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

HRID 331654

반응식

HRID 331654 반응식
[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]

참가 물질

7

반응물 5

HCID 1049PyridineHCID 6371PhosgeneHCID 679623-Chloro-4-(trifluoromethyl)anilineHCID 81531Diisopropylethylamine2회HCID 140537492[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methylazanium;methanesulfonate

생성물 1

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

시약·촉매·용매 1

HCID 6342Acetonitrile용매

실험 절차

To a solution of 3-chloro-4-(trifluoromethyl)aniline (0.60 g, 3.07 mmol), pyridine (0.24 g, 3.07 mmol), and DIEA (1.101 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%.

후처리

  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

출처 및 근거

ORD 기록
ord-90ac5400b8314683984cf1d1ab88357c
출처 데이터셋
uspto-grants-2014_11
특허 번호
US08877780B2

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