CN102964402B - Preparation method for dehydro-clindamycin-free clindamycin hydrochloride - Google Patents
Preparation method for dehydro-clindamycin-free clindamycin hydrochloride Download PDFInfo
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- CN102964402B CN102964402B CN201210471371.9A CN201210471371A CN102964402B CN 102964402 B CN102964402 B CN 102964402B CN 201210471371 A CN201210471371 A CN 201210471371A CN 102964402 B CN102964402 B CN 102964402B
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Abstract
The invention relates to a dehydro-clindamycin-free clindamycin hydrochloride and a preparation method and applications thereof, which are mainly applied to pharmaceutical enterprises in the medical industry. The preparation method disclosed by the invention comprises the following steps: dissolving dehydro-clindamycin-containing clindamycin hydrochloride serving as a raw material into water or an aqueous alcohol solution, adding palladium on carbon accounting for 1/10-1/200 of the amount of the raw material, and introducing hydrogen into the obtained mixture to react for 1-48 hours, so that dehydro-clindamycin is all reacted to generate clindamycin; and crystallizing clindamycin. According to the preparation method, dehydro-clindamycin can be reduced or removed, the impurities in clindamycin hydrochloride can be reduced, and the quality of pharmaceutical products can be improved.
Description
Technical field
The invention belongs to medical art, relate to a kind of not containing Dalacina and preparation method thereof and the application of dehydrogenation clindamycin.
Background technology
Dalacina, chemical name 6-(1-methyl-trans-4-propyl group-L-2-pyrrolidine formyl is amino)-1-sulfo--7(S)-pungent pyranoside the hydrochloride of chloro-6,7,8-tri-deoxidation-L-Su Shi-α-D-gala, structure is shown in formula 1:
Formula 1 Dalacina
Clindamycin was synthesized in 1966 by people such as Magerlein the earliest, and first Pu Qiang company of the U.S. trial-produces successfully, and obtained United States Patent (USP) power in 1969.China was developed jointly in 1975 succeeded in developing by North China Pharmaceutical Factory, Beijing Pharmaceutical Ind. Inst., and domestic a lot of producer puts into production afterwards.Multiple formulation listing such as existing clindamycin powder injection, injection, solution, capsule at present.
Dalacina belongs to lincomycin series antibiotics, and be the derivative of lincomycin, antimicrobial spectrum is identical with lincomycin, and anti-microbial activity comparatively lincomycin is strong 4 ~ 8 times.Dalacina effect is rapid, and without first pass effect, medicament contg not easily loses, and curative effect is reliable.To gram positive organism as Staphylococcus (comprising penicillin resistant strain), streptococcus, diphtheria corynebacterium, anthrax bacillus etc. have comparatively high antibacterial activity.Also have good anti-microbial activity to Grain-negative anerobe, it is extremely sensitive that Bacteroides comprises the large multipair this product such as bacteroides fragilis, Fusobacterium, dyspepsiacoccus, peptostreptococcus, Clostridium perfringens.Gram negative aerobic bacteria comprises hemophilus influenzae, neisseria and Mycoplasma all to this product resistance.This product and penicillin, paraxin, between cephalosporins and tetracyclines without crossing drug resistant, have partial intersection resistance with Macrolide, have complete intersection resistance with lincomycin.The mechanism of action of this product is combined with bacterial ribosome 50S subunit, stops the prolongation of peptide chain, thus the protein synthesis of anti-bacteria cell.This strain bacteriostatic, but when high density, also there is germicidal action to some bacterium.
Main containing impurity clindamycin B in Dalacina, table clindamycin, dehydrogenation clindamycin.
In the patent of China: in the synthesis technique (application number 201010200802.9) of U 10149a, provide the synthetic method of the simple Dalacina of a kind of technique, the method mainly contains step to be had: take U 10149a as raw material, with low-carbon (LC) alkyl halide hydrocarbon for solvent carries out chlorination, and products therefrom is completed in aqueous phase the hydrolysis reaction of sodium hydroxide, layering can obtain clindamycin free alkali, then this free alkali and hydrochloric acid are carried out salt-forming reaction and crystallization.The advantage of this technique is that method is simple, decreases the step using and react of material, improves the quality of product, and make the content of impurity table crin decline more than 80% ,≤2.0%, productive rate about improves 5%.But the content that wherein there is no about reducing or remove dehydrogenation clindamycin.
