CN104193765A - Method for synthesizing cefixime - Google Patents
Method for synthesizing cefixime Download PDFInfo
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- CN104193765A CN104193765A CN201410394997.3A CN201410394997A CN104193765A CN 104193765 A CN104193765 A CN 104193765A CN 201410394997 A CN201410394997 A CN 201410394997A CN 104193765 A CN104193765 A CN 104193765A
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- cefixime
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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 a method for synthesizing cefixime. The method comprises the following steps: (1) carrying out an amidation reaction between MICA ((Z)-2-(methoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid) sulfur-phosphorous active ester and 7-AVCA to obtain cefixime methyl ester, wherein the structure of the MICA sulfur-phosphorous active ester is as shown in the formula (II); (2) hydrolyzing the cefixime methyl ester to obtain cefixime. According to the synthesizing method, a new MICA active ester, namely (z)-2-(2-amino-4-thiazolyl)-methoxycarbonyl methylene imino-acetic acid-diethyl phosphoryl active ester, is adopted, a byproduct diethyl phosphate has small toxicity; and the diethyl phosphate is liquid and can be easily removed, the method is simple in steps and is high in yield.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to a kind of synthetic method of antibiotic.
Background technology
Cefixime Micronized, structure is as shown in formula I, in product, generally also contain three crystal water, for third generation oral cephalosporin, play germicidal action by anti-bacteria Cell wall synthesis, stable to most beta lactamases, many product penicillinases and cephalosporinase bacterial strain are still to this product sensitivity.Cefixime Micronized in vitro and in vivo to gram-positive cocci as streptococcus pneumoniae, micrococcus scarlatinae, gram negative bacillus is as hemophilus influenza (comprise produce enzyme strain), moraxelle catarrhalis (comprise and produce enzyme strain), intestinal bacteria, Proteus mirabilis, all good anti-microbial effects of tool of gonococcus (comprise and produce enzyme strain).Cefixime Micronized is also had an anti-microbial activity to streptococcus pneumoniae, para-influenza Bacillus, proteus vulgaris, Klebsiella Pneumoniae, Pasteurella multocida, Providian bacterium, Salmonella, Shigella, serratia marcesens, special-shaped citric acid bacteria, malonate citric acid bacteria in vitro, but its Clinical efficacy is not yet established.This product is poor to staphylococcus anti-microbial effect, to Pseudomonas aeruginosa, enterobacter, bacteroides fragilis, fusobacterium etc. without anti-microbial effect.It has the features such as wide spectrum, efficient, resistance to enzyme, low toxicity, is widely used anti-infective oral pharmaceutical clinically.
The synthetic general route of Cefixime Micronized of existing bibliographical information is as follows:
(1) MICA active ester (compound 7) preparation
(2) prepare Cefixime Micronized methyl esters (compound 3)
(3) Cefixime Micronized is prepared in hydrolysis
WO200610366A1 report adopts MICA (cefixime side chain) active ester (compound 7) and 7-AVCA gram of oxime parent nucleus (compound 2) in tetrahydrofuran (THF) (or other solvents) and aqueous systems, dripping organic bases (triethylamine etc.) maintains below 15 DEG C, reaction finishes to add ethyl acetate (or methylene dichloride) extraction, washing, water layer activated carbon decolorizing, filter, filtrate is hydrolyzed after reaction at 0～8 DEG C with sodium hydroxide solution, with dilute hydrochloric acid regulate pH to 4.8-5.2, add activated carbon decolorizing, filtration adds EDTA, regulate pH to 2.5 with dilute hydrochloric acid 35 DEG C of systems again, cooling, product filters, washing is dried to obtain Cefixime Micronized, its weight yield is 160%.This technique is that color is dark red while synthesizing MECEF (Cefixime Micronized methyl esters), needs could be hydrolyzed after activated carbon decolorizing, otherwise easily causes product colour partially dark; Though this technique is the synthetic Cefixime Micronized (compound 1) of one kettle way; But need to repeatedly decolour, yield is also on the low side.
CN101016305A report adopts MICA (cefixime side chain: compound 8) active ester and 7-AVCA (gram oxime parent nucleus) methyl chloride (or other solvents) and aqueous systems, dripping organic bases (triethylamine etc.) maintains at 10～15 DEG C, reaction finishes to add ethyl acetate and water extraction, regulate behind PH6～9 with acetic acid, be extracted with ethyl acetate again, washing, water layer adds EDTA and V-Brite B, activated carbon decolorizing, filter, filtrate adds an alkali metal salt, with 20% aqueous sodium hydroxide solution-5～-10 DEG C be hydrolyzed reaction after, with dilute hydrochloric acid adjusting PH to 5.0～5.5, add activated carbon decolorizing, millipore filtration, regulate PH to 2.5～2.6 with dilute hydrochloric acid 28～30 DEG C of systems again, cooling, product filters, washing, be dried to obtain Cefixime Micronized, its weight yield is 200～210%.When this technique is synthesized MECEF (Cefixime Micronized methyl esters), color is dark red, needs could be hydrolyzed after activated carbon decolorizing, otherwise easily causes product colour partially dark; Though this technique is the synthetic Cefixime Micronized of one kettle way; But need to repeatedly decolour; Simultaneously system need to add a large amount of an alkali metal salts to reduce product solubility, and at Crystallization Process, this just easily brings a large amount of inorganic salt in product into, thus cause product moisture content and salt content higher; Bring pretty troublesomely to final product is dry, easily cause product purity and stablize bad.(because the thermostability of beta-lactam cephalosporin compound own is poor); Separately in the time filtering, adopt micro-pore-film filtration, due to process using add a large amount of an alkali metal salts, in the time of technique micro-pore-film filtration, easily form and saltout, cause microporous membrane to block, produce pressure; Bring potential safety hazard to production.
US 6800755B2 (same to US2004/0082560A1) report adopts MECEF (Cefixime Micronized methyl esters) (compound 3) under water and ethyl acetate (or methylene dichloride or ethylene dichloride), splash into saleratus solution at 24～26 DEG C, make MECEF molten clear, moltenly cool to 0～1 DEG C after clear, drip 15% sodium hydroxide solution, drip after finishing and maintain 6～8 DEG C and react completely, with 19% salt acid for adjusting pH to 4.8～5.0, layering, water layer adds activated carbon decolorizing, filter, filtrate adds acetone solvent, with 8～10% hydrochloric acid 34-36 DEG C regulate pH to 2.45～2.55, cool to 1～3 DEG C.Filter, washing, vacuum-drying, obtains Cefixime Micronized, and hydrolysis weight yield only has 97.5%.Before acid adjustment, need solubilizing agent acetone, acetone easily causes product to run off with mother liquor, and yield is on the low side.
GB2330141 report adopts MECEF (Cefixime Micronized methyl esters: compound 3) in the system of methylene dichloride water, with being hydrolyzed into Cefixime Micronized under salt of wormwood and phase-transfer catalyst Tetrabutyl amonium bromide (CAS:5922-92-9) effect.The product colour, quality and the yield that obtain are all bad.
GB2330140 report adopts the system of MECEF (Cefixime Micronized methyl esters) at DMF water, with salt of wormwood, under catalysis, is hydrolyzed into Cefixime Micronized, then becomes Cefixime Micronized with hydrochloric acid acid adjustment.Solvent DMF is high boiling solvent, and residual DMF solvent easily causes product to be difficult for drying, and affects the quality of product; And DMF easily causes product to run off with mother liquor, and yield is low.
WO2001098309 report adopts MICA (cefixime side chain: compound 8) under dichloromethane solvent, use phosphorus pentachloride chloride, at N, under the silica-based urea catalysis of N-dimethyl, with the synthetic MECEF (Cefixime Micronized methyl esters) of ANVA, for MECEF, sodium hydroxide hydrolysis, hydrochloric acid acid adjustment obtain Cefixime Micronized.Process using phosphorus pentachloride pollutes larger.
WO98/06723 report adopts Cefixime Micronized crude product to become salt refining purification Cefixime Micronized by dicyclohexyl amine.This explained hereafter cost is higher.
The people such as Chen Xin have reported the synthesis technique (" Chinese microbiotic magazine " of optimizing Cefixime Micronized, the 9th phase of 201237 volumes), the method is taking 7-amino-3-vinyl-3-cephalo ring-4-carboxylic acid (be called for short 7-AVCA) and 2-(thiazolamine-4-yl)-2-[(Z)-methoxycarbonyl methoxyimino] acetic acid-2-benzothiazole thioesters (being called for short MICA active ester) is as starting raw material is through condensation, hydrolysis reaction obtains target product. and the purity of terminal objective product reaches 99.5%, it is simple to operate that the total recovery of two step reactions reaches this preparation process of 90%. conclusions, environmental pollution is little, being applicable to industrialized production. intermediate Cefixime Micronized methyl esters does not need to be directly used in hydrolysis reaction through overbaking, the easy Cefixime Micronized of preparing with high yield.
Cheng Xianbo, Hu Lipeng, LIU MEILING, Ye Shuxiang, the impact of the selection of reaction solvent on reaction effect and degree when Xu Chengmiao " Shanxi chemical industry " 6 phase-reports in-2009 have been studied with 7-AVCA and the synthetic Cefixime Micronized of the active methyl esters of Cefixime Micronized, and use relatively cheap and be easy to recovered solvent ethyl acetate tetrahydrofuran (THF) and acetone equal solvent are replaced, obtain good economic and social benefit.
Vertical English, Hebei University of Science and Technology: 2010-" pharmaceutical chemistry " report taking 2-(2-amino-4-thiazole)-2-[[(z)-(methoxycarbonyl) methoxy] imido]-acetic acid makes 2-(2-amino-4-thiazole)-2-[[(z with DM condensation as raw material under triphenylphosphine, triethylamine existence)-(methoxycarbonyl) methoxy] imido]-acetic acid-2-[4-morpholinodithio thioesters ester (compound 7).7-AVCA and 2-(thiazolamine-4-yl)-2-[[(Z) (methoxycarbonyl) methoxy] imines]-acetic acid-2-[4-morpholinodithio thioesters makes Cefixime Micronized methyl esters through amidate action, obtain cefixime trihydrate with sodium hydroxide hydrolysis Cefixime Micronized methyl esters again, total recovery 80%.
Chen Xin, Wang Chenzhu, Zhang Min " Chinese microbiotic magazine " ISTIC PKU-2012 9 phase-reports are optimized the synthesis technique of Cefixime Micronizeds. and method is taking 7-amino-3-vinyl-3-cephalo ring-4-carboxylic acid (being called for short 7-AVCA) and 2-(thiazolamine-4-yl)-2-[(Z)-methoxycarbonyl methoxyimino] acetic acid-2-benzothiazole thioesters (being called for short MICA active ester) is as starting raw material is through condensation, hydrolysis reaction obtains target product. and the purity of terminal objective product reaches 99.5%, it is simple to operate that the total recovery of two step reactions reaches this preparation process of 90%. conclusions, environmental pollution is little, being applicable to industrialized production. intermediate Cefixime Micronized methyl esters does not need to be directly used in hydrolysis reaction through overbaking, the easy Cefixime Micronized of preparing with high yield.
Fan Meiju, soup boils, Du Haisheng, Wang Yongjin " Shandong chemical industry " the synthetic activated thioester of cefixime side chain of 12 phase report cefixime side chain (methyl esters) in-2008, yield 82.8%, has industrial production and is worth.
Piao Meilan " Heilungkiang scientific and technical information " 17 phase-reports synthetic research to Cefixime Micronized side chain active ester herein in-2012.This technological reaction time is short, and cost is low, is applicable to industrial production.
2003CH00608 report MICA (cefixime side chain) and 2-methyl-5-(2-(5-methyl isophthalic acid, 3,4-thiadiazoles) dithio)-1,3,4-thiadiazoles is in acetonitrile solvent, at triethylamine, triphenylphosphine reaction generates S-sulfo--5-methyl isophthalic acid, 3,4-thiadiazoles-(Z)-2-(2-amino-4-thiazole)-methoxyl group carbon back methylene radical oxygen imines acetic ester (compound 4), compound 4 and AVCA (gram oxime parent nucleus) compound 2 are under the catalysis of THF/ water triethylamine, PH7-8.5, obtains Cefixime Micronized methyl esters (compound 3).
