CN103739619B - A kind of process for refining and purifying of high purity cefotetan acid - Google Patents
A kind of process for refining and purifying of high purity cefotetan acid Download PDFInfo
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- CN103739619B CN103739619B CN201410024372.8A CN201410024372A CN103739619B CN 103739619 B CN103739619 B CN 103739619B CN 201410024372 A CN201410024372 A CN 201410024372A CN 103739619 B CN103739619 B CN 103739619B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Abstract
The invention discloses a kind of process for refining and purifying of high purity cefotetan acid, completed the refining purification of cefotetan acid by seven steps.The process for refining and purifying of a kind of high purity cefotetan acid of the present invention, the method of main employing extraction and crystallization, obtained cefotetan acid crystal, by activated carbon decolorizing method, solve the problem that in the past obtained product colour is excessively dark, and by twice extraction and washing, by regulating pH value, obtained product purity is high.
Description
Technical field
The present invention relates to the process for refining and purifying of medicine, particularly relate to a kind of process for refining and purifying of high purity cefotetan acid.
Background technology
In the struggle of the mankind and infectious diseases, antibiotics serves extremely important effect.According to statistics, China's antibiotics accounts for the market share of whole medicine sales 14%, ranks first in all drug types.China's cephalosporin analog antibiotic is risen in early 1980s, cefotetan (Cefotetan), and No. CAS is 69712-56-7, is a kind of conventional pharmaceutical intermediate, is the s-generation cephalosporin analog antibiotic developed by Japanese Yamanouchi pharmacy.Its polarity is less, poorly water-soluble, and clinically for convenience of using, make dosage form with its sodium salt, conventional cefotetan acid adds sodium bicarbonate and becomes sodium salt, regulates pH=4.0 ~ 6.5, then adopts freeze-dry process to prepare freeze-dried powder.
The reaction that experience isomer transforms is needed, so the isomer of last product often containing more cefotetan acid in the process of preparation cefotetan acid.There is the method for various removing isomer at present, usually the method for alumina adsorption or resin absorption is selected to be separated by contamination precipitation, thus obtain relative purification cefotetan solution, the color of the cefotetan acid of producing in this way comparatively dark (usually reaching Y6 look), impurity still more, yield is low simultaneously.
Summary of the invention
The object of the present invention is to provide a kind of process for refining and purifying of high purity cefotetan acid, the method has simple to operate, the feature that product yield is high.
For achieving the above object, the present invention adopts following technical scheme:
A kind of process for refining and purifying of high purity cefotetan acid, described cefotetan acid is cephalosporin intermediate, cefotetan acid reacts obtained by 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium and 5-hydroxyl-4-carboxyl-5-sulfydryl isothiazole trisodium, and it comprises the following steps:
1) 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium and 5-hydroxyl-4-carboxyl-5-sulfydryl isothiazole trisodium are reacted and are generated cefotetan acid, cefotetan acid crude products in reaction solution is detected, when the tautomerism body burden of cefotetan acid in reaction solution is less than 8%, the cefotetan acid in reaction solution is purified;
2) regulate the pH value of reaction solution to 4-6, add organic solvent extraction, during extraction, stir 10-30min, after leaving standstill, form layering;
The weight ratio of described organic solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 2-3:1;
3) collect the organic solvent layer after layering, and add gac in water layer, decolouring 10-30min is stirred on limit, crosses and filters gac, and collect filtrate;
The weight ratio of described gac and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 0.05-0.2:1;
4) in collected filtrate, again add organic solvent extraction, regulate PH to 1-2, stratification, removing water layer, collects organic solvent layer;
The weight ratio of described organic solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 12-20:1;
5) combining step 3) and the organic solvent layer collected of step 4), and in organic solvent layer, add gac to decolour while stirring 10-30min, cross and filter gac, obtain filtrate;
The weight ratio of described gac and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 0.05-0.2:1;
6) step 5) gained filtrate concentrated, then in the filtrate after concentrated, instill recrystallisation solvent carry out stirred crystallization, Tc is 15-25 DEG C, and stirring velocity is 100-250 rev/min;
7) filter removing step 6) crystalline mother solution after crystallization, obtain the filter cake of crystallization, with recrystallisation solvent by gained filter cake washing once more than, by filter cake vacuum-drying under temperature is lower than 30 DEG C of conditions, obtain cefotetan acid powder crystal;
The weight ratio of described recrystallisation solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 20-53:1.
Described step 2) and step 4) in extract organic solvent used be one or more mixture in tetrahydrofuran (THF), ethyl acetate, butylacetate, butanone, normal hexane.
