Triethylamine → {3-methoxy-[1,2,4]-thiadiazol-5-yl}carbamoyl-L-leucine L-proline methyl ester

HRID 1275606Notes

Reaction equation

HRID 1275606 reaction equation
[NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH3:8])[N:3]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].C(N(CC)CC)C.[NH2:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32].Cl.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1>ClCCl.CN(C=O)C>[CH3:8][O:7][C:4]1[N:3]=[C:2]([NH:1][C:9]([NH:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:10])[S:6][N:5]=1.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1

Participants

7

Reactant 4

HCID 8471Triethylamine2×HCID 682631,1'-CarbonyldiimidazoleHCID 3141795-Amino-3-methoxy-1,2,4-thiadiazoleHCID 86756120L-leucine L-proline methyl ester hydrochloride

Product 1

HCID 70080342{3-methoxy-[1,2,4]-thiadiazol-5-yl}carbamoyl-L-leucine L-proline methyl esterYield 76.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

To 5-amino-3-methoxy-[1,2,4]thiadiazole (1.31 g, 10 mmol) in dichloromethane (15 mL) at room temperature was added 1,1'-carbonyldiimidazole, CDl, (1.78 g,11 mmol) followed by triethylamine (2.1 mL, 15 mmol). The resulting suspension was stirred under nitrogen for 2.5 h. Volatile materials were removed in vacuo and the residue was dissolved in DMF (20 mL). The latter was then added to a solution of L-leucine-L-proline methyl ester hydrochloride (4.18 g,15 mmol) and triethyl amine (2.1 mL, 15.1 mmol) in DMF (25 mL). The resulting mixture was heated at 120° C. for 2 h and then allowed to cool to room temperature. Volatile materials were removed in vacuo and the residue was diluted with ethyl acetate (250 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent mixture of hexane and ethyl acetate (1/1 and 2/3) afforded {3-methoxy-[1,2,4]-thiadiazol-5-yl}carbamoyl-L-leucine-L-proline methyl ester as a light yellow foam (3.2 g, 76.6%). M.p. 88-90° C.; 1H-NMR (CDCl3) δ12.75 (s, 1H, NH), 6.70 (d, J=12.0 Hz, 1H, NH), 4.79-4.87 (m, 1H, NCHpro), 4.54-4.59 (dd, J=11.8, 6.0 Hz, 1H, NCH), 4.12 (s, 3H, OMe), 3.64-3.90 (m, 2H, NCH2 pro), 1.56-2.26 (m, 6H, 3CH2), 0.94-1.12 (two d, J=9.7 Hz, 7H, 2CH3 +CH); 13C-NMR (CDCl3) δ178.3 (C3), 172.3, 171.1 (CO2), 165.9 (C5), 153.7 (NHC=ONH), 58.8, 56.6, 52.2, 49.8, 47.0 (CH2), 42.0 (CH2), 29.0 (CH2), 24.8 (CH2), 24.5, 23.2, 22.0; MS (m/z) 400 (M+ +1),326, 271, 243, 209,158, 130, 87.

Workup

  1. customVolatile materials were removed in vacuo
  2. dissolutionthe residue was dissolved in DMF (20 mL)
  3. temperatureto cool to room temperature
  4. customVolatile materials were removed in vacuo
  5. additionthe residue was diluted with ethyl acetate (250 mL) and water (100 mL)
  6. extractionThe aqueous layer was extracted with ethyl acetate (2×100 mL)
  7. dry with materialThe combined organic layers was dried (sodium sulfate)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification by column chromatography on silica gel using
  11. additiona solvent mixture of hexane and ethyl acetate (1/1 and 2/3)

Sources & evidence

ORD record
ord-69cb800bab8d445195c9bc5c85fdd8ca
Source dataset
uspto-grants-2000_12
Patent number
US06162791

Reaction notes

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