US6388070 report MICA (cefixime side chain) adds triethylamine at methylene dichloride-10 DEG C, drip two (2-oxo-3-oxazolidinyl) inferior phosphoryl chlorides, insulation reaction 1 hour, add 5-phenyl-1,3,4-oxadiazoles-2-mercaptan obtains S-sulfo-5-phenyl-1,3,4-oxadiazoles-(Z)-2-(2-amino-4-thiazole)-methoxyl group carbon back methylene radical oxygen imines acetic ester (compound 5), compound 4 and AVCA (gram oxime parent nucleus) compound 2 are at THF/ water, under triethylamine and DMF catalysis, obtain Cefixime Micronized methyl esters (compound 3).
PCT 2001098309 reports with MICA (cefixime side chain) and PCl5 reaction and makes MICA acyl chlorides (compound 6); chloride compounds 6 and 4-position diphenyl-methyl protecting group 7-AVCA parent nucleus (compound 11), obtain Cefixime Micronized (compound 1) through acidolysis.
CN 101812075 reports in MICA and Pentafluorophenol solvent acetone under triethylamine catalysis, obtain active substance (compound 9), (compound 9) and 7-AVCA, at acetone, obtain compound 3, compound 3 is through hydrolysis, and acid adjustment obtains (compound 1).
For above bibliographical information, we find under basic catalyst (as triethylamine etc.) effect, to carry out condensation reaction at synthetic Cefixime Micronized methyl esters process Raw MICA active ester and 7-AVCA by further investigation, the MICA active ester that above-mentioned bibliographical information adopts is 5-methyl isophthalic acid, 3,4-thiadiazoles active ester; 5-phenyl-1,3,4-oxadiazoles active ester and benzothiazole active ester.5-methyl isophthalic acid, 3,4-thiadiazoles active ester, 5-phenyl-1,3,4-oxadiazoles active ester and benzothiazole active ester are solid, remain in product and be difficult for removing, residual 5-methyl isophthalic acid, 3,4-thiadiazoles active ester, 5-phenyl-1,3,4-oxadiazoles active ester and benzothiazole active ester have carinogenicity.
Summary of the invention
The invention provides a kind of synthetic method of Cefixime Micronized, this synthetic method has adopted new synthetic intermediate, has avoided the use of the intermediate with carinogenicity.
A synthetic method for Cefixime Micronized, comprises the steps:
(1) there is amidate action in cefixime side chain sulphur phosphorus active ester and 7-AVCA, obtains Cefixime Micronized methyl esters;
The structure of described cefixime side chain sulphur 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 Micronized methyl esters is as shown in formula IV:
(2) step (1) obtains the reaction that is hydrolyzed of Cefixime Micronized methyl esters, obtains described Cefixime Micronized.
The present invention has adopted a kind of new MICA active ester-(z)-2-(2-amino-4-thiazolyl)-methoxyl group carbon back methylene radical acetimidic acid diethyl phosphinylidyne active ester (referred to as cefixime side chain sulphur phosphorus active ester) to synthesize Cefixime Micronized for starting raw material; the byproduct diethyl phosphoric acid carinogenicity finally obtaining is little; and because diethyl phosphoric acid is liquid; be easy to remove; residual few; this route steps is simple simultaneously, and yield is higher.
The reaction formula of step (1) is as follows:
In step (1), as preferably, described amidate action carries out in the mixed system of organic solvent and alkaline aqueous solution.As further preferred, the alkali in described alkaline aqueous solution is the mineral alkalis such as salt of wormwood, sodium carbonate, sheet alkali or potassium hydroxide, and more preferably sheet alkali, now, can avoid the intermediate Cefixime Micronized methyl esters obtaining to decompose effectively.The mass percentage concentration of alkaline aqueous solution is 1%～10%, and consumption makes in reaction process 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, comprising: tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methylene dichloride or chloroform etc.; As preferably, described organic solvent is tetrahydrofuran (THF), and the yield reacting while adopting tetrahydrofuran (THF) is the highest.The consumption of organic solvent, without strict especially requirement, fully dissolves raw material, is generally 5 times of left and right of described cefixime side chain sulphur phosphorus active ester quality.
