CN103709179B - A kind of synthesizing progress method of cefmetazole sodium - Google Patents
A kind of synthesizing progress method of cefmetazole sodium Download PDFInfo
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- CN103709179B CN103709179B CN201310696053.7A CN201310696053A CN103709179B CN 103709179 B CN103709179 B CN 103709179B CN 201310696053 A CN201310696053 A CN 201310696053A CN 103709179 B CN103709179 B CN 103709179B
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- 0 C[n]1nnnc1SCC(CS[C@@]1C2NC(C(Cl)Cl)=O)=C(*)N1C2=O Chemical compound C[n]1nnnc1SCC(CS[C@@]1C2NC(C(Cl)Cl)=O)=C(*)N1C2=O 0.000 description 4
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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
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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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 kind of method preparing cefmetazole sodium, the method is with 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt is for initial feed, through silanization, halogenation, methoxy, secondary silanization obtains 7 β-chloracetyl amido-7 α-methoxyl group-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid, then chain extending reaction is carried out to it, pass through into sour salify, obtain cefmetazole sodium.The method that the present invention prepares cefmetazole sodium has yield high (55 ~ 65%), product purity is high, utilize 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt replace 7-MAC be starting raw material, raw material sources is convenient, cheap, environmentally friendly, product purity is high, is applicable to the advantages such as suitability for industrialized production.
Description
Technical field the invention belongs to the preparation field of cephalosporin compound in medicine synthesis technique, particularly a kind of synthesizing progress method of cefmetazole sodium.
Background technology cefmetazole sodium, its English name is CefmetazoleSodium, chemical name is: (6R, 7S)-7-[2-[(cyanogen methyl) sulfo-] acetamido]-7-methoxyl group-3-[[(1-methyl isophthalic acid H-tetrazolium-5-base) sulfo-] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt, molecular formula: C
15h
16n
7naO
5s
3, molecular weight: 493.52, structural formula is:
Cefmetazole sodium is second generation cephalosporin, and be the semi-synthetic cephalic flexure mycin class microbiotic that Japan three is total to company's initiative, it has good stability to the wide spectrum beta-lactam that negative bacillus produces, and has good anti-microbial activity to bacteroides fragilis.The negative bacillus such as intestinal bacteria, klebostiella pneumoniae, Proteus mirabilis, Shigella, Salmonella have good susceptibility to this product; S. aureus L-forms, A group Hemolytic streptococcus, Bramhamella Catarrhalis are extremely sensitive to this product; Enterobacter, Rhodopseudomonas, Methicillin-resistant Staphylococcus aureus, streptococcus pneumoniae, meningococcus be insensitive or resistance to this product.Clinically for the microbial respiratory system infection of sensitivity, biliary tract infection, urinary system infection, Obstetric and Gynecologic Department bacteriological infection, skin soft-tissue infection and Post operation preventing infection etc.
Quiet and Li Xueyan discloses in volume the 4th phase (in December, 2006) at " Hebei University of Science and Technology's journal " the 27th and synthesizes cefmetazole with 7-ACA, Tosyl chloride for main raw material; reaction point four steps are carried out; total recovery is 75%; although this method yield still can; but material cost is higher, and be unfavorable for protection of the environment.
Application number be 200910014972.5 Chinese patent disclose a kind of cefmetazole sodium compound and preparation method thereof, with 7 beta-amino-7-methoxyl group-3-(1-methyl isophthalic acid H-5-thiomethyls)-3-cephem-4-benzyl carboxylate and cyanogen methyl sulphur sodium acetate hybrid reaction under Tosyl chloride existent condition, generate cefmetazole acid, add sodium hydroxide, the cefmetazole sodium of system.The method was owing to employing strong sodium hydroxide, and cause impurity too much, content is on the low side, and color is partially dark, so the synthesis result of product is unsatisfactory.
Application number be 201010116167.6 Chinese patent disclose a kind of preparation method of cefmetazole sodium, cefmetazole benzyl ester is produced with amino-7 α-methoxyl group-3-[(1-methyl isophthalic acid H-tetrazolium-5-base) the thiomethyl]-3-cephem-4-diphenylmethyl carboxylate of 7 β and cyanogen first mercaptoacetyl chlorine, take off benzyl ester with iron trichloride diethyl ether solution and obtain cefmetazole acid, cefmetazole sodium is changed into again with sodium bicarbonate, yield reaches 58 ~ 62%, but product purity is low, only have 92%.
Application number is the process for purification that the Chinese patent of 201010100852.X discloses a kind of cefmetazole sodium, cefmetazole sodium compound passes through acid-base reaction, macroporous resin and charcoal absorption, to reach purifying object, add production stage, cause total recovery to reduce, after macroporous resin adsorption cefmetazole, with a large amount of solvent wash-out, aftertreatment is complicated, considerably increases production cost.
At present, the most popular method of domestic scale operation cefmetazole sodium adopts 7-MAC to be starting raw material, but have that raw materials cost is high, toxicity large, complex process, the shortcomings such as synthesized product yield and product purity are all on the low side.
Summary of the invention the object of this invention is to provide a kind of method preparing cefmetazole sodium, and this preparation method has yield high (reaching 55 ~ 65%), and cost is low, environmentally friendly, and good product purity (reaching more than 99%), is applicable to the advantages such as suitability for industrialized production.
