CN104193765B - A kind of synthetic method of cefixime - Google Patents
A kind of synthetic method of cefixime Download PDFInfo
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- CN104193765B CN104193765B CN201410394997.3A CN201410394997A CN104193765B CN 104193765 B CN104193765 B CN 104193765B CN 201410394997 A CN201410394997 A CN 201410394997A CN 104193765 B CN104193765 B CN 104193765B
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- 0 C*(NCC(OC)=N)=C(C(O)=O)c1c[s]c(N)n1 Chemical compound C*(NCC(OC)=N)=C(C(O)=O)c1c[s]c(N)n1 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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Abstract
The invention discloses the synthetic method of a kind of cefixime, comprise the steps: that (1) cefixime side chain sulfur phosphorus active ester occurs amidation process with 7 AVCA, obtain described cefixime methyl ester, wherein, the structure of cefixime side chain sulfur phosphorus active ester is as shown in formula II；(2) step (1) obtains cefixime methyl ester and is hydrolyzed reaction, obtains described cefixime.This synthetic method have employed new MICA active ester: (z) 2 (2 amino 4 thiazolyl) methoxyl group carbon back methylene acetimidic acid diethylphosphoryl active ester; the side-product diethylphosphate toxicity obtained is little; and owing to diethylphosphate is liquid; it is prone to remove; this route steps is simple simultaneously, and yield is high.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to the synthetic method of a kind of antibiotics.
Background technology
Cefixime, structure is as shown in formula I, general possibly together with three water of crystallization in product, cephalo is administered orally for the third generation
Rhzomorph, is synthesized by suppression bacteria cell wall and plays bactericidal action, stable to most beta lactamases, many produce penicillinases and
Cephalosporinase bacterial strain is still sensitive to this product.Cefixime is in vitro and in vivo to gram-positive cocci such as streptococcus pneumoniae, change
Streptococcus pyogenes, gram negative bacilli such as hemophilus influenza (including producing enzyme strain), moraxelle catarrhalis (including producing enzyme strain), large intestine bar
Bacterium, proteus mirabilis, gonococcus (including producing enzyme strain) all have good antibacterial action.Cefixime is in vitro to pneumonia streptococcus
Bacterium, para-influenza Bacillus, proteus vulgaris, Klebsiella Pneumoniae, Pasteurella multocida, Providian bacterium, Salmonella, will are congratulated
Pseudomonas, serratia marcesens, special-shaped citric acid bacteria, malonate citric acid bacteria also have antibacterial activity, but its Clinical efficacy is not yet
Establish.This product is poor to staphylococcus antibacterial action, to Pseudomonas aeruginosa, Enterobacter, bacteroides fragilis, fusobacterium etc. without antibacterial
Effect.It has the features such as wide spectrum, enzyme efficient, resistance to, low toxicity, is the most widely used infection oral drugs.
The existing document report synthesis general route of cefixime is as follows:
(1) prepared by MICA active ester (compound 7)
(2) cefixime methyl ester (compound 3) is prepared
(3) cefixime is prepared in hydrolysis
WO200610366A1 report uses MICA (cefixime side chain) active ester (compound 7) and 7-AVCA gram of oxime
Parent nucleus (compound 2) is in oxolane (or other solvents) with aqueous systems, and dropping organic base (triethylamine etc.) maintains 15 DEG C
Hereinafter, reaction terminate to add ethyl acetate (or dichloromethane) extract, wash, water layer activated carbon decolorizing, filter, filtrate hydrogen-oxygen
After change sodium solution is hydrolyzed reaction at 0～8 DEG C, regulate pH to 4.8-5.2 with dilute hydrochloric acid, add activated carbon decolorizing, filter and add
EDTA, then regulate pH to 2.5, cooling with dilute hydrochloric acid 35 DEG C of systems, product filters, and washing is dried to obtain cefixime, its weight
Yield is 160%.It is that color is dark red during this technique synthesis MECEF (cefixime methyl ester), could water after needing activated carbon decolorizing
Solve, otherwise easily cause product colour the deepest；Though this technique is one pot process cefixime (compound 1)；But need repeatedly
Decolouring, yield is the most on the low side.
