CN101619069A - Preparation method of cefotiam hexetil hydrochloride - Google Patents
Preparation method of cefotiam hexetil hydrochloride Download PDFInfo
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Abstract
The invention discloses a preparation method of cefotiam hexetil hydrochloride, comprising the following steps: carrying out reaction on cefotiam an acetate to prepare cefotiam salt; carrying out reaction on the cefotiam salt and carbonic acid-1-iodine ethyl ester cyclohexyl to prepare cefotiam hexetil in the presence of potassium carbonate; and crystallizing and purifying the obtained cefotiam hexetil to prepare and obtain the cefotiam hexetil hydrochloride. The preparation method has simple operation in the preparation process; in particular the part of purifying the reaction product mainly adopts the combination of extraction and crystallization to obtain the finished product with high purity and good yield without being purified by chromatographic column. The prepared cefotiam hexetil hydrochloride has high purity, and is detected to have less than 3 percent of total impurity and less than 6 percent of the related impurity in the Japanese pharmacopeia according to the HPLC method, therefore, the prepared product is superior to the standard of the Japanese pharmacopeia. The yield of the prepared cefotiam hexetil is about 60 percent with low production cost, therefore, the invention is favorable for industrialized production.
Description
Technical field
The present invention relates to the medicine field of antibiotics, be specifically related to the preparation of cefotiam hexetil, relate in particular to a kind of preparation method of cefotiam hexetil hydrochloride.
Background technology
Cefotiam (CTM) is a second generation cephalosporin, and its structural formula is suc as formula shown in (I), and the cefotiam ethyl esterization can obtain cefotiam hexetil (Cefotiam hexetil), and its its structural formula is suc as formula shown in (II).
Cefotiam hexetil can be made into oral antibiotic, this oral antibiotic self there is no anti-microbial effect, being oral back is hydrolyzed to cefotiam rapidly and is absorbed at intestinal mucosa, cefotiam is identical with oral in the past cynnematin to the anti-microbial activity of gram-positive and negative bacterium, and stable to β-Nei Xiananmei, various bacteria such as clinical isolating streptococcus aureus, coagulase negative staphylococcus, streptococcus pneumoniae, gonococcus, anti-Ampicillin Trihydrate gonococcus all there is stronger anti-microbial activity.The cefotiam hexetil oral antibiotic can be treated infection such as responsive microbial pharyngolaryngitis, acute bronchitis, tonsillitis, pneumonia, pyelonephritis, urocystitis, pouring mattress urethritis, purulence acne, furuncle, erysipelas, perianal abscess, mazoitis, ocular infection or otitis media.
Therefore the cefotiam hexetil poor stability all is to adopt cefotiam hexetil hydrochloride when preparation and use, and the structural formula of cefotiam hexetil hydrochloride is suc as formula shown in (III).
Document (THE JOURNAL OF ANTIDIOTICS VOL.XXXIX NO.9,1986) provide a kind of method in by cefotiam potassium and carbonic acid-1-iodo-ethyl ester cyclohexyl prepared in reaction cefotiam hexetil in DMF, but this preparation method's yield is low, and the byproduct that obtains isomer Δ especially
2Higher relatively, greater than Japanese Pharmacopoeia specified standards 2%.
Also provide a kind of method in the document (THE JOURNAL OF ANTIDIOTICS VOL.XL NO.1,1986), and can control especially isomer Δ of byproduct by cefotiam potassium and carbonic acid-1-iodo-ethyl ester cyclohexyl prepared in reaction cefotiam hexetil in DMF
2Content, but still there is the lower problem of yield (yield has only 20%) in this method and complicated and needed post to handle to the product post-processing operation, is not suitable for industrialized production.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of method that adopts cefotiam salt to prepare high purity, high yield cefotiam hexetil hydrochloride is provided, this method is simple, be applicable to industrialization.
Above-mentioned purpose of the present invention is achieved by following scheme:
A kind of preparation method of cefotiam hexetil hydrochloride, this method comprises the steps:
(1) cefotiam and acetate prepared in reaction obtain cefotiam salt;
(2) step (1) is prepared gained cefotiam salt in the presence of salt of wormwood, and carbonic acid-1-iodo-ethyl ester cyclohexyl generation esterification;
(3) after the esterification of step (2) finishes, add organic solvent in reaction solution, the extraction back keeps organic solvent layer; Add hydrochloric acid in this organic solvent layer, the hydrochloric acid layer is collected in the extraction back;
(4) the hydrochloric acid layer pH that step (3) is obtained transfers to slightly acidic, uses organic solvent extraction then, the collected organic layer extraction liquid;
(5) with step (4) gained organic layer extraction liquid through crystallization, filter and to obtain cefotiam hexetil hydrochloride.
In the above-mentioned steps (1), acetate is selected sodium-acetate or Potassium ethanoate or the like acetate commonly used, prepares corresponding cefotiam salt after reacting with cefotiam, and the structural formula of cefotiam salt is suc as formula shown in (IV), and wherein M is Na, K etc.
In the above-mentioned steps (1), the reaction mol ratio of acetate and cefotiam is: cefotiam: acetate=1: (1～1.5).
In the above-mentioned steps (1), cefotiam and acetate react, and its reaction solvent can be selected one or more the mixed solvent in methyl alcohol, ethanol and the acetonitrile, particular methanol, concrete operations are: cefotiam is dissolved in the methyl alcohol preparation cefotiam methanol solution; Acetate is dissolved in the methyl alcohol preparation acetate methanol solution; Cefotiam methanol solution and the mixing of acetate methanol solution are reacted, prepare cefotiam salt; The amount ratio of cefotiam and reaction solvent is 1: 8～1: 12 (quality: volume).
In the above-mentioned steps (1), the temperature of described reaction can be selected-10～-5 ℃, and the reaction times is 1.5～2h.
In the above-mentioned steps (1), after reaction finishes, the cefotiam salt that generates is carried out crystallization treatment obtain cefotiam salt solid, crystallization treatment can adopt any one or more than one the mixed solvent in methyl alcohol, ethanol, Virahol, acetone, the ethyl acetate is joined in the reaction solution ,-5～10 ℃ of crystallizations 1～2 hour; The used solvent and the volume ratio of reaction solvent (methyl alcohol) are 1: 1 during crystallization treatment; Preferred solvent is a Virahol during crystallization treatment.
In the above-mentioned steps (2), salt of wormwood plays catalyzer, and the consumption of salt of wormwood is a cefotiam salt: salt of wormwood=1: (0.5～1), mol ratio.
In the above-mentioned steps (2), the structural formula of carbonic acid-1-iodo-ethyl ester cyclohexyl is shown in formula V, and the reaction mol ratio of cefotiam salt and carbonic acid-1-iodo-ethyl ester cyclohexyl is 1: (1～2).
In the above-mentioned steps (2), cefotiam salt is in the presence of salt of wormwood, and carbonic acid-1-iodo-ethyl ester cyclohexyl generation esterification, this esterification adopts N, and dinethylformamide (DMF) or N,N-dimethylacetamide (DMA) are as reaction solvent, concrete operations are: with DMF or DMA as solvent, in solvent, add cefotiam salt, add Anhydrous potassium carbonate and carbonic acid-1-iodo-ethyl ester cyclohexyl after the dissolving again, be stirred to reaction and finish; The amount ratio of cefotiam salt and reaction solvent (DMF or DMA) is 1: 10～1: 12 (quality: volume).
In the above-mentioned steps (2), the temperature of esterification is-5～10 ℃, and the reaction times is 5～15min, and the product of esterification is cefotiam hexetil.
The cefotiam hexetil poor stability, therefore when preparation and use, all be to adopt cefotiam hexetil hydrochloride, how in preparation process, purification step to be selected and condition optimizing, can be the key point that obtain the high purity cefotiam hexetil hydrochloride, also be an important research point of the present invention.
The present invention goes on foot purifying by the step among the above-mentioned preparation method (3)～(5) three, thereby prepares highly purified cefotiam hexetil hydrochloride, this three steps purifying is done further explained in detail below:
Above-mentioned steps (3) is the first step of the whole purge process of the present invention, at first utilize mixture and the water-soluble reaction thing (cefotiam of organic solvent with cefotiam hexetil and fat-soluble reactant, inorganic salt) separate, adding hydrochloric acid soln again and make it make it generate water-soluble stronger hydrochloride and other fat-soluble reactants separate, is purer cefotiam hexetil hydrochloride in the hydrochloric acid soln.
In the above-mentioned steps (3), esterification adds organic solvent after finishing in reaction solution, the cefotiam hexetil that esterification is generated is extracted into organic solvent layer from reaction solution, and then with hydrochloric acid cefotiam hexetil is extracted from organic solvent layer, be extracted in the hydrochloric acid layer; Described organic solvent can be selected any one or more than one the mixed solvent in acetone, ethyl acetate, the methylene dichloride, ethyl acetate; Described organic solvent mainly plays extraction, the consumption of organic solvent can be selected 1: 30～1: 50 and (at first utilize HPLC to detect product amount in the solution, the extraction solution consumption of 1g product is 30～50ml) described hydrochloric acid, selects pH can obtain better effect of extracting at the hydrochloric acid below 2; The consumption of described hydrochloric acid can be selected 1: 40～1: 50 (the same).
Above-mentioned steps (4) is second step of whole purge process, and purpose is to prepare for next step purifying; The hydrochloric acid layer pH that step (3) is obtained transfers to slightly acidic, cefotiam hexetil hydrochloride becomes fat-soluble cefotiam hexetil again, can be extracted in the organic solvent, described slightly acidic is a notion known in those skilled in the art, refer to that promptly pH is about 5～6, hydrochloric acid layer pH regulator to 5.5～6.5 that the present invention preferably obtains step (3).
In the above-mentioned steps (4), can adopt alkali lye that the hydrochloric acid layer pH that step (3) obtains transferred to slightly acidic, described alkali lye can adopt any one or more than one the mixed alkali liquor in sodium bicarbonate, sodium hydroxide or the potassium hydroxide; The sodium hydrogen carbonate solution of the preferred 0.1～0.3mol/L of alkali lye.
In the above-mentioned steps (4), the effect of organic solvent is an abstraction purification, and organic solvent can adopt any one or more than one the mixed solvent in acetone, ethyl acetate or the methylene dichloride, preferred methylene dichloride; The preferable amount of organic solvent is: the ratio of the described cefotiam of organic solvent and step (1) is 1: 20 (weight: volume).
In the above-mentioned steps (5),, separate out crystallization, make the preparation of cefotiam hexetil hydrochloride by regulating pH; The pH that adopts hydrogen chloride solution to regulate the organic layer extraction liquid is 1～2.
In the above-mentioned steps (5), the crystalline effect is exquisite the purification, the solvent that adopts during crystallization can be selected one or more the mix reagent in methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, methylene dichloride, ether, isopropyl ether, sherwood oil or the normal hexane, all can realize the present invention, any one or more than one mixed solvent in particular methanol, acetone, ethyl acetate or the methylene dichloride is more preferably methylene dichloride.
In the above-mentioned steps (5), the temperature during crystallization is a room temperature, and as 20～30 ℃, crystallization time is 1～3 hour.
