Triethylamine → N-(3-methoxy-1,2,4-thiadiazol-5-yl)-l-leucyl-l-proline methyl ester

HRID 992243Notes

Reaction equation

HRID 992243 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[C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=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:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 147635195-Chloro-3-methoxy-1,2,4-thiadiazoleHCID 70062410N-L-leucyl-L-proline methyl ester hydrochloride

Product 1

HCID 12052376N-(3-methoxy-1,2,4-thiadiazol-5-yl)-l-leucyl-l-proline methyl esterYield 53.9%

Reagents, catalysts & solvents 2

HCID 74236Tetrabutylammonium BromideCatalystHCID 6228DimethylformamideSolvent2×

Procedure

A solution of N-L-leucyl-L-proline methyl ester hydrochloride (5.6 g, 20 mmol, prepared according to the procedure by Jones, J. B. et al. in J. Med. Chem. 1995, 38, 3078) and triethylamine (5.6 mL, 40 mmol) in DMF (60 mL) was stirred at room temperature for 15 min. Then, a solution of 5-chloro-3-methoxy-[1,2,4]thiadiazole (1.51 g, 10 mmol) in DMF (10 mL) and tetrabutylammonium bromide (150 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 solution of sodium bicarbonate, 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 and 6/4) afforded N-(3-methoxy-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (1.92 g, 53.9%) as as an off-white foam. 1H-NMR (CDCl3) δ 7.10 (d, J=8.5 Hz, 1H, NHCH), 4.74 (m, 1H, NHCH), 4.57 (dd, J=8.6, 4.6 Hz, 1H, CHCO2), 3.92 (s, 3H, OMe), 3.85 (m, 1H), 3.69 (s, 3H, OMe), 3.62 (m, 1H), 2.17-2.23 (m, 1H), 1.95-2.07 (m, 4H), 1.77-1.82 (m, 1H), 1.59-1.66 (m, 1H), 0.97 (d, J=6.5 Hz 3H, Me), 0.94 (d, J=6.7 Hz, 3H, Me); MS (m/z) 357 (M++1), 228, 200, 130, 101, 70.

Workup

  1. customThe reaction mixture was quenched with water
  2. extractionextracted into ethyl acetate
  3. washThe organic layer was washed with a saturated solution of sodium bicarbonate, 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 and 6/4)

Sources & evidence

ORD record
ord-593ffc12287d421eb832da0d72abebd9
Source dataset
uspto-grants-2002_10
Patent number
US06468977B1

Reaction notes

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