For achieving the above object, the present invention adopts following technical scheme:
The total chemical equation of the present invention is as follows:
A kind of synthetic method of cefmetazole sodium of formula (VIII) structure,
The synthetic method of described cefmetazole sodium comprises the following steps:
A, silanization: 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, i.e. compound (I), add organic solvent wherein and be made into the solution that weight percent is 15 ~ 20%, after adding silylating reagent, room temperature reaction 1 ~ 2h, obtain silanization intermediate (II);
B, halogenation: by silanization intermediate (II), be cooled to-20 ~-80 DEG C, add the solution that organic bases and weight percent are the halide reagent of 3 ~ 5%, after stirring reaction 1 ~ 4h, obtain halogenation intermediate (III);
C, methoxy: in halogenation intermediate (III), add the methanol solution that weight percent is the first oxidising agent of 15 ~ 30%, after stirring reaction 0.5 ~ 2h, go out to react with You Ji Suan temper and regulate pH to 5 ~ 7, concentrating under reduced pressure, add after DMF carries out concentrated displacement, add ethyl acetate and obtain first oxidation intermediates (IV);
D, secondary silanization: in first oxidation intermediates (IV), add secondary silylating reagent, be 10 ~ 50 DEG C of stirring reaction 1 ~ 2h in temperature, the purified water adding 0 ~ 20 DEG C in reaction solution stirs 1 ~ 2h, leave standstill 2 ~ 3 little layereds, removing water layer, activated carbon decolorizing 0.5 ~ 2h is added in organic phase, cross and filter gac, filtrate obtains 7 β-chloracetyl amido-7 α-methoxyl group-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase through concentrating under reduced pressure)-3-cephem-4-carboxylic acid, i.e. compound (V);
The chain extending reaction of e, compound (V): S-cyanogen methyl-isothiourea hydrochloride is dissolved in DMF and is made into the solution that weight percent is 30 ~ 50%, be cooled to 0 ~-40 DEG C, add methanol solution, stirring reaction 1 ~ 2h that weight percent is 15 ~ 30% sodium methylates or lithium methoxide, obtain cefmetazole acid side chain solution;
Compound (V) is dissolved in ethyl acetate, be cooled to 0 ~-40 DEG C, add above-mentioned gained cefmetazole acid side chain solution, after stirring reaction 1 ~ 2h, 0 ~ 20 DEG C of purified water is added in reaction solution, with inorganic acid for adjusting pH to 1 ~ 3, then after carrying out standing 1 ~ 2 hour, layering, removing aqueous phase, activated carbon decolorizing 0.5 ~ 2h is added to organic phase, cross and filter gac, the product that filtrate obtains after concentrating under reduced pressure, dissolve with DMF, and regulate pH to 4 ~ 7 with organic bases, add cefmetazole amine salt crystal seed, stirring and crystallizing, remove filtrate after filtration again, drying is carried out to the crystal of separating out, obtained cefmetazole amine salt, i.e. compound (VI),
F, compound (VI) is added in water and ethyl acetate, be cooled to 0 ~ 10 DEG C, with inorganic acid for adjusting pH to 1 ~ 3, then layering is carried out, removing aqueous phase, by organic phase with after purified water washing, adds activated carbon decolorizing 0.5 ~ 2h in organic phase, cross and filter gac, filtrate regulates pH to 6 ~ 9 with mineral alkali, adds ethyl acetate, methyl iso-butyl ketone (MIBK), with inorganic acid for adjusting pH to 1 ~ 3, add cefmetazole acid crystal seed, stirring and crystallizing, crosses the mother liquor after filtering crystallization, dry crystal of separating out, obtained cefmetazole acid, i.e. compound (VII);
G, compound (VII) added in purified water, is cooled to 0 ~ 20 DEG C, regulate pH to 4 ~ 6 with mineral alkali, add activated carbon decolorizing 0.5 ~ 2h, cross and filter gac, filtrate through Freeze Drying Equipment freeze-drying, obtained cefmetazole sodium and compound (VIII).
In reactions steps, mineral acid used is one or more the mixture in hydrochloric acid, phosphoric acid, sulfuric acid; Organic bases used is one or more the mixture in triethylamine, quinoline, pyridine, dicyclohexyl amine, N, N-dimethyl benzylamine; Mineral alkali used is one or more the mixture in sodium bicarbonate, sodium carbonate, sodium hydroxide;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and organic bases mol ratio be 1:1 ~ 2;
Organic solvent used in described step (a) is one or more the mixture in methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, tetrahydrofuran (THF); Silylating reagent used is one or more the mixture in trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, the two trimethylsilyl ethanamide of N, O-, hexamethyldisilazane;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and silylating reagent mol ratio be 1:1 ~ 3.
Halide reagent used in described step (b) is one or more the mixture in phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, sulfur oxychloride;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and organic bases mol ratio be 1:1 ~ 2;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and halide reagent mol ratio be 1:0.5 ~ 2.0.
First oxidising agent used in described step (c) is one or more mixture of lithium methoxide, sodium methylate or potassium methylate; Organic acid used is one or both mixture of formic acid, acetic acid;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, first oxidising agent mol ratio be 1:10 ~ 17;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, DMF: the weight ratio of ethyl acetate is 1:2 ~ 10:5 ~ 15.
