CN103709179A - Synthesis and purification method of cefmetazole sodium - Google Patents
Synthesis and purification method of cefmetazole sodium Download PDFInfo
- Publication number
- CN103709179A CN103709179A CN201310696053.7A CN201310696053A CN103709179A CN 103709179 A CN103709179 A CN 103709179A CN 201310696053 A CN201310696053 A CN 201310696053A CN 103709179 A CN103709179 A CN 103709179A
- Authority
- CN
- China
- Prior art keywords
- cefmetazole
- acid
- add
- sodium
- cephem
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- 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
-
- 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
Abstract
The invention discloses a cefmetazole sodium preparation method. The cefmetazole sodium preparation method comprises the following steps: preparing 7beta-chloroacetamide- 7alpha-methoxyl-3-(1-methyl-1H-tetrazole-5-mercaptomethy)-3-cephem-4-carboxylic acid through silanization, halogenation, methoxylation and secondary silanization of 7beta-dichloroacetamido-3-(1-methyl-1H-tetrazole-5-mercaptomethy)-3-cephem-4-carboxylic acid triethylamine salt serving as a starting material, and then carrying out chain extension and acid and salt formation, thus obtaining cefmetazole sodium. The cefmetazole sodium preparation method has the advantages that the yield is high and reaches 55-65%, the product is high in purity, the 7beta-dichloroacetamido-3-(1-methyl-1H-tetrazole-5-mercaptomethy)-3-cephem-4-carboxylic acid triethylamine salt is used for replacing 7-MAC and serves as the starting material, the raw material is convenient in source, low in cost and environmentally friendly, the product is high in purity and suitable for industrial production. and the like.
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 Cefmetazole Sodium, chemical name is: (6R, 7S)-7-[2-[(cyanogen methyl) sulfo-] acetamido]-7-methoxyl group-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl) 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, is the semi-synthetic cephalic flexure mycin class microbiotic of Japanese San Gong company initiative, and the wide spectrum beta-lactam that it produces negative bacillus has good stability, and bacteroides fragilis is had to good anti-microbial activity.The negative bacillus such as intestinal bacteria, klebostiella pneumoniae, Proteus mirabilis, Shigella, Salmonella have good susceptibility to this product; Gold Portugal bacterium, A organize Hemolytic streptococcus, Bramhamella Catarrhalis is 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, the infection of Obstetric and Gynecologic Department bacterium, skin soft-tissue infection and hand postoperative infection prevention etc.
Quiet and Li Xueyan discloses in the 27th the 4th phase of volume (in December, 2006) at the journal > > of < < Hebei University of Science and Technology that to take 7-ACA, Tosyl chloride be that main raw material synthesizes cefmetazole; reaction minute 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 is that 200910014972.5 Chinese patent discloses a kind of cefmetazole sodium compound and preparation method thereof, with 7 beta-aminos-7-methoxyl group-3-(1-methyl isophthalic acid H-5-thiomethyl)-3-cephem-4-benzyl carboxylate and cyanogen methyl sulphur sodium acetate hybrid reaction under the condition of Tosyl chloride existence, generate cefmetazole acid, add sodium hydroxide, the cefmetazole sodium of system.The method, owing to having used excessively strong sodium hydroxide, causes impurity too much, and content is on the low side, and color is partially dark, so the synthetic result of product is unsatisfactory.
Application number is the preparation method that 201010116167.6 Chinese patent discloses a kind of cefmetazole sodium, with 7 β amino-7 α-methoxyl group-3-[(1-methyl isophthalic acid H-tetrazolium-5-yls) thiomethyl]-3-cephem-4-diphenylmethyl carboxylate and cyanogen first sulfydryl Acetyl Chloride 98Min. production cefmetazole benzyl ester, with iron trichloride diethyl ether solution, take off benzyl ester and obtain cefmetazole acid, with sodium bicarbonate, change into cefmetazole sodium again, 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, increased production stage, cause total recovery to reduce, after macroporous resin adsorption cefmetazole, with a large amount of solvent wash-outs, aftertreatment is complicated, has greatly increased production cost.
