CN110590812A - Preparation method of cefminox sodium - Google Patents
Preparation method of cefminox sodium Download PDFInfo
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- CN110590812A CN110590812A CN201911037677.1A CN201911037677A CN110590812A CN 110590812 A CN110590812 A CN 110590812A CN 201911037677 A CN201911037677 A CN 201911037677A CN 110590812 A CN110590812 A CN 110590812A
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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
- C07D501/14—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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Abstract
The invention provides a preparation method of cefminox sodium, which comprises the following steps: (1) dispersing a compound with a structure shown in a formula (VII) in an organic solvent A to prepare a solution or a suspension, adding a compound with a structure shown in a formula (VIII), and drying in vacuum to obtain a compound with a structure shown in a formula (VI); (2) dispersing a compound with a structure shown in a formula (VI) in an organic solvent C, dropwise adding a compound with a structure shown in a formula (V), and drying to obtain a compound with a structure shown in a formula (IV); (3) dispersing a compound with a structure shown in a formula (IV) in an organic solvent, and removing the solvent by rotary evaporation under a reduced pressure condition to obtain an organic phase containing the compound with the structure shown in the formula (II); (4) adding purified water into the solution containing the compound with the structure shown in the formula (II), heating, adjusting the pH value, adding the compound with the structure shown in the formula (III), stirring at a controlled temperature, transferring the water phase into a crystallizing tank, crystallizing, and drying under reduced pressure to obtain the heptahedonic sodium salt. The invention shortens the synthesis process, reduces the cost and has high product yield and purity.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of cefminox sodium.
Background
Cefminox sodium, english name: cefminox Sodium, chemical name: sodium (6R, 7S) -7 β - [ (S) -2- (2-amino-2-carboxyethylmercapto) acetylamino ] -7 α -methoxy-3- [ (1-methyl-1H-5-yl) thio ] methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-ene-2-carboxylate, predominantly in the form of a heptahydrate crystal of the formula: C16H20N7NaO7S3 & 7H 2O. The cefminox sodium has broad-spectrum antibacterial activity on gram-positive bacteria and gram-negative bacteria, and particularly has strong antibacterial action on escherichia coli, klebsiella, haemophilus influenzae, proteus and bacteroides fragilis. Can be used for treating respiratory infection, urinary infection, abdominal cavity infection, pelvic cavity infection and septicemia caused by above bacteria.
Patent CN 101696214 discloses a method for preparing cefminox sodium by using 7-MAC as an initial parent nucleus, firstly reacting with bromoacetyl bromide to generate 7 beta-bromoacetamido-7 alpha-methoxy-3- (1-methyl-1H-tetrazole-5-thiomethyl) -3-cephem-4-carboxylic acid diphenylmethyl ester, and finally condensing with D-cysteine hydrochloride to form salt under the action of sodium iodide. The synthetic route has the advantages of simple steps, high product purity after multiple times of purification and separation, complex procedures, easy operation confusion and low economic benefit, and is not suitable for commercial production because the three-step synthetic reaction needs 5 times of pH value adjustment, extraction, washing and drying, and the expensive 7-MAC is used as the initial parent nucleus.
CN102643295 mentions that D-cysteine firstly reacts with sodium methoxide to obtain (2S) -2-amino-3-mercaptopropionic acid disodium salt, meanwhile, the mercapto group of D-cysteine hydrochloride is activated to improve the reaction activity, and then the D-cysteine reacts with 7 beta-chloroacetamido-7 alpha-methoxy-3- (1-methyl-1H-tetrazole-5-thiomethyl) -3-cephem-4-carboxylic acid to generate cefminox sodium. The method has the advantages that sodium methoxide is used for activating D-cysteine hydrochloride to obtain a compound IV, the condensation difficulty of III and IV is reduced, the reaction yield can be improved, however, sodium methoxide is continuously added in the condensation stage of III and IV to serve as a catalyst and an acid-binding agent, the PH of the whole system can be rapidly increased, beta-lactam four-membered rings are easy to break due to the sensitivity of beta-lactam antibiotics to strong alkali, related substances are increased, and the purity of products cannot be guaranteed.
CN102321100 discloses a cefminox sodium prepared by condensation of 7 beta-bromoacetamido-7 alpha-methoxy-3- (1-methyl-1H-5-tetrazole) thiomethyl-3-cephem-4-carboxylic acid as an initial raw material and sodium bicarbonate as a catalyst with D-cysteine hydrochloride in the presence of water. The patent also describes a refinement method of cefminox sodium by using ethanol as an anti-solvent, but the purification and separation of the cefminox sodium crude product described in the patent need to pass through a chromatographic column filled with nonpolar macroporous resin X5, water is used as an eluent under normal pressure, the column passing time is long, the production efficiency is low, and the commercial mass production is difficult to realize.
EP0024879 discloses a process in which the 7 beta-haloamino group of 7 beta-haloacetamido-3- (1-methyl-1H-5-thiomethyl) -3-cephem-4-carboxylic acid is first condensed with D-cysteine hydrochloride, forming a cysteine side chain at the 7 beta position, modifying the 7 alpha position, to obtain (6R, 7S) -7 beta- [ (S) -2- (2-amino-2-carboxyethylmercapto) acetamido ] -7 alpha-methoxy-3- [ (1-methyl-1H-5-yl) thio ] methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-ene-2-carboxylic acid sodium salt. The idea of the synthetic route is to utilize the high reactivity of D-cysteine hydrochloride sulfydryl, firstly condense with halogenated acetamido at the 7 beta position, then add methoxyl at the 7 alpha position, sodium methoxide belongs to strong-basicity nucleophilic reagent, add more sodium methoxide with molar equivalent and carboxylic acid to form sodium salt, separate out pure cefminox sodium after the reaction is finished, add antisolvent for crystallization, the disadvantage is that strong-basicity sodium methoxide is liable to be afraid of cysteine at the 7 beta position side chain, bicyclic mother nucleus is unstable under strong basicity, amido bond is easy to break, impurity concentration is increased, crystallization 'oil outlet' probability is increased, and high-purity cefminox sodium cannot be obtained.