Dehydrogenation clindamycin content is in the feed 0.2% ~ 0.4%, due to it structure with clindamycin very close, preparation or purifying process in be difficult to removing, structural formula is shown in formula 2.
Formula 2 dehydrogenation Dalacina
Through consulting, at present the patent of relevant Dalacina and document are all relevant technological synthesis and how improve yield, improve crystal formation, and with regard to how, the report of purifying and removing impurity is little, and not about reducing or the relevant report of removal dehydrogenation clindamycin.
Summary of the invention
The object of this invention is to provide a kind of Dalacina preparation method not containing dehydrogenation clindamycin.The present invention can reduce or remove dehydrogenation clindamycin, reduces the impurity of Dalacina, improves the quality of pharmaceutical prod.
Technical solution of the present invention is, Dalacina containing dehydrogenation clindamycin is dissolved in water or moisture alcoholic solution, add the palladium carbon of material quantity 1/10 ~ 1/200, and pass into hydrogen reaction 1 ~ 48 hour, dehydrogenation clindamycin is wherein made all to react generation clindamycin, then crystallization treatment.
The above amount adding palladium carbon is 1/10 ~ 1/20 of material quantity.
The time of logical hydrogen reaction of the present invention is 1 ~ 5 hour.
The obtained reaction equation not containing the clindamycin of dehydrogenation clindamycin of the present invention is shown in formula 3,
Formula 3 dehydrogenation clindamycin is converted into the reaction equation of clindamycin
The Dalacina prepared by the present invention can be used for preparing not containing the Dalacina preparation of dehydrogenation clindamycin, also can be used for preparing not containing Clindamycin Phosphate raw material and the preparation of dehydrogenation Clindamycin Phosphate.
Advantage of the present invention is the dehydrogenation clindamycin can removed completely in Dalacina, reduces the impurity of Dalacina, improves the quality of pharmaceutical prod.
Accompanying drawing explanation
The Dalacina collection of illustrative plates (containing dehydrogenation clindamycin) of Fig. 1 before the inventive method preparation
The Dalacina collection of illustrative plates of Fig. 2 after the inventive method preparation (not containing dehydrogenation clindamycin)
Fig. 3 Clindamycin hydrochloride injection inspection spectrogram (not containing dehydrogenation clindamycin)
Fig. 4 Clindamycin Phosphate ingredient inspection spectrogram (not containing dehydrogenation Clindamycin Phosphate)
Fig. 5 Clindamycin Phosphate ingredient inspection spectrogram (containing dehydrogenation Clindamycin Phosphate)
Fig. 6 clindamycin phosphate injection inspection spectrogram (not containing dehydrogenation Clindamycin Phosphate)
Embodiment
Embodiment 1
Dalacina 30g being contained dehydrogenation clindamycin is dissolved in 60ml water, adds palladium catalyst carbon 0.3g, logical hydrogen 0.2Mpa, react 23 hours, make dehydrogenation clindamycin wherein all react generation clindamycin, filter de-carbon, in filtrate, add 100mlCH
2cl
2, drip 10%NaOH and regulate pH ≈ 10, extracting and demixing, adds 25ml CH after separatory in aqueous phase
2cl
2extraction, repeats 2 times, merges CH
2cl
2layer, in 35 DEG C of rotary evaporations, adds 300ml dissolve with ethanol after being spin-dried for.Drip dense HCl 7ml, separate out after 3 to 5 minutes.Wash with dehydrated alcohol after filtration, in 60 DEG C of vacuum-dryings and get final product.
