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

HRID 1694896Notes

Reaction equation

HRID 1694896 reaction equation
FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:33][N:34]1[CH2:39][C:38](=[O:40])[N:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])[CH2:36][C:35]1([CH3:49])[CH3:48])[C@@H:16]([OH:32])[CH2:17][C@H:18]([C:22](=[O:31])[NH:23][CH2:24][C:25]([C:28](=[O:30])[NH2:29])([CH3:27])[CH3:26])[CH:19]([CH3:21])[CH3:20])(C)(C)C.[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55].[C:59]([C:62]([CH3:94])([CH3:93])[CH2:63][NH:64][C:65](=[O:92])[C@H:66]([CH:89]([CH3:91])[CH3:90])[CH2:67][C@H:68]([OH:88])[C@@H:69]([NH2:87])[CH2:70][N:71]1[CH2:76][C:75](=[O:77])[N:74]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=2[Cl:84])[CH2:73][C:72]1([CH3:86])[CH3:85])(=[O:61])[NH2:60]>C(Cl)Cl.CO>[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55].[C:28]([C:25]([CH3:26])([CH3:27])[CH2:24][NH:23][C:22](=[O:31])[C@H:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][C@H:16]([OH:32])[C@@H:15]([NH2:14])[CH2:33][N:34]1[CH2:39][C:38](=[O:40])[N:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])[CH2:36][C:35]1([CH3:48])[CH3:49])(=[O:30])[NH2:29].[NH2:87][C@@H:69]([CH2:70][N:71]1[CH2:76][C:75](=[O:77])[N:74]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=2[Cl:84])[CH2:73][C:72]1([CH3:85])[CH3:86])[C@@H:68]([OH:88])[CH2:67][C@@H:66]([CH:89]([CH3:90])[CH3:91])[C:65]([NH:64][CH2:63][C:62]([CH3:94])([C:59](=[O:61])[NH2:60])[CH3:93])=[O:92]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 444972Fumaric AcidHCID 57519702(2s,4s,5s)-5-Amino-N-(3-Amino-2,2-Dimethyl-3-Oxopropyl)-6-[4-(2-Chlorophenyl)-2,2-Dimethyl-5-Oxopiperazin-1-Yl]-4-Hydroxy-2-(Propan-2-Yl)hexanamideHCID 66645450{(1S,2S,4S)-4-(2-Carbamoyl-2-methylpropylcarbamoyl)-1-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxy-5-methylhexyl}carbamic acid t-butyl ester

Product 1

HCID 71659969(2S,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid (2-carbamoyl-2-methylpropyl)amide hemifumarateYield 85.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

0.41 ml of trifluoroacetic acid (5.4 mmol) was added to a solution of 167 mg of {(1S,2S,4S)-4-(2-carbamoyl-2-methylpropylcarbamoyl)-1-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxy-5-methylhexyl}carbamic acid t-butyl ester obtained in Example (In) (0.28 mmol) in methylene chloride (0.82 ml) at room temperature, and the mixture was stirred at the same temperature for 50 minutes. After concentration under reduced pressure, a saturated sodium bicarbonate 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=100/10/1). 10.0 mg of fumaric acid (0.09 mmol) was added to a solution of 90 mg of (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid (2-carbamoyl-2-methylpropyl)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 methylene chloride (0.8 ml) was added to the residue. Diethyl ether (8 ml) was further added and the solid was collected by filtration to obtain 90 mg of the title compound (yield: 58%).

Workup

  1. concentrationAfter concentration under reduced pressure
  2. additiona saturated sodium bicarbonate 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=100/10/1)
  8. stirringthe mixture was stirred at room temperature for five minutes
  9. concentrationThe reaction mixture was concentrated under reduced pressure, and methylene chloride (0.8 ml)
  10. additionwas added to the residue
  11. additionDiethyl ether (8 ml) was further added
  12. filtrationthe solid was collected by filtration

Sources & evidence

ORD record
ord-6cfaf2530c55499281f26f8c30d5707c
Source dataset
uspto-grants-2012_04
Patent number
US08158790B2

Reaction notes

Loading…