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

HRID 1694998Notes

Reaction equation

HRID 1694998 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[Cl: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].[CH3:56][C:57]([CH3:88])([CH3:87])[CH2:58][NH:59][C:60](=[O:86])[C@H:61]([CH2:84][CH3:85])[CH2:62][C@H:63]([OH:83])[C@@H:64]([NH2:82])[CH2:65][N:66]1[CH2:71][C:70](=[O:72])[N:69]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=2[Cl:79])[CH2:68][C:67]1([CH3:81])[CH3:80]>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[Cl:44])[CH2:33][C:32]1([CH3:45])[CH3:46].[NH2:82][C@@H:64]([CH2:65][N:66]1[CH2:71][C:70](=[O:72])[N:69]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=2[Cl:79])[CH2:68][C:67]1([CH3:80])[CH3:81])[C@@H:63]([OH:83])[CH2:62][C@@H:61]([CH2:84][CH3:85])[C:60]([NH:59][CH2:58][C:57]([CH3:56])([CH3:88])[CH3:87])=[O:86]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 444972Fumaric AcidHCID 44610811(2r,4s,5s)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-2-ethyl-4-hydroxyhexanoic acid (2,2-dimethylpropyl)amideHCID 66645760{(1S,2S,4R)-4-(2,2-Dimethylpropylcarbamoyl)-1-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxyhexyl}carbamic acid t-butyl ester

Product 1

HCID 71660402(2R,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-2-ethyl-4-hydroxyhexanoic acid (2,2-dimethylpropyl)amide hemifumarateYield 81.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

0.97 ml of trifluoroacetic acid (12.6 mmol) was added to a solution of 243 mg of {(1S,2S,4R)-4-(2,2-dimethylpropylcarbamoyl)-1-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxyhexyl}carbamic acid t-butyl ester obtained in Example (106j) (0.42 mmol) in methylene chloride (2 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=100/10/1). 23 mg of fumaric acid (0.20 mmol) was added to a solution of 189 mg of (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-2-ethyl-4-hydroxyhexanoic acid (2,2-dimethylpropyl)amide obtained above (0.39 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 (0.5 ml) was added to the residue. Diethyl ether (5 ml) was further added and the solid was collected by filtration to obtain 175 mg of the title compound (yield: 77%).

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=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 (0.5 ml)
  10. additionwas added to the residue
  11. additionDiethyl ether (5 ml) was further added
  12. filtrationthe solid was collected by filtration

Sources & evidence

ORD record
ord-7ef07bbfa2ce41adbbd855eb1d591db1
Source dataset
uspto-grants-2012_04
Patent number
US08158790B2

Reaction notes

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