CN102675344A

CN102675344A - Method for preparing cefmenoxime hydrochloride

Info

Publication number: CN102675344A
Application number: CN2012101266287A
Authority: CN
Inventors: 翟昌梅; 王小丹
Original assignee: Shandong Lukang Pharmaceutical Co Ltd
Current assignee: Amicogen China Biopharm Co Ltd
Priority date: 2012-04-17
Filing date: 2012-04-17
Publication date: 2012-09-19

Abstract

The invention discloses a method for preparing cefmenoxime hydrochloride, which comprises the following steps: uniformly mixing 7-ACT hydrochloride shown in a formula II and AE active ester shown in a formula III under the condition that methylene dichloride and a solvent exist for condensation reaction and obtaining the cefmenoxime hydrochloride shown in a formula I after reaction. The method has the benefits that the cefmenoxime hydrochloride can be synthesized in one step, the cefmenoxime hydrochloride is not required to be separated, a reversely-dropping crystallization method is adopted, the synthetic line is short, the cost is low, the reaction conditions are wild, and the production is convenient; and the cefmenoxime hydrochloride product is high in yield and purity and low in color grade and has an important application value.

Description

The method for preparing Cefmenoxime Hemihydrochloride

Technical field

The present invention relates to a kind of preparation method of compound, especially relate to a kind of method for preparing Cefmenoxime Hemihydrochloride.

Background technology

Cefmenoxime Hemihydrochloride (cefmenoxime hydrochloride); Chemistry (6R by name; 7R)-and 7-[2-(2-amino-4-thiazolyl) (methoxyimino) kharophen]-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl)-sulphur] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formate hydrochlorate, its chemical structural formula is suc as formula shown in the I.

Formula I

Cefmenoxime Hemihydrochloride is by the exploitation of Japanese Takede Chemical Industries Ltd, the semi-synthetic Broad spectrum antibiotics produced, goes on the market in Japan in nineteen eighty-three, and gets into the U.S., Japan and other countries latest edition pharmacopeia, goes on the market in China in 2000.

Cefmenoxime Hemihydrochloride is a third generation cephalo, and Gram-negative and male aerophil and anerobes are all had anti-microbial effect.In the Gram-negative bacteria; Anti-microbial effect to intestinal bacteria, pneumobacillus is stronger slightly than cefotiam; Obviously be better than the Kefzol of the first-generation; The anti-microbial effect of influenza being bitten blood bacillus, Bacillus proteus, serratia marcesens, Citrobacter, enterobacter is also more intense, and Bacteroides is also had very strong anti-microbial effect.In gram-positive microorganism, also stronger to micrococcus scarlatinae, pneumococcal anti-microbial effect.Peptococcus, Peptostreptococcus also there is the strong antibiotic effect.Stable to beta lactamase.These article to the effect of Staphylococcus not as first and second cynnematin in generation, poor to Pseudomonas aeruginosa, enterobacteria and faecalis effect.Quiet notes 1g, blood medicine peak value 99.4 mcg/ml, intramuscular injection 0.5g is 10.8 mcg/ml, serum t _1/2Be about 1 hour.Metabolism hardly in vivo is mainly through renal excretion.Serum proteins combination rate 85%.These article are good to bile transport, and are higher at body fluid such as sputum, tonsilla, csf, hydrothorax, peritoneal exudate, kidney, bladder wall, uterus, uterine tube, ovary, pelvic cavity transudate, Cord blood, amniotic fluid and tissue distribution concentration.But transhipment seldom in milk.Be applicable to responsive microbial septicemia, meningitis, respiratory tract infection, pyothorax, liver and courage infection, peritonitis, urinary tract infection, genital system infection and burn and surgical wound infection etc.

At present, a lot of about Cefmenoxime Hemihydrochloride synthetic route document, like DE27132, US3262932, JP80-38349, JP84-53492, CN101555251A etc., but all have a complex synthetic route, productive rate is low and shortcoming such as production cost height.

Summary of the invention

The purpose of this invention is to provide a kind of method for preparing Cefmenoxime Hemihydrochloride.

The method for preparing Cefmenoxime Hemihydrochloride shown in the formula I provided by the invention; Comprise the steps: the mixing under the condition of methylene dichloride and solvent existence of AE active ester shown in 7-ACT hydrochloride shown in the formula II and the formula III is carried out condensation reaction, reaction finishes and obtains Cefmenoxime Hemihydrochloride shown in the formula shown I;

Formula I

Formula II formula III.