U.S. Pat. No. 4,43573,324,327 discloses a process for preparing cefminox sodium by using p-methoxybenzyl 7-phenylacetamido-3-chloromethyl-4-cephalosporanate as initial parent nucleus, substituting chloride ion at C3 with 1-methyl-5-mercaptotetrazole to obtain p-methoxybenzyl 7-phenylacetamido-3- (1-methyl-1H-5-thiomethyl) -3-cephem-4-cephalosporanate, removing carboxyl and amino protecting groups under acidic condition, and condensing with D-cysteine hydrochloride by using sodium bicarbonate as acid-binding agent. In the route, GCLE with protective groups on both 7-beta amino and 3-carboxyl is selected as a raw material, so that the possibility of damaging the groups by bases in the methoxylation process is reduced, but the subsequent deprotection process needs to be carried out in a hydrogen chloride atmosphere, so that the unsafe risk is higher, and meanwhile, due to the double protective groups in the parent nucleus, the effective mass ratio of molecules is low, and the yield of the whole synthesis route is low.
The synthetic routes for cefminox sodium disclosed above are summarized in two main categories. The first method is to take 7 alpha position methylated bicyclic mother nucleus (7-MAC) as an initial raw material, modify 1-methyl-5-mercapto tetrazole on the 3 rd position, then condense with D-cysteine hydrochloride to form a 7 beta position side chain, and finally salify and crystallize to obtain cefminox sodium salt; and the second one is that the dicyclic mother nucleus (GCLE) with carboxyl and amino groups both with protecting groups is used as initial material to obtain 7 alpha methoxy, and the initial material is acidified to eliminate protecting group and finally condensed with D-cysteine hydrochloride to form salt and obtain cefminox sodium salt. The first synthetic route is simple to operate, but raw materials are expensive, and the second synthetic route has little damage to other groups in the methoxylation process, but the deprotection conditions are harsh, and the risk coefficient is high.
Disclosure of Invention
In view of the above problems and drawbacks, the present invention provides a method for preparing cefminox sodium, which can be industrially produced.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of cefminox sodium comprises the following synthetic route:
wherein, the compound of formula (III), x is 0 or 1, y is 0 or 1;
the method comprises the following steps:
(1) dispersing a compound with a structure shown in a formula (VII) in an organic solvent A, stirring and uniformly mixing to prepare a solution or a suspension, adding a compound with a structure shown in a formula (VIII), stirring, quickly adding a reagent A into the system at the temperature of 10-30 ℃, stirring for reacting for 2 hours, dropwise adding a reagent B into the system after the reaction is finished for crystallization, filtering, pulping and washing the solvent B, filtering out the solvent, and drying in vacuum to obtain a compound with a structure shown in a formula (VI);
the organic solvent A is one or a combination of more of methanol, acetonitrile, acetone, tetrahydrofuran, dimethyl carbonate, N-dimethylformamide and N, N-dimethylacetamide;
preferably dimethyl carbonate;
the solvent B is one or a combination of acetone, water, tetrahydrofuran and ethyl acetate;
preferably acetone;
the reagent A is one of boron trifluoride, aluminum trichloride, zinc chloride and boron tribromide;
preferably boron trifluoride;
the reagent B is one of ammonia water, triethylamine, diisopropylethylamine, pyridine and N, N-dimethyl-4-pyridylamine;
preferably ammonia water;
(2) dispersing the compound with the structure shown in the formula (VI) prepared in the step (1) in an organic solvent C, uniformly stirring, slowly dropwise adding the compound with the structure shown in the formula (V), controlling the temperature to be-15-0 ℃ for reaction, adding a reagent C into the system after the reaction is finished, adjusting the pH, precipitating crystals, filtering, leaching a filter cake with a solvent D, and drying to obtain the compound with the structure shown in the formula (IV);
the organic solvent C is one or a combination of more of ethyl acetate, acetonitrile, acetone, tetrahydrofuran, dimethyl carbonate, N-dimethylformamide and N, N-dimethylacetamide;
preferably ethyl acetate;
the reagent C is one of triethylamine, diisopropylethylamine, pyridine, N-dimethyl-4-pyridylamine, phenylethylamine and benzhydrylamine;
preferably triethylamine;
the solvent D is one or a combination of acetone, ethyl acetate, tetrahydrofuran and acetonitrile;
preferably ethyl acetate;
(3) dispersing the compound with the structure shown in the formula (IV) prepared in the step (2) in an organic solvent E, uniformly stirring, cooling to-40-70 ℃, dropwise adding quinoline as an acid-binding agent, adding phosphorus pentachloride, performing chlorination stirring reaction for 40-60 min, monitoring residues by thin-layer chromatography (TLC), dropwise adding a methanol solution containing sodium methoxide, performing methoxylation stirring reaction for 60-90 min, performing rotary evaporation under reduced pressure to remove the solvent D, heating the system to 20-40 ℃, adding a reagent D, performing temperature control reaction for 30min, transferring the system into a hydrolysate which is pre-cooled to-10 ℃, wherein the hydrolysate contains a solvent F and purified water, performing high-speed stirring hydrolysis for 150-200 min, standing for layering, and discarding an aqueous phase containing salt and a leaving group to obtain an organic phase containing the compound with the structure shown in the formula (II);
