CN108117565B

CN108117565B - Solid-phase synthesis method of cefotaxime

Info

Publication number: CN108117565B
Application number: CN201611064683.2A
Authority: CN
Inventors: 胡国栋; 崔万胜; 商鼎
Original assignee: Shanghai Pharma Xinya Pharmaceutical Co ltd
Current assignee: Shanghai Pharma Xinya Pharmaceutical Co ltd
Priority date: 2016-11-28
Filing date: 2016-11-28
Publication date: 2021-02-26
Anticipated expiration: 2036-11-28
Also published as: CN108117565A

Abstract

The invention is applicable to the field of chemical pharmacy, and provides a method for preparing cefotaxime by a solid-phase synthesis method, which comprises bridging of a raw material 7-ACA and a solid phase, solid-phase synthesis and separation reaction of a product and the solid phase. The preparation method of cefotaxime avoids the steps of post-treatment, purification, drying and the like in the reaction process, greatly simplifies the reaction operation, reduces impurities in the reaction process, and improves the production benefit and the product quality.

Description

Solid-phase synthesis method of cefotaxime

Technical Field

The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of cefotaxime.

Background

Cefotaxime, chemical name (6R,7R) -3- [ (acetoxy) methyl ] -7- [ [ (2-amino-4-thiazolyl ] - (methoxyimino) acetyl ] amino ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, structural formula:

cefotaxime is the third generation cephalosporin and is widely applied to treating septicemia caused by sensitive bacteria, suppurative meningitis and infection of parts such as respiratory tract, urinary tract, biliary tract, bone and joint, skin and soft tissue, abdominal cavity, digestive tract, five sense organs, genitals and the like.

In the existing literature, the cefotaxime preparation process is operated in two steps, 7-ACA and AE-active ester react in dichloromethane under the action of amine compounds, hydrochloric acid is added for acidification, and then cooling crystallization is carried out to obtain cefotaxime; and secondly, salifying the cefotaxime. The crystallization condition of the two-step process operation is not good, the product quality is influenced, the using amount of the solvent is large, the pollution is serious, the production cost is high, and the product yield is low.

Disclosure of Invention

The invention aims to overcome the defects and provides a method for synthesizing cefotaxime in a solid phase, which solves the technical problems of low total yield, low purity and complex operation in the preparation process of cefotaxime in the prior art.

The invention provides a preparation method of solid-phase synthesis cefotaxime, which comprises the following steps: the method is characterized in that: 7-ACA is taken as a raw material, bridged with a solid phase carrier, and finally separated from a solid phase to prepare cefotaxime through acylation reaction.

The specific reaction equation is as follows:

the invention provides a preparation method of solid-phase synthesis cefotaxime, which comprises the following steps:

in a glazed glass column, 7-ACA and chloromethyl resin were reacted in an organic solvent to bridge them sufficiently with the solid phase carrier, after the reaction was completed, the solvent was removed with a stream of N2, and the resin was washed with dichloromethane and pyridine and directly subjected to the next reaction. The organic solvent is one or more of dichloromethane, DMF or DMSO.

Adding an organic solvent-organic alkali solution into a glazed glass column, stirring and cooling under the protection of nitrogen, adding 3 equivalents of 2- (2-amino-4-thiazolyl) -2- (methoxyimino) thiothiazole acetate (AE-active ester) at room temperature, and reacting for 6 hours. After the reaction was complete, the solvent was removed in a stream of N2 and the resin was washed with dichloromethane and pyridine. The organic solvent is a mixed solvent of dichloromethane and ethanol, and the organic base is one of triethylamine, pyridine or N-methylmorpholine.

Transferring the resin into a reaction bottle, adding a mixed solution of an organic solvent and an acid (the volume ratio of the solvent is 5:1), stirring at room temperature for 2h, cooling the reaction mixture to-20 ℃, adding a catalytic amount of another acid while stirring, reacting for 2h, raising the temperature to room temperature, continuing stirring for 6h, filtering, and removing the organic solvent in vacuum. Dissolving the obtained solid in organic solution, extracting with sodium salt aqueous solution, washing the obtained water layer with ethyl acetate, separating and purifying with active alumina column chromatography, and collecting eluate containing the target compound. Adding acetone into the eluent, cooling to 15 ℃, growing crystals, filtering, washing and drying. Cefotaxime crystals are obtained. The organic solvent is one or more of dichloromethane, tetrahydrofuran or ethyl acetate. The acid is selected from one or more of trifluoroacetic acid, HF, organic sulfonic acid or silicon-containing reagent. The sodium salt is sodium acetate.

The invention has the following functions and effects:

the preparation method of the solid-phase synthesis cefotaxime greatly simplifies the reaction procedure by omitting the post-treatment process after the reaction. The total reaction yield is more than 90 percent, and the purity is more than 99.5 percent. The total yield of the reaction is improved, the purity of the product is improved, and the production benefit is improved.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.

