Diisopropylethylamine → (3E)-4-(N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester

HRID 366131Notes

Reaction equation

HRID 366131 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.[OH:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH2:51][N:52]([CH3:69])[C:53](=[O:68])[C@H:54]([NH:66][CH3:67])[CH2:55][C:56]1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=1.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:66]([C@@H:54]([C:53](=[O:68])[N:52]([CH2:51][CH2:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[O:43][CH2:42][CH2:41][OH:40])[CH3:69])[CH2:55][C:56]1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=1)[CH3:67])([CH3:14])([CH3:15])[CH3:16]

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 10621356(2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamideHCID 10847814(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid

Product 1

HCID 59965085(3E)-4-(N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl esterYield 92%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

At 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (125 mg, 0.65 mmol) was added to a solution of (2E)-5-(tertbutoxycarbonylamino)-5-methylhex-2-enoic acid (158 mg, 0.65 mmol) and 1-hydroxy-7-azabenzotriazole (88 mg, 0.65 mmol) in N,N-dimethylformamide (3 ml) and dichloromethane (3 ml). The solution was stirred for 20 min at 0° C. A solution of (2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (265 mg, 0.65 mmol) in dichlromethane (3 ml) and ethyldiisopropylamine (0.11 ml, 0.65 mmol) were added successively. 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 with 10% aqueous sodium hydrogen sulfate solution (100 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using ethyl acetate/heptane (first: 2:1 (500 ml), then: 3:1) as elutent, to give 378 mg of (3E)-4-(N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester.

Workup

  1. customAt 0° C
  2. stirringThe reaction mixture was stirred for 16 h, while it
  3. temperaturewas warming up to room temperature
  4. washwashed with 10% aqueous sodium hydrogen sulfate solution (100 ml)
  5. extractionThe aqueous phase was extracted with ethyl acetate (2×50 ml)
  6. washThe combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (200 ml)
  7. dry with materialdried over magnesium sulfate
  8. customThe solvent was removed in vacuo
  9. customThe crude product was purified by flash chromatography on silica (60 g)

Sources & evidence

ORD record
ord-f6a274fc6251481389a77f5543d260d6
Source dataset
uspto-grants-2000_10
Patent number
US06127354

Reaction notes

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