4-Methylmorpholine → [N-(t-butyloxycarbonyl)statine]-glutamic acid dibenzyl ester

HRID 579897Notes

Reaction equation

[OH:1]N1C2C=CC=CC=2N=N1.C[N:12]1[CH2:17]C[O:15][CH2:14][CH2:13]1.[C:18]1([CH3:28])[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1.[CH2:29]([O:36][C:37](=[O:52])[C@H:38]([CH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[C:53]([O:57]C(N[C@H]([C@H](CC(=O)O)O)CC(C)C)=O)([CH3:56])([CH3:55])[CH3:54].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>C(Cl)Cl>[CH2:29]([O:36][C:37](=[O:52])[C@H:38]([CH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[NH2:39])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1.[C:53]([O:57][C:17]([NH:12][C@H:13]([C@H:14]([CH2:38][C:37](=[O:36])[OH:52])[OH:15])[CH2:28][CH:18]([CH3:19])[CH3:23])=[O:1])([CH3:56])([CH3:55])[CH3:54]

Participants

Conditions

Temperature: 20 °C

Procedure

N-hydroxybenzotriazole (324 mg., 2.4 mmoles), N-methyl-morpholine (202 mg., 2 mmoles), L-glutamic acid dibenzyl ester p-toluenesulfonate (995 mg., 2 mmoles), N-(t-butyloxycarbonyl)-statine (660 mg., 2.4 mmoles) and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho p-toluene sulfonate (1271 mg., 80% pure, 2.4 mmoles) were sequentially dissolved in methylene chloride (100 ml.) at 0° C. and the resulting solution stirred for 19 hours at 20° C. The reaction mixture was then washed consecutively with 5.5% aqueous HCl, saturated aqueous NaHCO3 solution and brine, and dried over anhydrous MgSO4After filtration and evaporation, 1269 g. of crude [N-(t-butyloxycarbonyl)statine]-glutamic acid dibenzyl ester was obtained as an oil (lH NMR, CDCl3, 5.2 delta, 2H s [benzyl CH2 ]). This oil (1269 g.) was dissolved in 10 ml. of 3.7N HCl/dioxane and the resulting solution allowed to stand for one hour at room temperature. The solution was then evaporated under high vacuum to a residue, which was triturated in ether and dried with nitrogen to yield 900 mg. of statine-glutamic acid dibenzyl ester hydrochloride as a foam (lH NMR, CDCl3, 5.2 delta, 2H s [benzyl CH2 ]). N-hydroxybenzotriazole (186 mg., 1.38 mmoles), N-methyl-morpholine (116 mg., 1.15 mmoles), a quantity of the statine-glutamic acid dibenzyl ester hydrochloride foam formed above (600 mg., 1.15 mmoles), N-(t-butyloxycarbonyl)-L-alanine (261 mg., 1.38 mmoles) and 1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide metho p-toluene sulfonate (732 mg., 80% pure, 1.38 mmoles) were sequentially dissolved in methylene chloride (60 ml.) at 0° C. and the resulting solution stirred for 19 hours at 20° C. The reaction mixture was then washed consecutively with 5.5% aqueous HCl, saturated aqueous NaHCO3 solution and brine, and dried over anhydrous MgSO4After filtration and evaporation, 743 mg. of crude product was obtained as a foam (lH NMR, CDCl3, 5.2 delta, 2H s [benzyl CH2 ]).

Workup

washThe reaction mixture was then washed consecutively with 5.5% aqueous HCl, saturated aqueous NaHCO3 solution and brine
customdried over anhydrous MgSO4After filtration and evaporation, 1269 g

Sources & evidence

ORD record: ord-1d52262c139a446388cead6afa88aeba
Source dataset: uspto-grants-1988_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US04749687

Reaction notes

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