CN101337969B - Synthetic method of antibiotic cefixime - Google Patents

Abstract

The invention relates to a synthesis method of cefixime that is bacteriophage. 7-azyl-3-vinyl cephalosporanic acid (7-AVCA) is used as starting material to react with MICA active ester first, and an intermediate MECEF of cefixime is obtained through separation; the intermediate MECEF is directly hydrolyzed to generate a cefixime product without separation; the condensation and the hydrolyzation in a synthesis route of the cefixime product is combined into one. The synthesis method has the advantages that the technologcial conditions are simple, the operation is convenient, the product yield is high, the product quality is stable, and the method is suitable for the large-scale industrialized production; two-step reactions are combined into one, an intermediate A is not needed to be separated, the operation is simplified, and the production period is shortened; the yield can reach 200 to 212 percent; the purity quotient is more than 99 percent; the curative effect of the product is increased. Expensive tetrahydrofuran which is used in the reaction is replaced by low-cost acetone, the problem that tetrahydrofuran is mixed with the other reaction solvent and cannot be recycled and reused is solved, the wastewater discharge is reduced, the manufacture cost is lowered, and the competitive ability of the product is increased.

Description

A kind of synthetic method of antibiotic cefixime

Technical field

What the present invention relates to is about a kind of synthetic method of third generation cephalosporin class microbiotic Cefixime Micronized, belongs to field of medicine preparing technology.

Background technology

Cefixime Micronized (Cefixime) is the earliest by the research and development of Japanese Fujisawa Pharmaceutical Co., Ltd, and in the cephem antibiotics of listing in 1987.As first orally active third generation cephalosporin, Cefixime Micronized is to have synthesized germicidal action by suppressing bacteria cell wall.Cefixime Micronized is to gram-positive microorganism, the equal tool good antibacterial activity of gram negative bacillus.Compare with existing oral β-Nei Xiananleikangshengsu, especially strengthened the activity of anti-Gram-negative bacteria.

The Cefixime Micronized chemistry is by name: (6R, 7R)-7-[(2Z)-(thiazolamine-4-yl) [(carboxyl methoxyl group) imino-] acetamido]-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.Structure is shown below:

The synthetic method of cefepime, classify according to starting raw material (parent nucleus), mainly contain following several according to the document of having reported: a kind of is to be starting raw material with 7-amino-3-vinyl cethalosporanic acid (7-AVCA), at first with the effect of MICA active ester, separate and obtain intermediate of cefixime A, intermediate of cefixime A hydrolysis again obtains Cefixime Micronized; Another kind is to be the method for the synthetic Cefixime Micronized of starting raw material with 7-phenylacetamide-3-chloromethyl-4-Cephalosporanic acid to methoxybenzyl ester (GCLE), as Chinese microbiotic magazine 2000:367-368.

In existing synthetic method, 7-AVCA and MICA active ester generation acylation reaction use tetrahydrofuran (THF) to make solvent usually, reclaim because tetrahydrofuran (THF) costs an arm and a leg and is difficult to, and therefore cause product cost higher, and the quality product that obtains are not high.Severe reaction conditions, long reaction time is unfavorable for continuity, large-scale industrial production.

Summary of the invention

Purpose of the present invention aims to provide a kind of synthetic method that is more suitable for large-scale industrial production, Cefixime Micronized that quality product is higher.

Technical scheme of the present invention: with 7-amino-3-vinyl cethalosporanic acid (7-AVCA) is starting raw material, at first with the effect of MICA active ester, separates obtaining intermediate of cefixime A, and intermediate A is without separation, and direct hydrolysis obtains the Cefixime Micronized product.This method comprises following processing step:

One, the weight ratio with 7-AVCA and MICA active ester is 1: 1.5-2 mixes and places the volume ratio of organic solvent and pure water is 1: 30～30: 1 mixed solvent, with adjusting PH with base value to 7.0～9.5, dissolving also obtains the Cefixime Micronized aqueous solution in temperature for acylation reaction takes place under-20～50 ℃ of conditions, divides water-yielding stratum; The Cefixime Micronized solution that obtains extracts with ethyl acetate solvent, the aqueous phase that obtains in extraction, the activated carbon that aqueous phase adds the 0.1-10% of 7-AVCA charging capacity decolours, and adds 0.1～10% EDTA of 7-AVCA charging capacity again, obtains the intermediate of cefixime A aqueous solution;

Two, the resulting intermediate of cefixime A aqueous solution in the processing step one is added the alkali reaction that is hydrolyzed, add the hydrochloric acid crystallization again and obtain Cefixime Micronized, its hydrochloric acid soln volumetric molar concentration is 1 mole/L～10 mole/L.