CN101016305A report uses MICA (cefixime side chain: compound 8) active ester and 7-AVCA (gram oxime mother
Core) chloromethane (or other solvents) and aqueous systems, dropping organic base (triethylamine etc.) maintains at 10～15 DEG C, and reaction terminates
Add ethyl acetate and water extraction, with after acetic acid regulation PH6～9, then be extracted with ethyl acetate, wash, water layer adds EDTA and
Sodium dithionite, activated carbon decolorizing, filter, and filtrate adds alkali metal salt, with 20% sodium hydrate aqueous solution-5～-10 DEG C
It is hydrolyzed after reaction, regulates PH to 5.0～5.5 with dilute hydrochloric acid, add activated carbon decolorizing, microporous filter, then with dilute hydrochloric acid 28
～30 DEG C of system regulation PH to 2.5～2.6, cooling, product filters, and washing is dried to obtain cefixime, and its weight yield is 200
～210%.During this technique synthesis MECEF (cefixime methyl ester), color is dark red, could hydrolyze, otherwise after needing activated carbon decolorizing
Easily cause product colour the deepest；Though this technique is one pot process cefixime；But need repeatedly to decolour；System needs simultaneously
Adding a large amount of alkali metal salt to reduce product solubility, at Crystallization Process, this is easy for bringing in product by a large amount of inorganic salts, from
And cause product moisture content and salt content higher；Be dried to final product bring pretty troublesome, easily cause product purity and stable the most not
Good.(because the heat stability of beta-lactam cephalosporin compound own is poor)；Micro-pore-film filtration is separately used when filtering, due to
Technique have employed the substantial amounts of alkali metal salt of interpolation, is easily formed when technique micro-pore-film filtration and saltouts, causes microporous membrane to block, and produces
Raw pressure；Potential safety hazard is brought to production.
US 6800755B2 (same to US2004/0082560A1) report uses MECEF (cefixime methyl ester) (compound 3)
Under water and ethyl acetate (or dichloromethane or dichloroethanes), instill saleratus solutions at 24～26 DEG C so that MECEF is molten
Clearly, molten clear after cool to 0～1 DEG C, the sodium hydroxide solution of dropping 15%, drip and maintain 6～8 DEG C of reactions after finishing completely, with 19%
Salt acid for adjusting pH is to 4.8～5.0, and layering, water layer adds activated carbon decolorizing, filters, and filtrate adds acetone solvent, with 8～10% hydrochloric acid
Regulate pH to 2.45～2.55 at 34-36 DEG C, cool to 1～3 DEG C.Filter, washing, vacuum drying, obtain cefixime, hydrolysis weight
Amount yield only has 97.5%.Needing solubilizer acetone before acid adjustment, acetone easily causes product and runs off with mother solution, and yield is inclined
Low.
GB2330141 report uses MECEF (cefixime methyl ester: compound 3) in the system of dichloromethane water, to use carbon
It is hydrolyzed into cefixime under acid potassium and phase transfer catalyst tetrabutyl ammonium bromide (CAS:5922-92-9) effect.The product obtained
Color, quality and yield are the most bad.
GB2330140 report uses MECEF (cefixime methyl ester) in the system of DMF water, and with potassium carbonate, catalysis is lower to be hydrolyzed
Become cefixime, then become cefixime with hydrochloric acid acid adjustment.Solvent DMF is high boiling solvent, and residual DMF solvent easily causes product
It is difficult to dry, affects the quality of product；And DMF easily causes product and runs off with mother solution, yield is low.
WO2001098309 report employing MICA (cefixime side chain: compound 8) is under dichloromethane solvent, with five
Phosphoryl chloride chlorination, lower and ANVA synthesis MECEF (cefixime methyl ester), MECEF hydrogen in the catalysis of N, N-dimethyl silica-based urea
Sodium oxide hydrolysis, hydrochloric acid acid adjustment obtain cefixime.It is bigger that technique uses phosphorus pentachloride to pollute.
WO98/06723 report uses cefixime crude product to become salt refining to purify cefixime by dicyclohexyl amine.This
Technique production cost is higher.
Chen Xin et al. reports the synthesis technique (" China's antibiotic magazine ", volume 201237 the 9th phase) optimizing cefixime,
The method is with 7-amino-3-vinyl-3-cephalo ring-4-carboxylic acid (being called for short 7-AVCA) and 2-(thiazolamine-4-base)-2-
[(Z)-methoxycarbonyl group methoxyimino] acetic acid-2-benzothiazole thioesters (be called for short MICA active ester) be initiation material through condensation,
Hydrolysis obtains target product. and the purity of terminal objective product reaches 99.5%, and the total recovery of two step reactions reaches 90%. conclusions
This preparation process is simple to operate, and environmental pollution is little, is suitable for industrialized great production. and intermediate cefixime methyl ester is not required to through overbaking
Being directly used in hydrolysis, simplicity prepares cefixime with high yield.