During reaction solution tetrahydrofuran (THF), normal hexane washing extraction, cefotetan acid wherein is generally not dissolved in or is dissolved on a small quantity in tetrahydrofuran (THF), normal hexane, so when first time is with tetrahydrofuran (THF), normal hexane washing extraction, the organic solvent layer obtained can not merge with the organic solvent layer be separated below.
When reaction solution is with butanone washing extraction, cefotetan acid wherein has sub-fraction to be dissolved in wherein, so when first time is with butanone washing extraction, in order to carry high product yield, the organic solvent layer obtained merges with the organic solvent layer be separated below.
In described step 6), recrystallisation solvent is one or more the mixture in methylene dichloride, Virahol, methyl alcohol, ethanol.
Described step 6), before adding recrystallisation solvent crystallization, first concentrates step 5) gained filtrate, and the concentrated rotatory evaporator that adopts carries out concentrating under reduced pressure.
Before crystallization, first concentrating under reduced pressure removes a part of mother liquor, can save crystallization required time.
In described step 1), in detection reaction liquid, the tautomerism body burden of cefotetan acid adopts high performance liquid chromatography;
In described step 6), stirred crystallization specifically comprises the following steps:
1) be transferred in three-necked bottle by the filtrate that step 5) obtains, control temperature 20-25 DEG C, stirring velocity 250 revs/min, drip the 15%-17% of recrystallisation solvent total amount, time for adding is 90-120 minute, stirred crystallization; At this moment the filtrate in three-necked bottle occurs muddy, and filtrate temperature is down to 15-20 DEG C, and stirring velocity is adjusted to 100 revs/min, stops dripping recrystallisation solvent, growing the grain 30-90 minute;
2) then stirring velocity is risen to 250 revs/min, temperature remains on 15-20 DEG C, and drip the 30%-35% of recrystallisation solvent total amount, time for adding is 90-120 minute, continues stirred crystallization; Stirring velocity is adjusted to 100 revs/min, stop dripping recrystallisation solvent, growing the grain 25-35 minute, now has a large amount of crystal grains in feed liquid;
3) stirring velocity is adjusted to 200 revs/min, temperature continues to remain on 15-20 DEG C, drips the 48%-52% of recrystallisation solvent total amount, time for adding 60-90 minute, continues stirred crystallization; The temperature of feed liquid is down to less than 5 DEG C, stops dripping recrystallisation solvent, stop stirring, growing the grain 2-3 hour, obtain cefotetan acid wet brilliant.
By regulating the temperature-time of crystallization, adopting stirred crystallization stage by stage, making gained crystal purity high, homogeneous.
Cefotetan acid is the intermediate in pharmaceutical synthesis, and its back intermediate is 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium.Because cefotetan acid reacts obtained by 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium and 5-hydroxyl-4-carboxyl-5-sulfydryl isothiazole trisodium, thus the present invention refine in purification relate to organic solvent, recrystallisation solvent, gac content all with the input amount of 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium for benchmark.
The process for refining and purifying of a kind of high purity cefotetan acid of the present invention, the method of main employing extraction and crystallization, obtained cefotetan acid crystal, by activated carbon decolorizing method, solve the problem that in the past obtained product colour is excessively dark, and by twice extraction and washing, by regulating pH value, obtained product purity is high.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.In addition should be understood that those skilled in the art can make various change or amendment to the present invention, and these equivalent form of values fall within the application's claims limited range equally after the content of having read the present invention's instruction.
A kind of process for refining and purifying of high purity cefotetan acid, described cefotetan acid is cephalosporin intermediate, cefotetan acid reacts obtained by 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium and 5-hydroxyl-4-carboxyl-5-sulfydryl isothiazole trisodium, and it comprises the following steps:
1) 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium and 5-hydroxyl-4-carboxyl-5-sulfydryl isothiazole trisodium are reacted and are generated cefotetan acid, cefotetan acid crude products in reaction solution is detected, when the tautomerism body burden of cefotetan acid in reaction solution is less than 8%, the cefotetan acid in reaction solution is purified;
2) regulate the pH value of reaction solution to 4-6, add organic solvent extraction, during extraction, stir 10-30min, after leaving standstill, form layering;
The weight ratio of described organic solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 2-3:1;
3) collect the organic solvent layer after layering, and add gac in water layer, decolouring 10-30min is stirred on limit, crosses and filters gac, and collect filtrate;
The weight ratio of described gac and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 0.05-0.2:1;
4) in collected filtrate, again add organic solvent extraction, regulate PH to 1-2, stratification, removing water layer, collects organic solvent layer;
The weight ratio of described organic solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 12-20:1;
5) combining step 3) and the organic solvent layer collected of step 4), and in organic solvent layer, add gac to decolour while stirring 10-30min, cross and filter gac, obtain filtrate;
6) step 5) gained filtrate concentrated, then in the filtrate after concentrated, instill recrystallisation solvent carry out stirred crystallization, Tc is 15-25 DEG C, and stirring velocity is 100-250 rev/min;
The weight ratio of described gac and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 0.05-0.2:1;
7) filter removing step 6) crystalline mother solution after crystallization, obtain the filter cake of crystallization, with recrystallisation solvent by gained filter cake washing once more than, by filter cake vacuum-drying under temperature is lower than 30 DEG C of conditions, obtain cefotetan acid powder crystal;
The weight ratio of described recrystallisation solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 20-53:1.
Described step 2) and step 4) in extract organic solvent used be one or more mixture in tetrahydrofuran (THF), ethyl acetate, butylacetate, butanone, normal hexane.
In described step 6), recrystallisation solvent is one or more the mixture in methylene dichloride, Virahol, methyl alcohol, ethanol.
Described step 6), before adding recrystallisation solvent crystallization, first concentrates step 5) gained filtrate, and the concentrated rotatory evaporator that adopts carries out concentrating under reduced pressure.
In described step 1), in detection reaction liquid, the tautomerism body burden of cefotetan acid adopts high performance liquid chromatography;
In described step 6), stirred crystallization specifically comprises the following steps:
1) be transferred in three-necked bottle by the filtrate that step 5) obtains, control temperature 20-25 DEG C, stirring velocity 250 revs/min, drip the 15%-17% of recrystallisation solvent total amount, time for adding is 90-120 minute, stirred crystallization; At this moment the filtrate in three-necked bottle occurs muddy, and filtrate temperature is down to 15-20 DEG C, and stirring velocity is adjusted to 100 revs/min, stops dripping recrystallisation solvent, growing the grain 30-90 minute;
2) then stirring velocity is risen to 250 revs/min, temperature remains on 15-20 DEG C, and drip the 30%-35% of recrystallisation solvent total amount, time for adding is 90-120 minute, continues stirred crystallization; Stirring velocity is adjusted to 100 revs/min, stop dripping recrystallisation solvent, growing the grain 25-35 minute, now has a large amount of crystal grains in feed liquid;
3) stirring velocity is adjusted to 200 revs/min, temperature continues to remain on 15-20 DEG C, drips the 48%-52% of recrystallisation solvent total amount, time for adding 60-90 minute, continues stirred crystallization; The temperature of feed liquid is down to less than 5 DEG C, stops dripping recrystallisation solvent, stop stirring, growing the grain 2-3 hour, obtain cefotetan acid wet brilliant.
Embodiment 1
In the charging capacity of cefotetan acid back intermediate 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium for 40g, detect in reaction solution for smooth tautomerism be 6.3% time, with 10%HCL, the PH of reaction solution is adjusted to 5.0, add tetrahydrofuran (THF) 80ml, stir 10min, layering, reclaim organic layer, activated carbon 2g is added to water layer, temperature is less than 25 DEG C and stirs 30min, filter, filtrate adds ethyl acetate 480ml, then with 10%HCL, the PH of mixed solution is adjusted to 1.0, temperature is less than 25 DEG C and stirs 10min, after layering, collect organic solvent layer, add activated carbon 2g wherein, temperature is less than 10 DEG C and stirs decolouring 10min, cross and filter gac, obtain filtrate, filter vacuum is concentrated into volume 150ml, methylene dichloride 800ml stirred crystallization is dripped under temperature is lower than 25 DEG C of conditions, after dropping terminates, growing the grain 3 hours at temperature is lower than 10 DEG C, filter, gained filter cake washed with dichloromethane, then vacuum-drying, obtain cefotetan acid 35.7g, look level is less than YG3, purity 99.52%.
