Diisopropylethylamine → {(3E)4-[N-((1R)-1-{N-[(1R)-1-((1S)-5-acetylamino-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamoyl}2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester

HRID 365434Notes

Reaction equation

Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH3:40][N:41]([CH3:82])[C:42](=[O:81])[C@@H:43]([NH:52][C:53](=[O:80])[C@H:54]([N:62]([CH3:79])[C:63](=[O:78])[CH:64]([NH:76][CH3:77])[CH2:65][C:66]1[CH:75]=[CH:74][C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:67]=1)[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25](=[O:27])[N:76]([C@@H:64]([C:63](=[O:78])[N:62]([C@@H:54]([C:53](=[O:80])[NH:52][C@H:43]([C:42](=[O:81])[N:41]([CH3:82])[CH3:40])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[CH3:79])[CH2:65][C:66]1[CH:75]=[CH:74][C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:67]=1)[CH3:77])([CH3:14])([CH3:15])[CH3:16]

Participants

Conditions

Temperature: 0 °C

Procedure

N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (279 mg, 1.46 mmol) was added at 0° C. to a solution of (2E)-5-(tert-butyoxycarbonylamino)-5-methylhex-2-enoic acid (355 mg, 1.46 mmol) and 1-hydroxy-7-azabenzotriazole (199 mg, 1.46 mmol). The reaction mixture was stirred for 20 min at 0° C. A solution of the crude hydrochloride salt of (2S)-6-acetylamino-2-{(2R)-2-[N-methyl-N-(2-(methylamino)-3-(2-naphthyl)propionyl)amino]-3-phenylpropionylamino}hexanoic acid N,N-dimethylamide (857 mg, 1.46 mmol) in N,N-dimethylformamide (10 ml) and dichloromethane (20 ml) and ethyidiisopropylamine (0.75 ml, 4.38 mmol) were added subsequently. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed wtih a 10% aqueous solution of sodium hydrogen sulfate (200 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were wshed with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (120 g), using dichloromethane/methanol (10:1) as eluent, to give 719 mg of {(3E)4-[N-((1R)-1-{N-[(1R)-1-((1S)-5-acetylamino-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamoyl}2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester.

Workup

stirringThe reaction mixture was stirred for 16 h, while it
temperaturewas warming up to room temperature
washwashed wtih a 10% aqueous solution of sodium hydrogen sulfate (200 ml)
extractionThe aqueous phase was extracted with ethyl acetate (2×100 ml)
dry with materialdried over magnesium sulfate
customThe solvent was removed in vacuo
customThe crude product was purified by flash chromatography on silica (120 g)

Sources & evidence

ORD record: ord-da174e23058d467ca35227414e1b9551
Source dataset: uspto-grants-2000_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06127341

Reaction notes

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