Cheng Xianbo, Hu Lipeng, LIU MEILING ,-2009 years 6 phases-reports of Ye Shuxiang, Xu Chengmiao " Shanxi chemical industry " have studied with 7-
When AVCA and cefixime activity methyl ester synthesis cefixime, the selection of reaction dissolvent is on reaction effect and the impact of degree, and makes
With solvent ethyl acetate that is relatively cheap and that be easily recycled, oxolane and acetone equal solvent are replaced, achieve preferably
Economic and social benefit.
Vertical English, Hebei University of Science and Technology: 2010-" pharmaceutical chemistry " reports with 2-(2-amino-4-thiazole)-2-[[(z)-(first
Epoxide carbonyl) methoxy] imido] and-acetic acid be raw material in the presence of triphenylphosphine, triethylamine with DM condensation prepare 2-(2-amino-4-
Thiazole)-2-[[(z)-(methoxycarbonyl) methoxy] imido]-acetic acid-2-[4-morpholinodithio thioesters ester (compound 7).7-AVCA with
2-(thiazolamine-4-base)-2-[[(Z) (methoxycarbonyl) methoxy] imines]-acetic acid-2-[4-morpholinodithio thioesters is through amide
Change reaction and prepare cefixime methyl ester, then obtain cefixime trihydrate, total recovery with sodium hydroxide hydrolysis cefixime methyl ester
80%.
Chen Xin, Wang Chenzhu, Zhang Min " China's antibiotic magazine " ISTIC PKU-2012 9 phase-report optimizes cefixime
Synthesis technique. method with 7-amino-3-vinyl-3-cephalo ring-4-carboxylic acid (be called for short 7-AVCA) and 2-(thiazolamine-
4-yl)-2-[(Z)-methoxycarbonyl group methoxyimino] acetic acid-2-benzothiazole thioesters (be called for short MICA active ester) is initiation material
Target product is obtained through condensation, hydrolysis. the purity of terminal objective product reaches 99.5%, and the total recovery of two step reactions reaches
This preparation process of 90%. conclusions is simple to operate, and environmental pollution is little, is suitable for industrialized great production. and intermediate cefixime methyl ester is not
Need to be directly used in hydrolysis through overbaking, simplicity prepares cefixime with high yield.
Fan Meiju, soup boils ,-2008 years 12 phase report cefixime side chain (first of Du Haisheng, Wang Yongjin " Shandong chemical industry "
Ester) synthesis activated thioester of cefixime side chain, yield 82.8%, there is commercial production and be worth.
The synthesis to cefixime pendant reactive ester herein of-2012 years 17 phases-reports of Piao Meilan " Heilungkiang scientific and technological information "
Study.This technological reaction time is short, low cost, is suitable for commercial production.
2003CH00608 report MICA (cefixime side chain) and 2-methyl-5-(2-(5-methyl isophthalic acid, 3,4-thiophene two
Azoles) dithio)-1,3,4-thiadiazoles are in acetonitrile solvent, at triethylamine, and triphenylphosphine reaction generates S-sulfur generation-5-methyl isophthalic acid,
3,4-thiadiazoles-(Z)-2-(2-amino-4-thiazole)-methoxyl group carbon back methylene oxygen Imine Acetate (compound 4), compound
4 with AVCA (gram oxime parent nucleus) compound 2 THF/ water triethylamine be catalyzed under, PH7-8.5, obtain cefixime methyl ester (compound
3)。
US6388070 report MICA (cefixime side chain) adds triethylamine at dichloromethane-10 DEG C, and dropping is double
(2-oxo-3-oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride, insulation reaction 1 hour, add 5-phenyl-1,3,4-oxadiazoles-2-mercaptan obtain
S-sulfur is for 5-phenyl-1,3,4-oxadiazoles-(Z)-2-(2-amino-4-thiazole)-methoxyl group carbon back methylene oxygen Imine Acetate
(compound 5), compound 4 and AVCA (gram oxime parent nucleus) compound 2, under THF/ water, triethylamine and DMF catalysis, obtain cephalo gram
Hydroxyimino methyl (compound 3).
PCT 2001098309 reports to react with MICA (cefixime side chain) and PCl5 and prepares MICA acyl chlorides (compound
6), chloride compounds 6 and 4-position benzhydryl protection group 7-AVCA parent nucleus (compound 11), obtain cefixime through acidolysis
(compound 1).
