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 1037490노트

반응식

HRID 1037490 반응식
[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

참가 물질

7

반응물 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

생성물 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

시약·촉매·용매 2

HCID 30318Osmium Tetroxide촉매HCID 6344Dichloromethane용매2회

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-6fc75c292bf349f2a12d13bb1987cf88
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08546434B2

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