the organic solvent E is one or a combination of more of dichloromethane, trichloromethane, carbon tetrachloride, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide;
preferably chloroform;
the reagent D is one of trimethylchlorosilane, trimethylbromosilane and trimethyliodosilane;
preferably trimethylchlorosilane;
the solvent F is one of ethyl acetate, acetonitrile, tetrahydrofuran and acetone;
preferably ethyl acetate;
(4) adding purified water into the solution containing the compound with the structure shown in the formula (II) prepared in the step (3), uniformly stirring, heating to 20-40 ℃, adjusting the pH to 7.0-8.5 by using sodium bicarbonate, adding the compound with the structure shown in the formula (III), stirring at a controlled temperature, carrying out condensation reaction for 3-6 h, standing for layering after the reaction is finished, discarding an organic phase, transferring a water phase into a crystallization tank, adding a solvent G at a low stirring speed, precipitating crystals, filtering, washing by using the solvent G, and drying under reduced pressure to obtain heptaspore minox sodium with the structure shown in the formula (I);
the solvent G is one or a combination of more of ethanol, propanol, glycol, isopropanol and glycerol;
preferably isopropanol;
compounds of formula (iii) are anhydrous D-cysteine (x ═ 0, y ═ 0), anhydrous D-cysteine hydrochloride (x ═ 1, y ═ 0), or D-cysteine hydrochloride monohydrate (x ═ 1, y ═ 1).
Preferably, the compound of formula (iii) is D-cysteine hydrochloride monohydrate (x ═ 1, y ═ 1).
In the step (1), the molar ratio of the compound with the structure of the formula (VII) to the compound with the structure of the formula (VIII) is 1 (1.5-3).
Preferably, in the step (1), the molar ratio of the compound with the structure of the formula (VII) to the compound with the structure of the formula (VIII) is 1 (1.5-2).
Further, in the step (1), the mass ratio of the compound with the structure of the formula (VII) to the organic solvent A is 1g (3-6) g; the ratio of the compound with the structure of the formula (VII) to the solvent B is 1g (5-10) ml; the mass ratio of the compound with the structure of the formula (VII) to the reagent A is 1g (1-4 g); the mass ratio of the compound with the structure shown in the formula (VII) to the reagent B is 1g (2-5 g).
Preferably, in the step (1), the mass ratio of the compound having the structure of formula (VII) to the organic solvent A is 1g: (4-5) g; the ratio of the compound with the structure of the formula (VII) to the solvent B is 1g (5-7) ml; the mass ratio of the compound with the structure of the formula (VII) to the reagent A is 1g (1-2) g; the mass ratio of the compound with the structure shown in the formula (VII) to the reagent B is 1g (2-3).
In the step (2), the molar ratio of the compound with the structure of the formula (VI) to the compound with the structure of the formula (V) is 1 (1.5-4).
Preferably, in the step (2), the molar ratio of the compound with the structure of the formula (VI) to the compound with the structure of the formula (V) is 1 (2-3).
Further, in the step (2), the ratio of the compound having the structure of the formula (VI) to the organic solvent C is 1g: (7-11) ml; the mass ratio of the compound with the structure of the formula (VI) to the solvent D is 1g: (4-8) g; the mass ratio of the compound with the structure of the formula (VI) to the reagent C is 1g (1.5-3 g).
Preferably, in the step (2), the ratio of the compound with the structure of the formula (VI) to the organic solvent C is 1g (7-9) ml; the mass ratio of the compound with the structure of the formula (VI) to the solvent D is 1g (4-5 g); the mass ratio of the compound with the structure of the formula (VI) to the reagent C is 1g (1.5-2 g).
Further, in the step (3), the ratio of the compound with the structure shown in the formula (IV) to the residual mass of the system after reduced pressure rotary evaporation is 1g (5-10) g; the proportion of the organic phase to the aqueous phase of the hydrolysate is 1g (5-10 g).
Preferably, in the step (3), the ratio of the compound with the structure shown in the formula (IV) to the residual mass of the system after reduced pressure rotary evaporation is 1g (7-8); the proportion of the organic phase to the aqueous phase of the hydrolysate is 1g (5-7 g).
Further, in the step (3), the molar ratio of the compound with the structure shown in the formula (IV) to the phosphorus pentachloride is 1 (2-6); the molar ratio of the compound with the structure of formula (IV) to sodium methoxide is 1 (10-16); the molar ratio of the compound with the structure shown in the formula (VII) to quinoline is 1 (2-6).
Preferably, in the step (3), the molar ratio of the compound with the structure of the formula (IV) to the phosphorus pentachloride is 1: (2-3); the molar ratio of the compound with the structure of formula (IV) to sodium methoxide is 1 (10-13); the molar ratio of the compound with the structure shown in the formula (VII) to quinoline is 1 (3-5).
Further, in the step (3), the ratio of the compound having the structure of formula (IV) to the organic solvent E is 1g: (15-25) ml; the mass ratio of the compound with the structure of the formula (IV) to the reagent D is 1g (1-5 g).