Secondary silylating reagent used in described step (d) is one or more the mixture in trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, the two trimethylsilyl ethanamide of N, O-, hexamethyldisilazane;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and secondary silylating reagent mol ratio be 1:5 ~ 8;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, purified water, activated carbon weight is than for 1:5 ~ 10:0.05 ~ 0.2.
In described step (e), described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, S-cyanogen methyl-isothiourea hydrochloride, sodium methylate or lithium methoxide mol ratio be 1:1 ~ 4:2 ~ 8;
Described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, ethyl acetate, purified water, gac, DMF, cefmetazole amine salt crystal seed weight ratio be 1:1 ~ 4:5 ~ 10:0.05 ~ 0.2:0.5 ~ 2.0:0.001 ~ 0.005.
In described step (f), cefmetazole amine salt, water, ethyl acetate weight ratio are 1:5 ~ 15:5 ~ 15.
In described step (f), cefmetazole amine salt, water, gac, ethyl acetate, methyl iso-butyl ketone (MIBK), cefmetazole acid crystal seed weight ratio are 1:5 ~ 15:0.05 ~ 0.2:0.5 ~ 3:0.5 ~ 3:0.001 ~ 0.005.
In described step (g), the weight ratio of cefmetazole acid used, purified water and gac is 1:2 ~ 5:0.05 ~ 0.2.
CMT is 7 β-chloracetyl amido-7 α-methoxyl group-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase) English of-3-cephem-4-carboxylic acid writes a Chinese character in simplified form;
DCT is 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase) English of-3-cephem-4-carboxylic acid triethylamine salt and compound (I) writes a Chinese character in simplified form;
DCT carries out substitution reaction with 5-sulfydryl-1-methyl tetrazole by 7-amino-cephalosporanic acid under boric carbonic acid dimethyl ester complex trifluoride exists, then carries out acylation reaction with dichloroacetyl chloride, and is prepared from triethylamine salify;
S-cyanogen methyl-isothiourea hydrochloride in step (e) has been chain extension effect in the reaction, and its preparation method is formed by chloromethyl cyanide and thiocarbamide direct polycondensation;
In this synthesis, other pharmaceutical chemicalss used are all purchased in Chemical Reagent Co., Ltd., Sinopharm Group.
Beneficial effect of the present invention is as follows:
1. adopt synthetic route of the present invention, use DCT to replace 7-MAC to be starting raw material, reduce material cost, total cost reduces by more than 20%.
2. adopt synthetic route of the present invention, carry out chlorination reaction with phosphorus pentachloride under cryogenic by intermediate DCT, carry out first oxidizing reaction with the methanol solution of sodium methylate or lithium methoxide, connect 7 methoxyl groups, advantage is that impurity growing amount is little, is conducive to improving finished product purity.
3. adopt synthetic route of the present invention, at low temperatures, first cefmetazole acid side chain solution is obtained by reacting with sodium methylate or lithium methoxide methanol solution by S-cyanogen methyl-isothiourea hydrochloride, and then carry out condensation with intermediate CMT, and with amine salt form crystallization, decrease the impurity level being brought into the next step by intermediate, finished product quality and stability are improved.
4. the present invention regulates the method for intermediate cefmetazole amine salt pH by mineral acid and mineral alkali, carry out of cefmetazole in organic phase and aqueous phase is shifted, by simply extracting, washing and the mode such as carbon decoloring, reach the object of purifying cefmetazole acid, the technique adopted, mild condition, simple to operate, products obtained therefrom yield is high, purity good.
5. the single maximum contaminant of cefmetazole sodium finished product obtained by the present invention and impurity summation are reduced to below 0.3% and 1.0% by 0.5% and 2.0% respectively, and quality product significantly improves.
6. a kind of method preparing cefmetazole sodium of the present invention, have yield high (reaching 55 ~ 65%), cost is low, environmentally friendly, and good product purity (reaching more than 99%), is applicable to the advantages such as suitability for industrialized production.
Wherein 7-MAC is cefoxitin-cycloserine-fructose agar, and namely the English of amino-7 α-methoxyl group-3-[(1-methyl isophthalic acid H-tetrazolium-5-base) the thiomethyl]-3-cephem-4-diphenylmethyl carboxylate of 7 β is write a Chinese character in simplified form.
Embodiment, below in conjunction with specific embodiment, sets forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.In addition should be understood that those skilled in the art can make various change or amendment to the present invention, and these equivalent form of values fall within the application's claims limited range equally after the content of having read the present invention's instruction.
Embodiment 1
(1) a, b, c, d tetra-steps, i.e. the preparation of CMT
350g methylene dichloride is added in 22g (0.041mol) DCT, add 10.6g (0.069mol) bromotrimethylsilane, after room temperature carries out Silanization reaction 1h, be cooled to-80 DEG C, add 8.2g (0.081mol) triethylamine, add the phosphorus pentachloride dichloromethane solution of 340g (0.065mol) 4wt%, carry out halogenating reaction, after stirring reaction 4h, add the lithium methoxide methanol solution of 175g (0.691mol) 15wt%, carry out first oxidizing reaction, after stirring reaction 2h, Yong Yi Suan temper goes out to react and regulates pH to 5 ~ 7, concentrating under reduced pressure, add 100gN, after dinethylformamide carries out reconcentration, resistates adds 200g ethyl acetate, add 42g (0.274mol) bromotrimethylsilane and carry out secondary silanization, 50 DEG C of stirring reaction 1h, reaction solution adds the water of 150g0 ~ 5 DEG C, layering, organic phase adds 2g activated carbon decolorizing 30min, filter, filtrate reduced in volume obtains CMT.
