1,2-Dichloroethane → HCID 66939810, compound

HRID 1947765Notes

Reaction equation

HRID 1947765 reaction equation
[NH2:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:8]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:4][CH:3]=1.[S:37]1[CH:41]=[C:40]([CH:42]([CH3:46])[C:43](O)=[O:44])[N:39]=[CH:38]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:21]([O:20][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C@@H:9]1[CH2:10][CH2:11][C@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:43](=[O:44])[CH:42]([C:40]3[N:39]=[CH:38][S:37][CH:41]=3)[CH3:46])=[CH:36][CH:35]=2)[N:8]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 21624170α-Methyl-4-thiazoleacetic acidHCID 66939623HCID 66939623, compound

Product 1

HCID 66939810HCID 66939810, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 50 mg (0.10 mmol) of tert-butyl(5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(3-fluorophenyl)methyl]pyrrolidine-1-carboxylate (i-4-c) and 2-(1,3-thiazol-4-yl)propanoic acid (15 mg, 0.10 mmol) in 3 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.2 mL, 0.10 mmol) followed by EDC (25 mg, 0.15 mmol) and DIEA (16.5 μL, 0.1 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×5 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (500 uM) eluting with 5% MeOH in dichloromethane to yield the product as a mixture of diastereomers. The two diastereomers were then separated by chiral HPLC employing a Daicel CHIRALPAK® AD® column (eluent: 40% IPA in Heptane). The first eluting diastereomer was designated as Isomer 1 and is a colorless solid. LC-MS: m/z (ES) 655 (MH)+, 677 (MNa)+. The second eluting diastereomer was designated as Isomer 2 and is also a colorless solid. m/z (ES) 654 (MH)+, 676 (MNa)+.

Workup

  1. washThe mixture was washed with water
  2. extractionextracted with dichloromethane (2×5 mL)
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuum
  6. customThe residue was purified by preparative TLC plate (500 uM)
  7. washeluting with 5% MeOH in dichloromethane
  8. customto yield the product
  9. additionas a mixture of diastereomers
  10. customThe two diastereomers were then separated by chiral HPLC

Sources & evidence

ORD record
ord-74777feb02a74aceadcdce6674bba7f1
Source dataset
uspto-grants-2013_03
Patent number
US08399480B2

Reaction notes

Loading…