Preferably, in the step (3), the ratio of the compound having the structure of formula (IV) to the organic solvent E is 1g: (20-25) ml; the mass ratio of the compound with the structure of the formula (IV) to the reagent D is 1g (2-3 g).
Further, in the step (4), the molar ratio of the compound with the structure of formula (IV) to the compound with the structure of formula (III) is 1 (1.1-3); the ratio of the compound with the structure of the formula (IV) to the solvent G is 1G: (1.5-3.5) ml.
Preferably, in the step (4), the molar ratio of the compound with the structure of formula (IV) to the compound with the structure of formula (III) is 1 (1.3-1.7); the ratio of the compound with the structure of the formula (IV) to the solvent G is 1G: (2.0-3.1) ml.
Further, the preparation method comprises the following steps:
(1) 40-50g of 7-amino-3- [ (acetoxy) methyl ] -8-oxo-5-thia-1-azabicyclo [4,2,0] -2-ene-2-carboxylic acid were dispersed in 250g of 200,250 g of dimethyl carbonate, stirring and mixing evenly, adding 30-32g of 1-methyl-5-mercapto tetrazole, stirring, under the condition of 10-30 ℃, rapidly adding boron trifluoride into the system, stirring and reacting for 2 hours, dropwise adding ammonia water into the system after the reaction is finished, crystallizing, filtering, pulping and washing with acetone, filtering out a solvent, and drying in vacuum to obtain 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid;
(2) dispersing 36.5-38.5g of 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (1) in 200g of ethyl acetate, uniformly stirring, slowly dropwise adding 75-90g of dichloroacetyl chloride, controlling the temperature to be minus 15-0 ℃ for reaction, adding 120g of triethylamine into the system after the reaction is finished, adjusting the pH, separating out crystals, filtering, leaching a filter cake with 215g of ethyl acetate, and drying to obtain 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid;
(3) dispersing 20-22g of 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (2) in 360ml of trichloromethane, uniformly stirring, cooling to-40 to-70 ℃, dropwise adding quinoline as an acid-binding agent, adding phosphorus pentachloride, carrying out chlorination and stirring reaction for 40-60 min, monitoring residues by thin-layer chromatography (TLC), dropwise adding a methanol solution containing sodium methoxide, carrying out methoxylation and stirring reaction for 60-90 min, carrying out rotary evaporation under reduced pressure to remove ethyl acetate, heating the system to 20-40 ℃, adding trimethylchlorosilane, carrying out temperature control reaction for 30min, transferring the system into a hydrolysate which is already cooled to-10 ℃, wherein the hydrolysate contains ethyl acetate and purified water, stirring at a high speed for hydrolysis for 150-200 min, standing for layering, and removing a water phase containing salt and a leaving group to obtain an organic phase containing 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid;
(4) adding purified water into the solution containing 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (3), uniformly stirring, heating to 20-40 ℃, adjusting the pH to 7.0-8.5 by using sodium bicarbonate, adding 3-10g of D-cysteine hydrochloride monohydrate, stirring at a controlled temperature, carrying out condensation reaction for 3-6H, standing for layering, discarding an organic phase, transferring a water phase into a crystallization tank, adding isopropanol at a low stirring speed, precipitating crystals, filtering, washing with isopropanol, and drying under reduced pressure to obtain (6R, 7S) -7 beta- [ (S) -2- (2-amino-2-carboxyethylmercapto) acetamido ] -7 alpha-methoxy-3 - [ (1-methyl-1H-5-yl) thio ] methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-ene-2-carboxylic acid sodium salt structural heptahydroximino sodium.
The invention takes boron trifluoride as a mother nucleus to react with 1-methyl-5-mercapto tetrazole, thereby effectively improving reaction selectivity and reaction activity. The invention takes dichloroacetyl chloride as the acylation reagent of 7 beta amino, and reduces the reaction toxicity compared with a bromoacylation reagent. According to the invention, triethylamine is used as a salifying separation reagent of the intermediate (VI), so that the yield of the intermediate is increased, the impurity wrapping in the product is reduced, and the product purity is improved. The invention takes low-toxicity sodium methoxide as a methoxylation reagent, and takes the low-toxicity sodium methoxide and an intermediate (VI) to have 7 alpha methoxy at the low temperature of-40 to-70 ℃, the reaction rate is controllable, and the conversion rate is high. After the methyl oxidation is finished, the intermediate (II) directly enters the next reaction in the form of existing reaction liquid, so that the purification and separation steps are omitted, and the operation procedures are reduced. The invention takes sodium bicarbonate as an acid-binding agent for the reaction of an intermediate (II) and D-cysteine hydrochloride, and simultaneously adjusts the pH of a system and forms salt with carboxylic acid. After the condensation reaction of the intermediate (II) and D-cysteine hydrochloride is finished, directly standing and layering to obtain a water solution containing high-purity cefminox sodium, and adding an antisolvent to precipitate a heptahedonic sponox sodium crystal. The invention takes 7-amino-3- [ (acetoxyl) methyl ] -8-oxo-5-thia-1-azabicyclo [4,2,0] -2-alkene-2-carboxylic acid (7-ACA) as the starting material, compared with the synthesis process taking 7-phenylacetylamino-3-chloromethyl-4-cephalosporanic acid p-methoxybenzyl ester (GCLE) as the starting mother nucleus, the invention has no step of removing protecting group, has shortened synthesis route, and compared with the synthesis process taking 7 beta-amino-7 alpha-methoxy-3- (1-methyl-1H-tetrazole-5-thiomethyl) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-alkene-2-formic acid diphenylmethyl ester (7-MAC) as the starting mother nucleus Compared with the prior art, the method can save high raw material cost.
The invention has the beneficial effects that:
(1) boron trifluoride is used as an initiator for the reaction of 7-ACA and 1-methyl-5-mercapto tetrazole, so that the reaction selectivity and the reaction activity are effectively improved;
(2) compared with a bromoacylation reagent, dichloroacetyl chloride is used as an acylation reagent of 7 beta-amino, so that the reaction toxicity is reduced; meanwhile, a series of elimination and rearrangement dechlorination are carried out when dichloroacetyl chloride reacts on the ketene imine intermediate, so that a required minox sodium structure is formed;
(3) low-toxicity sodium methoxide is used as a methoxylation reagent, methoxy is directly introduced at the low temperature of-40 to-70 ℃ in a ketene imine intermediate mode, carboxyl is simply protected through silanization, the complex process that the carboxyl and amino are protected through a stable protection group in the original various sodium minoxide processes is directly improved, deprotection is carried out through a catalyst after methyl oxidation, the reaction rate is controllable, and the conversion rate is high;
(4)7 beta-dichloroacetamido-7 alpha-methoxyl-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid enters the next reaction in a form of existing in reaction liquid, and purification and separation operations are omitted;
(5) sodium bicarbonate is used as an acid-binding agent for the reaction of 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid and D-cysteine hydrochloride, and the pH of the system is adjusted to form salt with the carboxylic acid;
(6)7 beta-dichloroacetamido-7 alpha-methoxyl-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid and D-cysteine hydrochloride are subjected to condensation reaction, standing and layering are carried out to obtain a water solution containing high-purity cefminox sodium, and a heptahedron cefminox sodium crystal can be directly separated out after an anti-solvent is added.
Detailed Description
The technical solutions of the present invention are described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The preparation method of cefminox sodium of the embodiment comprises the following steps:
(1) at normal temperature, 45g of 7-amino-3- [ (acetoxyl) methyl ] -8-oxo-5-thia-1-azabicyclo [4,2,0] -2-ene-2-carboxylic acid (7-ACA) and 200g of dimethyl carbonate are mixed and stirred uniformly, 31g of 1-methyl 5-mercapto-tetrazole is added, the mixture is stirred and heated to 30 ℃, 128.5g of boron trifluoride (40%) is rapidly added, the temperature is controlled for reaction for 120min, ammonia water (15%) is slowly dripped into the system after the reaction is finished until the system is turbid, crystal growth is carried out for 30min, suction filtration is carried out, 210g of acetone is beaten, washed, the solvent is filtered out, vacuum drying is carried out, and 46.5g of intermediate 7-amino-3- (1-methyl-1-H-tetraaza-5-thiomethyl) -3-cephem-4-carboxylic acid is obtained, the yield thereof was found to be 118.5%.
(2) At room temperature, 36.5g of intermediate 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid is added into 195.5g of ethyl acetate, the mixture is stirred and mixed uniformly, the temperature is reduced to-10 ℃, 78.5g of dichloroacetyl chloride is slowly dripped, after the dripping, the heat preservation reaction is carried out for 120min, 115 triethylamine is added into the system, the PH is adjusted to 5.3-5.7, the mixture is quickly stirred and crystallized, filtered, washed by 190g of ethyl acetate and dried in vacuum, 51g of intermediate 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid is obtained, and the yield is 138.8%.
(3) Dispersing 20g of intermediate 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid in 330ml of trichloromethane at room temperature, cooling to-50 ℃, dropwise adding 15g of quinoline, controlling the temperature, adding 20g of phosphorus pentachloride, reacting for 50min, dropwise adding 70g of sodium methoxide solution, reacting for 90min, depressurizing to spin out the trichloromethane after the reaction is finished, heating to 40 ℃, adding 40g of trimethylchlorosilane, keeping the temperature, reacting for 30min, transferring into hydrolysate precooled to-10 ℃ (16.5g of water and 79.5g of ethyl acetate), stirring, hydrolyzing for 200min, standing for layering, discarding the water phase, and remaining intermediate 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5) -thiomethyl) -3-cephem-4-carboxylic acid.
(4) Adding 80g of purified water into the organic phase containing the intermediate 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (3), stirring and heating to 40 ℃, adjusting the pH to 7.0-8.5 by using sodium bicarbonate, adding 7g of D-cysteine hydrochloride, controlling the temperature to react for 5 hours, standing and layering after the reaction is finished, discarding the organic phase, transferring the aqueous phase into a crystallization tank, reducing the stirring speed, adding 48ml of isopropanol, stirring for 3 hours, separating out crystals, performing suction filtration, washing with isopropanol, and performing vacuum drying to obtain 18.6g of heptahedonic sodium spore.
Example 2
The preparation method of cefminox sodium of the embodiment comprises the following steps:
(1) at normal temperature, 40g of 7-amino-3- [ (acetoxyl) methyl ] -8-oxo-5-thia-1-azabicyclo [4,2,0] -2-ene-2-carboxylic acid (7-ACA) and 220g of dimethyl carbonate are mixed and stirred uniformly, 31.5g of 1-methyl 5-mercapto-tetrazole is added, the mixture is stirred and heated to 30 ℃, 127.7g of boron trifluoride (40%) is rapidly added, the temperature is controlled for reaction for 120min, ammonia water (15%) is slowly dripped into the system after the reaction is finished until the system is turbid, the crystal growth is carried out for 30min, the mixture is filtered, 200g of acetone is beaten and washed, the solvent is filtered out, and the mixture is dried in vacuum, so as to obtain 48g of intermediate 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid, the yield thereof was found to be 120%.