In the aforesaid method, said solvent is alcoholic solvent and basic solvent.

Said alcoholic solvent is selected from least a in the alcohol that the total number of carbon atoms is 1-3, at least a in the monohydroxy-alcohol that preferred the total number of carbon atoms is 1-3, more preferably at least a in ethanol and the Virahol;

Said basic solvent is selected from a kind of in triethylamine, sodium hydrogencarbonate and the yellow soda ash, preferred triethylamine.

In the said step of condensation; The amount ratio of AE active ester, methylene dichloride and said basic solvent shown in 7-ACT hydrochloride, the formula III is 2g: 2.1g shown in the said formula II: 26ml: 2mL to 2g: 2.2g26ml: 2.5mL, preferred 2g: 2.1g: 26mL: 2mL; In the said reactions step, temperature is-10 ℃～10 ℃, and preferred-5 ℃～5 ℃, the time is 4～5 hours, preferred 5 hours.In this condensation reaction, whether reaction finishes and can pass through performance liquid chromatography monitoring reaction terminal point.

The said method for preparing Cefmenoxime Hemihydrochloride shown in the formula I also comprises the steps: after said condensation reaction finishes, and in reaction system, adds no salt solution and extracts; Get the gained organic phase more once, twice extraction gained water merged, after the methylene dichloride back extraction with no salt solution extraction; The pH value of regulating the gained water is to 6-7, and decolorization filtering is got filtrating, in acid solution, mixes and separates out crystal; After growing the grain, washing and the drying, obtain Cefmenoxime Hemihydrochloride shown in the said formula I.

Wherein, said acid solution is the mixed solution of being made up of aqueous hydrochloric acid and acetone; Said aqueous hydrochloric acid is preferably concentrated hydrochloric acid aqueous solution; Said aqueous hydrochloric acid is a concentrated hydrochloric acid aqueous solution; The mass percentage concentration of said concentrated hydrochloric acid aqueous solution is 30%-35%, preferred 35%.The volume ratio of said aqueous hydrochloric acid and said acetone is 1: 2-20, preferred 1: 20; Said separating out in the crystal step, temperature is 30-35 ℃, preferred 35 ℃; In the said growing the grain step, the time is 1.5-2 hour, and preferred 2 hours, temperature was 20-25 ℃, preferred 25 ℃; In the said washing step, can wash according to ordinary method with acetone again by first water.

The method for preparing Cefmenoxime Hemihydrochloride provided by the invention can the one-step synthesis Cefmenoxime Hemihydrochloride, need not separate cefmenoxime acid, and adopts the anti-crystallization mode that drips, and synthetic route is short, and cost is low, and reaction conditions is gentle, is convenient to produce; The product yield of gained Cefmenoxime Hemihydrochloride is high, and purity is high, and the look level is low, has important use and is worth.

Description of drawings

Fig. 1 is the infrared spectrum of Cefmenoxime Hemihydrochloride standard substance shown in the formula I.

Fig. 2 is the infrared spectrum of embodiment 1 preparation products therefrom.

Fig. 3 is the infrared spectrum of embodiment 2 preparation products therefroms.

Embodiment

Below in conjunction with specific embodiment the present invention is done further elaboration, but the present invention is not limited to following examples.Said method is ordinary method if no special instructions.Said raw material all can get from open commercial sources if no special instructions.

Embodiment 1:

The 500ml four-hole bottle adds methylene dichloride 260ml, 5ml ethanol and 35ml Virahol, cools to-7 ℃, adds compd A E active ester shown in 20g7-ACT hydrochloride and the 21g formula III successively, drips triethylamine 20ml, and 20min drips complete.Drip complete timing insulation and carried out condensation reaction 5 hours for-3 ℃.Use the performance liquid chromatography endpoint detection.Reaction is finished, and adds no salt solution 150ml, layering, and organic phase does not have salt solution with 90ml again and extracts once again, merges water, uses the methylene dichloride strip aqueous.Water adds 1 gram gac and 0.1 gram sodium sulfite anhy 96 decolouring 20min with acid for adjusting pH value to 6～7.Filter, filter cake is used the 70ml water washing.Other installs a 1000ml four-hole bottle, adds 35% concentrated hydrochloric acid of 180ml acetone and 9ml mass percentage concentration, and will filtrate drips in this mixed solution, and 35 ℃ of temperature controls are separated out white solid.In 25 ℃ of growing the grains 2 hours, suction filtration, with using the 100ml washing with acetone after the 100ml water washing, suction filtration is dry, product 24.5 grams, mass yield 122.5%.

