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

HRID 1768836Notes

Reaction equation

HRID 1768836 reaction equation
C(O[C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[O:7])(C)(C)C.Cl.[C:32]([O:36][C:37]([NH:39][C@H:40](C(O)=O)[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[O:7])[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 2734486(S)-2-((tert-Butoxycarbonyl)amino)-3-(thiazol-4-yl)propanoic acidHCID 57009174(2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-N-hexyl-4-hydroxy-2-methylhexanamide

Product 1

HCID 15045765(2R, 4S, 5S)-5-[N-(t-Butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-N-hexyl-4-hydroxy-2-methylhexanamideYield 83.4%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A mixture of 412 mg (0.96 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-N-hexyl-4-hydroxy-2-methylhexanamide (prepared as described in Preparation 7) and 8.0 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was mixed with benzene. The solvent was then removed by distillaticn under reduced pressure. This operation was repeated three times in total, and the final residue was dried in vacuo for 8 hours. The dried material was then suspended in 50 ml of anhydrous tetrahydrofuran, and 289 mg (1.06 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the resulting suspension. 0.17 ml (1.06 mmole) of 95% diethyl cyanophosphonate and 0.6 ml (4.3 mmole) of triethylamine were then added, in that order, whilst ice-cooling and under an atmosphere of nitrogen, to the resulting mixture, and the mixture was stirred for 15 hours. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, after which the residue was mixed with water and the crystals which deposited were collected by filtration. The crystals were then dissolved in methylene chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with diisopropyl ether to afford 465 mg of the title compound as a white powder, melting at 156°-158° C.

Workup

  1. distillationAt the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure
  2. additionthe residue was mixed with benzene
  3. customThe solvent was then removed by distillaticn under reduced pressure
  4. customwas dried in vacuo for 8 hours
  5. temperaturecooling and under an atmosphere of nitrogen, to the resulting mixture
  6. stirringthe mixture was stirred for 15 hours
  7. concentrationAt the end of this time, the reaction mixture was concentrated by distillation under reduced pressure
  8. additionafter which the residue was mixed with water
  9. filtrationthe crystals which deposited were collected by filtration
  10. dissolutionThe crystals were then dissolved in methylene chloride
  11. dry with materialdried over anhydrous magnesium sulfate
  12. customafter which the solvent was removed by distillation under reduced pressure
  13. customThe resulting residue was triturated with diisopropyl ether

Sources & evidence

ORD record
ord-342afa2dbdc64c1cb8742d821c06e9b2
Source dataset
uspto-grants-1995_01
Patent number
US05378689

Reaction notes

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