1,2-Dichloroethane → (R)-tert-Butyl 2-((R)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate

HRID 1874647Notes

Reaction equation

HRID 1874647 reaction equation
[C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:35][CH:36]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:51][CH:50]=1)[C@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>C(Cl)Cl>[CH2:56]([O:55][C:52]1[CH:53]=[CH:54][C:49]([C@@H:36]([NH:35][C:8](=[O:10])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:11])[C@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[CH:50][CH:51]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27246222-Phenylpropionic acid, (+)-HCID 67437465(R)-tert-butyl 2-(amino(4-(benzyloxy)phenyl)methyl)pyrrolidine-1-carboxylate

Product 1

HCID 86658402(R)-tert-Butyl 2-((R)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylateYield 17.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(S)-2-Phenylpropanoic acid (107 mg, 0.713 mmol), EDC (137 mg, 0.713 mmol), HOBt (109 mg, 0.713 mmol), and Hunig's base (249 μL, 1.426 mmol) in DCM (6480 μL) were stirred at room temperature for 10 min. (2R)-tert-Butyl 2-(amino(4-(benzyloxy)phenyl)methyl)pyrrolidine-1-carboxylate (248 mg, 0.648 mmol) was added and the solution stirred at room temperature for 4 h. The reaction was quenched with 10% aqueous citric acid and extracted with DCM (3×). The combined organic layers were washed with 10% aqueous citric acid (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10%→60% ethyl acetate in hexanes). Two diastereomers were obtained. (R)-tert-Butyl 2-((R)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (78 mg, 0.114 mmol, 17.54% yield) was obtained as a colorless oil (peak 1). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=6.29 Hz, 1H), 7.33-7.43 (m, 6 H), 7.11-7.23 (m, 4H), 7.06 (d, J=8.56 Hz, 2H), 6.82 (d, J=8.56 Hz, 2H), 4.99 (s, 2H), 4.50 (dd, J=10.83, 6.04 Hz, 1H), 4.01-4.11 (m, 1H), 3.28-3.49 (m, 3H), 1.76-2.07 (m, 2H), 1.53-1.68 (m, 2H), 1.50 (s, 9H), 1.40 (d, J=7.05 Hz, 3H); LRMS (ESI) m/e 515.40 [(M+H)+, calcd for C32H39N2O4 515.29]; m/e 513.60 [(M−H)−, calcd for C32H32N2O4 513.28]. (R)-tert-Butyl 2-((S)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (122 mg, 0.183 mmol, 28.2% yield) was obtained as a colorless oil (peak 2). 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J=6.30 Hz, 1H), 7.23-7.44 (m, 10H), 7.02 (d, J=8.56 Hz, 2H), 6.84 (d, J=8.56 Hz, 2H), 5.01 (s, 2H), 4.68-4.76 (m, 1H), 4.02-4.09 (m, 1H), 3.54 (q, J=7.13 Hz, 1H), 3.09-3.22 (m, 1H), 2.41-2.54 (m, 1H), 1.94-2.07 (m, 1H), 1.64-1.74 (m, 1H), 1.49 (d, J=7.05 Hz, 3H), 1.47 (s, 9H), 1.30-1.40 (m, 2H); LRMS (ESI) m/e 515.30 [(M+H)+, calcd for C32H39N2O4 515.29]; m/e 513.50 [(M−H)−, calcd for C32H32N2O4 513.28].

Workup

  1. additionwas added
  2. customThe reaction was quenched with 10% aqueous citric acid
  3. extractionextracted with DCM (3×)
  4. washThe combined organic layers were washed with 10% aqueous citric acid (2×), saturated aqueous sodium bicarbonate (2×), brine (1×)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography on silica gel (10%→60% ethyl acetate in hexanes)
  9. customTwo diastereomers were obtained

Sources & evidence

ORD record
ord-aa1ebb035f5c46259019764315e4d609
Source dataset
uspto-grants-2012_11
Patent number
US08304577B2

Reaction notes

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