CN 101812075 report in MICA and Pentafluorophenol solvent acetone triethylamine be catalyzed under, obtain active substance
(compound 9), (compound 9) and 7-AVCA, at acetone, obtain compound 3, and compound 3 is through hydrolysis, and acid adjustment obtains (compound
1)。
Reporting for document above, we find raw material MICA during synthesis cefixime methyl ester by further investigation
Active ester and 7-AVCA carry out condensation reaction under base catalyst (such as triethylamine etc.) acts on, and above-mentioned document report is used
MICA active ester is 5-methyl isophthalic acid, 3,4-thiadiazoles active ester；5-phenyl-1,3,4-oxadiazoles active ester and benzothiazole activity
Ester.5-methyl isophthalic acid, 3,4-thiadiazoles active ester, 5-phenyl-1,3,4-oxadiazoles active ester and benzothiazole active ester are solid,
Residual is difficult to remove in the product, the 5-methyl isophthalic acid of residual, 3,4-thiadiazoles active ester, 5-phenyl-1,3,4-oxadiazoles activity
Ester and benzothiazole active ester have carcinogenecity.
Summary of the invention
The invention provides the synthetic method of a kind of cefixime, this synthetic method have employed new synthetic intermediate, keeps away
Exempt from the use of the intermediate with carcinogenecity.
The synthetic method of a kind of cefixime, comprises the steps:
(1) there is amidation process with 7-AVCA in cefixime side chain sulfur phosphorus active ester, obtains cefixime methyl ester；
The structure of described cefixime side chain sulfur phosphorus active ester is as shown in formula II:
The structure of described 7-AVCA is as shown in formula III:
The structure of described cefixime methyl ester is as shown in formula IV:
(2) step (1) obtains cefixime methyl ester and is hydrolyzed reaction, obtains described cefixime.
Present invention employs a kind of new MICA active ester (z)-2-(2-amino-4-thiazolyl)-methoxyl group carbon back sub-
Methyl-imino acetic acid diethylphosphoryl active ester (referred to as cefixime side chain sulfur phosphorus active ester) is that initiation material closes
Becoming cefixime, the side-product diethylphosphate carcinogenecity finally given is little, and owing to diethylphosphate is liquid, it is easy to remove
Going, residual is few, and this route steps is simple simultaneously, and yield is higher.
The reaction equation of step (1) is as follows:
In step (1), as preferably, described amidation process is in the mixed system of organic solvent and alkaline aqueous solution
Carry out.As the most preferably, the described alkali in alkaline aqueous solution is potassium carbonate, sodium carbonate, sheet alkali or potassium hydroxide
Deng inorganic base, more preferably sheet alkali, now, it is possible to the intermediate cefixime methyl ester being effectively prevented from obtaining is decomposed.Alkali
Property aqueous solution mass percentage concentration be 1%～10%, consumption makes in course of reaction system pH maintain scope 7.0-9.0 to be advisable.
In step (1), described organic solvent is generally ether solvent or halogenated hydrocarbon solvent, including: oxolane, 1,
4-dioxane, dichloromethane or chloroform etc.；As preferably, described organic solvent is oxolane, when using oxolane
The yield of reaction is the highest.Raw material, without particularly severe requirement, is fully dissolved by the consumption of organic solvent, the most described
About 5 times of cefixime side chain sulfur phosphorus active ester quality.
In step (1), described amidation process is carried out under the effect of the sulfite ion of catalytic amount, described Asia
Sulfate ion comes from sodium sulfite aqueous solution, the aqueous solution of sodium sulfite and other aqueous solutions containing sulfurous acid ion salt
Deng.As preferably, described amidation process is carried out under the effect of sodium sulfite, and wherein, the consumption of sodium sulfite is for urging
Change amount, with molar amount, generally the 1%～about 5% of cefixime side chain sulfur phosphorus active ester.
In step (1), the temperature of described amidation process is 5～10 DEG C, and the response time is 5-7 hour.Reaction temperature
Control the most crucial, the too high meeting of temperature causes the decomposition of product.
In step (1), described cefixime side chain sulfur phosphorus active ester (in terms of MICA acid) and the mol ratio of 7-AVCA
It is 1～2:1, preferably 1.6:1.
The concrete operations of step (1) are usually and are dissolved into successively in organic solvent by various raw materials, are then controlling temperature
Under conditions of drip described alkaline aqueous solution, can effectively suppress the generation of side reaction.
As preferably, after the amidation process in step (1) completes, carry out following post processing:
After in reactant liquor, addition butyl acetate fully extracts, the aqueous phase separated contains cefixime methyl ester, is directly entered
Step (2) is hydrolyzed.Now, the intermediate obtained does not separates, directly " one kettle way " synthesis cefixime, and reaction efficiency is high.
