CN103739514B - Production method of chlortetracycline bisulfate - Google Patents
Production method of chlortetracycline bisulfate Download PDFInfo
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- CN103739514B CN103739514B CN201310716748.7A CN201310716748A CN103739514B CN 103739514 B CN103739514 B CN 103739514B CN 201310716748 A CN201310716748 A CN 201310716748A CN 103739514 B CN103739514 B CN 103739514B
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- duomycin
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Abstract
The invention discloses a production method of chlortetracycline bisulfate. The production method comprises the following steps: dropping a well prepared sulfuric acid/ethanol mixed solution in an ethanol suspension of a chlortetracycline base to dissolve the chlortetracycline base, filtering, then performing crystal growth by using ethanol, filtering, further washing with the ethanol, filtering, and finally performing vacuum drying to obtain the chlortetracycline bisulfate. According to the preparation method disclosed by the invention, the operation procedure is simplified, the production period is shortened, a single solvent is used to facilitate the recovery and the mechanical application of the solvent, the production cost is reduced, and the safety in production, the yield and the product quality are further improved. The chlortetracycline bisulfate prepared by the preparation method disclosed by the invention has the advantages of high yield, high titer, low solvent residue and good stability.
Description
Technical field
The present invention relates to a kind of production method of chlortetracycline bisulfate.
Background technology
Duomycin is streptomyces aureus (Streptomyces aureofaciens) biosynthetic activeconstituents, is tetracycline antibiotics.Isphamycin is the hydrochloride of duomycin, will be used for the treatment of conjunctivitis and trachoma as people with drug main, is now mainly used in the disease such as typhoid fever, dysentery characterized by white mucous stool for the treatment of livestock, also can be used as livestock growth promoter as veterinary medicine.Further developing in recent years along with livestock industry, the market demand of Isphamycin constantly expands.
Compared with Isphamycin, chlortetracycline bisulfate (Chlortetracycline Bisulfate) water-soluble very good, thus has higher pharmaceutical use.The water mixed liquid of chlortetracycline bisulfate is clarified very much, the small-particle not containing the blocking narrow and small hole of drinking water apparatus and syringe etc., and chlortetracycline bisulfate is specially adapted to inject and oral administration to poultry and other animals.
Duomycin (chlortetracycline bisulfate) Sha Ermaite (sulfadimidine hydrosulfate) soluble powder of being produced by Boehringer Ingelheim company, it is soluble in water and good to eat, even if when animal appetite goes down, it also can be made to take tap water containing this medicine.Duomycin Sha Ermaite soluble powder can be used for prevention and therapy pig bacterial enteritis, also contributes to maintaining the increase of its body weight when animal has atrophic rhinitis, contributes to the reduction of abscess of neck incidence.Period in a medicine, can not use other tsiklomitsin or sulfa drugs.Slaughter and eat first 15 days for the mankind, should administration be stopped.
About the preparation method of chlortetracycline bisulfate, domestic do not have bibliographical information, and external report is also less.Patent CA877949 " PROCESS FOR PREPARING CHLORTETRACYCLINE BISULFATE " and patent GB1223962 " IMPROVEMENTS IN OR RELATING TO CRYSTALLINE CHLORTETRACYCLINE BISULFATE " discloses a kind of preparation technology of chlortetracycline bisulfate, carry out according to following step: add duomycin alkali, tetrahydrofuran (THF), sulfuric acid/tetrahydrofuran (THF) mixed solution is added to this suspension, clear liquid is poured in another container or filter and remove a small amount of insolubles, then growing the grain, filter, washing, dry chlortetracycline bisulfate, in order to add Virahol when improving in yield mother liquor and add Virahol crystallization or crystallization again.Tetrahydrofuran (THF) belongs to low-flash inflammable liquid on the one hand, can generate volatile superoxide, bring huge hidden danger, be unfavorable for industry's enlarging production to safety in production; Cause solvent cost recovery to increase containing two kinds of solvents in mother liquor in addition, thus increase manufacturing cost, reduce the competitive power of product.
Patent US2871265 " PROCESS FOR PREPARING CHLORTETRACYCLINE SULFATE " discloses a kind of preparation technology of duomycin vitriol, carry out according to following step: add duomycin alkali, cellosolvo, sulfuric acid/cellosolvo mixed solution is added to this suspension, filter and remove a small amount of insolubles, then add propyl carbinol or methyl alcohol crystallization, growing the grain, filtration, washing, dry duomycin vitriol.Employing cellosolvo dissolves, and adds the dilution crystallization method of propyl carbinol or methyl alcohol crystallization, causes solvent cost recovery to increase on the one hand, thus increases manufacturing cost, reduce the competitive power of product in mother liquor containing two kinds of solvents; Chlortetracycline bisulfate solvate is generated on the other hand because alcohol can combine with chlortetracycline bisulfate, the solvent that can contain cellosolvo (≤18%) and propyl carbinol (≤15%) or methyl alcohol (≤7%) in product remains, and affects quality product.