At present, the most popular method of domestic scale operation cefmetazole sodium is that to adopt 7-MAC be starting raw material, but exist, raw materials cost is high, toxicity is large, complex process, and the product yield of synthesized and product purity be the shortcoming such as on the low side all.
Summary of the invention the object of this invention is to provide a kind of method of 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 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-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, be compound (I), adding wherein organic solvent to be made into weight percent is 15～20% solution, add after silylating reagent, room temperature reaction 1～2h, obtain silanization intermediate (II);
B, halogenation: by silanization intermediate (II), be cooled to-20～-80 ℃, adding organic bases and weight percent is the solution of 3～5% halide reagent, after stirring reaction 1～4h, obtains halogenation intermediate (III);
C, methoxy: in halogenation intermediate (III), adding weight percent is the methanol solution of 15～30% first oxidising agent, after stirring reaction 0.5～2h, with You Ji Suan temper, go out to react and regulate pH to 5～7, concentrating under reduced pressure, add DMF to concentrate after displacement, add ethyl acetate to obtain first oxidation intermediates (IV);
D, secondary silanization: in first oxidation intermediates (IV), add secondary silylating reagent, in temperature, be 10～50 ℃ of stirring reaction 1～2h, in reaction solution, add the purified water of 0～20 ℃ to stir 1～2h, standing 2～3 little layereds, remove water layer, in organic phase, add activated carbon decolorizing 0.5～2h, remove by 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 to DMF, and to be made into weight percent be 30～50% solution, be cooled to 0～-40 ℃, adding weight percent is methanol solution, the stirring reaction 1～2h of 15～30% sodium methylates or lithium methoxide, obtains cefmetazole acid side chain solution;
Compound (V) is dissolved in ethyl acetate, be cooled to 0～-40 ℃, add above-mentioned gained cefmetazole acid side chain solution, after stirring reaction 1～2h, in reaction solution, add 0～20 ℃ of purified water, with inorganic acid for adjusting pH to 1～3, then carry out after standing 1～2 hour, layering, remove water, to organic phase, add activated carbon decolorizing 0.5～2h, remove by filter gac, the product that filtrate obtains after concentrating under reduced pressure, with DMF, dissolve, and regulate pH to 4～7 with organic bases, add cefmetazole amine salt crystal seed, stirring and crystallizing, remove after filtration again filtrate, the crystal of separating out is dried, make cefmetazole amine salt, be compound (VI),
F, compound (VI) is added in water and ethyl acetate, be cooled to 0～10 ℃, with inorganic acid for adjusting pH to 1～3, then carry out layering, remove water, organic phase, with after purified water washing, is added to activated carbon decolorizing 0.5～2h in organic phase, remove by 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, removes by filter the mother liquor after crystallization, dry crystal of separating out, make cefmetazole acid, i.e. compound (VII);
G, compound (VII) is added in purified water, be cooled to 0～20 ℃, with mineral alkali, regulate pH to 4～6, add activated carbon decolorizing 0.5～2h, remove by filter gac, filtrate is through Freeze Drying Equipment freeze-drying, and making cefmetazole sodium is 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 triethylamine, quinoline, pyridine, dicyclohexyl amine, N, the mixture of one or more in N-dimethyl benzylamine; Mineral alkali used is one or more the mixture in sodium bicarbonate, sodium carbonate, sodium hydroxide;
Described 7 β-dichloro acetamide base-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 (a), organic solvent used is one or more the mixture in methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, tetrahydrofuran (THF); Silylating reagent used is trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, N, the mixture of one or more in the two trimethylsilyl ethanamides of O-, hexamethyldisilazane;
Described 7 β-dichloro acetamide base-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.
In described step (b), halide reagent used is one or more the mixture in phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, sulfur oxychloride;
Described 7 β-dichloro acetamide base-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;
Described 7 β-dichloro acetamide base-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.
In described step (c), first oxidising agent used 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-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase) mol ratio of-3-cephem-4-carboxylic acid triethylamine salt, first oxidising agent is 1:10～17;
Described 7 β-dichloro acetamide base-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.
In described step (d), secondary silylating reagent used is trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, N, the mixture of one or more in the two trimethylsilyl ethanamides of O-, hexamethyldisilazane;
Described 7 β-dichloro acetamide base-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;
Described 7 β-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, purified water, gac weight ratio are 1:5～10:0.05～0.2.
In described step (e), described 7 β-dichloro acetamide base-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;
Described 7 β-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase) weight ratio of-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.
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 methyltransferases) English of-3-cephem-4-carboxylic acid writes a Chinese character in simplified form;
DCT is 7 β-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt is that the English of compound (I) is write 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 reaction, and its preparation method is to be formed by chloromethyl cyanide and thiocarbamide direct polycondensation;
During this is synthetic, 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, using DCT to replace 7-MAC is starting raw material, has reduced material cost, and total cost reduces more than 20%.
2. adopt synthetic route of the present invention, by intermediate DCT, under cold condition, carry out chlorination reaction with phosphorus pentachloride, 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 improve finished product purity.
3. adopt synthetic route of the present invention, at low temperatures, by S-cyanogen methyl-isothiourea hydrochloride, first react and obtain cefmetazole acid side chain solution with sodium methylate or lithium methoxide methanol solution, and then carry out condensation with intermediate CMT, and with amine salt form crystallization, reduced the impurity level of 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, make cefmetazole shifting in organic phase and water, by modes such as simple extraction, washing and carbon decolorings, reach the object of purifying cefmetazole acid, the technique adopting, mild condition, simple to operate, products obtained therefrom yield is high, purity good.
5. the present invention's single maximum contaminant of prepared cefmetazole sodium finished product 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 of preparing cefmetazole sodium of the present invention, 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.
Wherein 7-MAC is cefoxitin-cycloserine-fructose agar, i.e. 7 β amino-7 α-methoxyl group-3-[(1-methyl isophthalic acid H-tetrazolium-5-yls) thiomethyl] English of-3-cephem-4-diphenylmethyl carboxylate writes a Chinese character in simplified form.
Embodiment, below in conjunction with specific embodiment, is further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.In addition should be understood that those skilled in the art can make various changes or modification to the present invention after having read the content of the present invention's instruction, these equivalent form of values fall within the application's claims limited range equally.
Embodiment 1
(1) a, b, c, tetra-steps of d, i.e. the preparation of CMT
In 22g (0.041mol) DCT, add 350g methylene dichloride, add 10.6g (0.069mol) bromotrimethylsilane, room temperature is carried out after Silanization reaction 1h, be cooled to-80 ℃, add 8.2g (0.081mol) triethylamine, the phosphorus pentachloride dichloromethane solution that adds 340g (0.065mol) 4wt%, carry out halogenating reaction, after stirring reaction 4h, the lithium methoxide methanol solution that adds 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 100g N, dinethylformamide carries out after reconcentration, resistates adds 200g ethyl acetate, add 42g (0.274mol) bromotrimethylsilane to carry out secondary silanization, 50 ℃ of stirring reaction 1h, reaction solution adds the water of 150g0～5 ℃, layering, organic phase adds 2g activated carbon decolorizing 30min, filter, the concentrated CMT that obtains of filtrate decompression.
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 35g DMF, be cooled to-40 ℃, the methanol solution that adds 28g (0.221mol) 30% lithium methoxide, after stirring reaction 2h, obtain cefmetazole acid side chain solution, standby; In prepared CMT, add 80g ethyl acetate, be cooled to-40 ℃, add cefmetazole acid side chain solution, after stirring reaction 2h, add 150g0～5 ℃ purified water, with 33% salt acid for adjusting pH to 1～3, layering organic phase adds 1.5g activated carbon decolorizing 2h, filters, filtrate decompression is concentrated, add 30g DMF, 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, make 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 ℃, with 25% phosphorus acid for adjusting pH to 1～3, layering, 100g purified water washing for organic phase, 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, dry, make cefmetazole acid 5.8g, yield 80.3%.