The structural confirmation data of this product are as shown in Figure 2, can know that with Fig. 1 contrast this product structure is correct, are Cefmenoxime Hemihydrochloride shown in the formula I.

Embodiment 2

The 50L retort adds methylene dichloride 26L, 5L ethanol and 35L Virahol, cools to-8 ℃, adds compd A E active ester shown in 2kg7-ACT hydrochloride and the 2.1kg formula III successively, drips triethylamine 2.0L, and 20min drips complete.Drip complete timing insulation and carried out condensation reaction 5 hours for-4 ℃.Use the performance liquid chromatography endpoint detection.Reaction is finished, and adds no salt solution 15L, layering, and organic phase does not have salt solution with 9L again and extracts once again, merges water, uses the methylene dichloride strip aqueous.Water adds 0.12kg gac and 0.012kg sodium sulfite anhy 96 decolouring 20min with acid for adjusting pH value to 6～7.Filter, filter cake is used the 7L water washing.Other prepares a 100L retort, and adding 18L acetone and 9L mass percentage concentration are 35% concentrated hydrochloric acid, and will filtrate drips in this mixed solution, and 35 ℃ of temperature controls are separated out white solid.In 25 ℃ of growing the grains 2 hours, suction filtration, with using the 12L washing with acetone after the 10L water washing, suction filtration is dry, product 2.51kg, mass yield is 125.5%.

The structural confirmation data of this product are as shown in Figure 3, can know that with Fig. 1 contrast this product structure is correct, are Cefmenoxime Hemihydrochloride shown in the formula I.

Claims

1. method for preparing Cefmenoxime Hemihydrochloride shown in the formula I; Comprise the steps: the mixing under the condition of methylene dichloride and solvent existence of AE active ester shown in 7-ACT hydrochloride shown in the formula II and the formula III is carried out condensation reaction, reaction finishes and obtains Cefmenoxime Hemihydrochloride shown in the formula shown I;

Formula I

Formula II formula III.

2. method according to claim 1 is characterized in that: said solvent is alcoholic solvent and basic solvent.

3. method according to claim 2 is characterized in that: said alcoholic solvent is selected from least a in the alcohol that the total number of carbon atoms is 1-3, at least a in the monohydroxy-alcohol that preferred the total number of carbon atoms is 1-3, more preferably at least a in ethanol and the Virahol;

4. according to the arbitrary described method of claim 1-3; It is characterized in that: the amount ratio of AE active ester, methylene dichloride and said basic solvent shown in 7-ACT hydrochloride, the formula III is 2g: 2.1g shown in the said formula II: 26ml: 2mL to 2g: 2.2g26ml: 2.5mL, preferred 2g: 2.1g: 26mL: 2mL; In the said step of condensation, temperature is-10 ℃～10 ℃, and preferred-5 ℃～5 ℃, the time is 4～5 hours, preferred 5 hours.

5. according to the arbitrary described method of claim 1-4, it is characterized in that: the said method for preparing Cefmenoxime Hemihydrochloride shown in the formula I also comprises the steps: after said condensation reaction finishes; In reaction system, add no salt solution and extract, get the gained organic phase more once, twice extraction gained water merged with no salt solution extraction; After the methylene dichloride back extraction; The pH value of regulating the gained water is to 6-7, and decolorization filtering is got filtrating, in acid solution, mixes and separates out crystal; After growing the grain, washing and the drying, obtain Cefmenoxime Hemihydrochloride shown in the said formula I.

6. method according to claim 5 is characterized in that: the mixed solution of said acid solution for being made up of aqueous hydrochloric acid and acetone.

7. method according to claim 6 is characterized in that: said aqueous hydrochloric acid is a concentrated hydrochloric acid aqueous solution; The mass percentage concentration of said concentrated hydrochloric acid aqueous solution is 30-35%, preferred 35%.

8. according to claim 6 or 7 described methods, it is characterized in that: the volume ratio of said aqueous hydrochloric acid and said acetone is 1: 2-20, preferred 1: 20.

9. according to the arbitrary described method of claim 5-8, it is characterized in that: said separating out in the crystal step, temperature is 30-35 ℃, preferred 35 ℃.

10. according to the arbitrary described method of claim 5-9, it is characterized in that: in the said growing the grain step, the time is 1.5-2 hour, and preferred 2 hours, temperature was 20-25 ℃, preferred 25 ℃.