Summary of the invention
In order to overcome above-mentioned the deficiencies in the prior art, the invention provides a kind of production method obtaining chlortetracycline bisulfate with single vehicle of ethanol.
The present invention for the technical scheme reaching above-mentioned technical purpose and adopt is: a kind of production method of chlortetracycline bisulfate, described production method comprises the steps:
Step 01: dissolve, filter: add ethanol A, duomycin alkali that weight ratio is 0.8 ~ 1.6:1 in dissolving vessel, and under normal temperature, drip sulfuric acid/ethanol B mixed solution that weight percentage is 20%, dropwise, control temperature 20 ~ 30 DEG C stirs 30min, then filters; In wherein said sulfuric acid/alcohol mixeding liquid, the weight ratio of ethanol B and sulfuric acid is 0.2 ~ 0.4:1;
Step 02: crystallization: filter complete, collect filtrate in crystallizer, control temperature 35 ~ 45 DEG C drips ethanol C again, and ethanol C dropwises, and is incubated 3 hours, slow cooling to 10 ~ 15 DEG C insulation 2 hours; The weight ratio of the duomycin alkali added in wherein said ethanol C and step 01 is 1.6 ~ 2.4:1;
Step 03: filter: filter and obtain filter cake, with ethanol D washing leaching cake, refilter to obtain wet-milling;
Step 04: dry: by wet-milling vacuum-drying, control temperature 40 ~ 50 DEG C, vacuum tightness-0.07 ~-0.10MPa, is dried to weight loss on drying≤2.0%, obtains chlortetracycline bisulfate dry powder.
Ethanol D in described step 03 and the weight ratio of duomycin alkali are 3.2 ~ 4.8:1.
Beneficial effect of the present invention shows:
1) solvent remains low: content≤15.0% specifying propyl carbinol in American Pharmacopeia, and adopts ethanol to make solvent, and ethanol content only has 5 ~ 6%; Ethanol and propyl carbinol belong to III class solvent together, and alcohol toxicity is lower than propyl carbinol.
2) cost is low: whole technological process uses single vehicle of ethanol, be convenient to the recovery of solvent, apply mechanically, and ethanol is cheap and easy to get, can be effectively cost-saving.
3) yield is high: reach more than 110% from duomycin alkali to chlortetracycline bisulfate primary crystallization weight yield; Duomycin alkali contained in auric sulfate mycin crystalline mother solution is easy to reclaim, and can further improve yield.
4) simple to operation: when propyl carbinol is solvent, before crystallization, during reacting liquid filtering, easy crystallization often needs heating, and filtration velocity is slow and affect yield; And when being solvent with ethanol, reaction solution is clarified very much, during filtration not easily crystallization, normal-temperature operation can, filtration velocity is also very fast.
5) product particle is even, is easy to filter, wash.
6) product is easy to dry: when adopting butanol crystal, weight loss on drying is difficult to qualified, and after improving temperature drying, the product item that can redden again that causing differentiates and give money as a gift and tire is defective and can not get qualified product; And adopting ethanol to be after solvent, product is easy to dry.
Preparation method of the present invention simplifies schedule of operation, shortens the production cycle, uses single solvent to be convenient to the recovery of solvent, and reduces production cost, improves safety in production property, yield and quality product.The chlortetracycline bisulfate yield that the present invention obtains is high, height of tiring, and solvent remains low, good stability.
Embodiment
By describing technology contents of the present invention, structural attitude in detail, being realized object and effect, be explained in detail below in conjunction with embodiment.
Embodiment 1
In preparing tank, add ethanol 8kg, control temperature less than 40 DEG C drips sulfuric acid 2kg, drips and finishes, and stirs 10min, saves backup under normal temperature; In dissolving vessel, add ethanol 8kg, duomycin alkali 10kg, drip sulfuric acid/alcohol mixeding liquid, dropwise under normal temperature, control temperature 20 DEG C stirs 30min, then filters; Filter complete, collect filtrate in crystallizer, control temperature 35 DEG C drips ethanol 16kg again, and ethanol dropwises, and is incubated 3 hours, slow cooling to 10 DEG C insulation 2 hours; Filtration obtains filter cake, with ethanol 32kg washing leaching cake, refilters to obtain wet-milling; Wet-milling vacuum-drying, control temperature 40 DEG C, vacuum tightness-0.07 ~-0.10Mpa are dried to weight loss on drying≤2.0%, must obtain chlortetracycline bisulfate 11.5kg, and weight yield is 115%.Quality product meets USP standard; 25 ± 2 DEG C, RH 75 ± 5% stores after 6 months, quality product meets USP standard.
