Trifluoroacetic acid → (2S,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid cyclopentylamide hemifumarate

HRID 1694900Notes

Reaction equation

HRID 1694900 reaction equation
FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:31][N:32]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:45])[CH2:34][C:33]1([CH3:47])[CH3:46])[C@@H:16]([OH:30])[CH2:17][C@H:18]([C:22](=[O:29])[NH:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:19]([CH3:21])[CH3:20])(C)(C)C.[C:49]([OH:56])(=[O:55])/[CH:50]=[CH:51]/[C:52]([OH:54])=[O:53].[CH:57]1([NH:62][C:63](=[O:90])[C@H:64]([CH:87]([CH3:89])[CH3:88])[CH2:65][C@H:66]([OH:86])[C@@H:67]([NH2:85])[CH2:68][N:69]2[CH2:74][C:73](=[O:75])[N:72]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=3[Cl:82])[CH2:71][C:70]2([CH3:84])[CH3:83])[CH2:61][CH2:60][CH2:59][CH2:58]1>C(Cl)Cl.CO>[C:49]([OH:56])(=[O:55])/[CH:50]=[CH:51]/[C:52]([OH:54])=[O:53].[CH:24]1([NH:23][C:22](=[O:29])[C@H:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][C@H:16]([OH:30])[C@@H:15]([NH2:14])[CH2:31][N:32]2[CH2:37][C:36](=[O:38])[N:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])[CH2:34][C:33]2([CH3:46])[CH3:47])[CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:85][C@@H:67]([CH2:68][N:69]1[CH2:74][C:73](=[O:75])[N:72]([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=2[Cl:82])[CH2:71][C:70]1([CH3:84])[CH3:83])[C@@H:66]([OH:86])[CH2:65][C@@H:64]([CH:87]([CH3:88])[CH3:89])[C:63]([NH:62][CH:57]1[CH2:58][CH2:59][CH2:60][CH2:61]1)=[O:90]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 444972Fumaric AcidHCID 24966530(2s,4s,5s)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid cyclopentylamideHCID 66645538{(1S,2S,4S)-1-[4-(2-Chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-4-cyclopentylcarbamoyl-2-hydroxy-5-methylhexyl}carbamic acid t-butyl ester

Product 1

HCID 131729635(2S,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid cyclopentylamide hemifumarateYield 86%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

0.75 ml of trifluoroacetic acid (9.8 mmol) was added to a solution of 193 mg of {(1S,2S,4S)-1-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-4-cyclopentylcarbamoyl-2-hydroxy-5-methylhexyl}carbamic acid t-butyl ester obtained in Example (3a) (0.33 mmol) in methylene chloride (1.5 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and diluted with a saturated sodium bicarbonate aqueous solution, 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=200/20/1). 33.5 mg of fumaric acid (0.29 mmol) was added to a solution of 144 mg of (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid cyclopentylamide obtained above (0.29 mmol) in methanol (3 ml), and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (1.5 ml) and ether (15 ml) were added to the residue. The solid was collected by filtration to obtain 153 mg of the title compound (yield: 86%).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. additiondiluted with a saturated sodium bicarbonate aqueous solution
  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=200/20/1)
  8. stirringthe mixture was stirred at room temperature for five minutes
  9. concentrationThe reaction mixture was concentrated under reduced pressure, and methylene chloride (1.5 ml) and ether (15 ml)
  10. additionwere added to the residue
  11. filtrationThe solid was collected by filtration

Sources & evidence

ORD record
ord-c47dddbb63c04b3f903741b3428a09aa
Source dataset
uspto-grants-2012_04
Patent number
US08158790B2

Reaction notes

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