Pyridine → Cetilistat

HRID 1169575Notes

Reaction equation

HRID 1169575 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].ClC([O-])=O.Cl[C:17]([O:19][CH3:20])=O.N1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCC>[CH2:17]([O:19][C:20]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:4][CH2:3][CH2:2][CH2:10][CH3:9]

Participants

7

Reactant 4

HCID 1049PyridineHCID 6586Methyl chloroformateHCID 762552-Amino-5-methylbenzoic acidHCID 21226386Carbonochloridate

Product 1

HCID 9952916CetilistatYield 31%

Reagents, catalysts & solvents 2

HCID 8003PentaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-Amino-5-methylbenzoic acid (2.71 g, 17.9 mmol, 0.87 eq.) was dissolved in pyridine (24 ml) and added to the chloroformate solution prepared above. The mixture was stirred at room temperature for 1.75 hours. Methyl chloroformate (13.6 ml, 176 mmol, 8.5 eq) was added slowly, then the mixture was left to stir at ambient temperature overnight. The mixture was diluted with ethyl acetate (20 ml) and washed with water (15 ml) and 10% aqueous citric acid (20 ml). The combined aqueous phases were extracted with ethyl acetate (20 ml). The organic extracts were combined and washed with water (20 ml) and brine (20 ml) then concentrated to give a solid. This was slurried in pentane (5 ml), filtered, then slurried in acetonitrile (5 ml), filtered and purified by flash chromatography on silica (1.5% diisopropylethylamine in dichloromethane) to give a white solid (2.51 g, 31%) δH (400 MHz, CDCl3) 0.87 (3H, t, J 6.8, CH2CH3), 1.24-1.45 (26H, m, 13×CH2), 1.75-1.83 (2H, m, OCH2CH2), 2.41 (3H, s, ArCH3), 4.41 (2H, t, J 6.7, OCH2), 7.30 (1H, d, J 8.3, ArH), 7.51 (1H, dd, J 8.5, 2.0, ArH), 7.90 (1H, d, J 1.1, ArH); m/z (ES+) 402 (MH+); MPt. 72-73° C.

Workup

  1. customprepared above
  2. waitthe mixture was left
  3. stirringto stir at ambient temperature overnight
  4. washwashed with water (15 ml) and 10% aqueous citric acid (20 ml)
  5. extractionThe combined aqueous phases were extracted with ethyl acetate (20 ml)
  6. washwashed with water (20 ml) and brine (20 ml)
  7. concentrationthen concentrated
  8. customto give a solid
  9. filtrationfiltered
  10. filtrationfiltered
  11. custompurified by flash chromatography on silica (1.5% diisopropylethylamine in dichloromethane)

Sources & evidence

ORD record
ord-aaabe8ca53394d9d8ae3c24c9a513dac
Source dataset
uspto-grants-2010_11
Patent number
US07825113B2

Reaction notes

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