Compared with prior art, the present invention has following beneficial effect:
1. the inventive method prepares gained cefotiam hexetil hydrochloride purity height, detects through the HPLC method, and the product total impurities that obtains is less than 3%, and Japanese Pharmacopoeia regulation relative substance illustrates that less than 6% the product of the inventive method preparation is better than the Japanese Pharmacopoeia standard;
The inventive method prepare the gained cefotiam hexetil hydrochloride yield about 60%, production cost is low, helps suitability for industrialized production;
3. the purifying to cefotiam hexetil hydrochloride mainly is to adopt the chromatographic column purifying in the traditional method, not only complicated operation bothers, and the used time is long, and the column chromatography productive rate is low, with a toll of 50%, and the present invention adopts extraction and crystallization phases bonded method, not only purge process is simple to operate, and the used time is short, and the product loss is few, only be about 12%, can obtain purity height, finished product that yield is good;
4. the present invention optimizes extracting used organic solvent in extraction and crystallisation process, finally obtains appropriate organic solvent (methylene dichloride), thereby makes water miscible substance dissolves, makes solvent crystallization become possibility.
Embodiment
Below in conjunction with specific embodiment the present invention is done description further, but specific embodiment is not done any qualification to the present invention.
The preparation of embodiment 1 cefotiam hexetil hydrochloride
The preparation method of present embodiment cefotiam hexetil hydrochloride, its concrete steps are as follows:
(1) add methyl alcohol 500ml in the 2000ml reaction flask, be cooled to-2 ℃, add cefotiam chloride 50g (0.084mol), dissolving obtains the cefotiam chloride methanol solution; Simultaneously Potassium ethanoate is dissolved into and prepares 5% potassium acetate methanol solution in the methanol solution; 5% potassium acetate methanol solution is got 250ml (0.105mol), slowly be added drop-wise in the cefotiam chloride methanol solution, drip off in 1 hour, stir 30min, add the 500ml Virahol, stir 1h, place-5 ℃ of following crystallizations 1 hour, filter, filter cake places 40 ℃ of vacuum drying ovens to be dried to constant weight, obtains cefotiam sylvite 39.4g;
(2) in the 500ml reaction flask, add DMF (200ml), be cooled to 3 ℃, add cefotiam potassium 20g (0.035mol), be stirred to dissolving fully, add Anhydrous potassium carbonate 2.42g (0.018mol), add carbonic acid-1-iodo-ethyl ester cyclohexyl 21.14g (0.07mol), stir, carry out esterification;
(3) behind the esterification 15min, add ethyl acetate 500ml in reaction solution, and add purified water 500ml, standing demix is collected ethyl acetate layer; Add 0.1mol/L hydrochloric acid 1000ml in ethyl acetate layer, stir, standing demix is collected the hydrochloric acid layer.
(4) in above-mentioned hydrochloric acid layer, add ethyl acetate 700ml, and regulate total system pH value to 6.5, standing demix then with 5% sodium hydrogen carbonate solution, collect ethyl acetate layer, ethyl acetate layer with anhydrous magnesium sulfate, the dry removal of impurities of activated carbon, is filtered, and filtrate is concentrated into 50g;
(5) add methyl alcohol 40ml in above-mentioned 50g concentrated solution, it is 1 that hydrogen chloride solution is regulated pH, and stirring and dissolving is complete, adds isopropyl ether 200ml, and stirred crystallization is filtered, and gets white cefotiam hexetil hydrochloride 11.9g.
In the present embodiment, the cefotiam hexetil hydrochloride yield is 59.5%, and white cefotiam hexetil hydrochloride detects with HPLC, and its isomery ratio is 1: 1.13, and purity is 98%.
