Triethylamine → N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester

HRID 1275603Notes

Reaction equation

HRID 1275603 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.[Cl:26][CH2:27][C:28]1[N:32]=[C:31](Cl)[S:30][N:29]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:31]1[S:30][N:29]=[C:28]([CH2:27][Cl:26])[N:32]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 3326105-Chloro-3-(chloromethyl)-1,2,4-thiadiazoleHCID 70062410N-L-leucyl-L-proline methyl ester hydrochloride

Product 1

HCID 12052380N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl esterYield 65.3%

Reagents, catalysts & solvents 2

HCID 74236Tetrabutylammonium BromideCatalystHCID 6228DimethylformamideSolvent2×

Procedure

A solution of N-L-leucyl-L-proline methyl ester hydrochloride (2.22 g, 8 mmol) and triethylamine (2.8 mL, 20 mmol) in DMF (50 mL) was stirred at room temperature for 15 min. Then, a solution of 3-chloromethyl-5-chloro-[1,2,4]thiadiazole (0.34 g, 2 mmol) in DMF (10 mL) and tetra-butylammonium bromide (100 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3, 6/4 and 1/1) afforded N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester as a white foam, 0.49 g, 65.3% yield. 1H-NMR (CDCl3) δ7.56 (d, J=8.2 Hz, 1H, NHCH), 4.78 (m, 1H, NHCH), 4.60 (dd, J=8.5, 4.6 Hz, 1H, CHCO2), 4.46 (s, 2H, CH2Cl), 4.09 (m, 1H), 3.69-3.73 (m, 1H), 3.74 (s, 3H, OMe), 2.25-2.30 (m, 1H), 1.68-2.11 (m, 6H), 0.99-1.03 (2d, 6H, 2Me); MS (m/z) 375 (M+ +1), 357, 305, 246, 218, 162, 150, 130.

Workup

  1. customThe reaction mixture was quenched with water
  2. extractionextracted into ethyl acetate
  3. washThe organic layer was washed with a saturated ammonium chloride solution, brine
  4. dry with materialdried (sodium sulfate)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification by column chromatography on silica gel using
  8. additiona mixture of hexane and ethyl acetate (7/3, 6/4 and 1/1)

Sources & evidence

ORD record
ord-52a93943edb543b2b4a6596dcbe09d2e
Source dataset
uspto-grants-2000_12
Patent number
US06162791

Reaction notes

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