Methyl morpholine oxide → (3R,4R)-benzyl 3-(((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate

HRID 1037490ノート

反応式

HRID 1037490 の反応式
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1.[F:28][C@@H:29]1[C@H:33]([CH:34]=O)[CH2:32][N:31]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C[N+]1([O-])CCOCC1>C(Cl)Cl.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][CH2:34][C@H:33]2[C@@H:29]([F:28])[CH2:30][N:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:32]2)[C:15]([CH3:18])([CH3:16])[CH3:17])[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1

参加物

7

反応物 4

HCID 82029Methyl morpholine oxideHCID 5049666Sodium triacetoxyborohydrideHCID 53482935(3R,4S)-benzyl 3-fluoro-4-formylpyrrolidine-1-carboxylateHCID 58473025(R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine

生成物 1

HCID 58473029(3R,4R)-benzyl 3-(((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate

試薬・触媒・溶媒 2

HCID 30318Osmium Tetroxide触媒HCID 6344Dichloromethane溶媒2 回

実験手順

To a solution of (R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine (2.55 g, 6.8 mmol) in CH2Cl2 (58 mL) was added the crude (3R,4S)-benzyl 3-fluoro-4-formylpyrrolidine-1-carboxylate (obtained from 1.4 equiv. of (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate) in CH2Cl2 (10 mL) and NaBH(OAc)3 (2.2 g, 10.2 mmol). The reaction mixture was then stirred for 16 h at room temperature. After quenched with saturated NaHCO3 aqueous solution, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude reductive amination product was contaminated by the HF eliminated alkene product, which was not separable on either silica column chromatography or preparative reverse phase HPLC. Therefore, the crude mixture (2.89 g) was dissolved in acetone and water (5:1, 120 mL). 4-Methylmorpholine N-oxide (667 mg, 5.7 mmol) and OsO4 (1.51 mL of a 4% w/v solution) were added to this reaction mixture, which was then stirred for over the weekend at room temperature. After removal of acetone in vacuo, the remaining aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The desired (3R,4R)-benzyl 3-(((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate was obtained on silica column chromatography (40% to 90% EtOAc in Hexanes, 2.16 g, 52%). LC/MS (uplc): MH+ 610.2, 0.99 min.

後処理

  1. customAfter quenched with saturated NaHCO3 aqueous solution
  2. extractionthe reaction mixture was extracted with EtOAc
  3. washThe organic layer was washed with water and brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionTherefore, the crude mixture (2.89 g) was dissolved in acetone
  8. stirringwas then stirred for over the weekend at room temperature
  9. customAfter removal of acetone in vacuo
  10. extractionthe remaining aqueous layer was extracted with EtOAc
  11. washThe organic layer was washed with water and brine
  12. dry with materialdried over anhydrous Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated

出典と根拠

ORDレコード
ord-6fc75c292bf349f2a12d13bb1987cf88
出典データセット
uspto-grants-2013_10
特許番号
US08546434B2

反応ノート

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