The chain extending reaction of e, CMT, the i.e. preparation of cefmetazole dicyclohexyl amine salt
In 13.9g (0.092mol) S-cyanogen methyl-isothiourea hydrochloride, add 35gN, dinethylformamide, be cooled to-40 DEG C, add the methanol solution of 28g (0.221mol) 30% lithium methoxide, after stirring reaction 2h, obtain cefmetazole acid side chain solution, for subsequent use; To in prepared CMT, add 80g ethyl acetate, be cooled to-40 DEG C, add cefmetazole acid side chain solution, after stirring reaction 2h, add 150g0 ~ 5 DEG C purified water, with 33% salt acid for adjusting pH to 1 ~ 3, layering organic phase adds 1.5g activated carbon decolorizing 2h, filters, filtrate reduced in volume, add 30gN, dinethylformamide, and regulate pH to 4 ~ 7 with dicyclohexyl amine, add 0.04g cefmetazole dicyclohexyl amine salt crystal seed, stirring and crystallizing, more after filtration, dry, obtained cefmetazole dicyclohexyl amine salt 19.2g, yield 72.2%.
The preparation of f, cefmetazole acid
10g (0.015mol) cefmetazole dicyclohexyl amine salt is added in 90g purified water and 90g ethyl acetate, be cooled to 0 ~ 10 DEG C, with 25% phosphorus acid for adjusting pH to 1 ~ 3, layering, organic phase 100g purified water is washed, layering organic phase adds 1.5g activated carbon decolorizing 30min, filters, and filtrate regulates pH to 6 ~ 9 with 10% sodium hydrogen carbonate solution, add 11g ethyl acetate, 22g methyl iso-butyl ketone (MIBK), with 25% phosphorus acid for adjusting pH to 1 ~ 3, add 0.03g cefmetazole acid crystal seed, stirring and crystallizing, filter, drying, obtained cefmetazole acid 5.8g, yield 80.3%.
The preparation of g, cefmetazole sodium
Added in 60g purified water by 20g cefmetazole acid, be cooled to 0 ~ 5 DEG C, add sodium bicarbonate, regulate pH to 4 ~ 6, add 1.5g activated carbon decolorizing 30min, after filtering, freeze-drying obtains cefmetazole sodium 20.4g, yield 97.5%.
Embodiment 2
(1) a, b, c, d tetra-steps, i.e. the preparation of CMT
400g trichloromethane is dissolved in by 22g (0.041mol) DCT, add 7.5g (0.069mol) trimethylchlorosilane, after room temperature carries out Silanization reaction 2h, be cooled to-50 DEG C, add 10.5g (0.081mol) quinoline, add the phosphorus pentachloride chloroform soln of 350g (0.050mol) 3wt%, carry out halogenating reaction, after stirring reaction 3h, add the methanol solution of sodium methylate of 180g (0.666mol) 20wt%, carry out first oxidizing reaction, after stirring reaction 1h, go out to react with Jia Suan temper and regulate pH to 5 ~ 7, concentrating under reduced pressure, add 150gN, after dinethylformamide carries out reconcentration, resistates adds 250g ethyl acetate, add 30g (0.276mol) trimethylchlorosilane and carry out secondary silanization, 30 DEG C of stirring reaction 2h, reaction solution adds the water of 200g5 ~ 10 DEG C, layering, organic phase adds 2g activated carbon decolorizing 1h, filter, filtrate reduced in volume obtains CMT.
The chain extending reaction of e, CMT, the i.e. preparation of cefmetazole dimethylbenzyl amine salt
In 15.2g (0.100mol) S-cyanogen methyl-isothiourea hydrochloride, add 45gN, dinethylformamide, be cooled to-20 DEG C, add the methanol solution of 40g (0.148mol) 20wt% sodium methylate, after stirring reaction 1h, obtain cefmetazole acid side chain solution, for subsequent use; To in prepared CMT, add 70g ethyl acetate, be cooled to-20 DEG C, add cefmetazole acid side chain solution, after stirring reaction 1h, add 180g5 ~ 10 DEG C purified water, with 18% salt acid for adjusting pH to 1 ~ 3, layering organic phase adds 3.0g activated carbon decolorizing 30min, filter, filtrate reduced in volume, adds 35gN, dinethylformamide, and with N, N-dimethyl benzylamine regulates pH to 4 ~ 7, adds 0.05g cefmetazole dimethylbenzyl amine salt crystal seed, stirring and crystallizing, again after filtration, drying, obtained cefmetazole dimethylbenzyl amine salt 17.6g, yield 71.3%.
