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Preparation method of cefditoren pivoxil

A technology of cefditoren pivoxil and phosphate ester, which is applied in the field of medicine, can solve the problems of messy reaction, difficult purification process, and many by-products, and achieve the effects of mild reaction conditions, high product purity, and high reactivity

Active Publication Date: 2019-02-15
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when AE active ester is used as an acylating agent, the reaction is prone to produce the toxic compound 2-mercaptobenzothiazole, and a large amount of organic solvent is used, which causes a burden on the environment, and the reaction of sodium salt in this method needs to be reacted under strong alkali , the amide bonds etc. in the product will be destroyed to a certain extent, and then react with iodomethyl pivalate, causing disordered reaction, many by-products, decreased yield, and due to by-products (such as E isomer etc. ) is similar to the product in nature and structure, and the purification process is particularly difficult
In addition, there are few studies on the starting material 7-ATCA at present, and most of the existing technologies use 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE) as raw material to pass through phosphorus ylide and then combine with 4 -Methyl-5-thiazole carboxaldehyde undergoes Wittig reaction to obtain 7-ATCA
Although this method has simple reaction and easy operation, the Wittig reaction yield is not high, the reaction is slow (generally 20~24h) and the selectivity is poor, and the E-type isomer by-product is mixed in the Z-type product, due to its structure, Similar properties, difficult to separate, and may even remain in the final cefditoren pivoxil, affecting drug efficacy and safety

Method used

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  • Preparation method of cefditoren pivoxil
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  • Preparation method of cefditoren pivoxil

Examples

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Effect test

Embodiment 1

[0026] Embodiment 1: the preparation of compound 4

[0027] Under nitrogen protection, 100mL of benzene, 40mmol of 7-ACA, 48mmol of hexamethyldisilazane, and 0.5mmol of pyridine were successively added to the reaction flask, stirred and heated to reflux for 2 hours, cooled to 0°C, and three Methyl iodosilane (TMSI) 44mmol, keep warm for 1h, add 38mmol of trifluoroethoxy phosphate, continue to react for 1h, add 36mmol of sodium hexamethyldisilazide, 60mmol of 15-crown-5, heat and reflux for 30min, cool to At room temperature, 38 mmol of 4-methylthiazole-5-carbaldehyde was added and reacted at room temperature for 6 h. After the reaction was completed, 100 mL of methanol was added to precipitate a solid, which was filtered, washed with 50 mL of THF, and dried under reduced pressure at 35°C to obtain 10.52 g of compound 4 with a yield of 85.48% and a purity of 99.88%, without E isomer.

Embodiment 2

[0028] Embodiment 2: the preparation of compound 4

[0029] Under the protection of nitrogen, add 100mL of benzene, 40mmol of 7-ACA, 40mmol of hexamethyldisilazane and 0.5mmol of pyridine in turn to the reaction flask, stir and heat up to reflux for 2h, cool the reaction solution to 0°C, drop three Methyl iodosilane (TMSI) 40mmol, keep warm for 1h, add 32mmol of trifluoroethoxy phosphate, continue the reaction for 1h, add 32mmol of sodium hexamethyldisilazide, 40mmol of 15-crown-5, heat and reflux for 30min, cool to At room temperature, 32 mmol of 4-methylthiazole-5-carbaldehyde was added and reacted at room temperature for 6 h. After the reaction was complete, 100 mL of methanol was added to precipitate a solid, which was filtered, washed with 50 mL of THF, and dried under reduced pressure at 35°C to obtain 8.53 g of compound 4 with a yield of 82.04%, a purity of 99.57%, and E-isomer 0.14%.

Embodiment 3

[0030] Embodiment 3: the preparation of compound 4

[0031]Under the protection of nitrogen, add 100mL of benzene, 40mmol of 7-ACA, 56mmol of hexamethyldisilazane, and 0.5mmol of pyridine in sequence in the reaction flask, stir and raise the temperature to reflux for 2h, cool the reaction solution to 0°C, dropwise add three Methyl iodosilane (TMSI) 48mmol, keep warm for 1h, add 44mmol of trifluoroethoxy phosphate, continue the reaction for 1h, add 40mmol of sodium hexamethyldisilazide, 80mmol of 15-crown-5, heat and reflux for 30min, cool to At room temperature, 44 mmol of 4-methylthiazole-5-carbaldehyde was added and reacted at room temperature for 6 h. After the reaction was complete, 100 mL of methanol was added to precipitate a solid, which was filtered, washed with 50 mL of THF, and dried under reduced pressure at 35°C to obtain 10.75 g of compound 4 with a yield of 82.83%, a purity of 99.64%, and E-isomer 0.09%.

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Abstract

The invention relates to a preparation method of cefditoren pivoxil. The preparation method comprises the following steps: 7-aminocephalosporanic acid(ACA) is taken as a starting material and subjected to a series of reactions such as iodination and the like after silylation protection to generate parent nucleus for cefditoren, namely 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)ethenyl]-3-cephem-4-carboxylic acid (7-ATCA); the compound 7-ATCA firstly reacts with sodium iso-octoate to form sodium salt and then reacts with ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate to generate a compound 2,namely cefditoren sodium, under the catalysis of immobilized penicillin acylase; and then the cefditoren sodium reacts with iodomethyl pivalate to obtain a target product, namely cefditoren pivoxil.The preparation method is mild in reaction conditions, environmentally-friendly, high in conversion rate, simple in process, high in content of cis isomers, easy to enlarge and suitable for industrialproduction.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a preparation method of cefditoren pivoxil. Background technique [0002] Cefditoren Pivoxil (Cefditoren Pivoxil), chemical name: 2,2-dimethylpropionyloxymethyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)- 2-Methoxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia- 1-Azabicyclo[4.2.0]oct-2-ene-2-carboxylate, a third-generation cephalosporin antibacterial drug, was developed by the Japanese Meiji Seika Company and was launched in Japan in 1994 under the trade name Meiact. This product is mainly used to treat infections caused by Gram-positive bacteria and Gram-negative bacteria, including infections caused by Streptococcus pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus, Proteus, etc. the therapeutic effect. Its structural formula is as follows: [0003] [0004] At present, the production of cefditoren pivoxil at home and abroad mainly adopts ...

Claims

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Application Information

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IPC IPC(8): C07D501/04C07D501/24
CPCC07D501/04C07D501/24
Inventor 李晓乐吴运伟刘江
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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