Diisopropylethylamine → N-[(1R)-1-((1S)-5-(acetylamino)-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamic acid tert-butyl ester

HRID 365432Notes

Reaction equation

HRID 365432 reaction equation
Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].O.ON1C2C=CC=CC=2N=N1.[CH3:44][N:45]([CH3:58])[C:46](=[O:57])[C@@H:47]([NH2:56])[CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:55])[CH3:54].C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@@H:22]([C:23](=[O:25])[NH:56][C@H:47]([C:46](=[O:57])[N:45]([CH3:58])[CH3:44])[CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:55])[CH3:54])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:21])([CH3:14])([CH3:15])[CH3:16]

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 7015127N-Boc-N-methyl-D-phenylalanineHCID 54182435(2S)-6-acetylamino-2-aminohexanoic acid dimethylamide

Product 1

HCID 54269170N-[(1R)-1-((1S)-5-(acetylamino)-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamic acid tert-butyl esterYield 88.3%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (824 mg, 4.30 mmol) was added at 0° C. to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (1.20 g, 4.30 mmol) and 1-hydroxybenzotriazole hydrate (659 mg, 4.30 mmol) in dichloromethane (15 ml) and N,N-dimethylformamide (15 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of the hydrochloride salt of (2S)-6-acetylamino-2-aminohexanoic acid dimethylamide (1.86 g, 6.44 mmol) in N,N-dimethylformamide (10 ml) was added. Ethyidiisopropylamine (2.98 ml, 17.2 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (200 ml). The aqueous solution was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and dried over magnesium sulfate. The solvent was removed. The crude product was purified by flash chromatography on silica (60 g), using dichloromethane/methanol (10:1) as eluent to give 1.81 g of N-[(1R)-1-((1S)-5-(acetylamino)-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamic acid tert-butyl ester.

Workup

  1. stirringThe reaction mixture was stirred for 16 h, while it
  2. temperaturewas warming up to room temperature
  3. washwashed with a 10% aqueous solution of sodium hydrogen sulfate (200 ml)
  4. extractionThe aqueous solution was extracted with ethyl acetate (2×100 ml)
  5. washThe combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (200 ml)
  6. dry with materialdried over magnesium sulfate
  7. customThe solvent was removed
  8. customThe crude product was purified by flash chromatography on silica (60 g)

Sources & evidence

ORD record
ord-c40579b470074f97a03ec33e677bef65
Source dataset
uspto-grants-2000_10
Patent number
US06127341

Reaction notes

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