The preparation of f, cefmetazole acid
10g (0.016mol) cefmetazole dimethylbenzyl amine salt is added in 120g purified water and 120g ethyl acetate, be cooled to 0 ~ 10 DEG C, with 50% salt acid for adjusting pH to 1 ~ 3, layering, organic phase 120g purified water is washed, layering organic phase adds 2g activated carbon decolorizing 1h, filters, and filtrate regulates pH to 6 ~ 9 with 5% sodium carbonate solution, add 15g ethyl acetate, 30g methyl iso-butyl ketone (MIBK), with 50% phosphorus acid for adjusting pH to 1 ~ 3, add 0.05g cefmetazole acid crystal seed, stirring and crystallizing, filter, drying, obtained cefmetazole acid 6.4g, yield 82.4%.
The preparation of g, cefmetazole sodium
Added in 50g purified water by 20g cefmetazole acid, be cooled to 5 ~ 10 DEG C, add sodium bicarbonate, regulate pH to 4 ~ 6, add 2g activated carbon decolorizing 1h, after filtering, freeze-drying obtains cefmetazole sodium 20.0g, yield 95.5%.
Embodiment 3
(1) a, b, c, d tetra-steps, i.e. the preparation of CMT
440g trichloromethane is added in 22g (0.041mol) DCT, add 13.8g (0.069mol) Iodotrimethylsilane, after room temperature carries out Silanization reaction 1h, be cooled to-30 DEG C, add 6.4g (0.081mol) pyridine, add the phosphorus pentachloride chloroform soln of 340g (0.065mol) 4wt%, carry out halogenating reaction, after stirring reaction 2h, add the lithium methoxide methanol solution of 160g (0.632mol) 15wt%, carry out first oxidizing reaction, after stirring reaction 1h, Yong Yi Suan temper goes out to react and regulates pH to 5 ~ 7, concentrating under reduced pressure, add 120gN, after dinethylformamide carries out reconcentration, resistates adds 240g ethyl acetate, add 55g (0.275mol) Iodotrimethylsilane and carry out secondary silanization, 40 DEG C of stirring reaction 2h, reaction solution adds the water of 180g5 ~ 10 DEG C, layering, organic phase adds 1.8g activated carbon decolorizing 1h, filter, filtrate reduced in volume obtains CMT.
The chain extending reaction of e, CMT, the i.e. preparation of cefmetazole dicyclohexyl amine salt
In 14.5g (0.096mol) S-cyanogen methyl-isothiourea hydrochloride, add 40gN, dinethylformamide, be cooled to-10 DEG C, add the methanol solution of 55g (0.217mol) 15wt% lithium methoxide, after stirring reaction 2h, obtain cefmetazole acid side chain solution, for subsequent use; To in prepared CMT, add 85g ethyl acetate, be cooled to-10 DEG C, add cefmetazole acid side chain solution, after stirring reaction 1h, add 170g5 ~ 10 DEG C purified water, with 18% salt acid for adjusting pH to 1 ~ 3, layering organic phase adds 2.5g activated carbon decolorizing 30min, filter, filtrate reduced in volume, adds 40gN, dinethylformamide, and regulate pH to 4 ~ 7 with dicyclohexyl amine, add 0.06g cefmetazole dicyclohexyl amine salt crystal seed, stirring and crystallizing, again after filtration, drying, obtained cefmetazole dicyclohexyl amine salt 19.8g, yield 74.5%.
The preparation of f, cefmetazole acid
10g (0.016mol) cefmetazole dicyclohexyl amine salt is added in 110g purified water and 110g ethyl acetate, be cooled to 0 ~ 10 DEG C, with 50% phosphorus acid for adjusting pH to 1 ~ 3, layering, organic phase 110g purified water is washed, layering organic phase adds 1.2g activated carbon decolorizing 2h, filters, and filtrate regulates pH to 6 ~ 9 with 5% sodium carbonate solution, add 10g ethyl acetate, 20g methyl iso-butyl ketone (MIBK), with 40% phosphorus acid for adjusting pH to 1 ~ 3, add 0.04g cefmetazole acid crystal seed, stirring and crystallizing, filter, drying, obtained cefmetazole acid 6.0g, yield 83.1%.
The preparation of g, cefmetazole sodium
Added in 55g purified water by 20g cefmetazole acid, be cooled to 0 ~ 5 DEG C, add sodium carbonate, regulate pH to 4 ~ 6, add 1.0g activated carbon decolorizing 2h, after filtering, freeze-drying obtains cefmetazole sodium 19.8g, yield 94.6%.
Embodiment 4
(1) a, b, c, d tetra-steps, i.e. the preparation of CMT
350g tetracol phenixin is added in 22g (0.041mol) DCT, add 8.5g (0.078mol) trimethylchlorosilane, after room temperature carries out Silanization reaction 1h, be cooled to-60 DEG C, add 8.0g (0.062mol) quinoline, add the phosphorus pentachloride carbon tetrachloride solution of 300g (0.072mol) 5wt%, carry out halogenating reaction, after stirring reaction 2h, add the methanol solution of sodium methylate of 110g (0.611mol) 30wt%, carry out first oxidizing reaction, after stirring reaction 30min, go out to react with Jia Suan temper and regulate pH to 5 ~ 7, concentrating under reduced pressure, add 180gN, after dinethylformamide carries out reconcentration, resistates adds 280g ethyl acetate, add 25g (0.230mol) trimethylchlorosilane and carry out secondary silanization, 45 DEG C of stirring reaction 2h, reaction solution adds the water of 200g0 ~ 5 DEG C, layering, organic phase adds 2.5g activated carbon decolorizing 1h, filter, filtrate reduced in volume obtains CMT.
