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1-Hydroxybenzotriazole → (R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate

HRID 1013746
Notes
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Reaction equation

HRID 1013746 reaction equation
[C:1](NCC(O)=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1(O)C2C=CC=CC=2N=N1.[OH:33][C:34]([C:36](F)(F)F)=O.[CH3:40][O:41][C:42]([C@@H:44]1[CH2:48][C:47]([F:50])([F:49])[CH2:46][NH:45]1)=[O:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([CH2:36][C:34]([N:45]3[CH2:46][C:47]([F:50])([F:49])[CH2:48][C@@H:44]3[C:42]([O:41][CH3:40])=[O:43])=[O:33])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 93124Fmoc-Gly-OHHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 668549754,4-Difluoro-L-proline methyl ester trifluoroacetate

Product 1

HCID 67318151(R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A round bottom flask was charged with Fmoc-glycine (756 mg, 2543 μmol), 1H-benzo[d][1,2,3]triazol-1-ol (412 mg, 3052 μmol), (S)-methyl-4,4-difluoropyrrolidine-2-carboxylate TFA salt (710 mg, 2543 μmol), Hunig'sBase (2221 μl, 12717 μmol) and 10.2 mL DMF. The mixture was stirred for 5 min at RT, and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (1350 mg, 3052 μmol) was added. The reaction mixture was stirred overnight at RT. The solution was diluted with DCM and washed with water. The organic layer was dried, filtered, and concentrated. The crude oil was purified by silica gel chromatography, 0-5% MeOH/DCM to provide (R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate. MS: [M+H]=445.

Workup

  1. stirringThe reaction mixture was stirred overnight at RT
  2. washwashed with water
  3. customThe organic layer was dried
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude oil was purified by silica gel chromatography, 0-5% MeOH/DCM

Sources & evidence

ORD record
ord-923ab1a7c39344e4abb044acc895df18
Source dataset
uspto-grants-2011_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07981891B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes