CN102964402A - Dehydro-clindamycin-free clindamycin hydrochloride and preparation method and applications thereof - Google Patents
Dehydro-clindamycin-free clindamycin hydrochloride and preparation method and applications thereof Download PDFInfo
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- CN102964402A CN102964402A CN2012104713719A CN201210471371A CN102964402A CN 102964402 A CN102964402 A CN 102964402A CN 2012104713719 A CN2012104713719 A CN 2012104713719A CN 201210471371 A CN201210471371 A CN 201210471371A CN 102964402 A CN102964402 A CN 102964402A
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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 technical field, relate to a kind of Dalacina that does not contain the dehydrogenation clindamycin and preparation method thereof and application.
Background technology
Dalacina, chemical name 6-(1-methyl-anti--4-propyl group-L-2-pyrrolidine formyl is amino)-the 1-sulfo--7(S)-chloro-6,7, the hot pyranoside hydrochloride of 8-three deoxidations-L-Su Shi-α-D-gala, structure is seen formula 1:
Formula 1 Dalacina
Clindamycin is synthetic in 1966 by people such as Magerlein the earliest, and the general strong company of the U.S. at first trial-produces successfully, and obtains United States Patent (USP) power in 1969.China was developed jointly and is succeeded in developing by North China Pharmaceutical Factory, Beijing Pharmaceutical Ind. Inst. in 1975, and domestic a lot of producer puts into production afterwards.A plurality of formulation listings such as at present existing clindamycin powder injection, injection, solution, capsule.
Dalacina belongs to lincomycin series antibiotics, is the derivative of lincomycin, and antimicrobial spectrum is identical with lincomycin, and anti-microbial activity is strong 4～8 times than lincomycin.The Dalacina effect is rapid, and without first pass effect, medicament contg is difficult for loss, and curative effect is reliable.Gram positive organism such as Staphylococcus (comprising the penicillin resistant strain), streptococcus, diphtheria corynebacterium, anthrax bacillus etc. there is higher anti-microbial activity.The Grain-negative anerobe is also had good anti-microbial activity, and Bacteroides comprises that bacteroides fragilis, Fusobacterium, dyspepsiacoccus, peptostreptococcus, Clostridium perfringens etc. are mostly extremely sensitive to this product.Gram negative aerobic bacteria comprises that hemophilus influenzae, neisseria and Mycoplasma are all to this product resistance.Without crossing drug resistant, with Macrolide the part crossing drug resistant is arranged between this product and penicillin, paraxin, cephalosporins and the tetracyclines, with lincomycin complete intersection resistance is arranged.The mechanism of action of this product is to be 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, some bacterium is also had germicidal action.
Mainly contain impurity clindamycin B in the Dalacina, table clindamycin, dehydrogenation clindamycin.
In the patent of China: in the synthesis technique of U 10149a (application number 201010200802.9), the synthetic method of the simple Dalacina of a kind of technique is provided, the method mainly contains step to be had: take U 10149a as raw material, carry out chlorination take low-carbon (LC) alkyl halide hydrocarbon as solvent, and products therefrom is finished the hydrolysis reaction of sodium hydroxide at aqueous phase, layering can get the clindamycin free alkali, again with this free alkali and hydrochloric acid carries out salt-forming reaction and crystallization gets final product.The advantage of this technique is that method is simple, has reduced the step of using and reacting of material, has improved the quality of product, makes the content decrease of impurity table crin more than 80% ,≤2.0%, and productive rate has improved 5% approximately.But wherein there is no the relevant content that reduces or remove the dehydrogenation clindamycin.
The content of dehydrogenation clindamycin in raw material is 0.2%～0.4%, because its structure is very approaching with clindamycin, is difficult to remove in the process of preparation or purifying, and structural formula is seen formula 2.
Formula 2 dehydrogenation Dalacinas
Through consulting, the patent of at present relevant Dalacina and document all are that relevant technological is synthetic and how to improve yield, improve crystal formation, with regard to how purifying and the report of removing impurity seldom, and not about reducing or remove the relevant report of dehydrogenation clindamycin.
Summary of the invention
A kind of Dalacina that does not contain the dehydrogenation clindamycin and preparation method thereof and application have been the purpose of this invention is to provide.The present invention can reduce or remove the dehydrogenation clindamycin, reduces the impurity of Dalacina, has improved the quality of pharmaceutical prod.
