Trifluoroacetic acid → (2S,4S,5S)-5-Amino-6-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid (2,2-dimethylpropyl)amide hemifumarate

HRID 1694948Notes

Reaction equation

HRID 1694948 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]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[CH3:46])[CH2:34][C:33]1([CH3:48])[CH3:47])[C@@H:16]([OH:30])[CH2:17][C@H:18]([C:22](=[O:29])[NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]([CH3:21])[CH3:20])(C)(C)C.[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]/[C:53]([OH:55])=[O:54].[CH3:58][C:59]([CH3:92])([CH3:91])[CH2:60][NH:61][C:62](=[O:90])[C@H:63]([CH:87]([CH3:89])[CH3:88])[CH2:64][C@H:65]([OH:86])[C@@H:66]([NH2:85])[CH2:67][N:68]1[CH2:73][C:72](=[O:74])[N:71]([C:75]2[CH:80]=[C:79]([F:81])[CH:78]=[CH:77][C:76]=2[CH3:82])[CH2:70][C:69]1([CH3:84])[CH3:83]>C(Cl)Cl.CO>[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]/[C:53]([OH:55])=[O:54].[CH3:28][C:25]([CH3:26])([CH3:27])[CH2:24][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]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[CH3:46])[CH2:34][C:33]1([CH3:47])[CH3:48].[NH2:85][C@@H:66]([CH2:67][N:68]1[CH2:73][C:72](=[O:74])[N:71]([C:75]2[CH:80]=[C:79]([F:81])[CH:78]=[CH:77][C:76]=2[CH3:82])[CH2:70][C:69]1([CH3:83])[CH3:84])[C@@H:65]([OH:86])[CH2:64][C@@H:63]([CH:87]([CH3:88])[CH3:89])[C:62]([NH:61][CH2:60][C:59]([CH3:92])([CH3:91])[CH3:58])=[O:90]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 444972Fumaric AcidHCID 24966888(2s,4s,5s)-5-Amino-6-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid (2,2-dimethylpropyl)amideHCID 66645581{(1S,2S,4S)-4-(2,2-Dimethylpropylcarbamoyl)-1-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-ylmethyl]-2-hydroxy-5-methylhexyl}carbamic acid t-butyl ester

Product 1

HCID 131729637(2S,4S,5S)-5-Amino-6-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid (2,2-dimethylpropyl)amide hemifumarateYield 75.7%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

0.69 ml of trifluoroacetic acid (8.96 mmol) was added to a solution of 177 mg of {(1S,2S,4S)-4-(2,2-dimethylpropylcarbamoyl)-1-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-ylmethyl]-2-hydroxy-5-methylhexyl}carbamic acid t-butyl ester obtained in Example (70g) (0.30 mmol) in methylene chloride (1.4 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=100/10/1). 14 mg of fumaric acid (0.12 mmol) was added to a solution of 122 mg of the resulting (2S,4S,5S)-5-amino-6-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid (2,2-dimethylpropyl)amide (0.25 mmol) in methanol (2 ml), and the mixture was stirred at room temperature for five minutes. The solvent was evaporated under reduced pressure to obtain 100 mg of the title compound (yield: 74%).

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=100/10/1)
  8. stirringthe mixture was stirred at room temperature for five minutes
  9. customThe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-e6eafca11eb041ee92ab4094c1f3c185
Source dataset
uspto-grants-2012_04
Patent number
US08158790B2

Reaction notes

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