Research finds that step (1) uses the aqueous solution containing sulfurous acid ion and organic solvent (oxolane or dichloromethane
Alkane equal solvent) when being mixed into reaction dissolvent, use inorganic base as catalyst, cefixime side chain sulfur phosphorus active ester and 7-
AVCA carries out being condensed good stability, and the cefixime methyl ester obtained is difficult to by caustic digestion, and it is few to produce impurity, and reaction color will not
Deepen, it is to avoid the shortcoming of the organic base catalytic reaction that document report uses.Research also finds as containing sulfite ion
Aqueous solution persistently play protection reduction in next procedure hydrolysis and acid adjustment process so that overall yield reach 200～
210% (weight yield), more than product content >=99.4%.
The reaction equation of step (2) is as follows:
As preferably, in step (2), described hydrolysis is carried out under the effect of inorganic base, and described inorganic base is
At least one in sodium hydroxide, potassium hydroxide, potassium bicarbonate and sodium bicarbonate.As most preferably, described inorganic base is hydrogen
Sodium oxide and the mixture of sodium bicarbonate, mass ratio is 1～2:1, preferably 1.4:1, and now, hydrolysis efficiency is high, secondary anti-
Should lack.In specific operation process, inorganic base can be dissolved in water 3～6 times of inorganic base quality (consumption of water be generally),
Then it is then added in cefixime methyl ester react, it is not necessary to the most separately add other organic solvent.
The hydrolysis temperature control of step (2) is at 0～15 DEG C, and the response time is monitored by HPLC, to intermediates content
During less than 0.1%, reaction terminates.
As preferably, in step (2), after described hydrolysis completes, carry out following post processing:
The pH of regulation reactant liquor is 4.5～5, is subsequently adding isobutanol, then regulates pH to 2.0-2.5, at-5 DEG C～0 DEG C knots
Crystalline substance, the solid leached is scrubbed, obtain described cefixime after drying.
By product last handling process having been carried out numerous studies discovery: use organic alcohol solvent to replace at product Crystallization Process
For low boiling acetone (Bp:56.1 DEG C), can efficiently reduce product centrifugal after with the loss of mother solution, improve product yield and
Solvent recovering rate；Use iso-butanol solvent to contribute to cefixime impurity dissolubility in water simultaneously, can improve further
The purity of product, reduces impurity and brings in product.Make more than product content >=99.4%.And also can avoid
CN101016305A patent report uses a large amount of alkali metal salt easily bring inorganic salt into in product, cause product salt and water
Part higher, cause product purity and the bad problem of stability.
As preferably, the preparation method of described cefixime side chain sulfur phosphorus active ester is as follows:
Under the effect of tri-n-butylamine, MICA and diethyl sulfo-phosphoryl chloride carry out acyl vulcanization reaction and obtain described cephalo
Gram oxime side-chain acid sulfur phosphorus active ester；
Shown in the structure of described MICA such as formula (V):
Reaction equation is as follows:
As preferably, reaction is carried out under the effect of the triethylene diethylamine of catalytic amount, and consumption is the mole of MICA
0.1～0.5%.
The mol ratio of described diethyl sulfo-phosphoryl chloride: MICA: tri-n-butylamine is 1.2:1:1, diethyl sulfo-phosphoryl
Chlorine uses the mode of dropping to add.
The temperature of reaction is-5～5 DEG C, and the time of reaction is 2～3 hours.
As preferably, reaction is carried out in dichloromethane, and after having reacted, decompression removes the concentration that dichloromethane obtains
Thing is directly entered step (1) and carries out described amidation process.The cefixime side chain sulfur phosphorus activity that this preparation method obtains
Ester needs not move through extra purification can carry out subsequent reactions.
The present invention is compared with existing document report technology, and first the present invention is during synthesis cefixime methyl ester, uses
Aqueous solution and organic solvent (oxolane or dichloromethane equal solvent) containing sulfurous acid ion are mixed into reaction dissolvent.Protect
Demonstrate,prove cefixime methyl ester building-up process color will not deepen, it is not necessary to decolouring directly can be carried out the reaction of lower one-step hydrolysis；Subtract
Decolour number of times less, improves the shade and quality of product.
Second, use butyl acetate (bp:126.14 DEG C) to substitute document report at extraction, hydrolytic process present invention process
Ethyl acetate (bP:77.14 DEG C) is solvent, solves ethyl acetate solvent and reclaims low problem.