The chain extending reaction of e, CMT, the i.e. preparation of cefmetazole dimethylbenzyl amine salt
In 16g (0.106mol) S-cyanogen methyl-isothiourea hydrochloride, add 30gN, dinethylformamide, be cooled to-25 DEG C, add the methanol solution of 40g (0.222mol) 30wt% sodium methylate, after stirring reaction 1h, obtain cefmetazole acid side chain solution, for subsequent use; To in prepared CMT, add 70g ethyl acetate, be cooled to-25 DEG C, add cefmetazole acid side chain solution, after stirring reaction 1h, add 200g0 ~ 5 DEG C purified water, with 50% phosphorus acid for adjusting pH to 1 ~ 3, layering organic phase adds 2.0g activated carbon decolorizing 1h, filters, filtrate reduced in volume, add 35gN, dinethylformamide, and regulate pH to 4 ~ 7 with N, N-dimethyl benzylamine, add 0.07g cefmetazole dimethylbenzyl amine salt crystal seed, stirring and crystallizing, more after filtration, dry, obtained cefmetazole dimethylbenzyl amine salt 17.9g, yield 72.5%.
The preparation of f, cefmetazole acid
10g (0.016mol) cefmetazole dimethylbenzyl amine salt is added in 150g purified water and 150g ethyl acetate, be cooled to 0 ~ 10 DEG C, with 20% sulphur acid for adjusting pH to 1 ~ 3, layering, organic phase 150g purified water is washed, layering organic phase adds 2.0g activated carbon decolorizing 1h, filters, and filtrate regulates pH to 6 ~ 9 with 10% sodium hydrogen carbonate solution, add 15g ethyl acetate, 30g methyl iso-butyl ketone (MIBK), with 30% phosphorus acid for adjusting pH to 1 ~ 3, add 0.06g cefmetazole acid crystal seed, stirring and crystallizing, filter, drying, obtained cefmetazole acid 6.6g, yield 84.9%.
The preparation of g, cefmetazole sodium
Added in 80g purified water by 20g cefmetazole acid, be cooled to 0 ~ 5 DEG C, add sodium bicarbonate, regulate pH to 4 ~ 6, add 3.0g activated carbon decolorizing 1h, after filtering, freeze-drying obtains cefmetazole sodium 20.6g, yield 98.4%.
Embodiment 5
A, b, c, d tetra-steps, i.e. the preparation of CMT
330g methylene dichloride is added in 22g (0.041mol) DCT, add 11.2g (0.073mol) bromotrimethylsilane, after room temperature carries out Silanization reaction 2h, be cooled to-45 DEG C, add 7.0g (0.069mol) triethylamine, add the phosphorus pentachloride dichloromethane solution of 400g (0.077mol) 4wt%, carry out halogenating reaction, after stirring reaction 1h, add the lithium methoxide methanol solution of 125g (0.658mol) 20wt%, carry out first oxidizing reaction, after stirring reaction 30min, Yong Yi Suan temper goes out to react and regulates pH to 5 ~ 7, concentrating under reduced pressure, add 140gN, after dinethylformamide carries out reconcentration, resistates adds 240g ethyl acetate, add 38g (0.248mol) bromotrimethylsilane and carry out secondary silanization, 40 DEG C of stirring reaction 1h, reaction solution adds the water of 160g0 ~ 5 DEG C, layering, organic phase adds 3.0g activated carbon decolorizing 30min, filter, filtrate reduced in volume obtains CMT.
The chain extending reaction of e, CMT, the i.e. preparation of cefmetazole dicyclohexyl amine salt
In 16.5g (0.109mol) S-cyanogen methyl-isothiourea hydrochloride, add 50gN, dinethylformamide, be cooled to-15 DEG C, add the methanol solution of 45g (0.237mol) 20wt% lithium methoxide, after stirring reaction 1h, obtain cefmetazole acid side chain solution, for subsequent use; To in prepared CMT, add 60g ethyl acetate, be cooled to-15 DEG C, add cefmetazole acid side chain solution, after stirring reaction 1h, add 170g0 ~ 5 DEG C purified water, with 40% sulphur acid for adjusting pH to 1 ~ 3, layering organic phase adds 1.5g activated carbon decolorizing 1h, filter, filtrate reduced in volume, adds 44gN, dinethylformamide, and regulate pH to 4 ~ 7 with dicyclohexyl amine, add 0.06g cefmetazole dicyclohexyl amine salt crystal seed, stirring and crystallizing, again after filtration, drying, obtained cefmetazole dicyclohexyl amine salt 20g, yield 75.3%.