Synthetic route is as follows:

Advantage of the present invention: substitute the tetrahydrofuran (THF) that is difficult to reclaim with cheap acetone, not only solved the recycling problem of solvent, also reduced the discharging of waste water, improved production capacity, can effectively reduce production costs.In the present invention; after 7-AVCA and the MICA active ester generation acylation reaction; it is necessary that the Cefixime Micronized mixed solution that adopts appropriate solvent that step of preparation process one is obtained extracts; can remove the by product mercaptobenzothiazole on the one hand; also can remove solvent used in the step of preparation process one on the other hand, and these solvents can be by the method recycling of rectifying.In the conventional synthetic method, need isolate intermediate A usually, among the present invention, with acidylate and hydrolysis and two is one, uses the one kettle way reaction, need not to isolate intermediate A, both simplify operation, shortened the production cycle, also improved yield and purity (yield: 200-21 2%; Purity: more than 99%).Improved the curative effect of product.

Embodiment:

Embodiment 1

In the reactor of 1000L, add 500L acetone, 50kgAVCA, the 75kgMICA-active ester, 50L methyl alcohol, the about 1.5h of dropping 25kg triethylamine under 5 ℃ (hour),, insulation reaction 4h under 5 degree (hour), sampling (intermediate is less than 0.3%).

After reaction finishes, reclaim acetone and methyl alcohol 40 ℃ of following underpressure distillation, the acetone and the methyl alcohol that reclaim can directly be applied mechanically, after having steamed, add the 400L pure water, the 400L ethyl acetate cools to 10 degree, static layering 30 minutes, collect water, water adds 200L ethyl acetate extraction twice, collects water and removes by filter insolubles.

Aqueous phase adds the 8kg activated carbon, stirs 30min, filters, and uses 200L pure water washing leaching cake, merging filtrate and washing lotion again.

Water adds 200L acetone and cools to below-10 degree, and the sodium hydroxide 80L of disposable adding 30% stirs 5min below-10 degree, and sampling (intermediate is less than 0.3%) reaction finishes.

Disposable adding 18% hydrochloric acid soln 60L, temperature rises to 10 degree, and the accent pH value is 5.0-5.2.Add 0.8kg Sulfothiorine, the 3kg activated carbon stirs 30min, filters, and uses 100L pure water washing leaching cake, merging filtrate and washing lotion again.Add EDTA0.5kg, be warming up to the 24-28 degree, regulating PH is 2.5, and temperature rises to 30 degree, stirs 30min.Be cooled to 10 degree, stir 1h, slowly be cooled to 2 degree again, stir 2h.Centrifuging, and with 200L pure water washing leaching cake, in 40-42 degree vacuum-drying 7h, to moisture be 10-12%, obtain Cefixime Micronized 106kg, yield is 212%.

Embodiment 2

In the reactor of 1000L, add 500L acetone, 50kgAVCA, the 90kgMICA-active ester, the 50L pure water drips the about 2.5h of 25kg triethylamine under 10 degree, insulation reaction 4h under 5 degree, sampling (intermediate is less than 0.3%).

After reaction finishes, reclaim acetone 45 ℃ of following underpressure distillation, the ketone that reclaims can directly be applied mechanically, after having steamed, add the 500L pure water, the 400L ethyl acetate cools to 10 degree, static layering 30 minutes, collect water, water adds 200L ethyl acetate extraction twice, collects water and removes by filter insolubles.

Aqueous phase adds the 3kg activated carbon, stirs 30min, filters, and uses 200L pure water washing leaching cake, merging filtrate and washing lotion again.

Water adds 200L acetone and cools to below-5 degree, and the sodium hydroxide 100L of disposable adding 20% stirs 10min below-5 degree, and sampling (intermediate is less than 0.3%) reaction finishes.

Disposable adding 10% hydrochloric acid soln 80L, temperature rises to 10 degree, and the accent pH value is 5.0-5.2.Add 0.8kg Sulfothiorine, the 3kg activated carbon stirs 30min, filters, and uses 100L pure water washing leaching cake, merging filtrate and washing lotion again.Add EDTA0.5kg, be warming up to the 24-28 degree, regulating PH is 2.5, and temperature rises to 30 degree, stirs 30min.Be cooled to 10 degree, stir 1h, slowly be cooled to 2 degree again, stir 2h.Centrifuging, and with 200L pure water washing leaching cake, in 50-52 degree vacuum-drying 7h, to moisture be 10-12%, obtain Cefixime Micronized 100kg, yield is 200%.

