Hydrochloric Acid → Cefepime chloride hydrochloride hydrate

HRID 234109Notes

Reaction equation

HRID 234109 reaction equation
[CH3:1][N+:2]1([CH2:7][C:8]2[CH2:29][S:28][C@@H:11]3[C@H:12]([NH:15][C:16](/[C:18](/[C:22]4[N:26]=[C:25]([NH2:27])[S:24][CH:23]=4)=[N:19]\[O:20][CH3:21])=[O:17])[C:13](=[O:14])[N:10]3[C:9]=2[C:30]([O-:32])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:33]>O>[CH3:1][N+:2]1([CH2:7][C:8]2[CH2:29][S:28][C@@H:11]3[C@H:12]([NH:15][C:16](/[C:18](/[C:22]4[N:26]=[C:25]([NH2:27])[S:24][CH:23]=4)=[N:19]\[O:20][CH3:21])=[O:17])[C:13](=[O:14])[N:10]3[C:9]=2[C:30]([OH:32])=[O:31])[CH2:3][CH2:4][CH2:5][CH2:6]1.[OH2:14].[ClH:33].[Cl-:33]

Participants

4

Reactant 2

HCID 313Hydrochloric Acid2×HCID 5479537Cefepime

Product 1

HCID 9571075Cefepime chloride hydrochloride hydrate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

When the N-acylation of the soluble silylated compound of Formula VI is complete as ascertained by known detection methods available in the art, for example, thin-layer chromatography, high pressure liquid chromatography and spectroscopic methods; then, according to the preferred process of the present invention, sufficient water is added to the reaction mixture to dissolve, if desired, visible solids and produce a diphasic solution of organic phase and water. The amount of water to be added to the reaction mixture is determined by the selection and quantity of the inert organic solvent used in the process and should be sufficient to give or cause phase separation. Once phase separation has occurred, it is advantageous to separate and discard the organic phase to produce an aqueous rich solution containing the desired antibiotic. The aqueous rich solution is then treated with a sufficient amount of an acid or soluble non-toxic salt thereof such as hydrochloric acid, sodium chloride, ammonium chloride, potassium chloride, sulfuric acid, sodium sulfate, potassium sulfate, ammonium sulfate, phosphoric acid, sodium phosphate, potassium phosphate, ammonium phosphate, nitric acid, sodium nitrate, potassium nitrate or the like to provide a sufficient amount of the desired counter anion to ensure crystallization of the desired cefepime salt and, optionally, diluted with an appropriate water-miscible organic solvent such as methyl ethyl ketone, acetone, isopropanol, butanol or the like to induce or complete crystallization. Preferably, the aqueous rich solution is treated with a sufficient amount of sulfuric acid to crystallize the sulfate salt of cefepime which is substantially free of the anti-isomer and the Δ2 isomer. The cefepime sulfate may then be converted to the preferred crystalline cefepime dihydrochloride monohydrate by the method described by Kaplan et al., in U.S. Pat. No. 4,910,301. The cefepime sulfate which is produced in the present process may be neutralized with a base and, preferably, with a weakly basic ion-exchange resin known in the art and, preferably, commercially available such as Amberlite LA2, Dowex WGR, Bio-Rad AG3-X4A, Amberlite IRA 93, Amberlite IRA 35 or the like to produce an aqueous or aqueous-organic solution containing the zwitterion form of cefepime. The solution is then treated with a sufficient amount of hydrochloric acid and, optionally, with a water-miscible organic solvent to induce the crystallization of the preferred crystalline cefepime dihydrochloride hydrate. Most preferably, the aqueous rich solution obtained from the anhydrous acylation of the present process is treated with a sufficient amount of hydrochloric acid to induce and ensure crystallization of said antibiotic, cefepime dihydrochloride hydrate when a water-miscible organic solvent such as acetone is added. The amount of water-miscible organic solvent to be added should be sufficient to produce complete crystallization of said antibiotic and, advantageously, in an amount of about 2 to about 9 volumes of the aqueous phase to produce the temperature stable crystalline cefepime dihydrochloride monohydrate or dihydrate which is substantially free of the anti-isomer and the Δ2 isomer.

Workup

  1. customcrystallization of the desired cefepime salt
  2. additionoptionally, diluted with an appropriate water-miscible organic solvent such as methyl ethyl ketone, acetone, isopropanol, butanol
  3. customcrystallization
  4. additionPreferably, the aqueous rich solution is treated with a sufficient amount of sulfuric acid
  5. customto crystallize the sulfate salt of cefepime which
  6. customThe cefepime sulfate which is produced in the present process
  7. custompreferably, commercially available such as Amberlite LA2, Dowex WGR, Bio-Rad AG3-X4A, Amberlite IRA 93, Amberlite IRA 35 or the like to produce an aqueous or aqueous-organic solution
  8. customthe crystallization of the preferred crystalline cefepime dihydrochloride hydrate
  9. customMost preferably, the aqueous rich solution obtained from the anhydrous acylation of the present process
  10. customcrystallization of said antibiotic, cefepime dihydrochloride hydrate when a water-miscible organic solvent such as acetone
  11. additionis added
  12. additionThe amount of water-miscible organic solvent to be added should
  13. customto produce complete
  14. customcrystallization of said antibiotic and, advantageously, in an amount of about 2 to about 9 volumes of the aqueous phase

Sources & evidence

ORD record
ord-813986ef1dfc4ba9ae4dcd459cece3e9
Source dataset
uspto-grants-1997_01
Patent number
US05594129

Reaction notes

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