3rd, use iso-butanol solvent to substitute low boiling acetone (Bp:56.1 DEG C) at product Crystallization Process, decrease product
With the number of dropouts of mother solution after Li Xin；Improve product yield and solvent recovering rate；Solve CN101016305A patent report simultaneously
Road uses a large amount of alkali metal salt easily bring a large amount of inorganic salt into in product, cause product moisture content higher, cause product purity
With stablize bad problem.
Finally, the present invention is that " one kettle way " synthesizes cefixime method, obtains product purity height, good stability, color good,
Technique weight total recovery can arrive more than 200%.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
(1) in tetra-mouthfuls of reaction bulbs of 2000mL, add 150g MICA (0.579mol), sequentially add 400ml dichloromethane
Alkane, 0.2g triethylene diethylamine (CAS:280-57-9) and 107.3g tri-n-butylamine (0.579mol), stirring cools to-5 DEG C, and
Control temperature of charge.Dropping diethyl sulfo-phosphoryl chloride 132g (0.7mol), drips complete, is incubated 0 DEG C～5 DEG C reaction 2～3 little
Time.Temperature control is at 20 DEG C, and P=-0.95MPa, decompression low temperature is evaporated off dichloromethane solvent, obtains light crocus oily cefixime side
Chain acid sulfur phosphorus active ester 200g, yield 84%.
(2) the crocus cefixime side chain sulfur phosphorus active ester that step (1) obtains, adds the stirring of 900mL oxolane
Dissolve, add 80g 7-AVCA (0.353mol), add 0.7g sodium sulfite.Dropping 100mL sodium hydrate aqueous solution (NaOH
The configuration of 18.4g+700mL water obtains), maintenance temperature 5～10 DEG C, insulation reaction 6 hours.Reaction adds butyl acetate after terminating
800mL, stirs 30 minutes, then stands 60 minutes, layering, collects lower aqueous layer.Water layer adds 400mL n-butyl acetate extraction one
Secondary, to stir 20 minutes, stand 60 minutes, layering, lower floor's aqueous phase collects hydrolysis bottle.
(3) aqueous phase that step (2) is collected cools to 0 DEG C, adds mixed ammonium/alkali solutions and (prepares mixed ammonium/alkali solutions in advance: will
34.5gNaOH and 24.5g sodium bicarbonate joins in 180mL purified water, stirs and molten is cooled to clearly and in advance 0 DEG C～5 DEG C, standby),
Finish, stir 15min, sampling HPLC at 0 DEG C～15 DEG C and detect intermediate ＜ 0.1%.Add 18% hydrochloric acid 100mL, regulate body
Be PH be 4.5～5.0, temperature control is at 3 DEG C～15 DEG C.Add the isobutanol of 800mL, with 18% hydrochloric acid regulation system pH to 2.0-
2.5, follow-up continuous insulation reaction 1h.Cooling to-5 DEG C～0 DEG C, maintain stirring insulation 2.5-3 hour, blowing rejection filter, with the purest
Change water washing, at 40 DEG C～45 DEG C of temperature drying under reduced pressure to moisture about 10.6%, obtain the cefixime of white crystalline powder,
Yield is 162g；Weight total recovery is 202%；HPLC=99.41%, finds no diethylphosphate residual after testing.Characterize
Data are as follows:
HR-MS(m/z):454.0487[M+]。
IR(KBr)ν(cm-1):3304(NH,NH2), 3300～2500 (carboxyl-OH), 2932 (CH2), 1769 (β-interior acyls
Amine-C=O), 1666 (carboxyl-C=O), 1634 (thiazole ring imines C=N), 1537 (C=C), 1082,1040 (C-N).
1H NMR(600MHz,Methanol-d4): 3.62 (d, J=17.4Hz, 1H, SCH2), 3.78 (d, J=17.4Hz,
1H,SCH2),4.76(s,2H,OCH2), 5.20 (d, J=4.8Hz, 1H, 6-CH), 5.31 (d, J=11.4Hz, 1H, vinyls
Hydrogen), 5.56 (d, J=18.0Hz, 1H, vinyl hydrogen), 5.87 (d, J=4.8Hz, 1H, 7-CH), 6.96 (s, 1H, thiazole 3-
H), 7.13 (q, J=28.8Hz, 1H, vinyl hydrogen).