(2) Adding 37.5g of intermediate 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid into 191.5g of ethyl acetate at room temperature, uniformly stirring, cooling to-15-0 ℃, slowly adding 86.2g of dichloroacetyl chloride dropwise, keeping the temperature for reaction for 120min after finishing dropwise adding, adding 113.8 triethylamine into the system, adjusting the pH to 5.3-5.7, quickly stirring for crystallization, performing suction filtration, washing with 182g of ethyl acetate, and performing vacuum drying to obtain 52.5g of intermediate 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid with the yield of 140%.
(3) Dispersing 21.5g of intermediate 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid in 350ml of trichloromethane at room temperature, cooling to-40-70 ℃, dropwise adding 15.2g of quinoline, controlling the temperature, adding 22g of phosphorus pentachloride, reacting for 50min, dropwise adding 67g of sodium methoxide solution, reacting for 90min, decompressing and spinning out the trichloromethane after the reaction is finished, heating to 40 ℃, adding 41.9g of trimethylchlorosilane, preserving heat, reacting for 30min, transferring into hydrolysate (15.6g of water and 81.7g of ethyl acetate) which is precooled to-10 ℃, stirring and standing for 200min, layering, discarding the water phase, and remaining intermediate 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetrad-tetra-acetamido-1-H-tetrad-amino-3-carboxylic acid An organic phase of N-5-thiomethyl) -3-cephem-4-carboxylic acid.
(4) And (3) adding 77g of purified water into the organic phase containing the intermediate 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (3), stirring and heating to 30 ℃, adjusting the pH to 7.0-8.5 by using sodium bicarbonate, adding 5.7g of D-cysteine hydrochloride monohydrate, controlling the temperature to react for 5 hours, standing and layering after the reaction is finished, discarding the organic phase, transferring the aqueous phase into a crystallization tank, reducing the stirring speed, adding 45ml of isopropanol, stirring for 3 hours, separating out crystals, performing suction filtration, washing with the isopropanol, and performing vacuum drying to obtain 20.3g of heptaspore minox sodium.
Example 3
The preparation method of cefminox sodium of the embodiment comprises the following steps:
(1) at normal temperature, 50g of 7-amino-3- [ (acetoxyl) methyl ] -8-oxo-5-thia-1-azabicyclo [4,2,0] -2-ene-2-carboxylic acid (7-ACA) and 250g of dimethyl carbonate are mixed and stirred uniformly, 32g of 1-methyl 5-mercapto-tetrazole is added, the mixture is stirred and heated to 30 ℃, 125g of boron trifluoride (40%) is rapidly added, the temperature is controlled for reaction for 120min, ammonia water (15%) is slowly dripped into the system after the reaction is finished until the system is turbid, crystal growth is carried out for 30min, suction filtration is carried out, 200g of acetone is beaten and washed, a solvent is filtered out, vacuum drying is carried out, and 47g of intermediate 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid is obtained, the yield thereof was found to be 119.2%.
(2) At room temperature, 38g of intermediate 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid is added into 185g of ethyl acetate, the mixture is stirred and mixed uniformly, the temperature is reduced to-10 ℃, 83.5g of dichloroacetyl chloride is slowly dripped, after the dripping is finished, the reaction is carried out for 120min under the condition of heat preservation, 117.5 g of triethylamine is added into the system, the PH is adjusted to 5.3-5.7, the mixture is quickly stirred and crystallized, is filtered, washed by 200g of ethyl acetate and dried in vacuum, and 54.3g of intermediate 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid is obtained, wherein the yield is 142%.
(3) Dispersing 21g of intermediate 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid in 340ml of trichloromethane at room temperature, cooling to-50 ℃, dropwise adding 16g of quinoline, controlling the temperature, adding 21g of phosphorus pentachloride, reacting for 50min, dropwise adding 65g of sodium methoxide solution, reacting for 90min, decompressing and spinning out the trichloromethane after the reaction is finished, heating to 40 ℃, adding 43g of trimethylchlorosilane, keeping the temperature, reacting for 30min, transferring into hydrolysate precooled to-10 ℃ (15g of water and 82.5g of ethyl acetate), stirring, hydrolyzing for 200min, standing for layering, discarding the water phase, and remaining intermediate 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5) containing the intermediate -thiomethyl) -3-cephem-4-carboxylic acid.
(4) And (3) adding 78g of purified water into the organic phase containing the intermediate 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (3), stirring and heating to 40 ℃, adjusting the pH to 7.0-8.5 by using sodium bicarbonate, adding 6.5g D-cysteine hydrochloride, controlling the temperature to react for 5 hours, standing and layering after the reaction is finished, discarding the organic phase, transferring the aqueous phase into a crystallization tank, reducing the stirring speed, adding 47ml of isopropanol, stirring for 3 hours, separating out crystals, performing suction filtration, washing with isopropanol, and performing vacuum drying to obtain 19.7g of heptahedonic sodium spore.
