Methyl chloroformate → (R)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate

HRID 41107노트

반응식

HRID 41107 반응식
FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([F:36])[C:18]=1[C:19]1[N:23]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][NH:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:21]=2[N:20]=1)[C:12]([NH:14][CH3:15])=[O:13].Cl[C:38]([O:40][CH3:41])=[O:39].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:36][C:17]1[CH:16]=[C:11]([C:12](=[O:13])[NH:14][CH3:15])[CH:10]=[C:9]([F:8])[C:18]=1[C:19]1[N:23]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:38]([O:40][CH3:41])=[O:39])[CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:21]=2[N:20]=1

참가 물질

5

반응물 3

HCID 6586Methyl chloroformateHCID 81531DiisopropylethylamineHCID 67173930(S)-3,5-difluoro-N-methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide trifluoroacetic acid salt

생성물 1

HCID 52953140(R)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate수율 24.6%

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

A mixture of (S)-3,5-difluoro-N-methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide trifluoroacetic acid salt (150 mg, 0.37 mmol), methyl chloroformate (0.058 mL, 0.75 mmol), and N,N-diisopropylethylamine (0.072 mL, 0.41 mmol) in DCM (10.00 mL) was stirred at room temperature for 30 min. The mixture was then concentrated under reduced pressure, and the residue was purified on preparative HPLC MS using the short high pH shallow gradient method (mobile phase: 30-50% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 10 min run; XBridge Prep C18 OBD, Waters reverse phase column; column size: 30×50 mm; particle size: 5 μm). This produced to afford (R)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate (41.7 mg, 24% yield) as a solid. The solid was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; and particle size: 5 μm). MS m/z 459.3 [M+H]+ (ESI), Rt 1.58 min. 1H NMR (400 MHz, methanol-d4) δ ppm 2.50 (s, 3H) 2.54 (dd, J=4.49, 3.71 Hz, 1H) 2.69-2.84 (m, 1H) 2.96 (s, 3H) 3.25 (td, J=11.91, 2.73 Hz, 1H), 3.55-3.64 (m, 2H), 3.66 (s, 3H), 3.74 (d, J=12.89 Hz, 1H), 3.96 (d, J=12.89 Hz, 1H), 4.16 (dd, J=15.23, 7.42 Hz, 1H), 4.37 (dd, J=15.23, 3.12 Hz, 1H), 7.26 (dd, J=8.59, 1.17 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=8.59 Hz, 1H), 7.64 (d, J=8.59 Hz, 2H). HRMS m/z calcd for C23H25F2N4O4 459.1838 [M+H]+. found 459.1849.

후처리

  1. concentrationThe mixture was then concentrated under reduced pressure
  2. customthe residue was purified on preparative HPLC MS
  3. custom10 min
  4. customThis produced

출처 및 근거

ORD 기록
ord-962ee4fb32174da2b7ab317398eb07d9
출처 데이터셋
uspto-grants-2013_09
특허 번호
US08530467B2

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