Trifluoroacetic acid → (2R,4S,5S)-5-Amino-6-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-2-ethyl-4-hydroxyhexanoic acid (2,2-dimethylpropyl)amide hemifumarate

HRID 1695004Notes

Reaction equation

HRID 1695004 reaction equation
FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:30][N:31]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])[CH2:33][C:32]1([CH3:46])[CH3:45])[C@@H:16]([OH:29])[CH2:17][C@H:18]([C:21](=[O:28])[NH:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][CH3:20])(C)(C)C.[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].CC(C)(C)CNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CN1CC(=O)N(C2C=CC=CC=2Cl)CC1(C)C>C(Cl)Cl.CO>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[CH3:26][C:24]([CH3:25])([CH3:27])[CH2:23][NH:22][C:21](=[O:28])[C@H:18]([CH2:19][CH3:20])[CH2:17][C@H:16]([OH:29])[C@@H:15]([NH2:14])[CH2:30][N:31]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])[CH2:33][C:32]1([CH3:45])[CH3:46].[NH2:14][C@@H:15]([CH2:30][N:31]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])[CH2:33][C:32]1([CH3:45])[CH3:46])[C@@H:16]([OH:29])[CH2:17][C@@H:18]([CH2:19][CH3:20])[C:21]([NH:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 444972Fumaric AcidHCID 24966889(2r,4s,5s)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-methylhexanoic acid (2,2-dimethylpropyl)amideHCID 66645545{(1S,2S,4R)-4-(2,2-Dimethylpropylcarbamoyl)-1-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-ylmethyl]-2-hydroxyhexyl}carbamic acid t-butyl ester

Product 1

HCID 131729646(2R,4S,5S)-5-Amino-6-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-2-ethyl-4-hydroxyhexanoic acid (2,2-dimethylpropyl)amide hemifumarateYield 83.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

0.43 ml of trifluoroacetic acid (5.6 mmol) was added to a solution of 105 mg of {(1S,2S,4R)-4-(2,2-dimethylpropylcarbamoyl)-1-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-ylmethyl]-2-hydroxyhexyl}carbamic acid t-butyl ester obtained in Example (110c) (0.19 mmol) in methylene chloride (1.0 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. After concentration under reduced pressure, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol/triethylamine=9/1/0-90/10/1). 9.7 mg of fumaric acid (0.08 mmol) was added to a solution of 77 mg of (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-methylhexanoic acid (2,2-dimethylpropyl)amide obtained above (0.17 mmol) in methanol (2 ml), and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and n-hexane (1 ml) was added to the residue. The solid was collected by filtration to obtain 69 mg of the title compound (yield: 71%).

Workup

  1. concentrationAfter concentration under reduced pressure
  2. additiona saturated sodium bicarbonate aqueous solution was added to the reaction mixture
  3. extractionfollowed by extraction with methylene chloride
  4. dry with materialThen, the organic layer was dried over anhydrous magnesium sulfate
  5. filtrationAfter filtration
  6. customthe solvent was evaporated under reduced pressure
  7. customthe residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol/triethylamine=9/1/0-90/10/1)
  8. stirringthe mixture was stirred at room temperature for five minutes
  9. concentrationThe reaction mixture was concentrated under reduced pressure, and n-hexane (1 ml)
  10. additionwas added to the residue
  11. filtrationThe solid was collected by filtration

Sources & evidence

ORD record
ord-1a5f1142e939424893a55d21fbb06110
Source dataset
uspto-grants-2012_04
Patent number
US08158790B2

Reaction notes

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