The preparation of g, cefmetazole sodium
20g cefmetazole acid is added in 60g purified water, be cooled to 0～5 ℃, add sodium bicarbonate, regulate pH to 4～6, add 1.5g activated carbon decolorizing 30min, after filtering, freeze-drying makes cefmetazole sodium 20.4g, yield 97.5%.
Embodiment 2
(1) a, b, c, tetra-steps of d, i.e. the preparation of CMT
To in 22g (0.041mol) DCT, be dissolved in 400g trichloromethane, add 7.5g (0.069mol) trimethylchlorosilane, room temperature is carried out after Silanization reaction 2h, be cooled to-50 ℃, add 10.5g (0.081mol) quinoline, the phosphorus pentachloride chloroform soln that adds 350g (0.050mol) 3wt%, carry out halogenating reaction, after stirring reaction 3h, the methanol solution of sodium methylate that adds 180g (0.666mol) 20wt%, carry out first oxidizing reaction, after stirring reaction 1h, with Jia Suan temper, go out to react and regulate pH to 5～7, concentrating under reduced pressure, add 150g N, dinethylformamide carries out after reconcentration, resistates adds 250g ethyl acetate, add 30g (0.276mol) trimethylchlorosilane to carry out secondary silanization, 30 ℃ of stirring reaction 2h, reaction solution adds the water of 200g5～10 ℃, layering, organic phase adds 2g activated carbon decolorizing 1h, filter, the concentrated CMT that obtains of filtrate decompression.
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 45g DMF, be cooled to-20 ℃, the methanol solution that adds 40g (0.148mol) 20wt% sodium methylate, after stirring reaction 1h, obtain cefmetazole acid side chain solution, standby; In prepared CMT, add 70g ethyl acetate, be cooled to-20 ℃, add cefmetazole acid side chain solution, after stirring reaction 1h, add 180g5～10 ℃ purified water, with 18% salt acid for adjusting pH to 1～3, layering organic phase adds 3.0g activated carbon decolorizing 30min, filter, filtrate decompression is concentrated, adds 35g DMF, 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, dry, make 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 ℃, with 50% salt acid for adjusting pH to 1～3, layering, 120g purified water washing for organic phase, 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, dry, make cefmetazole acid 6.4g, yield 82.4%.
The preparation of g, cefmetazole sodium
20g cefmetazole acid is added in 50g purified water, be cooled to 5～10 ℃, add sodium bicarbonate, regulate pH to 4～6, add 2g activated carbon decolorizing 1h, after filtering, freeze-drying makes cefmetazole sodium 20.0g, yield 95.5%.
Embodiment 3
(1) a, b, c, tetra-steps of d, i.e. the preparation of CMT
In 22g (0.041mol) DCT, add 440g trichloromethane, add 13.8g (0.069mol) Iodotrimethylsilane, room temperature is carried out after Silanization reaction 1h, be cooled to-30 ℃, add 6.4g (0.081mol) pyridine, the phosphorus pentachloride chloroform soln that adds 340g (0.065mol) 4wt%, carry out halogenating reaction, after stirring reaction 2h, the lithium methoxide methanol solution that adds 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 120g N, dinethylformamide carries out after reconcentration, resistates adds 240g ethyl acetate, add 55g (0.275mol) Iodotrimethylsilane to carry out secondary silanization, 40 ℃ of stirring reaction 2h, reaction solution adds the water of 180g5～10 ℃, layering, organic phase adds 1.8g activated carbon decolorizing 1h, filter, the concentrated CMT that obtains of filtrate decompression.
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 40g DMF, be cooled to-10 ℃, the methanol solution that adds 55g (0.217mol) 15wt% lithium methoxide, after stirring reaction 2h, obtain cefmetazole acid side chain solution, standby; In prepared CMT, add 85g ethyl acetate, be cooled to-10 ℃, add cefmetazole acid side chain solution, after stirring reaction 1h, add 170g5～10 ℃ purified water, with 18% salt acid for adjusting pH to 1～3, layering organic phase adds 2.5g activated carbon decolorizing 30min, filter, filtrate decompression is concentrated, adds 40g N, 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, dry, make 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 ℃, with 50% phosphorus acid for adjusting pH to 1～3, layering, 110g purified water washing for organic phase, 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, dry, make cefmetazole acid 6.0g, yield 83.1%.
The preparation of g, cefmetazole sodium
20g cefmetazole acid is added in 55g purified water, be cooled to 0～5 ℃, add sodium carbonate, regulate pH to 4～6, add 1.0g activated carbon decolorizing 2h, after filtering, freeze-drying makes cefmetazole sodium 19.8g, yield 94.6%.
Embodiment 4
(1) a, b, c, tetra-steps of d, i.e. the preparation of CMT
In 22g (0.041mol) DCT, add 350g tetracol phenixin, add 8.5g (0.078mol) trimethylchlorosilane, room temperature is carried out after Silanization reaction 1h, be cooled to-60 ℃, add 8.0g (0.062mol) quinoline, the phosphorus pentachloride carbon tetrachloride solution that adds 300g (0.072mol) 5wt%, carry out halogenating reaction, after stirring reaction 2h, the methanol solution of sodium methylate that adds 110g (0.611mol) 30wt%, carry out first oxidizing reaction, after stirring reaction 30min, with Jia Suan temper, go out to react and regulate pH to 5～7, concentrating under reduced pressure, add 180g N, dinethylformamide carries out after reconcentration, resistates adds 280g ethyl acetate, add 25g (0.230mol) trimethylchlorosilane to carry out secondary silanization, 45 ℃ of stirring reaction 2h, reaction solution adds the water of 200g0～5 ℃, layering, organic phase adds 2.5g activated carbon decolorizing 1h, filter, the concentrated CMT that obtains of filtrate decompression.
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 30g DMF, be cooled to-25 ℃, the methanol solution that adds 40g (0.222mol) 30wt% sodium methylate, after stirring reaction 1h, obtain cefmetazole acid side chain solution, standby; In prepared CMT, add 70g ethyl acetate, be cooled to-25 ℃, add cefmetazole acid side chain solution, after stirring reaction 1h, add 200g0～5 ℃ purified water, with 50% phosphorus acid for adjusting pH to 1～3, layering organic phase adds 2.0g activated carbon decolorizing 1h, filters, and filtrate decompression is concentrated, add 35g N, dinethylformamide, and with N, N-dimethyl benzylamine regulates pH to 4～7, add 0.07g cefmetazole dimethylbenzyl amine salt crystal seed, stirring and crystallizing, more after filtration, dry, make 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 ℃, with 20% sulphur acid for adjusting pH to 1～3, layering, 150g purified water washing for organic phase, 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, dry, make cefmetazole acid 6.6g, yield 84.9%.
The preparation of g, cefmetazole sodium
20g cefmetazole acid is added in 80g purified water, be cooled to 0～5 ℃, add sodium bicarbonate, regulate pH to 4～6, add 3.0g activated carbon decolorizing 1h, after filtering, freeze-drying makes cefmetazole sodium 20.6g, yield 98.4%.
Embodiment 5
A, b, c, tetra-steps of d, i.e. the preparation of CMT
In 22g (0.041mol) DCT, add 330g methylene dichloride, add 11.2g (0.073mol) bromotrimethylsilane, room temperature is carried out after Silanization reaction 2h, be cooled to-45 ℃, add 7.0g (0.069mol) triethylamine, the phosphorus pentachloride dichloromethane solution that adds 400g (0.077mol) 4wt%, carry out halogenating reaction, after stirring reaction 1h, the lithium methoxide methanol solution that adds 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 140g N, dinethylformamide carries out after reconcentration, resistates adds 240g ethyl acetate, add 38g (0.248mol) bromotrimethylsilane to carry out secondary silanization, 40 ℃ of stirring reaction 1h, reaction solution adds the water of 160g0～5 ℃, layering, organic phase adds 3.0g activated carbon decolorizing 30min, filter, the concentrated CMT that obtains of filtrate decompression.
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 50g DMF, be cooled to-15 ℃, the methanol solution that adds 45g (0.237mol) 20wt% lithium methoxide, after stirring reaction 1h, obtain cefmetazole acid side chain solution, standby; In prepared CMT, add 60g ethyl acetate, be cooled to-15 ℃, add cefmetazole acid side chain solution, after stirring reaction 1h, add 170g0～5 ℃ purified water, with 40% sulphur acid for adjusting pH to 1～3, layering organic phase adds 1.5g activated carbon decolorizing 1h, filter, filtrate decompression is concentrated, adds 44g N, 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, dry, make 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 ℃, with 16% salt acid for adjusting pH to 1～3, layering, 130g purified water washing for organic phase, 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, dry, make cefmetazole acid 5.9g, yield 81.7%.
The preparation of g, cefmetazole sodium
20g cefmetazole acid is added in 90g purified water, be cooled to 0～5 ℃, add sodium carbonate, regulate pH to 4～6, add 2.5g activated carbon decolorizing 30min, after filtering, freeze-drying makes 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-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, be compound (I), adding wherein organic solvent to be made into weight percent is 15～20% solution, add after silylating reagent, room temperature reaction 1～2h, obtain silanization intermediate (II);
B, halogenation: by silanization intermediate (II), be cooled to-20～-80 ℃, adding organic bases and weight percent is the solution of 3～5% halide reagent, after stirring reaction 1～4h, obtains halogenation intermediate (III);
C, methoxy: in halogenation intermediate (III), adding weight percent is the methanol solution of 15～30% first oxidising agent, after stirring reaction 0.5～2h, with You Ji Suan temper, go out to react and regulate pH to 5～7, concentrating under reduced pressure, add DMF to concentrate after displacement, add ethyl acetate to obtain first oxidation intermediates (IV);
D, secondary silanization: in first oxidation intermediates (IV), add secondary silylating reagent, in temperature, be 10～50 ℃ of stirring reaction 1～2h, in reaction solution, add the purified water of 0～20 ℃ to stir 1～2h, standing 2～3 little layereds, remove water layer, in organic phase, add activated carbon decolorizing 0.5～2h, remove by 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 to DMF, and to be made into weight percent be 30～50% solution, be cooled to 0～-40 ℃, adding weight percent is methanol solution, the stirring reaction 1～2h of 15～30% sodium methylates or lithium methoxide, obtains cefmetazole acid side chain solution;
Compound (V) is dissolved in ethyl acetate, be cooled to 0～-40 ℃, add above-mentioned gained cefmetazole acid side chain solution, after stirring reaction 1～2h, in reaction solution, add 0～20 ℃ of purified water, with inorganic acid for adjusting pH to 1～3, then carry out after standing 1～2 hour, layering, remove water, to organic phase, add activated carbon decolorizing 0.5～2h, remove by filter gac, the product that filtrate obtains after concentrating under reduced pressure, with DMF, dissolve, and regulate pH to 4～7 with organic bases, add cefmetazole amine salt crystal seed, stirring and crystallizing, remove after filtration again filtrate, the crystal of separating out is dried, make cefmetazole amine salt, be compound (VI),
F, compound (VI) is added in water and ethyl acetate, be cooled to 0～10 ℃, with inorganic acid for adjusting pH to 1～3, then carry out layering, remove water, organic phase, with after purified water washing, is added to activated carbon decolorizing 0.5～2h in organic phase, remove by 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, removes by filter the mother liquor after crystallization, dry crystal of separating out, make cefmetazole acid, i.e. compound (VII);
G, compound (VII) is added in purified water, be cooled to 0～20 ℃, with mineral alkali, regulate pH to 4～6, add activated carbon decolorizing 0.5～2h, remove by filter gac, filtrate is through Freeze Drying Equipment freeze-drying, and making cefmetazole sodium is compound (VIII).
2. the synthetic method of the cefmetazole sodium of a kind of formula according to claim 1 (VIII) structure, 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 triethylamine, quinoline, pyridine, dicyclohexyl amine, N, the mixture of one or more in 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 according to claim 1 (VIII) structure, is characterized in that:
In described step (a), organic solvent used is one or more the mixture in methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, tetrahydrofuran (THF); Silylating reagent used is trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, N, the mixture of one or more in the two trimethylsilyl ethanamides of O-, hexamethyldisilazane;
Described 7 β-dichloro acetamide base-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 according to claim 1 (VIII) structure, is characterized in that:
In described step (b), halide reagent used is one or more the mixture in phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, sulfur oxychloride;
Described 7 β-dichloro acetamide base-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;
Described 7 β-dichloro acetamide base-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 according to claim 1 (VIII) structure, is characterized in that:
In described step (c), first oxidising agent used 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-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase) mol ratio of-3-cephem-4-carboxylic acid triethylamine salt, first oxidising agent is 1:10～17;
Described 7 β-dichloro acetamide base-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.
6. the synthetic method of the cefmetazole amine salt of a kind of formula according to claim 1 (VIII) structure, is characterized in that:
In described step (d), secondary silylating reagent used is trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, N, the mixture of one or more in the two trimethylsilyl ethanamides of O-, hexamethyldisilazane;
Described 7 β-dichloro acetamide base-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;
Described 7 β-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase)-3-cephem-4-carboxylic acid triethylamine salt, purified water, gac weight ratio are 1:5～10:0.05～0.2.
7. the synthetic method of the cefmetazole amine salt of a kind of formula according to claim 1 (VIII) structure, is characterized in that:
In described step (e), described 7 β-dichloro acetamide base-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;
Described 7 β-dichloro acetamide base-3-(1-methyl isophthalic acid H-tetrazolium-5-thiopurine methyltransferase) weight ratio of-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 according to claim 1 (VIII) structure, is characterized in that:
In described step (f), 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 according to claim 1 (VIII) structure, is characterized in that:
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.
10. the synthetic method of the cefmetazole sodium of a kind of formula according to claim 1 (VIII) structure, 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310696053.7A CN103709179B (en) | 2013-12-17 | 2013-12-17 | A kind of synthesizing progress method of cefmetazole sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310696053.7A CN103709179B (en) | 2013-12-17 | 2013-12-17 | A kind of synthesizing progress method of cefmetazole sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103709179A true CN103709179A (en) | 2014-04-09 |
| CN103709179B CN103709179B (en) | 2016-03-30 |
Family
ID=50402567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310696053.7A Active CN103709179B (en) | 2013-12-17 | 2013-12-17 | A kind of synthesizing progress method of cefmetazole sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103709179B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017287A (en) * | 2015-08-18 | 2015-11-04 | 齐鲁安替（临邑）制药有限公司 | Preparation method for cephamycin intermediate |
| CN105330677A (en) * | 2015-12-15 | 2016-02-17 | 南京金浩医药科技有限公司 | Preparation method of cefmetazole |
| CN106290680A (en) * | 2015-05-20 | 2017-01-04 | 重庆药友制药有限责任公司 | The analysis method of the intermediate S-cyanogen methyl isothiourea of cefmetazole acid |
| CN108299471A (en) * | 2017-01-12 | 2018-07-20 | 重庆常捷医药有限公司 | A kind of improvement preparation process of cefmetazole intermediate |
| CN108424418A (en) * | 2017-02-15 | 2018-08-21 | 山东致纯医药科技有限公司 | A kind of Flomoxef sodium impurity |
| CN109293680A (en) * | 2018-09-26 | 2019-02-01 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of cefoperazone acid |
| CN110590812A (en) * | 2019-10-29 | 2019-12-20 | 重庆天地药业有限责任公司 | Preparation method of cefminox sodium |
| 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 (5)
| 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 |
| JPS5720958B2 (en) * | 1974-05-08 | 1982-05-04 | ||
| 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 |
-
2013
- 2013-12-17 CN CN201310696053.7A patent/CN103709179B/en active Active
Patent Citations (5)
| 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 |
| JPS5720958B2 (en) * | 1974-05-08 | 1982-05-04 | ||
| 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 |
|---|
| 安静，李雪艳: "头孢美唑合成方法研究", 《河北科技大学学报》, vol. 27, no. 4, 31 December 2006 (2006-12-31), pages 288 - 293 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106290680A (en) * | 2015-05-20 | 2017-01-04 | 重庆药友制药有限责任公司 | The analysis method of the intermediate S-cyanogen methyl isothiourea of cefmetazole acid |
| CN105017287A (en) * | 2015-08-18 | 2015-11-04 | 齐鲁安替（临邑）制药有限公司 | Preparation method for cephamycin intermediate |
| CN105017287B (en) * | 2015-08-18 | 2018-01-12 | 齐鲁安替（临邑）制药有限公司 | A kind of preparation method of cephamycin intermediate |
| CN105330677A (en) * | 2015-12-15 | 2016-02-17 | 南京金浩医药科技有限公司 | Preparation method of cefmetazole |
| CN105330677B (en) * | 2015-12-15 | 2017-11-28 | 南京金浩医药科技有限公司 | A kind of preparation method of cefmetazole sodium |
| CN108299471A (en) * | 2017-01-12 | 2018-07-20 | 重庆常捷医药有限公司 | A kind of improvement preparation process of cefmetazole intermediate |
| CN108424418A (en) * | 2017-02-15 | 2018-08-21 | 山东致纯医药科技有限公司 | A kind of Flomoxef sodium impurity |
| CN109293680A (en) * | 2018-09-26 | 2019-02-01 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of cefoperazone acid |
| 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 |
| CN110590812A (en) * | 2019-10-29 | 2019-12-20 | 重庆天地药业有限责任公司 | Preparation method of cefminox sodium |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103709179B (en) | 2016-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103709179B (en) | A kind of synthesizing progress method of cefmetazole sodium | |
| CN102391289B (en) | Synthetic methods of ceftazidime intermediate and ceftazidime | |
| US20050119478A1 (en) | Process for preparing cephalosporins with salified intermediate | |
| CN105229019B (en) | The Preparation Method And Their Intermediate of Epi-ADM | |
| CN105254648B (en) | A kind of synthetic method of cephalo dimension star and its sodium salt | |
| CN102633819A (en) | Preparation method of cefoxitin | |
| CN101704827B (en) | Synthesis method of cefathiamidine compound | |
| CN103319503A (en) | Preparation method of cefdinir | |
| CN108299471B (en) | Improved preparation process of cefmetazole intermediate | |
| CN104230956B (en) | A kind of preparation method of cefoxitin | |
| JPH0273090A (en) | Novel production of cephem prodrug ester | |
| CN101486720B (en) | Method for synthesizing cefodizime sodium compound | |
| CN103665001A (en) | Method for preparing antibacterial cefdinir | |
| CN102925525A (en) | Method for producing cefoxitin acid | |
| CN102532168A (en) | Synthesis method of cefoperazone acid | |
| CA1077926A (en) | Bis-trimethylsilyl cefamandole and process thereof | |
| CN108299469B (en) | Preparation method of cefotiam hydrochloride | |
| CN113185538B (en) | Preparation method of cefpodoxime acid | |
| CN105461740B (en) | The preparation method of cefmetazole acid | |
| CN101550148B (en) | Refining method of Cefpodoxime proxetil compound | |
| CN110684039A (en) | Preparation method of cefoxitin lactone | |
| CN113372363B (en) | Preparation method of descarbamoyl cefuroxime | |
| CN109422767B (en) | Methoxycephalosporin intermediate, preparation method thereof and synthesis method of cefminox sodium | |
| IE910464A1 (en) | A process for the preparation of¹7-amino-3-methoxymethylceph-3-em-4-carboxylic acid | |
| WO2004035593A1 (en) | An improved process for the preparation of cefadroxil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |