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

HRID 41105

反応式

HRID 41105 の反応式
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C:25]2[C:33]([F:34])=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][C:26]=2[F:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N+:37]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN.C(O)C>CN(C=O)C>[F:34][C:33]1[CH:32]=[C:28]([C:29](=[O:31])[NH:37][CH3:36])[CH:27]=[C:26]([F:35])[C:25]=1[C:16]1[N:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]2)[C:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=2[N:17]=1

参加物

6

反応物 4

HCID 702EthanolHCID 6329MethylamineHCID 27340594-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlorideHCID 67169642(R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acid

生成物 1

HCID 67173392(R)-tert-butyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate収率 100%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

(R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acid (750 mg, 1.54 mmol) was added to DMT-MM (408 mg, 1.69 mmol) in DMF (30.00 mL) under N2. The resulting suspension was stirred for 30 min. Afterward, methylamine 33% (by weight) solution in absolute ethanol (0.458 mL, 1.69 mmol) was added, and the mixture was stirred for 3 hr. The mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in EtOAc and washed sequentially with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material 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; and particle size 5 μm). This produced (S)-tert-butyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate as an oil, which was used without further purification (1.4 g, >100% yield) in the next step. The oil 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, particle size: 5 μm). MS m/z 501.4 [M+H]+ (ESI), Rt 1.85 min.

後処理

  1. stirringthe mixture was stirred for 3 hr
  2. concentrationThe mixture was then concentrated under reduced pressure
  3. dissolutionthe resulting residue was dissolved in EtOAc
  4. washwashed sequentially with water and brine
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude material was purified on preparative HPLC MS
  9. custom10 min
  10. customThis produced (S)-tert-butyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate as an oil, which was used without further purification (1.4 g, >100% yield) in the next step
  11. custom2.25 min

出典と根拠

ORDレコード
ord-05068f8c6f9e4a69b7fcfa3a1b34c82e
出典データセット
uspto-grants-2013_09
特許番号
US08530467B2

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