Hydrochloric Acid → (2S, 4S, 5S)-5-{N-[2(R)-Benzyl-3-(morpholinocarbonyl)propionyl]-3-[4-thiazolyl)-L-alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide

HRID 2380101Notes

Reaction equation

HRID 2380101 reaction equation
C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])C(O)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 142130822(R)-benzyl-3-(morpholinocarbonyl)propionic acidHCID 14989089(2S, 4S, 5S)-5-[N-(t-Butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide

Product 1

HCID 14989057(2S, 4S, 5S)-5-{N-[2(R)-Benzyl-3-(morpholinocarbonyl)propionyl]-3-[4-thiazolyl)-L-alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamideYield 78%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A mixture of 500 mg (0.90 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)] in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature and under an atmosphere of nitrogen for 30 minutes, and then the reaction mixture was concentrated by evaporation under reduced pressure. Diethyl ether was added to the residue, and then the solvent was removed by distillation under reduced pressure. The same operation was repeated in total three times. The resulting residue was dried by evaporation under reduced pressure for 8 hours, and then the residue was suspended in 10 ml of anhydrous tetrahydrofuran. 275 mg (0.92 mmoles) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension, and then 0.15 ml (0.99 mmoles) of diethyl cyanophosphate and 0.42 ml (3.01 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure and the residue was purified by silica gel thin layer chromatography (using an 8:1 by volume mixture of methylene chloride and methanol as the developing solvent) and then recrystallization of the product from ethyl acetate, to give 500 mg (yield 78%) of the title compound as white crystals, melting at 150°-152° C.

Workup

  1. concentrationthe reaction mixture was concentrated by evaporation under reduced pressure
  2. additionDiethyl ether was added to the residue
  3. customthe solvent was removed by distillation under reduced pressure
  4. customThe resulting residue was dried by evaporation under reduced pressure for 8 hours
  5. temperaturecooling and under an atmosphere of nitrogen
  6. stirringThe mixture was then stirred for 8 hours
  7. customafter which the solvent was removed by distillation under reduced pressure
  8. customthe residue was purified by silica gel thin layer chromatography (
  9. additionby volume mixture of methylene chloride and methanol as the developing solvent) and then
  10. customrecrystallization of the product from ethyl acetate

Sources & evidence

ORD record
ord-f9131805cc044a0a908e84b81f4060b1
Source dataset
uspto-grants-1994_11
Patent number
US05364844

Reaction notes

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