Hydrochloric Acid → (2S, 4S, 5S)-5-[N-(t-Butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide

HRID 2380100Notes

Reaction equation

HRID 2380100 reaction equation
C(O[C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:19])[CH3:18])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:30]([O:34][C:35]([NH:37][C@H:38](C(O)=O)[CH2:39][C:40]1[N:41]=[CH:42][S:43][CH:44]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1.O1CCCC1>[C:30]([O:34][C:35]([NH:37][C@H:38]([C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:18])[CH3:19])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:39][C:40]1[N:41]=[CH:42][S:43][CH:44]=1)=[O:36])([CH3:33])([CH3:31])[CH3:32]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 2734486(S)-2-((tert-Butoxycarbonyl)amino)-3-(thiazol-4-yl)propanoic acidHCID 14989081(2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide

Product 1

HCID 14989089(2S, 4S, 5S)-5-[N-(t-Butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamideYield 91%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 1.20 g (3.00 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide (prepared as described in Preparation 23) in 20 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes under an atmosphere of nitrogen. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then diethyl ether was added to the residue. The solvent was then removed by distillation under reduced pressure from the resulting solution. The same operation was repeated in total three times, and the residue was then dried under reduced pressure for 8 hours. At the end of this time, 900 mg (3.30 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to a suspension of the dried material in 20 ml of anhydrous tetrahydrofuran, and then 0.50 ml (3.30 mmoles) of diethyl cyanophosphate and 0.92 ml (6.60 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 5 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from diisopropyl ether, to give 1.51 g (yield 91%) or the title compound as white crystals, melting at 203°-205° C.

Workup

  1. concentrationAt the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure
  2. additiondiethyl ether was added to the residue
  3. customThe solvent was then removed by distillation under reduced pressure from the resulting solution
  4. customthe residue was then dried under reduced pressure for 8 hours
  5. temperaturecooling and under an atmosphere of nitrogen
  6. stirringThe mixture was then stirred for 5 hours
  7. customafter which the solvent was removed by distillation under reduced pressure
  8. customthe residue was purified by medium pressure silica gel column chromatography (
  9. additionby volume mixture of methylene chloride and methanol as eluent),
  10. customfollowed by recrystallization from diisopropyl ether
  11. customto give 1.51 g (yield 91%)

Sources & evidence

ORD record
ord-15a81c9ea9c648f5b8fba0bd57e6205e
Source dataset
uspto-grants-1994_11
Patent number
US05364844

Reaction notes

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