCID 679623-Chloro-4-(trifluoromethyl)anilineHCID 81531Diisopropylethylamine2×HCID 140537492[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methylazanium;methanesulfonate

Product 1

HCID 445393241-(3-Chloro-4-(trifluoromethyl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureaYield 40%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of 3-chloro-4-(trifluoromethyl)aniline (0.60 g, 3.07 mmol), pyridine (0.24 g, 3.07 mmol), and DIEA (1.10 ml, 6.14 mmol) in acetonitrile (5 mL) was added phosgene (1.54 mL, 2.91 mmol, 20% in toluene) via syringe at 0° C. After 30 min, (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methanaminium methanesulfonate (0.84 g, 2.27 mmol) was added in one portion followed by additional DIEA (1.1 ml, 6.14 mmol). The resulting suspension was stirred for 1.5 h and allowed to warm to room temperature. After 1.5 h, the reaction was quenched by the addition of 1 N HCl (20 ml) and the precipitated solid was filtered, washed with water and air-dried. The crude product was purified further by reslurrying with acetonitrile (10 mL) followed by precipitation from DMF (5 mL) water. The product was isolated by filtration, washed with Et2O and dried in vacuo to give 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea as an off-white solid (420 mg, 40%). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 45/55, CH3CN/0.1% H3PO4, 4.76 min (98.7%); mp: 274-276° C.; 1H NMR (DMSO-d6) δ 1.90-2.16 (m, 1H), 2.26-2.45 (m, 1H), 2.59 (d, J=19.6 Hz, 1H), 2.82-3.00 (m, 1H), 4.25-4.52 (m, 4H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 7.05 (t, J=5.9 Hz, 1H), 7.39-7.49 (m, 2H), 7.53 (s, 1H), 7.69 (dd, J=4.2, 8.2 Hz, 2H), 7.91 (s, 1H), 9.32 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.20, 42.83, 47.12, 51.58, 115.58, 118.19, 118.60, 118.98, 121.44, 121.94, 122.96, 125.05, 126.93, 128.31, 128.38, 130.38, 131.14, 142.41, 144.32, 145.28, 154.66, 167.92, 171.00, 172.85. LCMS: MH=495; Anal Calcd for C22H18ClF3N4O4+0.28H2O: C, 52.86%; H, 3.74%; N, 11.21%; Cl, 7.09%; F; 11.40%. Found: C, 52.60%; H, 3.41% ; N, 11.01%; Cl, 7.23%; F, 11.63%.

Workup

  1. waitAfter 1.5 h
  2. customthe reaction was quenched by the addition of 1 N HCl (20 ml)
  3. filtrationthe precipitated solid was filtered
  4. washwashed with water
  5. customair-dried
  6. customThe crude product was purified further
  7. customfollowed by precipitation from DMF (5 mL) water
  8. customThe product was isolated by filtration
  9. washwashed with Et2O
  10. customdried in vacuo

Sources & evidence

ORD record
ord-f4682a6dd36e42d0a510ef40a0a964a8
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Linked notes

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