The preparation of embodiment 2 cefotiam hexetil hydrochlorides
The preparation method of present embodiment cefotiam hexetil hydrochloride, its concrete steps are as follows:
(1) add methyl alcohol 500ml in the 2000ml reaction flask, be cooled to-2 ℃, add cefotiam chloride 50g (0.084mol), dissolving obtains the cefotiam chloride methanol solution; Simultaneously sodium-acetate is dissolved into and prepares 5% sodium acetate methanol solution in the methanol solution; 5% sodium acetate methanol solution is got 200ml, slowly be added drop-wise in the cefotiam chloride methanol solution, drip off in 1 hour, stir 30min, add the 500ml Virahol, stir 1h, place-5 ℃ of following crystallizations 1 hour, filter, filter cake places 40 ℃ of vacuum drying ovens to be dried to constant weight, obtains cefotiam sylvite 41.6g;
(2) in the 500ml reaction flask, add DMF 200ml, be cooled to 3 ℃, add cefotiam potassium 20g (0.035mol), be stirred to dissolving fully, add Anhydrous potassium carbonate 3.63g (0.027mol), add carbonic acid-1-iodo-ethyl ester cyclohexyl 21.14g (0.07mol), stir and carry out esterification;
(3) behind the esterification 10min, the ethyl acetate 700ml that in reaction solution, adds, and add purified water 350ml, standing demix is collected ethyl acetate layer; Add 0.2mol/L hydrochloric acid 500ml in ethyl acetate layer, stir, standing demix is collected the hydrochloric acid layer;
(4) in above-mentioned hydrochloric acid layer, add ethyl acetate 700ml, and regulate total system pH value to 6, standing demix then with 5% sodium hydrogen carbonate solution, collect ethyl acetate layer, ethyl acetate layer with anhydrous magnesium sulfate, the dry removal of impurities of activated carbon, is filtered, and filtrate being concentrated into remains to 50g;
(5) add methyl alcohol 40ml in above-mentioned 50g concentrated solution, hydrogen chloride solution is regulated total system pH to 1.5, and stirring and dissolving is complete, adds isopropyl ether 300ml, and stirred crystallization is filtered, and gets white cefotiam hexetil hydrochloride 12.1g.
In the present embodiment, the yield of white cefotiam hexetil hydrochloride is 60.5%, and white cefotiam hexetil hydrochloride detects with HPLC, and its isomery ratio is 1: 1.11, and purity is 97.5%.
The optimization of embodiment 3 extraction conditionss
A kind of preparation method of cefotiam hexetil hydrochloride, this method comprises the steps:
(1) cefotiam and acetate prepared in reaction obtain cefotiam salt;
(2) step (1) is prepared gained cefotiam salt in the presence of salt of wormwood, and carbonic acid-1-iodo-ethyl ester cyclohexyl generation esterification;
(3) after the esterification of step (2) finishes, add organic solvent in reaction solution, the extraction back keeps organic solvent layer; Add hydrochloric acid in this organic solvent layer, the hydrochloric acid layer is collected in the extraction back;
(4) the hydrochloric acid layer pH that step (3) is obtained transfers to slightly acidic, uses organic solvent extraction then, the collected organic layer extraction liquid;
(5) with step (4) gained organic layer extraction liquid through crystallization, filter and to obtain cefotiam hexetil hydrochloride.
Among the above-mentioned preparation method, (4) step wherein is the committed step of purge process, determined and product can be extracted into organic solvent layer to greatest extent, thereby crystallization obtains the cefotiam hexetil hydrochloride of high purity, high yield, so present embodiment is optimized two aspects of this step:
1, the extraction optimization of organic solvent
The organic solvent that present embodiment selects methylene dichloride, ethyl acetate, acetone, acetonitrile, methyl alcohol, Virahol, hexanaphthene and these several those skilled in the art of ether to be used always when carrying out extraction test compares test to them.
All with isopropyl ether as recrystallisation solvent, the hydrochloric acid layer pH that step (3) is obtained transfers to 5.8.
(1) the hydrochloric acid layer pH that step (3) is obtained transfers to 5.8, uses ethyl acetate extraction then, collects the ethyl acetate layer extraction liquid; The ethyl acetate layer extraction liquid is splashed into isopropyl ether solution, and the result has the indefinite form crystallization to separate out very soon, is gathered into agglomerate subsequently, sinks to container bottom, and dry back HPLC detects foreign matter content 37%.
(2) the hydrochloric acid layer pH that step (3) is obtained transfers to 5.8, uses acetone extract then, collects acetone layer extraction liquid; Acetone layer extraction liquid splashed into isopropyl ether solution, and the result has the crystallization of faint yellow indefinite form agglomerate to separate out very soon, sinks to container bottom, and dry back HPLC detects foreign matter content 56%.