The quality of cefminox sodium prepared according to the procedure of examples 1 to 3 is as shown in Table 1 below:
table 1:
the above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A preparation method of cefminox sodium is characterized by comprising the following steps: the synthetic route is as follows:
wherein, the compound of formula (III), x is 0 or 1, y is 0 or 1;
the method comprises the following steps:
(1) dispersing a compound with a structure shown in a formula (VII) in an organic solvent A, stirring and uniformly mixing to prepare a solution or a suspension, adding a compound with a structure shown in a formula (VIII), stirring, quickly adding a reagent A into the system at the temperature of 10-30 ℃, stirring for reacting for 2 hours, dropwise adding a reagent B into the system after the reaction is finished for crystallization, filtering, pulping and washing the solvent B, filtering out the solvent, and drying in vacuum to obtain a compound with a structure shown in a formula (VI);
the organic solvent A is one or a combination of more of methanol, acetonitrile, acetone, tetrahydrofuran, dimethyl carbonate, N-dimethylformamide and N, N-dimethylacetamide;
the solvent B is one or a combination of acetone, water, tetrahydrofuran and ethyl acetate;
the reagent A is one of boron trifluoride, aluminum trichloride, zinc chloride and boron tribromide;
the reagent B is one of ammonia water, triethylamine, diisopropylethylamine, pyridine and N, N-dimethyl-4-pyridylamine;
(2) dispersing the compound with the structure shown in the formula (VI) prepared in the step (1) in an organic solvent C, uniformly stirring, slowly dropwise adding the compound with the structure shown in the formula (V), controlling the temperature to be-15-0 ℃ for reaction, adding a reagent C into the system after the reaction is finished, adjusting the pH, precipitating crystals, filtering, leaching a filter cake with a solvent D, and drying to obtain the compound with the structure shown in the formula (IV);
the organic solvent C is one or a combination of more of ethyl acetate, acetonitrile, acetone, tetrahydrofuran, dimethyl carbonate, N-dimethylformamide and N, N-dimethylacetamide;
the reagent C is one of triethylamine, diisopropylethylamine, pyridine, N-dimethyl-4-pyridylamine, phenylethylamine and benzhydrylamine;
the solvent D is one or a combination of acetone, ethyl acetate, tetrahydrofuran and acetonitrile;
(3) dispersing the compound with the structure shown in the formula (IV) prepared in the step (2) in an organic solvent E, uniformly stirring, cooling to-40-70 ℃, dropwise adding quinoline as an acid-binding agent, adding phosphorus pentachloride, performing chlorination stirring reaction for 40-60 min, monitoring residues by thin-layer chromatography (TLC), dropwise adding a methanol solution containing sodium methoxide, performing methoxylation stirring reaction for 60-90 min, performing rotary evaporation under reduced pressure to remove the solvent D, heating the system to 20-40 ℃, adding a reagent D, performing temperature control reaction for 30min, transferring the system into a hydrolysate which is pre-cooled to-10 ℃, wherein the hydrolysate contains a solvent F and purified water, performing high-speed stirring hydrolysis for 150-200 min, standing for layering, and discarding an aqueous phase containing salt and a leaving group to obtain an organic phase containing the compound with the structure shown in the formula (II);
the organic solvent E is one or a combination of more of dichloromethane, trichloromethane, carbon tetrachloride, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide;
the reagent D is one of trimethylchlorosilane, trimethylbromosilane and trimethyliodosilane;
the solvent F is one of ethyl acetate, acetonitrile, tetrahydrofuran and acetone;
(4) adding purified water into the solution containing the compound with the structure shown in the formula (II) prepared in the step (3), uniformly stirring, heating to 20-40 ℃, adjusting the pH to 7.0-8.5 by using sodium bicarbonate, adding the compound with the structure shown in the formula (III), stirring at a controlled temperature, carrying out condensation reaction for 3-6 h, standing for layering after the reaction is finished, discarding an organic phase, transferring a water phase into a crystallization tank, adding a solvent G at a low stirring speed, precipitating crystals, filtering, washing by using the solvent G, and drying under reduced pressure to obtain heptaspore minox sodium with the structure shown in the formula (I);
the solvent G is one or a combination of more of ethanol, propanol, glycol, isopropanol and glycerol;
compounds of formula (iii) are anhydrous D-cysteine (x ═ 0, y ═ 0), anhydrous D-cysteine hydrochloride (x ═ 1, y ═ 0), or D-cysteine hydrochloride monohydrate (x ═ 1, y ═ 1).
2. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: in the step (1), the molar ratio of the compound with the structure of the formula (VII) to the compound with the structure of the formula (VIII) is 1 (1.5-3).
3. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: in the step (1), the mass ratio of the compound with the structure shown in the formula (VII) to the organic solvent A is 1g (3-6); the ratio of the compound with the structure of the formula (VII) to the solvent B is 1g (5-10) ml; the mass ratio of the compound with the structure of the formula (VII) to the reagent A is 1g (1-4 g); the mass ratio of the compound with the structure of the formula (VII) to the reagent B is 1g: (2-5) g.
4. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: in the step (2), the molar ratio of the compound with the structure of the formula (VI) to the compound with the structure of the formula (V) is 1 (1.5-4).
5. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: in the step (2), the ratio of the compound with the structure of the formula (VI) to the organic solvent C is 1g (7-11) ml; the mass ratio of the compound with the structure of the formula (VI) to the solvent D is 1g (4-8); the mass ratio of the compound with the structure of the formula (VI) to the reagent C is 1g (1.5-3 g).
6. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: in the step (3), the ratio of the compound with the structure shown in the formula (IV) to the residual mass of the system after reduced pressure rotary evaporation is 1g (5-10 g); the proportion of the organic phase to the aqueous phase of the hydrolysate is 1g (5-10 g).
7. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: in the step (3), the molar ratio of the compound with the structure shown in the formula (IV) to the phosphorus pentachloride is 1 (2-6); the molar ratio of the compound with the structure of formula (IV) to sodium methoxide is 1 (10-16); the molar ratio of the compound with the structure shown in the formula (VII) to quinoline is 1 (2-6).
8. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: in the step (3), the ratio of the compound with the structure of the formula (IV) to the organic solvent E is 1g (15-25) ml; the mass ratio of the compound with the structure of the formula (IV) to the reagent D is 1g (1-5 g).
9. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: in the step (4), the molar ratio of the compound with the structure of formula (IV) to the compound with the structure of formula (III) is 1 (1.1-3); the ratio of the compound with the structure of the formula (IV) to the solvent G is 1G (1.5-3.5) ml.
10. The method for preparing cefminox sodium according to claim 1, which comprises the following steps: the method comprises the following steps:
(1) 40-50g of 7-amino-3- [ (acetoxy) methyl ] -8-oxo-5-thia-1-azabicyclo [4,2,0] -2-ene-2-carboxylic acid were dispersed in 250g of 200,250 g of dimethyl carbonate, stirring and mixing evenly, adding 30-32g of 1-methyl-5-mercapto tetrazole, stirring, under the condition of 10-30 ℃, rapidly adding boron trifluoride into the system, stirring and reacting for 2 hours, dropwise adding ammonia water into the system after the reaction is finished, crystallizing, filtering, pulping and washing with acetone, filtering out a solvent, and drying in vacuum to obtain 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid;
(2) dispersing 36.5-38.5g of 7-amino-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (1) in 200g of ethyl acetate, uniformly stirring, slowly dropwise adding 75-90g of dichloroacetyl chloride, controlling the temperature to be minus 15-0 ℃ for reaction, adding 120g of triethylamine into the system after the reaction is finished, adjusting the pH, separating out crystals, filtering, leaching a filter cake with 215g of ethyl acetate, and drying to obtain 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid;
(3) dispersing 20-22g of 7 beta-dichloroacetamido-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (2) in 360ml of trichloromethane, uniformly stirring, cooling to-40 to-70 ℃, dropwise adding quinoline as an acid-binding agent, adding phosphorus pentachloride, carrying out chlorination and stirring reaction for 40-60 min, monitoring residues by thin-layer chromatography (TLC), dropwise adding a methanol solution containing sodium methoxide, carrying out methoxylation and stirring reaction for 60-90 min, carrying out rotary evaporation under reduced pressure to remove ethyl acetate, heating the system to 20-40 ℃, adding trimethylchlorosilane, carrying out temperature control reaction for 30min, transferring the system into a hydrolysate which is already cooled to-10 ℃, wherein the hydrolysate contains ethyl acetate and purified water, stirring at a high speed for hydrolysis for 150-200 min, standing for layering, and removing a water phase containing salt and a leaving group to obtain an organic phase containing 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid;
(4) adding purified water into the solution containing 7 beta-dichloroacetamido-7 alpha-methoxy-3- (1-methyl-1-H-tetranitrogen-5-thiomethyl) -3-cephem-4-carboxylic acid prepared in the step (3), uniformly stirring, heating to 20-40 ℃, adjusting the pH to 7.0-8.5 by using sodium bicarbonate, adding 3-10g of D-cysteine hydrochloride monohydrate, stirring at a controlled temperature, carrying out condensation reaction for 3-6H, standing for layering, discarding an organic phase, transferring a water phase into a crystallization tank, adding isopropanol at a low stirring speed, precipitating crystals, filtering, washing with isopropanol, and drying under reduced pressure to obtain (6R, 7S) -7 beta- [ (S) -2- (2-amino-2-carboxyethylmercapto) acetamido ] -7 alpha-methoxy-3 - [ (1-methyl-1H-5-yl) thio ] methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-ene-2-carboxylic acid sodium salt structural heptahydroximino sodium.
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| US3960845A (en) * | 1974-03-22 | 1976-06-01 | Sankyo Company Limited | Process for preparing 7β-acylamino-7α-alkoxycephalosporins or 6β-acylamino-6α-alkoxypenicillins |
| CN101302226A (en) * | 2008-06-12 | 2008-11-12 | 齐鲁安替制药有限公司 | Preparation of cephamycine intermediate compound |
| CN102268021A (en) * | 2011-06-16 | 2011-12-07 | 哈药集团制药总厂 | Preparation method of cefminox sodium |
| CN103709179A (en) * | 2013-12-17 | 2014-04-09 | 福建省福抗药业股份有限公司 | Synthesis and purification method of cefmetazole sodium |
| CN105330677A (en) * | 2015-12-15 | 2016-02-17 | 南京金浩医药科技有限公司 | Preparation method of cefmetazole |
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| US3960845A (en) * | 1974-03-22 | 1976-06-01 | Sankyo Company Limited | Process for preparing 7β-acylamino-7α-alkoxycephalosporins or 6β-acylamino-6α-alkoxypenicillins |
| CN101302226A (en) * | 2008-06-12 | 2008-11-12 | 齐鲁安替制药有限公司 | Preparation of cephamycine intermediate compound |
| CN102268021A (en) * | 2011-06-16 | 2011-12-07 | 哈药集团制药总厂 | Preparation method of cefminox sodium |
| CN103709179A (en) * | 2013-12-17 | 2014-04-09 | 福建省福抗药业股份有限公司 | Synthesis and purification method of cefmetazole sodium |
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