Embodiment 2
In the charging capacity of cefotetan acid back intermediate 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium for 40g, detect in reaction solution for smooth tautomerism be 5.2% time, with 10%HCL, the PH of reaction solution is adjusted to 6.0, add normal hexane 120ml, 30min is stirred lower than 25 DEG C in temperature, layering, reclaims organic solvent layer, activated carbon 8g is added to water layer, temperature stirs 10min lower than under 25 DEG C of conditions, filter, butanone 800ml is added in filtrate, then with 10%HCL, the PH of mixed solution is adjusted to 2.0, 30min is stirred under temperature is lower than 25 DEG C of conditions, after layering, collect organic solvent layer, merge the organic solvent layer of twice, add activated carbon 8g wherein, 30min is stirred under temperature is lower than 10 DEG C of conditions, cross and filter gac, obtain filtrate, filter vacuum is concentrated into volume 300ml, Virahol 2120ml crystallization is dripped at temperature is lower than 25 DEG C, after dropping terminates, in temperature lower than 10 DEG C of growing the grains 3 hours, filter, filter cake Virahol alkane washs, then vacuum-drying, obtain cefotetan acid 36.2g, look level is less than YG3, purity 99.60%.
Embodiment 3
In the charging capacity of cefotetan acid back intermediate 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium for 40g, detect in reaction solution for smooth tautomerism be 4.2% time, with 10%HCL, the PH of reaction solution is adjusted to 5.5, add butanone 100ml, 25min is stirred lower than 25 DEG C in temperature, layering, organic solvent layer is continued to employ, reclaim organic solvent layer, activated carbon 4g is added to water layer, temperature stirs 20min lower than under 25 DEG C of conditions, filter, butanone 600ml is added in filtrate, then with 10%HCL, the PH of mixed solution is adjusted to 1.5, 20min is stirred lower than 25 DEG C in temperature, after layering, collect organic solvent layer, merge the organic solvent layer of two secondary clearings, add activated carbon 4g wherein, 20min is stirred under temperature is lower than 10 DEG C of conditions, cross and filter gac, obtain filtrate, filter vacuum is concentrated into volume 200ml, ethanol 1200ml crystallization at temperature is lower than 25 DEG C, after dropping terminates, in temperature lower than 10 DEG C of growing the grains 3 hours, filter, filter cake washing with alcohol, then vacuum-drying, obtain cefotetan acid 36.9g, look level is less than YG3, purity 99.51%.
Embodiment 4
In the charging capacity of cefotetan acid back intermediate 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium for 40g, detect in reaction solution for smooth tautomerism be 4.5% time, with 10%HCL, the PH of reaction solution is adjusted to 5.4, add butanone 60ml, 18min is stirred lower than 25 DEG C in temperature, layering, organic solvent layer is continued to employ, activated carbon 3.2g is added to water layer, temperature stirs 20min lower than under 25 DEG C of conditions, filter, butanone 720ml is added in filtrate, then with 10%HCL, the PH of mixed solution is adjusted to 1.2, 20min is stirred lower than 25 DEG C in temperature, after layering, collect organic solvent layer, merge the organic solvent layer of two secondary clearings, add activated carbon 3.2g wherein, 20min is stirred under temperature is lower than 10 DEG C of conditions, cross and filter gac, obtain filtrate, filter vacuum is concentrated into volume 180ml, methyl alcohol 1600ml crystallization at temperature is lower than 25 DEG C, after dropping terminates, in temperature lower than 10 DEG C of growing the grains 3 hours, filter, filter cake methanol wash, then vacuum-drying, obtain cefotetan acid 35.3g, look level is less than YG3, purity 99.65%.
Embodiment 5
In the charging capacity of cefotetan acid back intermediate 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium for 40g, detect in reaction solution for smooth tautomerism be 4.8% time, with 10%HCL, the PH of reaction solution is adjusted to 5.3, add butanone 88ml, 26min is stirred lower than 25 DEG C in temperature, layering, organic solvent layer is continued to employ, activated carbon 3.6g is added to water layer, temperature stirs 20min lower than under 25 DEG C of conditions, filter, butanone 560ml is added in filtrate, then with 10%HCL, the PH of mixed solution is adjusted to 1.4, 20min is stirred lower than 25 DEG C in temperature, after layering, collect organic solvent layer, merge the organic solvent layer of two secondary clearings, add activated carbon 3.6g wherein, 20min is stirred under temperature is lower than 10 DEG C of conditions, cross and filter gac, obtain filtrate, filter vacuum is concentrated into volume 150ml, methylene dichloride 2000ml crystallization at temperature is lower than 25 DEG C, after dropping terminates, in temperature lower than 10 DEG C of growing the grains 3 hours, filter, filter cake washed with dichloromethane, then vacuum-drying, obtain cefotetan acid 35.8g, look level is less than YG3, purity 99.55%.