In step (1), described amidate action carries out under the effect of the sulfite ion of catalytic amount, and described sulfurous acid ion comes from the aqueous solution and other aqueous solution that contains sulfurous acid ion salt etc. of sodium sulfite aqueous solution, S-WAT.As preferably, described amidate action carries out under the effect of sodium bisulfite, and wherein, the consumption of S-WAT is catalytic amount, in molar weight, is generally 1%～5% left and right of cefixime side chain sulphur phosphorus active ester.
In step (1), the temperature of described amidate action is 5～10 DEG C, and the reaction times is 5-7 hour.The control of temperature of reaction is comparatively crucial, and excess Temperature can cause the decomposition of product.
In step (1), described cefixime side chain sulphur phosphorus active ester (taking MICA acid) is 1～2:1 with the mol ratio of 7-AVCA, is preferably 1.6:1.
The concrete operations of step (1) are generally that various raw materials are dissolved in organic solvent successively, then under the condition of controlling temperature, drip described alkaline aqueous solution, can effectively suppress the generation of side reaction.
As preferably, after the amidate action in step (1) completes, carry out following aftertreatment:
After adding butylacetate fully to extract in reaction solution, the water separating contains Cefixime Micronized methyl esters, directly enters step (2) and is hydrolyzed.Now, the intermediate obtaining does not separate, directly " one kettle way " synthetic Cefixime Micronized, and reaction efficiency is high.
When research finds that step (1) adopts the aqueous solution that contains sulfurous acid ion and organic solvent (tetrahydrofuran (THF) or methylene dichloride equal solvent) to be mixed into reaction solvent, adopt mineral alkali as catalyzer, cefixime side chain sulphur phosphorus active ester and 7-AVCA carry out condensation good stability, the Cefixime Micronized methyl esters obtaining is difficult for being decomposed by alkali, and it is few to produce impurity, reaction color can not be deepened, the shortcoming that the organic base catalytic of having avoided bibliographical information to adopt reacts.Research is also found to continue to play protection reductive action as the aqueous solution that contains sulfite ion in next procedure hydrolysis and acid adjustment process, makes overall yield reach 200～210% (weight yields), more than product content >=99.4%.
The reaction formula of step (2) is as follows:
As preferably, in step (2), described hydrolysis reaction carries out under the effect of mineral alkali, and described mineral alkali is at least one in sodium hydroxide, potassium hydroxide, saleratus and sodium bicarbonate.As most preferably, described mineral alkali is the mixture of sodium hydroxide and sodium bicarbonate, and mass ratio is 1～2:1, is preferably 1.4:1, and now, hydrolysis reaction efficiency is high, and side reaction is few.In specific operation process, mineral alkali can be dissolved in (consumption of water is generally 3～6 times of mineral alkali quality) in water, and then join in Cefixime Micronized methyl esters and react, not need separately to add again other organic solvent.
The hydrolysis reaction temperature control of step (2) is at 0～15 DEG C, and the reaction times monitors by HPLC, and while being less than 0.1% to intermediate content, reaction finishes.
As preferably, in step (2), after described hydrolysis reaction completes, carry out following aftertreatment:
Regulating the pH of reaction solution is 4.5～5, then adds isopropylcarbinol, then regulates pH to 2.0-2.5, and-5 DEG C～0 DEG C crystallization, the solid leaching obtains described Cefixime Micronized after washing, being dried.