Fig. 1, Fig. 2 are the inspection collection of illustrative plates of the Dalacina raw material before and after prepared by application preparation method of the present invention, and visible application preparation method of the present invention can be prepared not containing the Dalacina raw material of dehydrogenation clindamycin.Preparation Dalacina collection of illustrative plates, after the production Fig. 2 and preparation before Fig. 1 retention time in the equal one_to_one corresponding in all peaks, there is not new peak, namely do not generate new impurity.
Embodiment 2
The Dalacina that 20g contains dehydrogenation clindamycin is dissolved in 80ml water and 20ml methyl alcohol, add palladium catalyst carbon 2.0g, logical hydrogen 0.4MPa stirring reaction 1 hour, makes dehydrogenation clindamycin wherein all react generation clindamycin, filter de-carbon, in filtrate, add 60ml CH
2cl
2, drip 10%NaOH17.5ml, extracting and demixing, adds 20ml CH after separatory in water layer
2cl
2extraction, repeats twice, merges CH
2cl
2layer, in 45 DEG C of rotary evaporations, adds dehydrated alcohol 200ml and dissolves after being spin-dried for.Separate out gradually after dripping dense HCl 5ml.Filter, in 60 DEG C of vacuum-dryings after cooling crystallization for some time.
Embodiment 3
The Dalacina that 20g contains dehydrogenation clindamycin is dissolved in 80ml water and 30ml ethanol, add palladium catalyst carbon 0.1g, continue slowly logical hydrogen stirring reaction 48 hours, make dehydrogenation clindamycin wherein all react generation clindamycin, filter de-carbon, in filtrate, add 60ml CH
2cl
2, drip 10%NaOH17.5ml, extracting and demixing, adds 20ml CH after separatory in water layer
2cl
2extraction, repeats twice, merges CH
2cl
2layer, in 45 DEG C of rotary evaporations, adds dehydrated alcohol 200ml and dissolves after being spin-dried for.Separate out gradually after dripping dense HCl 5ml.Filter, in 60 DEG C of vacuum-dryings after cooling crystallization for some time.
Embodiment 4
The Dalacina that 20g contains dehydrogenation clindamycin is dissolved in 80ml water and 40ml Virahol, add palladium catalyst carbon 1.0g, logical hydrogen 0.4MPa stirring reaction 5 hours, makes dehydrogenation clindamycin wherein all react generation clindamycin, filter de-carbon, in filtrate, add 60ml CH
2cl
2, drip 10%NaOH17.5ml, extracting and demixing, adds 20ml CH after separatory in water layer
2cl
2extraction, repeats twice, merges CH
2cl
2layer, in 45 DEG C of rotary evaporations, adds dehydrated alcohol 200ml and dissolves after being spin-dried for.Separate out gradually after dripping dense HCl 5ml.Filter, in 60 DEG C of vacuum-dryings after cooling crystallization for some time.
The preparation of embodiment 5 Clindamycin hydrochloride injection
Get 70% water for injection of preparation total amount, add Citric Acid and Sodium Citrate, regulate pH4.5 ~ 4.8, add the Dalacina prepared by embodiment 1, dissolve completely, control pH4.3 ~ 4.7.Add gac to stir, filter de-carbon through 0.22 μm of metre filter, filtrate carries out embedding and through 100 DEG C of sterilizing 15min, chilling and get final product.
The preparation of embodiment 6 Clindamycin Phosphate raw material
Referenced patent----and a kind of preparation method of Clindamycin Phosphate (number of patent application: 200710071197.8), Fig. 4 is that the Dalacina prepared with embodiment 2 is for raw material; Fig. 5 is with the Dalacina containing dehydrogenation clindamycin for raw material, and the method according to above-mentioned patent prepares Clindamycin Phosphate.Visible, Dalacina prepared by application the present invention can be used for preparing not containing the Clindamycin Phosphate raw material of dehydrogenation Clindamycin Phosphate.