Claims (6)
1. the process for refining and purifying of a high purity cefotetan acid, described cefotetan acid is cephalosporin intermediate, cefotetan acid reacts obtained by 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium and 5-hydroxyl-4-carboxyl-5-sulfydryl isothiazole trisodium, it is characterized in that: it comprises the following steps:
1) 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium and 5-hydroxyl-4-carboxyl-5-sulfydryl isothiazole trisodium are reacted and are generated cefotetan acid, cefotetan acid crude products in reaction solution is detected, when the tautomerism body burden of cefotetan acid in reaction solution is less than 8%, the cefotetan acid in reaction solution is purified;
2) regulate the pH value of reaction solution to 4-6, add organic solvent extraction, during extraction, stir 10-30min, after leaving standstill, form layering;
The weight ratio of described organic solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 2-3:1;
3) collect the organic solvent layer after layering, and add gac in water layer, decolouring 10-30min is stirred on limit, crosses and filters gac, and collect filtrate;
The weight ratio of described gac and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 0.05-0.2:1;
4) in collected filtrate, again add organic solvent extraction, regulate pH to 1-2, stratification, removing water layer, collects organic solvent layer;
The weight ratio of described organic solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 12-20:1;
5) combining step 3) and the organic solvent layer collected of step 4), and in organic solvent layer, add gac to decolour while stirring 10-30min, cross and filter gac, obtain filtrate;
The weight ratio of described gac and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 0.05-0.2:1;
6) step 5) gained filtrate concentrated, then in the filtrate after concentrated, instill recrystallisation solvent carry out stirred crystallization, Tc is 15-25 DEG C, and stirring velocity is 100-250 rev/min;
7) filter removing step 6) crystalline mother solution after crystallization, obtain the filter cake of crystallization, with recrystallisation solvent by gained filter cake washing once more than, by filter cake vacuum-drying under temperature is lower than 30 DEG C of conditions, obtain cefotetan acid powder crystal;
The weight ratio of described recrystallisation solvent and 7-a-methoxyl group-7-chloro acetylamino-3-methyl tetrazyl thiomethyl Cephalosporanic acid sodium is 20-53:1.
2. the process for refining and purifying of a kind of high purity cefotetan acid according to claim 1, is characterized in that: described step 2) and step 4) in extract organic solvent used be one or more mixture in tetrahydrofuran (THF), ethyl acetate, butylacetate, butanone, normal hexane.
3. the process for refining and purifying of a kind of high purity cefotetan acid according to claim 1, is characterized in that: in described step 6), recrystallisation solvent is one or more the mixture in methylene dichloride, Virahol, methyl alcohol, ethanol.
4. the process for refining and purifying of a kind of high purity cefotetan acid according to claim 1, it is characterized in that: described step 6) is before adding recrystallisation solvent crystallization, first concentrate step 5) gained filtrate, the concentrated rotatory evaporator that adopts carries out concentrating under reduced pressure.
5. the process for refining and purifying of a kind of high purity cefotetan acid according to claim 1, is characterized in that: in described step 1), in detection reaction liquid, the tautomerism body burden of cefotetan acid adopts high performance liquid chromatography.
6. the process for refining and purifying of a kind of high purity cefotetan acid according to claim 1, is characterized in that: in described step 6), stirred crystallization specifically comprises the following steps:
1) be transferred in three-necked bottle after step 5) gained filtrate being concentrated, control temperature 20-25 DEG C, stirring velocity 250 revs/min, drip the 15%-17% of recrystallisation solvent total amount, time for adding is 90-120 minute, stirred crystallization; At this moment the filtrate in three-necked bottle occurs muddy, and filtrate temperature is down to 15-20 DEG C, and stirring velocity is adjusted to 100 revs/min, stops dripping recrystallisation solvent, growing the grain 30-90 minute;
2) then stirring velocity is risen to 250 revs/min, temperature remains on 15-20 DEG C, and drip the 30%-35% of recrystallisation solvent total amount, time for adding is 90-120 minute, continues stirred crystallization; Stirring velocity is adjusted to 100 revs/min, stop dripping recrystallisation solvent, growing the grain 25-35 minute, now has a large amount of crystal grains in feed liquid;
3) stirring velocity is adjusted to 200 revs/min, temperature continues to remain on 15-20 DEG C, drips the 48%-52% of recrystallisation solvent total amount, time for adding 60-90 minute, continues stirred crystallization; The temperature of feed liquid is down to less than 5 DEG C, stops dripping recrystallisation solvent, stop stirring, growing the grain 2-3 hour, obtain cefotetan acid wet brilliant.
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| CN102250125A (en) * | 2011-05-20 | 2011-11-23 | 海南合瑞制药股份有限公司 | Preparation method of cefotetan |
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