The first embodiment is as follows: bridging of 7-ACA with solid phase carriers

In a glass-frit column, 25g of 7-ACA was reacted with chloromethyl resin in 100ml of DMF to bridge it sufficiently with the solid phase carrier, after the reaction was completed, the solvent was removed with a stream of N2, and the resin was washed with dichloromethane and pyridine and directly subjected to the next reaction.

Example two: preparation of solid phase bridged cefotaxime

After a glass frit column, dichloromethane (75ml) -triethylamine (8g) solution was added to the column, stirred under nitrogen, and 25g thiothiazole 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetate was added at room temperature and reacted for 6 h. After the reaction was complete, the solvent was removed in a stream of N2 and the resin was washed with dichloromethane and pyridine.

Example three: separation reaction of cefotaxime and solid phase

Transferring the resin into a reaction bottle, adding 100ml of dichloromethane and 20ml of trifluoroacetic acid solution, stirring at room temperature for 2h, cooling the reaction mixture to-20 ℃, adding 5ml of trifluoromethanesulfonic acid under stirring, reacting for 2h, raising the temperature to room temperature, continuing stirring for 6h, filtering, and removing the organic solvent in vacuum. Dissolving the obtained solid in 100ml tetrahydrofuran and ethyl acetate solution, extracting with sodium acetate aqueous solution, washing the obtained water layer with ethyl acetate, separating and purifying with active alumina column chromatography, and collecting the elution effluent containing the target compound. Adding acetone into the eluent, cooling to 15 ℃, growing the crystals for 1h, continuously and slowly dripping acetone solution, cooling to 0 ℃, stirring, growing the crystals for 1h, filtering, washing and drying. Cefotaxime crystals are obtained. The total yield of the reaction was 93% and the purity was 99.6%.

Claims

1. A preparation method of solid-phase synthesis cefotaxime is characterized by comprising the following steps: 7-ACA is taken as a raw material, is bridged with a solid phase carrier, and is finally separated from a solid phase to prepare cefotaxime through acylation reaction;

the specific reaction equation is as follows:

the solid phase carrier is selected from polystyrene-divinyl benzene cross-linked resin, polyacrylamide and polyethylene-glycol resin,

wherein, depending on the reactive group introduced, these resins include chloromethyl resin, carboxyl resin, amino resin or hydrazide type resin;

the specific process steps are as follows:

step one, reacting 7-ACA and chloromethyl resin in an organic solvent in a glaze glass column to enable the reaction to be fully bridged with a solid phase carrier, removing the solvent by using N2 flow after the reaction is finished, washing the resin by using dichloromethane and pyridine, and directly carrying out the next reaction;

step two, adding an organic solvent-organic alkali solution into a glazed glass column, stirring and cooling under the protection of nitrogen, adding 3 equivalents of 2- (2-amino-4-thiazolyl) -2- (methoxyimino) thiothiazole acetate at room temperature, reacting for 6 hours, removing the solvent in N2 flow after the reaction is finished, and washing the resin by using dichloromethane and pyridine;

and step three, transferring the resin into a reaction bottle, adding an organic solvent and a mixed solution of an acid and/or a silicon-containing reagent, wherein the volume ratio of the solvent is 5:1, stirring at room temperature for 2 hours, cooling the reaction mixture to-20 ℃, adding another acid with a catalytic amount under stirring, heating to room temperature after reacting for 2 hours, continuing stirring for 6 hours, filtering, removing the organic solvent in vacuum, dissolving the obtained solid in the organic solution, extracting with a sodium salt aqueous solution, washing the obtained water layer with ethyl acetate, performing chromatographic separation and purification with an activated alumina column, collecting an elution effluent containing a target compound, adding acetone into the eluate, cooling to 15 ℃, growing crystals, filtering, washing, and drying to obtain the cefotaxime crystal.

2. A process for the preparation of cefotaxime in solid phase according to claim 1, wherein:

in the first step, the organic solvent is selected from one or more of dichloromethane, DMF or DMSO.

3. A process for the preparation of cefotaxime in solid phase according to claim 1, wherein:

in the second step, the organic solvent is a mixed solvent of dichloromethane and ethanol, and the organic base is one of triethylamine, pyridine or N-methylmorpholine.

4. A process for the preparation of cefotaxime in solid phase according to claim 1, wherein:

in the third step, the organic solvent is one or more of dichloromethane, tetrahydrofuran or ethyl acetate;

the acid is selected from one or more of trifluoroacetic acid, HF and organic sulfonic acid;

the sodium salt is sodium acetate.

5. A process for the preparation of cefotaxime according to claim 1, wherein:

the deprotection system adopted for separating from the solid phase carrier comprises trifluoroacetic acid, HF, organic sulfonic acid TFMSA, organic sulfonic acid MSA, a silicon-containing reagent TMSBr and a silicon-containing reagent TMSOTf.