Technical solution of the present invention is, the Dalacina that contains the dehydrogenation clindamycin is dissolved in water or the moisture alcoholic solution, the palladium carbon that adds material quantity 1/10 ~ 1/200, and passed into hydrogen reaction 1 ~ 48 hour, make dehydrogenation clindamycin wherein all react generation clindamycin, then crystallization treatment.
The above amount that adds 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 reaction equation that makes the clindamycin that does not contain the dehydrogenation clindamycin of the present invention is seen formula 3,
Dalacina by the present invention's preparation can be used for preparing the Dalacina preparation that does not contain the dehydrogenation clindamycin, also can be used for preparing the Clindamycin Phosphate raw material and the preparation that do not contain the dehydrogenation Clindamycin Phosphate.
Advantage of the present invention is the dehydrogenation clindamycin that can remove fully in the Dalacina, reduces the impurity of Dalacina, has improved the quality of pharmaceutical prod.
Description of drawings
The Dalacina collection of illustrative plates (contain dehydrogenation clindamycin) of Fig. 1 before the inventive method preparation
The Dalacina collection of illustrative plates (do not contain dehydrogenation clindamycin) of Fig. 2 after the inventive method preparation
Fig. 3 Clindamycin hydrochloride injection check spectrogram (not containing the dehydrogenation clindamycin)
Fig. 4 Clindamycin Phosphate ingredient inspection spectrogram (not containing the dehydrogenation Clindamycin Phosphate)
Fig. 5 Clindamycin Phosphate ingredient inspection spectrogram (containing the dehydrogenation Clindamycin Phosphate)
Fig. 6 clindamycin phosphate injection check spectrogram (not containing the dehydrogenation Clindamycin Phosphate)
Embodiment
Embodiment 1
The Dalacina that 30g is contained the dehydrogenation clindamycin is dissolved in the 60ml water, adds palladium catalyst carbon 0.3g, logical hydrogen 0.2Mpa, reacted 23 hours, make dehydrogenation clindamycin wherein all react the generation clindamycin, filter de-carbon, in filtrate, add 100mlCH
2Cl
2, dripping 10%NaOH and regulate pH ≈ 10, extracting and demixing adds 25ml CH in aqueous phase behind the separatory
2Cl
2Extraction repeats 2 times, merges CH
2Cl
2Layer in 35 ℃ of rotary evaporations, is spin-dried for rear adding 300ml dissolve with ethanol.Drip dense HCl 7ml, separate out after 3 to 5 minutes.Washes with dehydrated alcohol after filtering, in 60 ℃ of vacuum-dryings and get final product.
Fig. 1, Fig. 2 use the check collection of illustrative plates that preparation method of the present invention prepares the Dalacina raw material of front and back, as seen use preparation method of the present invention and can prepare the Dalacina raw material that does not contain the dehydrogenation clindamycin.
Embodiment 2
The Dalacina that 20g is contained the dehydrogenation clindamycin is dissolved in 80ml water and the 20ml methyl alcohol, add palladium catalyst carbon 2.0g, logical hydrogen 0.4MPa stirring reaction 1 hour makes dehydrogenation clindamycin wherein all react the generation clindamycin, filter de-carbon, in filtrate, add 60ml CH
2Cl
2, dripping 10%NaOH17.5ml, extracting and demixing adds 20ml CH in water layer behind the separatory
2Cl
2Extraction repeats twice, merges CH
2Cl
2Layer in 45 ℃ of rotary evaporations, adds dehydrated alcohol 200ml dissolving after being spin-dried for.Separate out gradually after dripping dense HCl 5ml.The cooling crystallization filtered after for some time, in 60 ℃ of vacuum-dryings.
The Dalacina that 20g is contained the dehydrogenation clindamycin is dissolved in 80ml water and the 30ml ethanol, add palladium catalyst carbon 0.1g, continue slowly logical hydrogen and stirring reaction 48 hours, make dehydrogenation clindamycin wherein all react the generation clindamycin, filter de-carbon, in filtrate, add 60ml CH
2Cl
2, dripping 10%NaOH17.5ml, extracting and demixing adds 20ml CH in water layer behind the separatory
2Cl
2Extraction repeats twice, merges CH
2Cl
2Layer in 45 ℃ of rotary evaporations, adds dehydrated alcohol 200ml dissolving after being spin-dried for.Separate out gradually after dripping dense HCl 5ml.The cooling crystallization filtered after for some time, in 60 ℃ of vacuum-dryings.