13C NMR(600MHz,Methanol-d4):24.9(2-C),59.1(6-C),60.4(7-C),71.9(-OCH2),
113.1 (thiazole 3-C), 117.7 (vinyl 2-C), 126.8 (4-C), 127.7 (3-C), 133.4 (vinyl 1-C), 141.2
(thiazole 4-C), 150.1 (thiazole 2-C), 164.2 (C=N=O), 165.3 (CONH), 165.6 (beta-lactam-C=O),
171.6(3-COOH),174.0(10-COOH)。
Embodiment 2
Prepare crocus cefixime side chain sulfur phosphorus active ester according to (1) step in above-described embodiment 1, add 900mL
Oxolane stirring and dissolving, adds 80g 7-AVCA (0.353), drips 100mL sodium hydrate aqueous solution (NaOH 18.4g+
The configuration of 700mL water obtains), maintenance temperature 5～10 DEG C, insulation reaction 6 hours.Reaction terminates to add ethyl acetate 800mL, stirring
30 minutes, stand 60 minutes, layering；Lower aqueous layer is collected.Water layer adds 400mL ethyl acetate and extracts once.Stir 20 points
Clock.Stand 60 minutes, layering；Lower floor's aqueous phase collects hydrolysis bottle.
Aqueous phase cools to 0 DEG C, adds mixed ammonium/alkali solutions and (prepares mixed ammonium/alkali solutions in advance: by 34.5gNaOH and 24.5g carbon
Acid hydrogen sodium joins in 180mL purified water, stirs and molten is cooled to clearly and in advance 0 DEG C～5 DEG C, standby), finish, stir at 0 DEG C～15 DEG C
Mix 15min, sampling HPLC and detect intermediate ＜ 0.1%.Adding 18% hydrochloric acid 100mL, regulation system PH is 4.5～5.0, temperature control
At 3 DEG C～15 DEG C.Add the acetone of 800mL, by 18% hydrochloric acid regulation system pH to 2.0-2.5, follow-up continuous insulation reaction 1h.Fall
Temperature to-5 DEG C～0 DEG C, maintains stirring insulation 2.5-3 hour, blowing rejection filter, washs by appropriate purified water, subtract at 40 DEG C～45 DEG C
Pressing dry and dry obtain the cefixime of yellow crystalline powder to moisture about 10.6%, yield is 150g；Weight total recovery is
187%；HPLC=99.02%, finds no diethylphosphate residual after testing.
Embodiment 3
The crocus cefixime side chain sulfur phosphorus active ester that in examples detailed above 1, (1) step prepares, adds 900mL tetrahydrochysene
Furan stirring and dissolving, adds 80g 7-AVCA (0.353), drips 100mL sodium hydrate aqueous solution (NaOH 18.4g+700mL water
Configuration obtains), maintenance temperature 5～10 DEG C, insulation reaction 6 hours.Reaction terminates to add butyl acetate 800mL, stirs 30 minutes,
Stand 60 minutes, layering；Lower aqueous layer is collected.Water layer adds 400mL n-butyl acetate extraction once.Stir 20 minutes.Stand
60 minutes, layering；Lower floor's aqueous phase collects hydrolysis bottle.
(3) aqueous phase cools to 0 DEG C, adds mixed ammonium/alkali solutions and (prepares mixed ammonium/alkali solutions in advance: by 34.5gNaOH and 24.5g
Sodium bicarbonate joins in 180mL purified water, stirs and molten is cooled to clearly and in advance 0 DEG C～5 DEG C, standby), finish, at 0 DEG C～15 DEG C
Stirring 15min, sampling HPLC detect intermediate ＜ 0.1%.Adding 18% hydrochloric acid 100mL, regulation system PH is 4.5～5.0, control
Temperature is at 3 DEG C～15 DEG C.Add the isobutanol of 800mL, by 18% hydrochloric acid regulation system pH to 2.0-2.5, follow-up continuous insulation reaction
1h.Cool to-5 DEG C～0 DEG C, maintain stirring insulation 2.5-3 hour, blowing rejection filter, wash by appropriate purified water, at 40 DEG C～45
DEG C drying under reduced pressure, to moisture about 10.6%, obtains the cefixime of yellow crystalline powder, and yield is 158g；Weight total recovery is
197%；HPLC=98.78%, finds no diethylphosphate residual after testing.
