Dicyclohexylcarbodiimide → 3-methoxy-5-(N-carbobenzyloxy-L-phenylalanyl-L-alaninamido)-[1,2,4]thiadiazole

HRID 992249Notes

Reaction equation

HRID 992249 reaction equation
[NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH3:8])[N:3]=1.[C:9]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:33](O)=[O:34])[CH3:32])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:8][O:7][C:4]1[N:3]=[C:2]([NH:1][C:33](=[O:34])[C@H:31]([CH3:32])[NH:30][C:28](=[O:29])[C@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[S:6][N:5]=1

Participants

7

Reactant 5

HCID 10868Dicyclohexylcarbodiimide2×HCID 757711-HydroxybenzotriazoleHCID 152128N-Benzyloxycarbonylphenylalanylalanine2×HCID 3141795-Amino-3-methoxy-1,2,4-thiadiazoleHCID 27960291-Hydroxybenzotriazole hydrate

Product 1

HCID 120523903-methoxy-5-(N-carbobenzyloxy-L-phenylalanyl-L-alaninamido)-[1,2,4]thiadiazole

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 5-amino-3-methoxy-[1,2,4]thiadiazole (0.37 g, 2.8 mmol) and N-carbobenzyloxy-L-phenylalanyl-L-alanine, N-Cbz-Phe-Ala-OH, (1.0 g, 2.7 mmol) in DMF (25 mL) was added 1,3-dicyclohexylcarbodiimide, DCC, (0.56 g, 2.7 mmol). After stirring for 30 min, 1-hydroxybenzotriazole hydrate, HOBT, (0.36 g, 2.7 mmol) was added and the resulting mixture was stirred at room temperature for 20 h. Volatile materials were removed in vacuo and the residue was purified by column chromatography on silica gel using a solvent mixture of dichloromethane and methanol (96/4) thereby affording the title compound as a white solid (1.2 g). Further purification by cristallization and chromatography on silica gel gave 3-methoxy-5-(N-carbobenzyloxy-L-phenylalanyl-L-alaninamido]-[1,2,4]thiadiazole (0.87 g, 67% yield). M.p. 161-162° C.; 1H-NMR (CDCl3) 7.14-7.38 (m, 12H, 10Ar—H and 2 NH), 5.92 (br. s, 1H, NH), 5.06 (s, 2H, OCH2), 4.38 (m, 1H, CHCH2Ar), 4.00 (m, 1H, CHCH3), 3.97 (s, 3H, OMe), 3.00-3.08 (m, 2H, CHCH2Ar), 1.34 (d, J=8.9 Hz, 3H, Me); MS (m/z) 484 (M++1), 416, 361, 316, 285, 185, 132, 75. The latter compound was also prepared by using diphenylphosphoryl azide and triethylamine instead of DCC/HOBT in 27.7% yield.

Workup

  1. stirringthe resulting mixture was stirred at room temperature for 20 h
  2. customVolatile materials were removed in vacuo
  3. customthe residue was purified by column chromatography on silica gel using
  4. additiona solvent mixture of dichloromethane and methanol (96/4)

Sources & evidence

ORD record
ord-8936cf478bbe42afa4f062fa1f2c4688
Source dataset
uspto-grants-2002_10
Patent number
US06468977B1

Reaction notes

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