Embodiment 3,

With the weight ratio of 7-AVCA and MICA active ester is that the volume ratio of mixing and place acetone and methyl alcohol at 1: 1.5 is that the volume ratio of 1: 30 and pure water water is 1: 30 a mixed solvent, with sodium hydroxide or potassium hydroxide adjust pH to 7.0, dissolving also obtains intermediate of cefixime A solution in temperature for acylation reaction takes place under-20 ℃ of conditions; The intermediate of cefixime A solution that obtains extracts with ethyl acetate solvent, the aqueous phase that obtains in extraction, 0.1% the activated carbon that aqueous phase adds the 7-AVCA charging capacity decolours, and adds 0.1% EDTA of 7-AVCA charging capacity again, obtains the intermediate of cefixime A aqueous solution; The weight ratio of acetone and methyl alcohol is 1: 1,

After acylation reaction finishes; be located at 40 ℃ of following underpressure distillation and reclaim acetone and methyl alcohol; the acetone and the methyl alcohol that reclaim can directly be applied mechanically; after having steamed, add 3 times pure water of 7-AVCA charging capacity, 2 times ethyl acetate of 7-AVCA charging capacity cools to 10 degree; static layering 30 minutes; collect water, water adds 2 times ethyl acetate extraction twice of 7-AVCA charging capacity, collects water and removes by filter insolubles.

Aqueous phase adds activated carbon, stir 30min, filter, use the pure water washing leaching cake again, merging filtrate and washing lotion add acetone and cool to below-10 degree at water, 1.5 times 30% sodium hydroxide of disposable adding 7-AVCA charging capacity stirs 5min below-10 degree, sampling, intermediate are less than 0.3%, and reaction finishes.

Hydrochloric acid soln is disposable adding, it is 18% hydrochloric acid soln, temperature rises to 10 degree, and transferring pH value is 5.0, adds 0.2% Sulfothiorine of 7-AVCA charging capacity, 0.2% the EDTA that adds the 7-AVCA charging capacity, be warming up to 24 degree, regulating PH is 2.5, and temperature rises to 30 degree, stir 30min, be cooled to 10 degree, stirring 1h (hour), slowly be cooled to 2 degree again, stir 2h, centrifuging, and use the pure water washing leaching cake, in 40 degree vacuum-drying 7h, to moisture be 10%, obtain yield and be 202% Cefixime Micronized.

Embodiment 4,

With the weight ratio of 7-AVCA and MICA active ester is that mixing in 1: 1.75 and the volume ratio that places acetonitrile and tetrahydrofuran (THF) and pure water are 1: 1 mixed solvent, with salt of wormwood and yellow soda ash adjust pH to 8.5, dissolving and be acylation reaction to take place under 20 ℃ of conditions obtain intermediate of cefixime A solution in temperature; The intermediate of cefixime A solution that obtains extracts with ethyl acetate solvent, and the aqueous phase that obtains in extraction adds 5% gac and decolours, and adds 5% EDTA of 7-AVCA charging capacity again, obtains the intermediate of cefixime A aqueous solution; Acetonitrile and tetrahydrofuran (THF) weight ratio are 1: 1,

After acylation reaction finishes; 3～8 times the pure water that adds the 7-AVCA charging capacity; 6 times ethyl acetate of 7-AVCA charging capacity cools to 10 degree; static layering 30 minutes; collect water; water adds 6 times ethyl acetate extraction twice of 7-AVCA charging capacity, collects water and removes by filter insolubles.

Aqueous phase adds activated carbon, stir 30min, filter, use the pure water washing leaching cake again, merging filtrate and washing lotion, add acetone and cool to below-10 degree at water, 2 times 30% sodium hydroxide of disposable adding 7-AVCA charging capacity stirs 5min, sampling below-10 degree, intermediate is less than 0.3%, and reaction finishes.

Hydrochloric acid soln is disposable adding, it is 18% hydrochloric acid soln, temperature rises to 10 degree, and transferring pH value is 5.1, adds 2.5% Sulfothiorine of 7-AVCA charging capacity, 2.5% the EDTA that adds the 7-AVCA charging capacity, be warming up to 26 degree, regulating PH is 2.5, and temperature rises to 30 degree, stir 30min, be cooled to 10 degree, stir 1h, slowly be cooled to 2 degree again, stir 2h, centrifuging, and use the pure water washing leaching cake, in 41 degree vacuum-drying 7h, to moisture be 11%, obtain yield and be 190% Cefixime Micronized.

Embodiment 5

With the weight ratio of 7-AVCA and MICA active ester is that mixing in 1: 2 and the volume ratio that places acetone and pure water are 30: 1 mixed solvent, with adjusting PH with base value to 9.5, dissolving and be acylation reaction to take place under 50 ℃ of conditions obtain intermediate of cefixime A solution in temperature; The intermediate of cefixime A solution that obtains extracts with ethyl acetate solvent, the aqueous phase that obtains in extraction, 10% the gac that adds the 7-AVCA charging capacity decolours, and adds 10% EDTA of 7-AVCA charging capacity again, obtains the intermediate of cefixime A aqueous solution.