Find by product last handling process having been carried out to large quantity research: adopt organic alcohol solvent to substitute lower boiling acetone (Bp:56.1 DEG C) at product Crystallization Process, can effectively reduce product centrifugal after with the loss of mother liquor, improved product yield and solvent recovering rate; Adopt iso-butanol solvent to contribute to the solubleness of Cefixime Micronized impurity in water simultaneously, can further improve the purity of product, reduce impurity and bring in product.More than making product content >=99.4%.And also can avoid adopting a large amount of an alkali metal salts easily to bringing inorganic salt in product in CN101016305A patent report, cause that product salt and moisture content are higher, cause the bad problem of product purity and stability.
As preferably, the preparation method of described cefixime side chain sulphur phosphorus active ester is as follows:
Under the effect of tri-n-butylamine, MICA and o,o-diethylthiophosphoryl chloride carry out acyl vulcanization reaction and obtain described cefixime side chain sulphur phosphorus active ester;
The structure of described MICA is suc as formula shown in (V):
Reaction formula is as follows:
As preferably, reaction is carried out under the effect of the triethylene diethylamine of catalytic amount, 0.1～0.5% of the molar weight that consumption is MICA.
Described o,o-diethylthiophosphoryl chloride: MICA: the mol ratio of tri-n-butylamine is 1.2:1:1, o,o-diethylthiophosphoryl chloride adopts the mode dripping 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 methylene dichloride, and after react, decompression is removed enriched material that methylene dichloride obtains and directly entered the amidate action of step (1) described in carrying out.The cefixime side chain sulphur phosphorus active ester that this preparation method obtains does not need can carry out subsequent reactions through extra purification.
The present invention is compared with existing bibliographical information technology, and first the present invention, in synthetic Cefixime Micronized methyl esters process, has adopted the aqueous solution and the organic solvent (tetrahydrofuran (THF) or methylene dichloride equal solvent) that contain sulfurous acid ion to be mixed into reaction solvent.Ensure that Cefixime Micronized methyl esters building-up process color can not deepen, do not needed decolouring directly just can carry out lower one-step hydrolysis reaction; Reduce decolouring number of times, improved the shade and quality of product.
The second, the ethyl acetate (bP:77.14 DEG C) that substitutes bibliographical information at extraction, hydrolytic process process using N-BUTYL ACETATE of the present invention (bp:126.14 DEG C) is solvent, has solved ethyl acetate solvent and has reclaimed low problem.
The 3rd, adopt iso-butanol solvent to substitute lower boiling acetone (Bp:56.1 DEG C) at product Crystallization Process, reduce the number of dropouts with mother liquor after product is centrifugal; Product yield and solvent recovering rate are improved; Solve in CN101016305A patent report simultaneously and adopted a large amount of an alkali metal salts easily to bringing a large amount of inorganic salt in product, caused that product moisture content is higher, caused product purity and stablize bad problem.
Finally, the present invention is " one kettle way " synthetic Cefixime Micronized method, obtains that product purity is high, good stability, color be good, and technique weight total recovery can arrive more than 200%.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
(1) in 2000mL four-hole reaction flask, add 150g MICA (0.579mol), add successively again 400ml methylene dichloride, 0.2g triethylene diethylamine (CAS:280-57-9) and 107.3g tri-n-butylamine (0.579mol), stirring cools to-5 DEG C, and controls temperature of charge.Drip o,o-diethylthiophosphoryl chloride 132g (0.7mol), dropwise, be incubated 0 DEG C～5 DEG C reactions 2～3 hours.Temperature control is at 20 DEG C, P=-0.95MPa, and decompression low temperature steams except dichloromethane solvent, obtains light safran oily cefixime side chain sulphur phosphorus active ester 200g, yield 84%.
(2) the safran cefixime side chain sulphur phosphorus active ester that step (1) obtains, adds 900mL tetrahydrofuran (THF) stirring and dissolving, adds 80g 7-AVCA (0.353mol), adds 0.7g sodium bisulfite.Drip 100mL aqueous sodium hydroxide solution (configuration of NaOH 18.4g+700mL water obtains), 5～10 DEG C of holding temperatures, insulation reaction 6 hours.After reaction finishes, add butylacetate 800mL, stir 30 minutes, then leave standstill 60 minutes, layering, collects lower aqueous layer.Water layer adds 400mL n-butyl acetate extraction once again, stirs 20 minutes, leaves standstill 60 minutes, layering, and lower floor's water is collected hydrolysis bottle.
