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 404843Notes

Reaction equation

HRID 404843 reaction equation
[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

Participants

5

Reactant 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

Product 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-carboxylateYield 64.6%

Reagents, catalysts & solvents 1

HCID 24386Thionyl ChlorideSolvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-850dcbc2c3044855a4880fa0fa7dc7b3
Source dataset
uspto-grants-2014_06
Patent number
US08748626B2

Reaction notes

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