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0 °C

To a solution of 10.45 g (34.5 mmol) of N-Boc-L-glutamic acid-α-tertbutyl ester (BACHEM) in 100 mL of methylene chloride under nitrogen is added 3.5 g (17.0 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 h and filtered under nitrogen. The anhydride solution is then added to a solution of 6.42 g (14.9 mmol) of the compound of Example 20 in 75 mL of methylene chloride under nitrogen. The reaction is stirred overnight and is concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC). This material is redissolved in 100 mL of methylene chloride under nitrogen and cooled to 0° C. prior to the addition of 135 mL of TFA. The stirred reaction is allowed to warm to ambient temperature overnight and is concentrated in vacuo. The crude product is dissolved in 80 mL of acetonitrile/water (1:1) and the pH is adjusted to 9 with 1 M K2CO3. The solution is cooled to 0° C. and 1.1 mL (11 mmol) of acetic anhydride and 11 mL (11 mmol) of 1 M K2CO3 is added every 30 min for 5 h; during the course of this reaction the pH is maintained at 9 and the reaction temperature is kept below 5° C. After the last addition, the reaction is allowed to warm to ambient temperature overnight. The pH was adjusted to 4 with 3 M HCl and the reaction concentrated to 300 mL. Purification by reverse phase chromatography (Waters Delta prep-3000) gives N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-traizol-3-yl]acetylhydrazide.

1. filtrationfiltered under nitrogen
2. stirringThe reaction is stirred overnight
3. concentrationis concentrated in vacuo
4. customPurification by silica gel chromatography (Waters Prep-500A)
5. customgives pure material by thin-layer chromatography (TLC)
6. customThe stirred reaction
7. temperatureto warm to ambient temperature overnight
8. concentrationis concentrated in vacuo
9. dissolutionThe crude product is dissolved in 80 mL of acetonitrile/water (1:1)
10. temperatureThe solution is cooled to 0° C.
11. customduring the course of this reaction the pH
12. temperatureis maintained at 9
13. customis kept below 5° C
14. additionAfter the last addition
15. temperatureto warm to ambient temperature overnight
16. concentrationthe reaction concentrated to 300 mL
17. customPurification by reverse phase chromatography (Waters Delta prep-3000)