(3) water that step (2) is collected cools to 0 DEG C, add mixed ammonium/alkali solutions (to prepare in advance mixed ammonium/alkali solutions: 34.5gNaOH and 24.5g sodium bicarbonate are joined in 180mL purified water, stir molten clear and be chilled in advance 0 DEG C～5 DEG C, for subsequent use), finish, stir 15min at 0 DEG C～15 DEG C, sampling HPLC detects intermediate < 0.1%.Add 18% hydrochloric acid 100mL, regulation system PH is 4.5～5.0, and temperature control is at 3 DEG C～15 DEG C.Add the isopropylcarbinol of 800mL, with 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 and stir insulation 2.5-3 hour, blowing rejection filter, with appropriate purified water washing, to moisture approximately 10.6%, obtains the Cefixime Micronized of white crystalline powder at 40 DEG C～45 DEG C temperature drying under reduced pressure, and output is 162g; Weight total recovery is 202%; HPLC=99.41%, finds no diethyl phosphoric acid residual after testing.Characterization data is as follows:
HR-MS(m/z):454.0487[M
+]。
IR (KBr) ν (cm
-1): 3304 (NH, NH
2), 3300～2500 (carboxyl-OH), 2932 (CH
2), 1769 (beta-lactam-C=O), 1666 (carboxyl-C=O), 1634 (thiazole ring imines C=N), 1537 (C=C), 1082,1040 (C-N).
1h NMR (600MHz, Methanol-d
4): 3.62 (d, J=17.4Hz, 1H, SCH
2), 3.78 (d, J=17.4Hz, 1H, SCH
2), 4.76 (s, 2H, OCH
2), 5.20 (d, J=4.8Hz, 1H, 6-CH), 5.31 (d, J=11.4Hz, 1H, vinyl 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-d
4): 24.9 (2-C), 59.1 (6-C), 60.4 (7-C), 71.9 (OCH
2), 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
Make safran cefixime side chain sulphur phosphorus active ester according to (1) step in above-described embodiment 1, add 900mL tetrahydrofuran (THF) stirring and dissolving, add 80g 7-AVCA (0.353), drip 100mL aqueous sodium hydroxide solution (configuration of NaOH 18.4g+700mL water obtains), 5～10 DEG C of holding temperatures, insulation reaction 6 hours.Reaction finishes to add ethyl acetate 800mL, stirs 30 minutes, leaves standstill 60 minutes, layering; Lower aqueous layer is collected.Water layer adds 400mL ethyl acetate to extract once again.Stir 20 minutes.Leave standstill 60 minutes, layering; Lower floor's water is collected hydrolysis bottle.
Water cools to 0 DEG C, add mixed ammonium/alkali solutions (to prepare in advance mixed ammonium/alkali solutions: 34.5gNaOH and 24.5g sodium bicarbonate are joined in 180mL purified water, stir molten clear and be chilled in advance 0 DEG C～5 DEG C, for subsequent use), finish, stir 15min at 0 DEG C～15 DEG C, sampling HPLC detects intermediate < 0.1%.Add 18% hydrochloric acid 100mL, regulation system PH is 4.5～5.0, and temperature control is at 3 DEG C～15 DEG C.Add the acetone of 800mL, with 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 and stir insulation 2.5-3 hour, blowing rejection filter, with appropriate purified water washing, to moisture approximately 10.6%, obtains the Cefixime Micronized of yellow crystalline powder at 40 DEG C～45 DEG C drying under reduced pressure, and output is 150g; Weight total recovery is 187%; HPLC=99.02%, finds no diethyl phosphoric acid residual after testing.
Embodiment 3
The safran cefixime side chain sulphur phosphorus active ester that in above-mentioned example 1, (1) step makes, add 900mL tetrahydrofuran (THF) stirring and dissolving, add 80g 7-AVCA (0.353), drip 100mL aqueous sodium hydroxide solution (configuration of NaOH 18.4g+700mL water obtains), 5～10 DEG C of holding temperatures, insulation reaction 6 hours.Reaction finishes to add butylacetate 800mL, stirs 30 minutes, leaves standstill 60 minutes, layering; Lower aqueous layer is collected.Water layer adds 400mL n-butyl acetate extraction once again.Stir 20 minutes.Leave standstill 60 minutes, layering; Lower floor's water is collected hydrolysis bottle.
