Trifluoroacetic acid → 2-[(3R*,4S*)-1-{[2-Chloro-6-(difluoromethyl)phenyl]methyl}-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetic acid

HRID 446032Notes

Reaction equation

HRID 446032 reaction equation
C([O:5][C:6](=[O:41])[CH2:7][C@@:8]1([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34](OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[O:26])[C@H:12]([CH3:13])[CH2:11][N:10]([CH2:14][C:15]2[C:20]([CH:21]([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:24])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[C:56]1(C=O)[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1>[Cl:24][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH:21]([F:22])[F:23])[C:15]=1[CH2:14][N:10]1[CH2:11][C@@H:12]([CH3:13])[C@@:8]([CH2:7][C:6]([OH:5])=[O:41])([C:25](=[O:26])[NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]=3)[CH2:30][CH2:29]2)[CH2:9]1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 51845401-Cyclohexene-1-carboxaldehydeHCID 86678250tert-Butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(difluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate

Product 1

HCID 712938062-[(3R*,4S*)-1-{[2-Chloro-6-(difluoromethyl)phenyl]methyl}-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetic acidYield 26.9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

tert-Butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(difluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 12a (332 mg, 0.553 mmol) was dissolved in dichloromethane (3.0 ml), trifluoroacetic acid (3.0 ml) was added thereto, and the mixture was then left to stand at mom temperature. After two hours and 30 minutes, the reaction liquid was concentrated and azeotropically distilled with dichloromethane twice to give an intermediate. 186 mg of the resulting intermediate (372 mg) was dissolved in tetrahydrofuran (5 ml), triethylamine (116 μl, 0.831 mmol) and cyclohex-1-ene-1-carbaldehyde (91.5 mg, 0.831 mmol) were added, and the mixture was left to stand at room temperature. After 30 minutes, sodium triacetoxyborohydride (176 mg, 0.831 mmol) was added thereto, and the mixture was stirred at mom temperature. After 10 hours and 50 minutes, the mixture was concentrated. The residue was purified by silica gel column chromatography (ODS, elution solvent: water/methanol) to give the title compound (80 mg).

Workup

  1. waitthe mixture was then left
  2. custom30 minutes, the reaction liquid
  3. concentrationwas concentrated
  4. distillationazeotropically distilled with dichloromethane twice
  5. customto give an intermediate
  6. waitthe mixture was left
  7. customto stand at room temperature
  8. waitAfter 30 minutes
  9. waitAfter 10 hours
  10. concentration50 minutes, the mixture was concentrated
  11. customThe residue was purified by silica gel column chromatography (ODS, elution solvent: water/methanol)

Sources & evidence

ORD record
ord-debf94882ced40988ee51b37c0c17bf8
Source dataset
uspto-grants-2013_07
Patent number
US08476301B2

Reaction notes

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