Isopropyl Benzoate → ethyl 3-(1-((2S,3aR,6aR)-3a-((S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate

HRID 1400074Notes

Reaction equation

HRID 1400074 reaction equation
[F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]([C@@:18]23[CH2:25][CH2:24][CH2:23][C@@H:22]2[CH2:21][C:20](=O)[CH2:19]3)=[O:17])[CH:4]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:36]=[C:37]([CH:43]=[CH:44][CH:45]=2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:30]1.[BH4-].[Na+].C(=O)(O)[O-].[Na+].C(OC(C)C)(=O)C1C=CC=CC=1>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]([C@@:18]23[CH2:25][CH2:24][CH2:23][C@@H:22]2[CH2:21][C@H:20]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]4[CH:36]=[C:37]([CH:43]=[CH:44][CH:45]=4)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:30]2)[CH2:19]3)=[O:17])[CH:4]=1

Participants

9

Reactant 5

HCID 13654Isopropyl BenzoateHCID 516892Sodium BicarbonateHCID 4311764Sodium borohydrideHCID 57880398Ethyl 3-(piperidin-4-yl)benzoateHCID 89823414(3aR,6aR)-3a-((1S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)hexahydropentalen-2(1H)-one

Product 1

HCID 86698132ethyl 3-(1-((2S,3aR,6aR)-3a-((S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate

Reagents, catalysts & solvents 3

HCID 11026Titanium isopropoxideCatalystHCID 887MethanolSolventHCID 63651,1-DichloroethaneSolvent

Procedure

A mixture of Example 9E (200 mg, 0.5 mmol), ethyl 3-(piperidin-4-yl)benzoate (125 mg, 0.56 mmol) in dichloroethane (20 mL) was added titanium(IV) isopropoxide (0.6 ml, 2.03 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. Sodium borohydride (96.7 mg, 2.54 mmol) and methanol (1 mL) were added to the reaction mixture and stirred for another 2 hours. LC-MS indicated that the reaction was complete. Aqueous Sodium bicarbonate (20 mL) was added to the reaction mixture. The reaction mixture was extracted with dichloromethane (3×30 mL). The organic fractions were dried with sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (eluent: 20 to 80% ethylacetate in petroleum ether) on silica to give a mixture of the title compound and isopropyl benzoate.

Workup

  1. stirringstirred for another 2 hours
  2. extractionThe reaction mixture was extracted with dichloromethane (3×30 mL)
  3. dry with materialThe organic fractions were dried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by chromatography (eluent: 20 to 80% ethylacetate in petroleum ether) on silica
  7. customto give

Sources & evidence

ORD record
ord-fe7e532311b34cbb8636b2921fb2e7a1
Source dataset
uspto-grants-2014_12
Patent number
US08906911B2

Reaction notes

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