Methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-YL)methyl]benzoate → Eprosartan

HRID 1808664

Reaction equation

HRID 1808664 reaction equation
[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:23]([CH:26]([CH2:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)C(OCC)=O)([OH:25])=[O:24]>C1CCCCC1>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:6]([CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:26](/[C:23]([OH:25])=[O:24])\[CH2:32][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:8][N:9]=1

Participants

4

Reactant 2

HCID 10334966Methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-YL)methyl]benzoateHCID 14952883Ethyl 2-carboxy-3-(2-thienyl)propionate

Product 1

HCID 5281037EprosartanYield 57.5%

Reagents, catalysts & solvents 1

HCID 8078CyclohexaneSolvent

Conditions

Temperature
27.5 °C

Procedure

Methyl 4-[[2-butyl-5-formyl-1H-imidazol-1-yl]methyl]benzoate (32 gm) and ethyl 2-carboxy-3-(2-thienyl)propionate (57.15 gm) are added to cyclohexane (292 ml) under stirring at 25-30° C., the contents are heated to reflux (80-85° C.) for 2 hours under dean stark to separate the traces of water. The reaction mass is cooled to 50° C. and then slowly added a freshly prepared catalyst solution of propanoic acid (22.93 ml) in cyclohexane (53 ml) and piperidine (10.66 ml). The resulting mass is heated to reflux (80-85° C.) for 20 hours, and to the reaction mass drop wise was added a 50% NaOH solution (64 gm of NaOH in 256 ml of water) after reflux at 50° C. and then the reaction mass is heated to reflux for 2 hours. The reaction mass is cooled to 60° C., the layers separated, to the aqueous layer was added ethanol (192 ml) and then the pH of the mass is adjusted to 5.0 to 5.1 at 60° C. with 6N HCl solution (66 ml of HCl and 66 ml of water). The resulting mass was cooled to 20-25° C. and stirred for 2 hours. The mass was filtered, washed with water (100 ml) and then dried at 70-75° C. to give 26 gm of crude eprosartan free base (HPLC purity: 98.2%).

Workup

  1. temperaturethe contents are heated
  2. temperatureto reflux (80-85° C.) for 2 hours under dean stark
  3. customto separate the traces of water
  4. temperatureThe reaction mass is cooled to 50° C.
  5. additionslowly added a freshly prepared catalyst solution of propanoic acid (22.93 ml) in cyclohexane (53 ml) and piperidine (10.66 ml)
  6. temperatureThe resulting mass is heated
  7. temperatureto reflux (80-85° C.) for 20 hours
  8. additionto the reaction mass drop wise was added a 50% NaOH solution (64 gm of NaOH in 256 ml of water)
  9. temperatureafter reflux at 50° C.
  10. temperaturethe reaction mass is heated
  11. temperatureto reflux for 2 hours
  12. temperatureThe reaction mass is cooled to 60° C.
  13. customthe layers separated, to the aqueous layer
  14. additionwas added ethanol (192 ml)
  15. customis adjusted to 5.0 to 5.1 at 60° C. with 6N HCl solution (66 ml of HCl and 66 ml of water)
  16. temperatureThe resulting mass was cooled to 20-25° C.
  17. stirringstirred for 2 hours
  18. filtrationThe mass was filtered
  19. washwashed with water (100 ml)
  20. customdried at 70-75° C.

Sources & evidence

ORD record
ord-8986578b37df4c32bb210bab26f12b2d
Source dataset
uspto-grants-2013_01
Patent number
US08361507B2

Linked notes

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