(3) the hydrochloric acid layer pH that step (3) is obtained transfers to 5.8, uses dichloromethane extraction then, collects the dichloromethane layer extraction liquid; The dichloromethane layer extraction liquid is splashed into isopropyl ether solution, and the crystallization of the very fast adularescent indefinite form of result is separated out, and is suspended in the container, does not assemble, and leaves standstill 15min after being added dropwise to complete, and filters, and HPLC detects behind the crystallizing and drying, foreign matter content 2.1%.
(4) the hydrochloric acid layer pH that step (3) is obtained transfers to 5.8, then with hexanaphthene extraction, collecting ring hexane layer extraction liquid; Hexanaphthene layer extraction liquid splashed into isopropyl ether solution, only produce small amount of crystalline.
(5) the hydrochloric acid layer pH that step (3) is obtained transfers to 5.8, uses extracted with diethyl ether then, collects the ether layer extraction liquid; The ether layer extraction liquid is splashed into isopropyl ether solution, only produce small amount of crystalline.
Its excess-three kind organic solvent acetonitrile, methyl alcohol and Virahol all do not produce crystallization.
As can be seen from the above-described embodiment, these three kinds of organic solvents of acetonitrile, methyl alcohol and Virahol can not produce crystallization during as extraction agent; These four kinds of organic solvents of ethyl acetate, acetone, hexanaphthene and ether are during as extraction agent, and crystallization velocity is difficult to control, and product easily takes place to assemble and forms yellow grume; Methylene dichloride is during as extraction agent, the fast and product crystallization purity height of crystallization velocity, output height.
Therefore, the foregoing description has obtained optimum organic solvent extract---methylene dichloride by the screening to organic solvent extract commonly used.
2, the optimization of pH value of solution
As organic solvent extract, as recrystallisation solvent, the hydrochloric acid layer pH that step (3) is obtained transfers to respectively to less than 5.5,5.5～6.5 with greater than 6.5 (or 7) with isopropyl ether with methylene dichloride.
(1) the hydrochloric acid layer pH that step (3) is obtained transferred to pH less than 5.5 o'clock, and the muddy thickness of hydrochloric acid layer can't extract, and along with pH increases, solution is clarified gradually, and the while is thickness no longer.
(2) the hydrochloric acid layer pH that step (3) is obtained transfers to pH5.5～6.5 o'clock, and methylene dichloride can be extracted into organic layer with product more than 95%, after handling through secondary crystallization, can obtain purity height, product that productive rate is high.
(3) the hydrochloric acid layer pH that step (3) is obtained transfers to pH greater than 6.5 or at 7 o'clock, and HPLC detects that the poly-content that contains thing increases to 30% in the product.
By the foregoing description as can be seen, when PH 5.5～6.5 the time, not only can guarantee extraction fully, and foreign matter content is low in the product.
Claims (10)
1, a kind of preparation method of cefotiam hexetil hydrochloride is characterized in that this method comprises the steps:
(1) cefotiam and acetate prepared in reaction obtain cefotiam salt;
(2) step (1) is prepared gained cefotiam salt in the presence of salt of wormwood, and carbonic acid-1-iodo-ethyl ester cyclohexyl generation esterification;
(3) after the esterification of step (2) finishes, add organic solvent in reaction solution, the extraction back keeps organic solvent layer; Add hydrochloric acid in this organic solvent layer, the hydrochloric acid layer is collected in the extraction back;
(4) the hydrochloric acid layer pH that step (3) is obtained transfers to slightly acidic, uses organic solvent extraction then, the collected organic layer extraction liquid;
(5) with step (4) gained organic layer extraction liquid through crystallization, filter and to obtain cefotiam hexetil hydrochloride.
2, according to the described preparation method of claim 1, it is characterized in that in the described step (1), acetate is sodium-acetate or Potassium ethanoate, the reaction mol ratio of cefotiam and acetate is 1: 1～1.5.