Embodiment 7 prepares clindamycin phosphate injection
EDTA.2Na is added in the water for injection let cool toward newly boiling, after stirring and dissolving, the Clindamycin Phosphate alternately adding sodium hydroxide solution and prepare by Fig. 4 in embodiment 6, dissolves completely rear moisturizing to full dose, add sodium bisulfite, stir molten clear after regulate pH6.3 ~ 6.5.Add gac to stir, filter de-carbon through 0.22 μm of metre filter, filtrate is carried out embedding and be get final product.
Fig. 3: the Dalacina prepared with embodiment 1, for raw material, prepares Clindamycin hydrochloride injection by the method for embodiment 5, not containing dehydrogenation clindamycin in the injection liquid of gained.Visible, Dalacina prepared by application the present invention can be used for preparing not containing the salt acid esters clindamycin formulation of dehydrogenation clindamycin.
Fig. 6 is visible, and Dalacina prepared by application the present invention can be used for preparing not containing the Clindamycin Phosphate preparation of dehydrogenation Clindamycin Phosphate.
Claims (3)
1. one kind does not contain the Dalacina preparation method of dehydrogenation clindamycin, it is characterized in that the Dalacina containing dehydrogenation clindamycin being that material dissolution is in water or moisture alcoholic solution, add the palladium carbon of 1/10 ~ 1/200 of material quantity, and pass into hydrogen reaction 1 ~ 48 hour, dehydrogenation clindamycin is wherein made all to react generation clindamycin, then crystallization treatment.
2. according to claim 1 a kind of not containing the Dalacina preparation method of dehydrogenation clindamycin, the amount that it is characterized in that adding palladium carbon is 1/10 ~ 1/20 of material quantity.
3. according to claim 1 a kind of not containing the Dalacina preparation method of dehydrogenation clindamycin, it is characterized in that the time of described logical hydrogen reaction is 1 ~ 5 hour.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4895934A (en) * | 1988-08-22 | 1990-01-23 | E. I. Du Pont De Nemours And Company | Process for the preparation of clindamycin phosphate |
| CN101205245A (en) * | 2007-12-06 | 2008-06-25 | 河南天方药业股份有限公司 | Method for preparing hydrochloric acid clindamycinum |
| CN101830946A (en) * | 2010-05-05 | 2010-09-15 | 南阳普康药业有限公司 | Method for synthesizing clindamycin phosphate |
| CN101891779A (en) * | 2010-06-17 | 2010-11-24 | 张家港市信谊化工有限公司 | Process for synthesizing clindamycin phosphate |
| CN101891778A (en) * | 2010-06-17 | 2010-11-24 | 张家港市信谊化工有限公司 | Process for synthesizing clindamycin hydrochloride |
| CN102702279A (en) * | 2012-06-15 | 2012-10-03 | 安徽省皖北药业股份有限公司 | Method for preparing clindamycin hydrochloride |
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2012
- 2012-11-20 CN CN201210471371.9A patent/CN102964402B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4895934A (en) * | 1988-08-22 | 1990-01-23 | E. I. Du Pont De Nemours And Company | Process for the preparation of clindamycin phosphate |
| CN101205245A (en) * | 2007-12-06 | 2008-06-25 | 河南天方药业股份有限公司 | Method for preparing hydrochloric acid clindamycinum |
| CN101830946A (en) * | 2010-05-05 | 2010-09-15 | 南阳普康药业有限公司 | Method for synthesizing clindamycin phosphate |
| CN101891779A (en) * | 2010-06-17 | 2010-11-24 | 张家港市信谊化工有限公司 | Process for synthesizing clindamycin phosphate |
| CN101891778A (en) * | 2010-06-17 | 2010-11-24 | 张家港市信谊化工有限公司 | Process for synthesizing clindamycin hydrochloride |
| CN102702279A (en) * | 2012-06-15 | 2012-10-03 | 安徽省皖北药业股份有限公司 | Method for preparing clindamycin hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| 盐酸克林霉素注射液的处方以及制剂工艺;周琴音;《当代医学》;20070930(第124期);第132-135页 * |
| 胡跃飞,等.钯/碳.《现代有机合成试剂-性质、制备和反应》.化学工业出版社,2006,(第1版),第5-6页. * |
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