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Ceftolozax sulfate and its preparation method and application

A technology of ceftolozax and sulfuric acid, applied in the field of pharmaceutical chemical synthesis, can solve problems such as low safety, environmental pollution, and high cost

Active Publication Date: 2022-04-19
湖南润星制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] There are various drawbacks such as severe reaction conditions, high cost, low safety and environmental pollution in the above-mentioned preparation of ceftolozaxa sulfate technology, so it is necessary to explore a method for preparing ceftolozaxa sulfate with low process cost, simplicity and efficiency, and suitable for industrialized production

Method used

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  • Ceftolozax sulfate and its preparation method and application
  • Ceftolozax sulfate and its preparation method and application
  • Ceftolozax sulfate and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1 provides a kind of preparation method of ceftolozax sulfate, comprises the steps:

[0060] A) Preparation of Intermediate II

[0061] Intermediate I (20.0g, 54mmol) was dissolved in dichloromethane (250mL), 10% sodium bicarbonate (70g, 83mmol) solution was added, cooled in an ice bath, fluorenylmethoxycarbonyl chloride (16.0g, 62mmol) was added slowly, 0 Reaction at ℃ for 6 h, rotary evaporation to dryness under reduced pressure, extraction with dichloromethane, washing with brine, drying over anhydrous sodium sulfate, rotary evaporation to dryness under reduced pressure, the obtained crude product was recrystallized from a mixed solvent of ethyl acetate-petroleum ether, Intermediate II was obtained as an off-white to solid (31.5 g), with a yield of 98%.

[0062] B) Preparation of Intermediate III

[0063] {2-[3-(1-Methyl-5-(tritylamino)-1H-pyrazol-4-yl)ureido]ethyl}carbamate tert-butyl ester (30.0g, 55mmol) was dissolved in N,N-dimethylformamide (500mL)...

Embodiment 2

[0069] Embodiment 2 provides a kind of preparation method of ceftolozax sulfate, comprises the steps:

[0070] A) Preparation of Intermediate II

[0071] Intermediate I (25.0g, 68mmol) was dissolved in 1,2-dichloroethane (300mL), added 10% sodium carbonate (122g, 115mmol) solution, cooled in an ice bath, and slowly added fluorenylmethoxycarbonyl chloride (23.0g, 89mmol), reacted at 5°C for 3h, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Crystallization gave Intermediate II as an off-white to solid (39.0 g), yield 97%.

[0072] B) Preparation of Intermediate III

[0073] {2-[3-(1-Methyl-5-(tritylamino)-1H-pyrazol-4-yl)ureido]ethyl}carbamate tert-butyl ester (43.0g, 80mmol) was dissolved in N, N-dimethylformamide (600mL), add hexamethyldisilazide (47.0g, 0.23mol), then add intermediate II (39.0g, 66mmol) and potassium iodide (20.0g, 0.12m...

Embodiment 3

[0079] Embodiment 3 provides a kind of preparation method of ceftriaxone sulfate, comprises the steps:

[0080] A) Preparation of Intermediate II

[0081] Intermediate I (85.0g, 0.23mol) was dissolved in chloroform (1000mL), 10% potassium carbonate (630.0g, 0.46mol) solution was added, cooled in an ice bath, fluorenylmethoxycarbonyl chloride (88.0g, 0.34mol) was added slowly, Reaction at 15°C for 2 h, rotary evaporation to dryness under reduced pressure, extraction with dichloromethane, washing with brine, drying over anhydrous sodium sulfate, rotary evaporation to dryness under reduced pressure, the obtained crude product was recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain Intermediate II, off-white to solid (130.0 g), yield 95%.

[0082] B) Preparation of Intermediate III

[0083] {2-[3-(1-methyl-5-(tritylamino)-1H-pyrazol-4-yl)ureido]ethyl}carbamate tert-butyl ester (155.0g, 0.29mol) In N,N-dimethylformamide (2000mL), add hexamethyldisilazi...

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Abstract

The present invention proposes a kind of ceftolozam sulfate and its preparation method and application, described method comprises the following steps: pair intermediate I (7-amino-3-chloromethyl-3-cefazolin-4-carboxylic acid to Methoxybenzyl ester) reacts with fluorenylmethoxycarbonyl chloride to obtain intermediate II; intermediate II and {2-[3-(1-methyl-5-(tritylamino)-1H-pyrazole ‑4‑base) ureido group] ethyl} tert-butyl carbamate reacts to obtain intermediate III; intermediate III is carried out under the second alkaline solvent system to carry out amino deprotection reaction to obtain intermediate IV; intermediate IV Reaction with intermediate V in an acid-binding agent alkali solvent system to obtain ceftolozax sulfate. The preparation method of ceftolozax sulfate of the present invention adopts mild reaction types and reaction conditions, simplifies and optimizes the reaction conditions, the impurities in each step are less, the reaction is controllable, the pollutants are produced less, and the yield is higher. It has the effect of green environmental protection.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a cefolozaxa sulfate and a preparation method and application thereof. Background technique [0002] Cefolozane is a fifth-generation cephalosporin antibacterial drug invented and developed by Astellas Pharma for the treatment of infections caused by Gram-negative bacteria. The medicinal form of ceftolozane is the sulfate salt, namely ceftolozane sulfate (Cefolozane sulfate), its chemical name is (6R,7R)-7-((Z)-2-(5-amino-1,2, 4-thiadiazol-3-yl)-2-(((2-carboxyprop-2-yl)oxy)imino)acetamido)-3-((5-amino-4-(3-(2 -Aminoethyl)ureido)-1-methyl-1H-pyrazol-2-ium-2-yl)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0 ] Oct-2-ene-2-carboxysulfate, its chemical structural formula is as follows: [0003] [0004] According to published patents and bibliographical reports, there are mainly the following synthetic routes for the preparation of ceftolozax sulfate, which ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/46C07D501/06C07D501/18C07D501/38C07D501/24A61K31/546A61P31/04A23L33/10
CPCC07D501/46C07D501/06C07D501/18C07D501/38C07D501/24A61P31/04A23L33/127A23V2002/00A23V2200/30
Inventor 张瑜黄艳陈健
Owner 湖南润星制药有限公司
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