3, according to the described preparation method of claim 1, it is characterized in that in the described step (2), the reaction mol ratio of cefotiam salt and salt of wormwood is 1: 0.5～1, the reaction mol ratio of cefotiam salt and carbonic acid-1-iodo-ethyl ester cyclohexyl is 1: 1～2.
4,, it is characterized in that in the described step (2) that esterification adopts N according to the described preparation method of claim 1, dinethylformamide or N, the N-N,N-DIMETHYLACETAMIDE is as reaction solvent, and esterification reaction temperature is-5～10 ℃, and reaction time of esterification is 5～15min.
5,, it is characterized in that organic solvent described in step (3) and the step (4) is any one or more than one the mixed solvent in acetone, ethyl acetate or the methylene dichloride according to the described preparation method of claim 1.
6,, it is characterized in that the pH of hydrochloric acid soln is less than 2 in the described step (3) according to the described preparation method of claim 1.
7, according to the described preparation method of claim 1, it is characterized in that in the described step (4), adopt alkali lye that the hydrochloric acid layer pH that step (3) obtains transferred to slightly acidic, described alkali lye is any one or more than one the mixed alkali liquor in sodium bicarbonate, sodium hydroxide or the potassium hydroxide.
8,, it is characterized in that in the described step (5) that using the pH of hydrogen chloride solution regulating step (4) gained organic layer extraction liquid is 1～2, carries out crystallization, filtration treatment then according to the described preparation method of claim 1.
9, according to the described preparation method of claim 1, it is characterized in that in the described step (5), adopt organic solvent that the organic layer extraction liquid is carried out crystallization treatment, described organic solvent is one or more the mix reagent in methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, methylene dichloride, ether, isopropyl ether, sherwood oil or the normal hexane.
10, according to the described preparation method of claim 1, it is characterized in that in the described step (5), Tc is 20～30 ℃, crystallization time is 1～3 hour.
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| CN101948476A (en) * | 2010-09-19 | 2011-01-19 | 苏州致君万庆药业有限公司 | Method for preparing cefotiam hexetil hydrochloride |
| CN101955493A (en) * | 2010-08-03 | 2011-01-26 | 宁宗超 | Method for preparing cefotiam hexetil hydrochloride and composition of cefotiam hexetil hydrochloride |
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| CN101948476A (en) * | 2010-09-19 | 2011-01-19 | 苏州致君万庆药业有限公司 | Method for preparing cefotiam hexetil hydrochloride |
| CN102127093A (en) * | 2010-12-22 | 2011-07-20 | 徐家祥 | Refining process for Cefotiam hexetil hydrochloride |
| CN102424687A (en) * | 2011-11-01 | 2012-04-25 | 湖南方盛制药股份有限公司 | Preparation method of cefotiam hexetil hydrochloride |
| CN103030650A (en) * | 2012-11-23 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing cefotiam hexetil and method for preparing cefotiam hexetil dihydrochloride |
| CN103641848A (en) * | 2013-11-28 | 2014-03-19 | 山东鑫泉医药有限公司 | Method for refining cefotiam hexetil hydrochloride |
| CN103641848B (en) * | 2013-11-28 | 2015-08-19 | 山东鑫泉医药有限公司 | The process for purification of cefotiam hexetil hydrochloride |
| CN105968106A (en) * | 2016-05-12 | 2016-09-28 | 浙江永宁药业股份有限公司 | Synthesis method for 2-(2-aminothiazole-4-yl)-N-(2-oxyazetidin-3-yl) acetamide |
| CN105968106B (en) * | 2016-05-12 | 2019-07-12 | 浙江永宁药业股份有限公司 | The synthetic method of 2- (thiazolamine -4- base)-N- (2- oxygroup azetidin -3- base) acetamide |
| CN106632398A (en) * | 2016-09-24 | 2017-05-10 | 北京满格医药科技有限公司 | Method for preparing cefotiam hexetil |
| CN107814812A (en) * | 2017-11-02 | 2018-03-20 | 广州市桐晖药业有限公司 | The preparation method of cefotiam hexetil |
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