Embodiment 4
The Dalacina that 20g is contained the dehydrogenation clindamycin is dissolved in 80ml water and the 40ml Virahol, add palladium catalyst carbon 1.0g, logical hydrogen 0.4MPa stirring reaction 5 hours makes dehydrogenation clindamycin wherein all react the generation clindamycin, filter de-carbon, in filtrate, add 60ml CH
2Cl
2, dripping 10%NaOH17.5ml, extracting and demixing adds 20ml CH in water layer behind the separatory
2Cl
2Extraction repeats twice, merges CH
2Cl
2Layer in 45 ℃ of rotary evaporations, adds dehydrated alcohol 200ml dissolving after being spin-dried for.Separate out gradually after dripping dense HCl 5ml.The cooling crystallization filtered after for some time, in 60 ℃ of vacuum-dryings.
The preparation of embodiment 5 Clindamycin hydrochloride injections
Get 70% water for injection of preparation total amount, add Citric Acid and Sodium Citrate, regulate pH4.5 ~ 4.8, add the Dalacina of pressing embodiment 1 preparation, behind the dissolve complete, control pH4.3 ~ 4.7.Add gac and stir, filter de-carbon and filter through 0.22 μ m strainer, filtrate is carried out embedding and through 100 ℃ of sterilization 15min, chilling and get final product.
The preparation of embodiment 6 Clindamycin Phosphate raw materials
Referenced patent----(number of patent application: 200710071197.8), Fig. 4 is that Dalacina take embodiment 2 preparations is as raw material for a kind of preparation method of Clindamycin Phosphate; Fig. 5 be the Dalacina that contains the dehydrogenation clindamycin be raw material, prepare Clindamycin Phosphate according to the method for above-mentioned patent.As seen, the Dalacina of application the present invention preparation can be used for preparing the Clindamycin Phosphate raw material that does not contain the dehydrogenation Clindamycin Phosphate.
Embodiment 7 preparation clindamycin phosphate injections
In the water for injection that lets cool that newly boils, add EDTA.2Na, after the stirring and dissolving, the Clindamycin Phosphate that alternately adds sodium hydroxide solution and prepare by Fig. 4 among the embodiment 6, moisturizing is to full dose behind the dissolve complete, add sodium bisulfite, stir molten clear rear pH6.3 ~ 6.5 of regulating.Add gac and stir, filter de-carbon and filter through 0.22 μ m strainer, filtrate is carried out embedding and be get final product.
Fig. 3: take the Dalacina of embodiment 1 preparation as raw material, prepare Clindamycin hydrochloride injection by the method for embodiment 5, do not contain the dehydrogenation clindamycin in the injection liquid of gained.As seen, the Dalacina of application the present invention preparation can be used for preparing the salt acid esters clindamycin preparation that does not contain the dehydrogenation clindamycin.
Fig. 6 as seen, the Dalacina of using the present invention's preparation can be used for preparing the Clindamycin Phosphate preparation that does not contain the dehydrogenation Clindamycin Phosphate.
Claims (4)
1. Dalacina preparation method who does not contain the dehydrogenation clindamycin, it is characterized in that be material dissolution in water or moisture alcoholic solution to the Dalacina that contains the dehydrogenation clindamycin, 1/10～1/200 the palladium carbon that adds material quantity, and passed into hydrogen reaction 1～48 hour, make dehydrogenation clindamycin wherein all react generation clindamycin, then crystallization treatment.
2. a kind of Dalacina preparation method who does not contain the dehydrogenation clindamycin according to claim 1, the amount that it is characterized in that adding palladium carbon is 1/10～1/20 of material quantity.
3. a kind of Dalacina preparation method who does not contain the dehydrogenation clindamycin according to claim 1, the time that it is characterized in that described logical hydrogen reaction is 1～5 hour.
4. application that does not contain the Dalacina of dehydrogenation clindamycin is characterized in that can be used for preparing the Dalacina preparation that does not contain the dehydrogenation clindamycin, also can be used for preparing the Clindamycin Phosphate raw material and the preparation that do not contain the dehydrogenation Clindamycin Phosphate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111647030A (en) * | 2020-06-18 | 2020-09-11 | 新宇药业股份有限公司 | Method for improving purity of clindamycin hydrochloride |
Citations (6)
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|---|---|---|---|---|
| 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 |
-
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 |
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| 周琴音: "盐酸克林霉素注射液的处方以及制剂工艺", 《当代医学》, no. 124, 30 September 2007 (2007-09-30), pages 132 - 135 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111647030A (en) * | 2020-06-18 | 2020-09-11 | 新宇药业股份有限公司 | Method for improving purity of clindamycin hydrochloride |
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