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

HRID 1768833Notes

Reaction equation

HRID 1768833 reaction equation
C(O[C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:10]([OH:18])[CH2:11][C@@H:12]([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:27]([O:31][C:32]([NH:34][C@H:35](C(O)=O)[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[C@@H:10]([OH:18])[CH2:11][C@@H:12]([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 2734486(S)-2-((tert-Butoxycarbonyl)amino)-3-(thiazol-4-yl)propanoic acidHCID 15045750(2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2,N-dimethylhexanamide

Product 1

HCID 15045762(2R, 4S, 5S)-5-[N-(t-Butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2, N-dimethylhexanamideYield 90.9%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A mixture of 200 mg (0.56 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2,N-dimethylhexanamide (prepared as described in Preparation 5) and 4 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 solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with benzene; the solvent was then removed by distillation under reduced pressure. This operation was repeated three times in total. After drying the final residue in vacuo for 8 hours, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran. 150 mg (1.68 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were then added to the suspension. After this, 0.1 ml (0.67 mmole) of 95% diethyl cyanophosphonate and 0.23 ml (1.68 mmole) of triethylamine were added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 15 hours. At the end of this time, the reaction solvent was stripped from the mixture by distillation under reduced pressure and the residue was mixed with water. The precipitate which deposited was collected by filtration and washed with water. It was then dissolved in methylene chloride and the resulting solution was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 260 mg of the title compound as a pale yellow powder, melting at 158°-160° C.

Workup

  1. customAt the end of this time, the solvent was removed by distillation under reduced pressure
  2. additionthe resulting residue was mixed with benzene
  3. customthe solvent was then removed by distillation under reduced pressure
  4. dry with materialAfter drying the final residue in vacuo for 8 hours
  5. temperaturecooling and under an atmosphere of nitrogen
  6. stirringThe mixture was then stirred for 15 hours
  7. distillationAt the end of this time, the reaction solvent was stripped from the mixture by distillation under reduced pressure
  8. additionthe residue was mixed with water
  9. filtrationThe precipitate which deposited was collected by filtration
  10. washwashed with water
  11. dissolutionIt was then dissolved in methylene chloride
  12. dry with materialthe resulting solution was dried over anhydrous magnesium sulfate
  13. customThe solvent was then removed by distillation under reduced pressure

Sources & evidence

ORD record
ord-873a4d3b062240b79809db21d1f22c69
Source dataset
uspto-grants-1995_01
Patent number
US05378689

Reaction notes

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