After acylation reaction finishes; reclaim acetone 40 ℃ of following underpressure distillation; the acetone that reclaims can directly be applied mechanically; after having steamed, add 8 times pure water of 7-AVCA charging capacity, 10 times ethyl acetate of 7-AVCA charging capacity cools to 10 degree; static layering 30 minutes; collect water, water adds 10 times ethyl acetate extraction twice of 7-AVCA charging capacity, collects water and removes by filter insolubles.

Add activated carbon, stir 30min, filter, use the pure water washing leaching cake again, merging filtrate and washing lotion, add acetone and cool to below-10 degree at water, 2.5 times of disposable adding 7-AVCA charging capacity 30% sodium hydroxide at the following 5min that stirs of-10 degree, is taken a sample, intermediate is less than 0.3%, and reaction finishes.

Hydrochloric acid soln is disposable adding, it is 18% hydrochloric acid soln, temperature rises to 10 degree, and transferring pH value is 5.2, adds 5% Sulfothiorine of 7-AVCA charging capacity, 5% the EDTA that adds the 7-AVCA charging capacity, be warming up to the 24-28 degree, regulating PH is 2.5, and temperature rises to 30 degree, stir 30min, be cooled to 10 degree, stir 1h, slowly be cooled to 2 degree again, stir 2h, centrifuging, and use the pure water washing leaching cake, in 42 degree vacuum-drying 7h, to moisture be 12%, obtain yield and be 200% Cefixime Micronized.

Embodiment 6

With the weight ratio of 7-AVCA and MICA active ester is that mixing in 1: 2 and the volume ratio that places acetone and water are 1: 5 mixed solvent, with adjusting PH with base value to 9, dissolving also obtains intermediate of cefixime A solution in temperature under-10 ℃ or the 25 ℃ of conditions acylation reaction taking place, and divides water-yielding stratum; The intermediate of cefixime A solution that obtains extracts with ethyl acetate solvent, the aqueous phase that obtains in extraction, and 6% the gac that adds the 7-AVCA charging capacity decolours, and adds 6% EDTA again, obtains the intermediate of cefixime A aqueous solution;

After acylation reaction finishes; reclaim acetone 40 ℃ of following underpressure distillation; the acetone that reclaims can directly be applied mechanically; after having steamed, add 3～8 times pure water of 7-AVCA charging capacity, 5 times ethyl acetate of 7-AVCA charging capacity cools to 10 degree; static layering 30 minutes; collect water, water adds 5 times ethyl acetate extraction twice of 7-AVCA charging capacity, collects water and removes by filter insolubles.

Aqueous phase adds activated carbon, stir 30min, filter, use the pure water washing leaching cake again, merging filtrate and washing lotion, add acetone and cool to below-10 degree at water, 1.9 times 30% potassium hydroxide of disposable adding 7-AVCA charging capacity stirs 5min, sampling below-10 degree, intermediate is less than 0.3%, and reaction finishes.

Hydrochloric acid soln is disposable adding, it is 18% hydrochloric acid soln, temperature rises to 10 degree, and transferring pH value is 5.0, adds 5% Sulfothiorine of 7-AVCA charging capacity, 5% the EDTA that adds the 7-AVCA charging capacity, be warming up to the 24-28 degree, regulating PH is 2.5, and temperature rises to 30 degree, stir 30min, be cooled to 10 degree, stir 1h, slowly be cooled to 2 degree again, stir 2h, centrifuging, and use the pure water washing leaching cake, in 40 degree vacuum-drying 7h, to moisture be 10%, obtain yield and be 185% Cefixime Micronized.

Claims (1)

1. the synthetic method of an antibiotic cefixime is characterized in that this method comprises following processing step,

One, be 1 with 7-AVCA and MICA active ester with weight ratio: 1.5-2 mixes and places the volume ratio of organic solvent and pure water is 1: 30～30: 1 mixed solvent, with adjusting PH with base value to 7.0～9.5, dissolving also obtains the Cefixime Micronized aqueous solution in temperature for acylation reaction takes place under-20～50 ℃ of conditions, divides water-yielding stratum; The Cefixime Micronized solution that obtains extracts with ethyl acetate solvent, the activated carbon that the aqueous phase that obtains in extraction adds the 0.1-10% of 7-AVCA charging capacity decolours, add 0.1～10% EDTA of 7-AVCA charging capacity again, obtain the intermediate of cefixime A aqueous solution; Described organic solvent is meant acetonitrile, acetone;

Two, the resulting intermediate of cefixime A aqueous solution in the processing step one is added the alkali reaction that is hydrolyzed, add the hydrochloric acid crystallization again and obtain Cefixime Micronized, its hydrochloric acid soln volumetric molar concentration is 1 mole/L～10 mole/L.