Claims (7)
1. the synthetic method of a cefixime, it is characterised in that comprise the steps:
(1) there is amidation process with 7-AVCA in cefixime side chain sulfur phosphorus active ester, obtains cefixime methyl ester；
The structure of described cefixime side chain sulfur phosphorus active ester is as shown in formula II:
The structure of described 7-AVCA is as shown in formula III:
(2) step (1) obtains cefixime methyl ester and is hydrolyzed reaction, obtains described cefixime；
The preparation method of described cefixime side chain sulfur phosphorus active ester is as follows:
Under the effect of tri-n-butylamine, MICA and diethyl sulfo-phosphoryl chloride carry out reacting and obtain described cefixime side chain
Sulfur phosphorus active ester；
The reaction preparing cefixime side chain sulfur phosphorus active ester is carried out under the effect of the triethylene diethylamine of catalytic amount；
The reaction preparing cefixime side chain sulfur phosphorus active ester is carried out in dichloromethane, and after having reacted, decompression removes
The concentrate that dichloromethane obtains is directly entered step (1) and carries out described amidation process.
The synthetic method of cefixime the most according to claim 1, it is characterised in that in step (1), described amidatioon
Reaction is carried out in the mixed system of organic solvent and alkaline aqueous solution.
The synthetic method of cefixime the most according to claim 2, it is characterised in that in step (1), described is organic molten
Agent is oxolane.
The synthetic method of cefixime the most according to claim 1, it is characterised in that in step (1), described amidatioon
Reaction is carried out under the effect of sodium sulfite.
5. according to the synthetic method of the cefixime described in any one of Claims 1 to 4, it is characterised in that the acyl in step (1)
After aminating reaction completes, carry out following post processing:
After in reactant liquor, addition butyl acetate fully extracts, the aqueous phase separated contains cefixime methyl ester, is directly entered step
(2) it is hydrolyzed.
The synthetic method of cefixime the most according to claim 1, it is characterised in that in step (2), described hydrolysis is anti-
Should carry out under the effect of inorganic base, described inorganic base is at least one in sodium hydroxide, potassium hydroxide and sodium bicarbonate.
The synthetic method of cefixime the most according to claim 1, it is characterised in that in step (2), described hydrolysis is anti-
After should completing, carry out following post processing:
The pH of regulation reactant liquor is 4.5～5, is subsequently adding isobutanol, then regulates pH to 2.0-2.5 ,-5 DEG C～0 DEG C crystallizations,
The solid leached is scrubbed, obtain described cefixime after drying.
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| CN110343120B (en) * | 2019-08-15 | 2021-07-02 | 浙江普洛得邦制药有限公司 | Preparation method of 3-methyl cefdinir |
| CN111689988A (en) * | 2020-07-01 | 2020-09-22 | 心邀（深圳）生物科技有限公司 | Cefixime impurity and synthesis method thereof |
| CN112409382A (en) * | 2020-11-26 | 2021-02-26 | 浙江普洛得邦制药有限公司 | Synthesis method of cefetamet pivoxil hydrochloride |
| CN114805394A (en) * | 2022-05-27 | 2022-07-29 | 山东普洛得邦医药有限公司 | Synthesis method of cefixime |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4409214A (en) * | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical, Co., Ltd. | 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof |
| WO2003040148A1 (en) * | 2001-11-09 | 2003-05-15 | Antibioticos S.P.A. | A process for the preparation of cefixime via alkyl-or aryl-sulfonates |
| CN101016305A (en) * | 2007-02-12 | 2007-08-15 | 河源市制药工程技术研究开发中心 | Method of synthesizing cefixime |
| CN101337969A (en) * | 2008-08-12 | 2009-01-07 | 苏州万庆药业有限公司 | Synthetic method of antibiotic cefixime |
| CN101812075A (en) * | 2010-05-07 | 2010-08-25 | 郝志艳 | Cefixime compound and novel preparation method thereof |
-
2014
- 2014-08-12 CN CN201410394997.3A patent/CN104193765B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4409214A (en) * | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical, Co., Ltd. | 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof |
| WO2003040148A1 (en) * | 2001-11-09 | 2003-05-15 | Antibioticos S.P.A. | A process for the preparation of cefixime via alkyl-or aryl-sulfonates |
| CN101016305A (en) * | 2007-02-12 | 2007-08-15 | 河源市制药工程技术研究开发中心 | Method of synthesizing cefixime |
| CN101337969A (en) * | 2008-08-12 | 2009-01-07 | 苏州万庆药业有限公司 | Synthetic method of antibiotic cefixime |
| CN101812075A (en) * | 2010-05-07 | 2010-08-25 | 郝志艳 | Cefixime compound and novel preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 头孢克肟侧链的合成研究;傅雪晶，等;《合成化学》;20041231;第12卷(第4期);第348-350,364页 * |
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