Embodiment 2
In preparing tank, add ethanol 12kg, control temperature less than 40 DEG C drips sulfuric acid 3kg, drips and finishes, and stirs 15min, saves backup under normal temperature; In dissolving vessel, add ethanol 15kg, duomycin alkali 10kg, drip sulfuric acid/alcohol mixeding liquid, dropwise under normal temperature, control temperature 25 DEG C stirs 30min, then filters; Filter complete, collect filtrate in crystallizer, control temperature 40 DEG C drips ethanol 20kg again, and ethanol dropwises, and is incubated 3 hours, slow cooling to 12 DEG C insulation 2 hours; Filtration obtains filter cake, with ethanol 40kg washing leaching cake, refilters to obtain wet-milling; Wet-milling vacuum-drying, control temperature 45 DEG C, vacuum tightness-0.07 ~-0.10Mpa are dried to weight loss on drying≤2.0%, obtain chlortetracycline bisulfate 11.2kg, and weight yield is 112%.Quality product meets USP standard; 25 ± 2 DEG C, RH 75 ± 5% stores after 6 months, quality product meets USP standard.
Embodiment 3
In preparing tank, add ethanol 16kg, control temperature less than 40 DEG C drips sulfuric acid 4kg, drips and finishes, and stirs 20min, saves backup under normal temperature; In dissolving vessel, add ethanol 16kg, duomycin alkali 10kg, drip sulfuric acid/alcohol mixeding liquid, dropwise under normal temperature, control temperature 30 DEG C stirs 30min, then filters; Filter complete, collect filtrate in crystallizer, control temperature 45 DEG C drips ethanol 24kg again, and ethanol dropwises, and is incubated 3 hours, slow cooling to 15 DEG C insulation 2 hours; Filtration obtains filter cake, with ethanol 48kg washing leaching cake, refilters to obtain wet-milling; Wet-milling vacuum-drying, control temperature 50 DEG C, vacuum tightness-0.07 ~-0.10Mpa are dried to weight loss on drying≤2.0%, obtain chlortetracycline bisulfate 11.1kg, weight yield is 111%.Quality product meets USP standard; 25 ± 2 DEG C, RH 75 ± 5% stores after 6 months, quality product meets USP standard.
Its detected result is as following table:
Table 1 embodiment 1 ~ embodiment 3 detected result
Table 2 embodiment 1 ~ embodiment 3 detected result (25 ± 2 DEG C, RH 75 ± 5% store after 6 months)
The foregoing is only embodiments of the invention; not thereby the scope of the claims of the present invention is limited; every utilize description of the present invention to do equivalent structure or equivalent flow process conversion; or be directly or indirectly used in other relevant technical fields, be all in like manner included in scope of patent protection of the present invention.
Claims (2)
1. a production method for chlortetracycline bisulfate, is characterized in that: it comprises the steps:
Step 01: dissolve, filter: add ethanol A, duomycin alkali that weight ratio is 0.8 ~ 1.6:1 in dissolving vessel, and under normal temperature, drip sulfuric acid/ethanol B mixed solution that weight percentage is 20%, dropwise, control temperature 20 ~ 30 DEG C stirs 30min, then filters; In wherein said sulfuric acid/ethanol B mixed solution, the weight ratio of sulfuric acid and duomycin alkali is 0.2 ~ 0.4:1;
Step 02: crystallization: filter complete, collect filtrate in crystallizer, control temperature 35 ~ 45 DEG C drips ethanol C again, and ethanol C dropwises, and is incubated 3 hours, slow cooling to 10 ~ 15 DEG C insulation 2 hours; The weight ratio of the duomycin alkali added in wherein said ethanol C and step 01 is 1.6 ~ 2.4:1;
Step 03: filter: filter and obtain filter cake, with ethanol D washing leaching cake, refilter to obtain wet-milling;
Step 04: dry: by wet-milling vacuum-drying, control temperature 40 ~ 50 DEG C, vacuum tightness-0.07 ~-0.10MPa, is dried to weight loss on drying≤2.0%, obtains chlortetracycline bisulfate dry powder.
2. the production method of a kind of chlortetracycline bisulfate according to claim 1, is characterized in that: the ethanol D in described step 03 and the weight ratio of duomycin alkali are 3.2 ~ 4.8:1.
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| CN106316794B (en) * | 2016-08-22 | 2019-02-26 | 浦城正大生化有限公司 | The recovery method of ethyl alcohol in aureomycin hydrochloride crystalline mother solution |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2871265A (en) * | 1956-09-27 | 1959-01-27 | American Cyanamid Co | Process for preparing chlortetracycline sulfate |
| GB1223962A (en) * | 1968-02-28 | 1971-03-03 | Diamond Shamrock Corp | Improvements in or relating to crystalline chlortetracycline bisulfate |
| CN102898326A (en) * | 2012-10-31 | 2013-01-30 | 金河生物科技股份有限公司 | Preparation method of chlortetracycline hydrochloride |
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2013
- 2013-12-24 CN CN201310716748.7A patent/CN103739514B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2871265A (en) * | 1956-09-27 | 1959-01-27 | American Cyanamid Co | Process for preparing chlortetracycline sulfate |
| GB1223962A (en) * | 1968-02-28 | 1971-03-03 | Diamond Shamrock Corp | Improvements in or relating to crystalline chlortetracycline bisulfate |
| CN102898326A (en) * | 2012-10-31 | 2013-01-30 | 金河生物科技股份有限公司 | Preparation method of chlortetracycline hydrochloride |
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