Methanol → Meropenem Trihydrate

HRID 589654Notes

Reaction equation

HRID 589654 reaction equation
[CH3:1][C@H:2]1[C:9]([S:10][C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:12]2)=[C:8]([C:21]([OH:23])=[O:22])[N:7]2[C@H:3]1[C@@H:4]([C@H:24]([OH:26])[CH3:25])[C:5]2=[O:6].[OH:27]P([O-])(O)=O.[K+].C(Cl)Cl.C[OH:37]>O1CCCC1.O.[Zn]>[CH3:1][C@H:2]1[C:9]([S:10][C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])[CH2:12]2)=[C:8]([C:21]([OH:23])=[O:22])[N:7]2[C@H:3]1[C@@H:4]([C@H:24]([OH:26])[CH3:25])[C:5]2=[O:6].[OH2:27].[OH2:37].[OH2:6]

Participants

8

Reactant 4

HCID 887MethanolHCID 6344DichloromethaneHCID 441130MeropenemHCID 516951Monobasic potassium phosphate

Product 1

HCID 441129Meropenem Trihydrate

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
27 °C

Procedure

20 g of meropenem-PNB was dissolved in 200 mL of tetrahydrofuran. 60 g of potassium phosphate monobasic (KH2PO4) dissolved in 400 mL of water was added thereto and heated to 27° C. 80 g of zinc powder was slowly added portionwise and stirred between 25 to 35° C. for 1 hour. After the completion of the reaction was confirmed, 220 mL of methylene chloride was added and stirred for 10 minutes, and then filtered to remove zinc powder. The aqueous layer was separated and washed 2 times with 100 mL of methylene chloride, by which tetrahydrofuran present in the aqueous layer was removed completely. The aqueous layer was cooled and developed in a column filled with adsorption resin SP-207 for adsorption. The resin column was washed with 2 L of water to remove potassium phosphate salt used in the reaction and impurities, and developed with 2 L of 60% methanol to elute meropenem completely. The fractions containing meropenem were collected and a buffer solution of N-methylmorpholine/acetic acid (pH 6.5) was added thereto, and concentration was conducted to a volume 10 times greater than the weight of meropenem-PNB. 1100 mL of acetone was added to generate crystal and stirred at room temperature for 1 hour. After filtration and drying, 9.78 g of meropenem trihydrate was obtained.

Workup

  1. additionwas added
  2. stirringstirred for 10 minutes
  3. filtrationfiltered
  4. customto remove zinc powder
  5. customThe aqueous layer was separated
  6. washwashed 2 times with 100 mL of methylene chloride
  7. customby which tetrahydrofuran present in the aqueous layer was removed completely
  8. temperatureThe aqueous layer was cooled
  9. additionfilled with adsorption resin
  10. washThe resin column was washed with 2 L of water
  11. customto remove potassium phosphate salt
  12. customused in the reaction and impurities
  13. washto elute meropenem completely
  14. additionThe fractions containing meropenem
  15. customwere collected
  16. additiona buffer solution of N-methylmorpholine/acetic acid (pH 6.5) was added
  17. concentrationconcentration
  18. addition1100 mL of acetone was added
  19. stirringstirred at room temperature for 1 hour
  20. filtrationAfter filtration
  21. customdrying

Sources & evidence

ORD record
ord-e631d673e2df43378ae2fcc514566dbc
Source dataset
uspto-grants-2016_01
Patent number
US09233963B2

Reaction notes

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