The preparation of f, cefmetazole acid
10g (0.016mol) cefmetazole dicyclohexyl amine salt is added in 130g purified water and 130g ethyl acetate, be cooled to 0 ~ 10 DEG C, with 16% salt acid for adjusting pH to 1 ~ 3, layering, organic phase 130g purified water is washed, layering organic phase adds 1.5g activated carbon decolorizing 1h, filters, and filtrate regulates pH to 6 ~ 9 with 5% sodium hydrogen carbonate solution, add 13g ethyl acetate, 28g methyl iso-butyl ketone (MIBK), with 30% phosphorus acid for adjusting pH to 1 ~ 3, add 0.05g cefmetazole acid crystal seed, stirring and crystallizing, filter, drying, obtained cefmetazole acid 5.9g, yield 81.7%.
The preparation of g, cefmetazole sodium
Added in 90g purified water by 20g cefmetazole acid, be cooled to 0 ~ 5 DEG C, add sodium carbonate, regulate pH to 4 ~ 6, add 2.5g activated carbon decolorizing 30min, after filtering, freeze-drying obtains cefmetazole sodium 19.7g, yield 94.1%.
Claims (10)
1. a synthetic method for the cefmetazole sodium of formula (VIII) structure,
The synthetic method of described cefmetazole sodium comprises the following steps:
A, silanization: 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, i.e. compound (I), add organic solvent wherein and be made into the solution that weight percent is 15 ~ 20%, after adding silylating reagent, room temperature reaction 1 ~ 2h, obtain silanization intermediate (II);
B, halogenation: by silanization intermediate (II), be cooled to-20 ~-80 DEG C, add the solution that organic bases and weight percent are the halide reagent of 3 ~ 5%, after stirring reaction 1 ~ 4h, obtain halogenation intermediate (III);
C, methoxy: in halogenation intermediate (III), add the methanol solution that weight percent is the first oxidising agent of 15 ~ 30%, after stirring reaction 0.5 ~ 2h, go out to react with You Ji Suan temper and regulate pH to 5 ~ 7, concentrating under reduced pressure, add after DMF carries out reconcentration, add ethyl acetate and obtain first oxidation intermediates (IV);
D, secondary silanization: in first oxidation intermediates (IV), add secondary silylating reagent, be 10 ~ 50 DEG C of stirring reaction 1 ~ 2h in temperature, the purified water adding 0 ~ 20 DEG C in reaction solution stirs 1 ~ 2h, leave standstill 2 ~ 3 little layereds, removing water layer, activated carbon decolorizing 0.5 ~ 2h is added in organic phase, cross and filter gac, filtrate obtains 7 β-chloracetyl amido-7 α-methoxyl group-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid, i.e. compound (V) through concentrating under reduced pressure;
The chain extending reaction of e, compound (V): S-cyanogen methyl-isothiourea hydrochloride is dissolved in DMF and is made into the solution that weight percent is 30 ~ 50%, be cooled to 0 ~-40 DEG C, add methanol solution, stirring reaction 1 ~ 2h that weight percent is 15 ~ 30% sodium methylates or lithium methoxide, obtain cefmetazole acid side chain solution;
Compound (V) is dissolved in ethyl acetate, be cooled to 0 ~-40 DEG C, add above-mentioned gained cefmetazole acid side chain solution, after stirring reaction 1 ~ 2h, 0 ~ 20 DEG C of purified water is added in reaction solution, with inorganic acid for adjusting pH to 1 ~ 3, then after carrying out standing 1 ~ 2 hour, layering, removing aqueous phase, activated carbon decolorizing 0.5 ~ 2h is added to organic phase, cross and filter gac, the product that filtrate obtains after concentrating under reduced pressure, dissolve with DMF, and regulate pH to 4 ~ 7 with organic bases, add cefmetazole amine salt crystal seed, stirring and crystallizing, remove filtrate after filtration again, drying is carried out to the crystal of separating out, obtained cefmetazole amine salt, i.e. compound (VI),
F, compound (VI) is added in water and ethyl acetate, be cooled to 0 ~ 10 DEG C, with inorganic acid for adjusting pH to 1 ~ 3, then layering is carried out, removing aqueous phase, by organic phase with after purified water washing, activated carbon decolorizing 0.5 ~ 2h is added in organic phase, cross and filter gac, filtrate regulates pH to 6 ~ 9 with mineral alkali, add ethyl acetate, methyl iso-butyl ketone (MIBK), with inorganic acid for adjusting pH to 1 ~ 3, add cefmetazole acid crystal seed, stirring and crystallizing, cross the mother liquor after filtering crystallization, dry crystal of separating out, obtained cefmetazole acid, i.e. compound (VII),
G, compound (VII) is added in purified water, be cooled to 0 ~ 20 DEG C, regulate pH to 4 ~ 6 with mineral alkali, add activated carbon decolorizing 0.5 ~ 2h, excessively filter gac, filtrate through Freeze Drying Equipment freeze-drying, obtained cefmetazole sodium and compound (VIII);
Organic solvent used in described step (a) is one or more the mixture in methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, tetrahydrofuran (THF); Silylating reagent used is one or more the mixture in trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, the two trimethylsilyl ethanamide of N, O-, hexamethyldisilazane;
Halide reagent used in described step (b) is one or more the mixture in phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, sulfur oxychloride;
First oxidising agent used in described step (c) is one or more mixture of lithium methoxide, sodium methylate or potassium methylate; Organic acid used is one or both mixture of formic acid, acetic acid;
Secondary silylating reagent used in described step (d) is one or more the mixture in trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, the two trimethylsilyl ethanamide of N, O-, hexamethyldisilazane.
