Methanesulfonyl chloride → (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(methylsulfonamido)-1-oxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide

HRID 571180노트

반응식

HRID 571180 반응식
[NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][C:13]([O:15][C@H:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]4[CH2:41][CH2:40]4)[CH:28]=3)[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl.N1C=CC=CC=1>[Cl:24][C:23]1[CH:22]=[N+:21]([O-:25])[CH:20]=[C:19]([Cl:26])[C:18]=1[CH2:17][C@@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:15][C:13](=[O:14])[CH2:12][N:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:3][CH:4]=2)[C:8]1=[O:11]

참가 물질

5

반응물 2

HCID 31297Methanesulfonyl chlorideHCID 86681602(S)-4-(2-(2-(6-amino-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide

생성물 1

HCID 86681603(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(methylsulfonamido)-1-oxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide수율 75%

시약·촉매·용매 2

HCID 1049Pyridine용매HCID 6344Dichloromethane용매2회

실험 절차

(S)-4-(2-(2-(6-amino-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.08 mmol) was dissolved in CH2Cl2 (2 ml) and pyridine (50 μl), then methanesulfonyl chloride was added (11 mg, 0.1 mmol) at 0° C. The mixture was stirred at RT for 2 hours, then diluted with CH2Cl2 (20 ml) and quenched with HCl 1N aqueous solution (30 ml). The two phases were separated, and the organic phase washed with HCl 1N aqueous solution (2×20 ml), dried over Na2SO4 and evaporated under vacuum. The crude was purified by preparative HPLC (Method 2) to yield 41 mg of the title compound. (Yield 75%). 1H NMR (400 MHz, acetone) δ ppm 8.71-8.92 (m, 1H), 8.22 (s, 2H), 7.73 (m, 1H), 7.59 (m, 2H), 7.15-7.30 (m, 2H), 7.05 (dd, J=8.38, 1.76 Hz, 1H), 6.93 (t, 1H, CHF2), 6.15 (dd, J=9.70, 4.85 Hz, 1H), 4.49 (s, 2H), 4.44 (d, J=3.53 Hz, 2H), 3.98 (d, J=7.06 Hz, 2H), 3.55 (dd, J=14.11, 9.26 Hz, 1H), 3.32 (dd, J=14.11, 4.85 Hz, 1H), 3.05 (s, 3H), 1.29 (m, 1H), 0.55-0.69 (m, 2H), 0.27-0.47 (m, 2H); MS/ESI+ 686.51 [MH]+.

후처리

  1. customquenched with HCl 1N aqueous solution (30 ml)
  2. customThe two phases were separated
  3. washthe organic phase washed with HCl 1N aqueous solution (2×20 ml)
  4. dry with materialdried over Na2SO4
  5. customevaporated under vacuum
  6. customThe crude was purified by preparative HPLC (Method 2)

출처 및 근거

ORD 기록
ord-52d70e72555741ccb07abb36ec05dee3
출처 데이터셋
uspto-grants-2015_05
특허 번호
US09024027B2

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