[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].C1CCC([N:27]=[C:28]=[N:29]C2CCCCC2)CC1.ON1C(=O)CCC1=O.N#CN.[Na].Cl.[Cl-].[Na+]>C1COCC1.O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:18]([NH:29][C:28]#[N:27])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8]L-Pyroglutamyl-L-phenylalanine (4.10 g, 0.0148 mol) was allowed to react with DCC (3.37 g, 0.0163 mol) and N-hydroxysuccinimide (1.88 g, 0.0163 mol) in 60 ml of THF at ice bath temperature for 3 hours, and then at room temperature overnight. The reaction mixture was filtered and the filtrate was added drop-wise to a solution of sodium cyanamide (1.90 g, 0.0297 mol) in 60 ml of distilled water at ice bath temperature. The reaction was allowed to proceed at this temperature for 6 hours. The reaction mixture (pH 8) was then neutralized to pH 7 with 10% HCl, saturated with sodium chloride, and extracted with ethyl acetate (2×50 ml). The aqueous portion (pH 6.2) was acidified to pH 1.5 with 10% HCl and extracted with EtOAc/THF (3:1) (100 ml) and ethyl acetate (2×50 ml). The combined organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo to give 4.20 g (94.5% yield) of crude product as an off-white solid residue. This was crystallized from abs. EtOH/diethyl ether to give 1.36 g (crop 1) of 15. The filtrate was concentrated and crystallized in the same manner to give 9.53 g (crop 2), giving a total yield of 42.5%. Mp 163°-165° C.; [α]D23 +7.81° (c 1.0, MeOH); TLC: Rf =0.29 in CHCl3 /MeOH/AcOH (80:20:5), detected by UV quenching and orange color with ferricyanide spray reagent; IR (Nujol, cm-1) 3350 (NH), 3020 (C6H5), 2160 (C≡N), 1650-1690 (C=O); NMR (methanol-d4, δ from TMS) 7.22 (s, --C6H5), 4.5-4.7 (q, --NH--CH--C=O), 4.0-4.2 (m, --NH--CH--C=O), 2.8-3.2 (m, --CH2 --C6H5), 1.7-2.6 (m, cycl. O=C--CH2 --CH2 --) Anal. Calcd for C15H16N4O3 : C, 59.99; H, 5.37; N, 18.66. Found: C, 59.61; H, 5.61; N, 18.40.
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