(3) water cools to 0 DEG C, add mixed ammonium/alkali solutions (to prepare in advance mixed ammonium/alkali solutions: 34.5gNaOH and 24.5g sodium bicarbonate are joined in 180mL purified water, stir molten clear and be chilled in advance 0 DEG C～5 DEG C, for subsequent use), finish, stir 15min at 0 DEG C～15 DEG C, sampling HPLC detects intermediate < 0.1%.Add 18% hydrochloric acid 100mL, regulation system PH is 4.5～5.0, and temperature control is at 3 DEG C～15 DEG C.Add the isopropylcarbinol of 800mL, with 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 and stir insulation 2.5-3 hour, blowing rejection filter, with appropriate purified water washing, to moisture approximately 10.6%, obtains the Cefixime Micronized of yellow crystalline powder at 40 DEG C～45 DEG C drying under reduced pressure, and output is 158g; Weight total recovery is 197%; HPLC=98.78%, finds no diethyl phosphoric acid residual after testing.
Claims (10)
1. a synthetic method for Cefixime Micronized, is characterized in that, comprises the steps:
(1) there is amidate action in cefixime side chain sulphur phosphorus active ester and 7-AVCA, obtains Cefixime Micronized methyl esters;
The structure of described cefixime side chain sulphur 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 the reaction that is hydrolyzed of Cefixime Micronized methyl esters, obtains described Cefixime Micronized.
2. the synthetic method of Cefixime Micronized according to claim 1, is characterized in that, in step (1), described amidate action carries out in the mixed system of organic solvent and alkaline aqueous solution.
3. the synthetic method of Cefixime Micronized according to claim 2, is characterized in that, in step (1), described organic solvent is tetrahydrofuran (THF).
4. the synthetic method of Cefixime Micronized according to claim 1, is characterized in that, in step (1), described amidate action carries out under the effect of sodium bisulfite.
5. according to the synthetic method of the Cefixime Micronized described in claim 1～4 any one, it is characterized in that, after the amidate action in step (1) completes, carry out following aftertreatment:
After adding butylacetate fully to extract in reaction solution, the water separating contains Cefixime Micronized methyl esters, directly enters step (2) and is hydrolyzed.
6. the synthetic method of Cefixime Micronized according to claim 1, it is characterized in that, in step (2), described hydrolysis reaction carries out under the effect of mineral alkali, and described mineral alkali is at least one in sodium hydroxide, potassium hydroxide and sodium bicarbonate.
7. the synthetic method of Cefixime Micronized according to claim 1, is characterized in that, in step (2), after described hydrolysis reaction completes, carries out following aftertreatment:
Regulating the pH of reaction solution is 4.5～5, then adds isopropylcarbinol, then regulates pH to 2.0-2.5, and-5 DEG C～0 DEG C crystallization, the solid leaching obtains described Cefixime Micronized after washing, being dried.
8. the synthetic method of Cefixime Micronized according to claim 1, is characterized in that, the preparation method of described cefixime side chain sulphur phosphorus active ester is as follows:
Under the effect of tri-n-butylamine, MICA reacts with o,o-diethylthiophosphoryl chloride and obtains described cefixime side chain sulphur phosphorus active ester.
9. the synthetic method of Cefixime Micronized according to claim 8, is characterized in that, prepares the reaction of cefixime side chain sulphur phosphorus active ester and carries out under the effect of the triethylene diethylamine of catalytic amount.
10. the synthetic method of Cefixime Micronized according to claim 8 or claim 9, it is characterized in that, prepare the reaction of cefixime side chain sulphur phosphorus active ester carries out in methylene dichloride, after having reacted, decompression is removed enriched material that methylene dichloride obtains and is directly entered step (1) and carry out described amidate action.
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