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Synthesis Method of cefcapene pivoxil hydrochloride

A technology of cefcapine hydrochloride and a synthesis method, which is applied in the direction of organic chemistry and the like, can solve the problems of high corrosion resistance requirements of reaction vessels, poor product quality, complicated operations, etc., and achieves great implementation value, gentle reaction conditions, and simple operation. Effect

Active Publication Date: 2012-07-04
SHANDONG RUNZE PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Through our practice and comparison, we found that the above-mentioned related patents are complicated to operate and cumbersome to apply, and the quality of the products obtained according to the synthetic route is poor. For example, there are many kinds of hydrolysis reagents for the hydrolysis of the protecting group, such as trifluoroacetic acid and boron trifluoride , aluminum trichloride, etc., such strong acid compounds have high requirements on the corrosion resistance of the reaction vessel, and also require a low temperature of about -50°C during the reaction, which is cumbersome to operate

Method used

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  • Synthesis Method of cefcapene pivoxil hydrochloride
  • Synthesis Method of cefcapene pivoxil hydrochloride
  • Synthesis Method of cefcapene pivoxil hydrochloride

Examples

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Effect test

Embodiment 1

[0026] Example 1: Synthesis of 7-DACA

[0027] 266 kg of water and 10.6 kg of sodium hydroxide were stirred and dissolved, then 174 kg of acetone and 2.5 kg of boric acid were added while cooling down, the temperature was lowered to -20~-15°C, 33 kg of 7-ACA was added, and the temperature was controlled for 60 minutes to dissolve them all. After adding 29 kg of 6N hydrochloric acid dropwise, transfer it to 840 kg of water. The mixed solution is at about 13°C. Slowly add 6N hydrochloric acid to adjust the pH value to about 6.4. Continue to adjust the pH value to 3.2 under temperature control for 30 minutes. Stir at temperature control for 60 minutes, centrifuge Filter, first wash with 120 kg of water, then wash twice with 40 kg of acetone. With dehydration, drying under normal pressure below 40°C for 30-60 minutes to obtain about 20 kilograms of products with moisture below 1.0%.

Embodiment 2

[0028] Embodiment 2: the synthesis of carbonyl tert-butyl cefcapene acid

[0029] A. The preparation of the mother nucleus: add 34.8 kg of methanol, add 15 kg of 7-DACA, add 14.5 kg of triethylamine dropwise at 0-5°C for about 10-15 minutes, and stir at this temperature for about 90-120 minutes to dissolve all . After dissolving, lower it to below 0°C for later use.

[0030] B, side chain acid preparation: add 187 kilograms of ethyl acetate, cefcapine pivoxil side chain acid ((Z)-2-(2-carbonyl tert-butoxyaminothiazol-4-yl)-2-pentane in the dry kettle enoic acid) 23.3 kg, cooled to 0°C, 10.3 kg of methanesulfonyl chloride was added dropwise at this temperature, and 9.14 kg of pyridine was added dropwise at -5~0°C. Temperature control reaction for 2 hours, 1.5 hours sampling side chain acid residual less than 3% is the reaction end point. Cool down to -10°C for dropwise addition.

[0031] Add the side chain acid chloride solution of B to the prepared hydrolyzed material solu...

Embodiment 3

[0032] Embodiment 3: the synthesis of carbonyl tert-butoxy cefcapene pivoxil

[0033] Add 32 kg of cefcapene acid, add 200 kg of DMF to dissolve, control the temperature at 20-25°C, slowly add 1.5 kg of potassium iodide, cool down to 0-5°C, add 13.6 kg of chloromethyl pivalate dropwise in about 30 minutes, and control the temperature React for 3 hours, take a sample to detect that the residual cefcapenic acid is less than 0.5%, add 300 kg of dichloromethane, 0.5 kg of tetraheptylammonium bromide, add 400 kg of water dropwise, pay attention to cooling, the reaction exotherm is obvious, stir for 30 minutes to separate layers, The obtained aqueous phase was extracted once with 50 kg of dichloromethane, the obtained organic phase was washed and separated with 5% sodium bicarbonate, the aqueous phase was extracted with the above-mentioned dichloromethane, the combined organic phases were concentrated to dryness.

[0034] 68 kg of ethyl acetate was added to the concentrated solution...

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Abstract

The invention belongs to the technical field of antibiotic drug synthesis, in particular to a synthesis methodof cefcapene pivoxil hydrochloride. The invention is mainly used for process improvement and optimization of cefcapene pivoxil, and the advantage of the synthesis process of cefcapene pivoxil are obvious; new catalytic agents are used, such as phenol, boric acid and other reagents, thereby improving the product quality, increasing the yield, simplifying the operating steps and realizing greater productivity effect and social effect.

Description

(1) Technical field [0001] The invention belongs to the technical field of antibiotic drug synthesis, in particular to a method for synthesizing cefcapene hydrochloride. (2) Background technology [0002] Cefcapene pivoxil hydrochloride is a third-generation cephalosporin belonging to broad-spectrum antibiotics. There is no domestic detailed report on the synthesis method of cefcapene pivoxil hydrochloride. According to the introduction of relevant patents, there are mainly JP-A-62-89, JP-4-628549, JP2006022042A, WO2008155615A2, and US4731362 and patents such as CN101111498A, among which, Japanese Patent Application No. 62-89, Japanese Patent Application No. 4-628549, JP2006022042A protect the crystal form and crystallization solvent of the product, WO2008155615A2 patent, CN101111498A patent, Patent No. US4731361 and Patent No. US4731362 protect the synthetic route reagents and synthetic routes, and their synthetic methods are basically as follows: [0003] The 7-aminoceph...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/34C07D501/04
Inventor 孙鹏韩振玉郭合广王明庆
Owner SHANDONG RUNZE PHARMA
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