Diisopropylethylamine → (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate

HRID 404843ノート

反応式

HRID 404843 の反応式
[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.[CH2:9]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C@H:29]([NH:34][CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:37]1)[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O>[CH2:9]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C@H:29]([N:34]([CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[CH2:37]1)[C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1

参加物

5

反応物 3

HCID 81531DiisopropylethylamineHCID 446666Tetrahydro-2-furoic acid, (-)-HCID 86693891(3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate

生成物 1

HCID 86693893(3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate収率 64.6%

試薬・触媒・溶媒 1

HCID 24386Thionyl Chloride溶媒

実験手順

The solution of (S)-(−)-2-tetrahydrofuroic acid (50 mg, 0.43 mmol) in thionyl chloride (0.5 mL) was refluxed for 30 min, and the volatile materials were completely concentrated in vacuo. The crude product was then dissolved in dichloromethane (0.3 mL), which was then added to a solution of (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (40 mg, 0.066 mmol) and N,N-diisopropylethylamine (34 μL, 0.197 mmol). After the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the desired (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (30 mg, 64.6%). LC/MS (uplc): MH+ 706.0, 1.40 min.

後処理

  1. concentrationthe volatile materials were completely concentrated in vacuo
  2. dissolutionThe crude product was then dissolved in dichloromethane (0.3 mL)
  3. customThe reaction mixture was quenched with saturated NaHCO3 solution
  4. extractionextracted with EtOAc
  5. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by preparative reverse phase HPLC
  9. extractionwas then extracted with EtOAc
  10. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo

出典と根拠

ORDレコード
ord-850dcbc2c3044855a4880fa0fa7dc7b3
出典データセット
uspto-grants-2014_06
特許番号
US08748626B2

反応ノート

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