Preparation method of ceftaroline fosamil intermediate parent nucleus

A technology for ceftaroline fosamil and intermediates is applied in the field of preparation of ceftaroline fosamil intermediate parent nucleus, and can solve problems such as troublesome quality control of intermediates, high toxicity of methanesulfonyl chloride, low product yield and the like

Active Publication Date: 2015-09-16
国药集团致君(苏州)制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] However, it uses methanesulfonyl chloride to activate the hydroxyl group to form a leaving group. Methanesulfonyl chloride is more toxic and will cause more δ-3 isomers during the activation process, with a ratio of 7% to 8%. Afterwards, the yield is 81%, and the ratio of δ-3 isomer is about 6%, which will bring great troubles to the quality control of purification and intermediates, resulting in lower product yields

Method used

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  • Preparation method of ceftaroline fosamil intermediate parent nucleus
  • Preparation method of ceftaroline fosamil intermediate parent nucleus
  • Preparation method of ceftaroline fosamil intermediate parent nucleus

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[0033] The invention provides a kind of preparation method of ceftaroline axetil intermediate core, comprising the following steps: A) reacting 3-hydroxycephalosporin and activating reagent under the condition that acid-binding agent and organic solvent exist, obtain activated intermediate; the activating reagent is p-toluenesulfonyl chloride, benzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, trifluoroacetic anhydride or trifluoromethanesulfonic anhydride; B) the activated intermediate and 4-( 4-pyridyl)-2-mercaptothiazole reaction to obtain an intermediate shown in formula (I); C) reacting the intermediate shown in formula (I) with a quaternizing agent to obtain a pyridinium salt; D) deprotecting the pyridinium salt to obtain the ceftaroline axetil intermediate nucleus shown in formula (II);

[0034]

[0035] The present invention uses 3-hydroxycephalosporin as a raw material, and the raw material is easy to get; the activating reagent is preferably p-toluenesulfo...

Embodiment 1

[0055] 1.1 1000g (2mol) 3-hydroxy cephalosporin, 304g (2.2mol) K 2 CO 3 Add 4L DMF to a four-neck flask, stir at room temperature for 0.5h, then cool in an ice-salt bath to -8°C to -10°C, slowly add 420g (2.42mol) p-toluenesulfonyl chloride (TosCl) dropwise, the reaction releases heat, control The dropping speed keeps the temperature of the reaction system not higher than -5°C. After the dropwise addition is completed, keep the reaction temperature in the ice-salt bath at -5°C~-8°C, and stir for 2 hours. After the raw materials are completely reacted by TLC, pour the reaction solution slowly. Pour into 40L of ice water, a large amount of solids precipitated, stirred at room temperature for 1 hour, then suction filtered, the filter cake was washed once with water, washed once with n-heptane compacted with water, dried in a blast drying oven at 60°C for 8-9 hours, and 1.3kg of off-white was obtained. Solid, the activated intermediate 7β-phenylacetamido-3-(4-methylbenzenesulfony...

Embodiment 2

[0065] 2.1 Mix 10kg (20mol) 3-hydroxycephalosporin, 3kg (22mol) K 2 CO 3Add 40L DMF to the reaction kettle, stir at room temperature for 1 hour, then cool in an ice-salt bath to -8°C to -10°C, slowly add 4.2kg (24.2mol) p-toluenesulfonyl chloride (TosCl) dropwise, the reaction releases heat, and the dropwise Make the temperature of the reaction system not higher than -5°C. After the dropwise addition, keep the reaction temperature in the ice-salt bath at -5°C~-8°C, and stir for 2 hours. After the raw materials are completely reacted by TLC, slowly pour the reaction solution into In 400L of ice water, a large amount of solids were precipitated, stirred at room temperature for 1 hour, then suction filtered, the filter cake was washed once with water, and dried in a vacuum oven at 40°C until the water content was less than 1%, and 13kg of off-white solid was obtained, which was the activated intermediate 7β-phenylacetyl Diphenylmethyl amino-3-(4-methylbenzenesulfonyloxy)-3-cephe...

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Abstract

The invention provides a preparation method of ceftaroline fosamil intermediate parent nucleus, which comprises the following steps: 3-hydroxycephem and an activation reagent are reacted under existence condition of an acid binding agent and an organic solvent to obtain an activated intermediate; the activation reagent comprises p-toluene sulfonyl chloride, benzenesulfonyl choride, 4-nitrobenzene sulfonyl chloride, trifluoroactic anhydride or trifluoromethanesulfonic anhydride; the activated intermediate and 4-(4-pyridyl)-2-mercaptothiazole are reacted, then is reacted to a quaternized reagent to obtain pyridinium salt; and then deprotection is carried out to obtain the ceftaroline fosamil intermediate parent nucleus. Compared with the prior art, The p-toluene sulfonyl chloride, benzenesulfonyl choride, 4-nitrobenzene sulfonyl chloride, trifluoroactic anhydride or trifluoromethanesulfonic anhydride are used for substituting the usage of a severe toxicity material, reaction security is increased, due to increasing steric hindrance of an activating group, rate for generating a delta-3 isomer is reduced, and purity and yield of the reaction products are increased.

Description

technical field [0001] The invention belongs to the technical field of cephalosporin antibacterial drugs, in particular to a preparation method of a ceftaroline axetil intermediate core. Background technique [0002] Ceftaroline is the fifth-generation cephalosporin antibiotic, which is derived from the fourth-generation cephalosporin cefazolam. It was developed by Takeda Pharmaceutical Company of Japan, and Forest Laborstories of the United States obtained market authorization. It was approved by the FDA on October 29, 2010. Approved for marketing, for the treatment of adult community-acquired bacterial enteritis, acute bacterial skin and soft tissue infections, including infections caused by MRSA. Ceftaroline axetil is the prodrug of ceftaroline, which increases its stability and will be rapidly hydrolyzed into ceftaroline in the body to exert its drug effect. Ceftaroline axetil has strong antibacterial activity against most Gram-negative bacteria, Gram-negative anaerobic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/18C07D501/04
CPCY02P20/55C07D501/18C07D501/04
Inventor 吴茂江王军辉陈超张清泉赵亚
Owner 国药集团致君(苏州)制药有限公司
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