Citric Acid → 4-((4-(((Tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino) methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid

HRID 529342Notes

Reaction equation

HRID 529342 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C@@H:21]2[CH2:23][C@H:22]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15][CH2:14]1)[C:6]([O-:8])=[O:7])#[N:2].[K+].[C:31]([O-:34])([O-])=[O:32].[Na+].[Na+].C(O)(=O)[CH2:38][C:39]([CH2:44]C(O)=O)([C:41](O)=O)O>C1COCC1.O>[C:39]([O:34][C:31]([N:20]([CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:14][CH2:15]1)[C@@H:21]1[CH2:23][C@H:22]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])([CH3:44])([CH3:41])[CH3:38]

Participants

6

Reactant 3

HCID 311Citric AcidHCID 10340Sodium CarbonateHCID 68388386HCID 68388386, compound

Product 1

HCID 683884464-((4-(((Tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino) methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acidYield 31.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of potassium 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (1 g, 2.57 mmol) in a mixture of THF (20 mL) and water (4 mL) was added Na2CO3 (0.680 g, 6.42 mmol), Boc-anhydride (0.715 mL, 3.08 mmol) at RT. Then the reaction mixture was stirred at RT for 16 h. Reaction mixture was diluted with water and pH (˜6) was adjusted with citric acid solution (aq) and then extracted with EtOAc (3×70 mL). The combined organic layer was washed with brine (80 mL), dried over Na2SO4 and concentrated to afford the crude residue (1.2 g). Crude was further purified by Prep HPLC and isolated 4-((4-(((tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid (400 mg, 0.812 mmol, 31.6% yield). LCMS (ES) m/e 490.11 (M+H)+.

Workup

  1. customReaction mixture
  2. extractionextracted with EtOAc (3×70 mL)
  3. washThe combined organic layer was washed with brine (80 mL)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. customto afford the crude residue (1.2 g)
  7. customCrude was further purified by Prep HPLC

Sources & evidence

ORD record
ord-346b98928c5d412bb5522538a926cab0
Source dataset
uspto-grants-2016_05
Patent number
US09346840B2

Reaction notes

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