2. the synthetic method of the cefmetazole sodium of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In reactions steps, mineral acid used is one or more the mixture in hydrochloric acid, phosphoric acid, sulfuric acid; Organic bases used is one or more the mixture in triethylamine, quinoline, pyridine, dicyclohexyl amine, N, N-dimethyl benzylamine; Mineral alkali used is one or more the mixture in sodium bicarbonate, sodium carbonate, sodium hydroxide;
3. the synthetic method of the cefmetazole sodium of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In described step (a), described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and silylating reagent mol ratio are 1:1 ~ 3.
4. the synthetic method of the cefmetazole amine salt of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In described step (b), described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and organic bases mol ratio are 1:1 ~ 2;
In described step (b), described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and halide reagent mol ratio are 1:0.5 ~ 2.0.
5. the synthetic method of the cefmetazole sodium of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In described step (c), the mol ratio of described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, first oxidising agent is 1:10 ~ 17;
In described step (c), the weight ratio of described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, DMF, ethyl acetate is 1:2 ~ 10:5 ~ 15.
6. the synthetic method of the cefmetazole amine salt of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In described step (d), described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt and secondary silylating reagent mol ratio are 1:5 ~ 8;
In described step (d), described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, purified water, activated carbon weight are than being 1:5 ~ 10:0.05 ~ 0.2.
7. the synthetic method of the cefmetazole amine salt of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In described step (e), described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, S-cyanogen methyl-isothiourea hydrochloride, sodium methylate or lithium methoxide mol ratio are 1:1 ~ 4:2 ~ 8;
In described step (e), the weight ratio of described 7 β-dichloroacetyl amido-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, ethyl acetate, purified water, gac, DMF, cefmetazole amine salt crystal seed is 1:1 ~ 4:5 ~ 10:0.05 ~ 0.2:0.5 ~ 2.0:0.001 ~ 0.005.
8. the synthetic method of the cefmetazole sodium of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In described step (f), add in water and ethyl acetate by compound (VI), this step cefmetazole amine salt, water, ethyl acetate weight ratio are 1:5 ~ 15:5 ~ 15.
9. the synthetic method of the cefmetazole sodium of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In described step (f), by organic phase with after purified water washing, activated carbon decolorizing 0.5 ~ 2h is added in organic phase, cross and filter gac, filtrate regulates pH to 6 ~ 9 with mineral alkali, add ethyl acetate, methyl iso-butyl ketone (MIBK), this step cefmetazole amine salt, water, gac, ethyl acetate, methyl iso-butyl ketone (MIBK), cefmetazole acid crystal seed weight ratio are 1:5 ~ 15:0.05 ~ 0.2:0.5 ~ 3:0.5 ~ 3:0.001 ~ 0.005.
10. the synthetic method of the cefmetazole sodium of a kind of formula (VIII) structure according to claim 1, is characterized in that:
In described step (g), the weight ratio of cefmetazole acid used, purified water and gac is 1:2 ~ 5:0.05 ~ 0.2.
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| CN108299471B (en) * | 2017-01-12 | 2021-03-12 | 重庆常捷医药有限公司 | Improved preparation process of cefmetazole intermediate |
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| CN109293680B (en) * | 2018-09-26 | 2020-06-16 | 华北制药河北华民药业有限责任公司 | Preparation method of cefoperazone acid |
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| CN112110940A (en) * | 2020-10-22 | 2020-12-22 | 山西海泰电子材料有限公司 | Crystallization method of cefmetazole acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3960845A (en) * | 1974-03-22 | 1976-06-01 | Sankyo Company Limited | Process for preparing 7β-acylamino-7α-alkoxycephalosporins or 6β-acylamino-6α-alkoxypenicillins |
| CN101550151A (en) * | 2009-05-07 | 2009-10-07 | 张锡芬 | Cefmetazole sodium compound and synthetic method thereof |
| CN101787040A (en) * | 2010-03-02 | 2010-07-28 | 哈药集团制药总厂 | Method for preparing cefmetazole sodium |
| CN102268021A (en) * | 2011-06-16 | 2011-12-07 | 哈药集团制药总厂 | Preparation method of cefminox sodium |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5720958B2 (en) * | 1974-05-08 | 1982-05-04 |
-
2013
- 2013-12-17 CN CN201310696053.7A patent/CN103709179B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3960845A (en) * | 1974-03-22 | 1976-06-01 | Sankyo Company Limited | Process for preparing 7β-acylamino-7α-alkoxycephalosporins or 6β-acylamino-6α-alkoxypenicillins |
| CN101550151A (en) * | 2009-05-07 | 2009-10-07 | 张锡芬 | Cefmetazole sodium compound and synthetic method thereof |
| CN101787040A (en) * | 2010-03-02 | 2010-07-28 | 哈药集团制药总厂 | Method for preparing cefmetazole sodium |
| CN102268021A (en) * | 2011-06-16 | 2011-12-07 | 哈药集团制药总厂 | Preparation method of cefminox sodium |
Non-Patent Citations (1)
| Title |
|---|
| 头孢美唑合成方法研究;安静，李雪艳;《河北科技大学学报》;20061231;第27卷(第4期);第288-293页 * |
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