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Preparation method of cefozopran side chain acid

A technology of cefazolam and side chain acid, which is applied in the field of preparation of cefazolam side chain acid, can solve problems such as inconvenience of industrialized production and operation, and achieve the effects of shortening reaction time, shortening reaction period and reducing cost

Inactive Publication Date: 2011-07-20
BENGBU BBCA MEDICINE SCI DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] Japanese patent JP195064 reports that the synthesis method of this step needs to be separated by a chromatographic column, and the reaction time is 24 hours, which is inconvenient for industrial production.

Method used

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  • Preparation method of cefozopran side chain acid
  • Preparation method of cefozopran side chain acid
  • Preparation method of cefozopran side chain acid

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0038] The first step: preparation of compound III

[0039] 1) Preparation of sodium methoxide liquid, dissolving sodium methoxide in methanol to prepare a sodium methoxide solution with a concentration of 30% (mg / ml).

[0040] 2) Add 9.3g (0.0959mol) potassium thiocyanate to a 250mL three-necked flask containing 50mL methanol, then add 10g (0.0318mol) benzenesulfonyl-2-carbamoyl-2-methoxyiminoacetamide oxime (Compound II), after stirring at room temperature for 1 hour, quickly add 0.45 g of sodium methoxide solid, and the reaction is completed in about 10 hours. Cool with cold water, filter the insoluble matter, wash the insoluble matter with about 30 mL of methanol, and combine the washing liquid and the filtrate. Then carry out vacuum distillation, add ethyl acetate (20mL) to the residue, cool, filter the insoluble matter, wash with ethyl acetate to obtain off-white powdery solid 4.5g, mp: 168-170°C, HPLC normalized content: 98.89%, yield 70.3%.

[0041] The second step: ...

Embodiment 2

[0044] The first step: preparation of compound III

[0045] 9.3g (0.0959mol) of potassium thiocyanate was added into a 250mL three-necked flask containing 50mL of methanol, and then 10g (0.0318mol) of benzenesulfonyl-2-carbamoyl-2-methoxyiminoacetamide oxime (compound II), after stirring at room temperature for 1 hour, add 0.50 g of sodium hydride solid powder, and the reaction is completed in about 10 hours. Cool with cold water, filter the insoluble matter, wash the insoluble matter with about 30 mL of methanol, combine the washing liquid with the filtrate, and then carry out Distilled under reduced pressure, added ethyl acetate (20mL) to the residue, cooled, filtered the insoluble matter, washed with ethyl acetate to obtain 4.6g off-white powdery solid, mp: 168-170°C, HPLC normalized content: 98.89% , yield 71.8%.

[0046] The preparation method of cefazolam side chain acid is the same as in Example 1.

Embodiment 3

[0048] The sodium hydride in the preparation process of compound III in Example 2 was changed to 0.5 g of potassium hydride, and the rest remained unchanged to obtain 4.55 g of compound III with a yield of about 71.1%.

[0049] The preparation method of cefazolam side chain acid is the same as embodiment 1

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Abstract

The invention relates to a preparation method of cefozopran side chain acid, namely (Z)-2-(5-amino-1,2,4-thiadiazole-3-radical)-2-methoxyimino acetic acid (compound IV). The method comprises the following steps of: undergoing a ring-closure reaction on O-tosyl-2-carbamyl-2-methoxyimino acetamide oxime (compound II) serving as a starting raw material and potassium thiocyanate under the catalysis of a catalyst; and performing alkaline hydrolysis and acidification to obtain an end product. The cefozopran side chain acid is an important intermediate for synthesizing cefozopran. The process for synthesizing the cefozopran side chain acid in the prior art is modified and optimized, so that the method has the advantages of high yield, lower cost and mild reaction condition, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a kind of preparation method of cephalosporin intermediate, in particular to a kind of preparation method of cefazolam side chain acid. Background technique [0002] Cefozopran, as shown in compound I, chemical name: 1-[[(6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazole-3 -yl)(methoxyimino)acetyl]amino]-2-carboxylic acid-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl] Methyl]imidazol[1,2-b]pyridazine inner salt, other names are: 7b-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)- Methoxyiminoacetamido]-3-[(imidazol[1,2-b]pyridazinium-1-yl)methyl]-3-cephem-4-carboxylic acid inner salt. [0003] This product is the fourth-generation cephalosporin first researched and developed by Takeda Corporation of Japan. In 1995, it was launched in Japan for the first time under the trade name of Firstcin. The dosage form is injection powder with specifications of 0.5g and 1g. [0004] [0005] Compound I [0006] This product has broad-spec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/08
Inventor 徐景侠韦亚锋
Owner BENGBU BBCA MEDICINE SCI DEV