CN104163840A - Roxithromycin refining method - Google Patents
Roxithromycin refining method Download PDFInfo
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- CN104163840A CN104163840A CN201310392774.9A CN201310392774A CN104163840A CN 104163840 A CN104163840 A CN 104163840A CN 201310392774 A CN201310392774 A CN 201310392774A CN 104163840 A CN104163840 A CN 104163840A
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- roxithromycin
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Abstract
The invention discloses a roxithromycin refining method comprising the following steps: (1) a roxithromycin crude product is dispersed in a mixed solvent formed by mixing lower alcohol and acetone; the mixture is heated until clarified, such that a mixture is obtained; (2) the mixture obtained in the step (1) is cooled until crystals are precipitated; the temperature is maintained at a low temperature and the material is stirred, or a polar solvent is dropped and the material is stirred, such that crystals are fully precipitated; and filtering, washing and drying are carried out, such that refined roxithromycin is obtained. According to the roxithromycin refining method, the mixed solvent formed by mixing lower alcohol and acetone is used for dispersing crude roxithromycin, and refining is carried out with heating dissolving and cooling precipitation processes, such that impurity removing effect is good, and product yield is high. The refined roxithromycin has high purity. The product has good color, uniform particle size, and low broken crystal amount. With the refining method, after fractionation recovery, the mixed solution can be reused. The amount of produced waste liquid is low, and cost is low. The process is simple, and operation is convenient. The method is suitable for large-scale industrial productions.
Description
Technical field
The invention belongs to Roxithromycin preparing technical field, be specifically related to a kind of process for purification of Roxithromycin.
Background technology
Roxithromycin is macrolide antibiotics of new generation, is the derivative of erythromycin, and Main Function is in gram-positive microorganism, anerobe, chlamydozoan and mycoplasma etc.Vitro antibacterial activity and the erythromycin of Roxithromycin are similar, and vivo bacteria corrosion action than the strong 1-4 of erythromycin doubly, clinical in the microbial bronchitis of sensitivity, pneumonia, tonsillitis, department of eye infection, urinary system infection, Skin and soft tissue infection etc.
Roxithromycin molecular structure is:
At " European Pharmacopoeia 6.3 ", (EP6.3) in version, the related impurity of Roxithromycin part has A, B, C, D, E, F, G, H, I, J, K, and its concrete source is as follows:
A---Erythromycin A, by bringing in raw material;
The destruction product of B---descladinosylation;
C---erythromycin A-9 oxime, brings in raw material;
D---trans Roxithromycin, is generated by trans oxime;
E---Roxithromycin C, is generated by Erythromycin C oxime;
F---N demethylation Roxithromycin, is generated by N demethylation oxime;
G---the impurity in side chain reacts generation with oxime;
H---Roxithromycin B, is generated by berythromycin oxime;
I---two replacement Roxithromycins;
J---the impurity in side chain reacts generation with oxime;
K---the impurity in side chain reacts generation with oxime.
The content of these impurity in coarse silk erythromycin reaches more than 3%, has had a strong impact on stability and the drug effect of Roxithromycin.The process for purification of existing Roxithromycin is the mixed solvent that adopts organic solvent or organic solvent and water, coarse silk erythromycin is carried out to purifying, general only for one or both impurity in coarse silk erythromycin, and not high for the comprehensive clearance of all impurity, the mass yield of product is also lower; Meanwhile, the most complex process of existing method, long flow path, is not suitable for applying.
Summary of the invention
The object of this invention is to provide a kind of process for purification of Roxithromycin, the comprehensive removal effect of impurity is good, and mass yield is high, and products obtained therefrom purity is high.
In order to realize above object, the technical solution adopted in the present invention is: a kind of process for purification of Roxithromycin, comprises the following steps:
1) Roxithromycin crude product is dispersed in the mixed solvent that lower alcohol and acetone is mixed to form, is heated to clarification, obtain mixture;
2) after step 1) gained mixture is cooled to crystal separates out, under cold condition, be incubated and stir or drip polar solvent and stir, after crystal is fully separated out, filtering, wash and dry, to obtain final product.
In described mixed solvent, the volume ratio of lower alcohol and acetone is 10:90～90:10.Preferred 30:70～the 70:30 of the volume ratio of lower alcohol and acetone in described mixed solvent.
Described lower alcohol is that carbonatoms is 1～4 alcohol.
Described lower alcohol is methyl alcohol or ethanol.
The amount of every Crow erythromycin crude product mixed solvent used is 1～10ml.Preferably 3～the 6ml of amount of every Crow erythromycin crude product mixed solvent used.
The temperature heating described in step 1) is 50～60 DEG C; Step 2) described in bake out temperature be 50～55 DEG C.
Step 2) described in low temperature be-20～-5 DEG C, soaking time is 1.5～3h.
Step 2) described in polar solvent be water, methane amide or acetonitrile.
Step 2) described in the add-on of polar solvent equate with the usage quantity of mixed solvent described in step 1).
Step 2) described in washing be with the mixed solvent of 0～5 DEG C, the solid after filtering to be washed, or the solid after to filtration washs with polar solvent.
The process for purification of Roxithromycin of the present invention, carries out heating for dissolving after the mixed solvent that adopts lower alcohol and acetone to be mixed to form disperses coarse silk erythromycin, the cooling technique of separating out is refined again, and Impurity removal is effective, and product yield is high; The purity of the refining Roxithromycin of gained is high, and products obtained therefrom appearance luster is good simultaneously, epigranular, and broken grain is few, and hardness of crystals is also significantly improved.Process for purification of the present invention, mixing solutions, after fractionation is reclaimed, can be reused, and the waste liquid of generation is few, and cost is low; Technique is simple, easy to operate, is applicable to large-scale industrial production.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1
The process for purification of the Roxithromycin of the present embodiment, comprises the following steps:
1) 100g Roxithromycin crude product is dispersed in the mixed solvent that 50ml methyl alcohol and 50ml acetone is mixed to form, is heated to 50 DEG C and is dissolved to clarification, obtain mixture;
2) after step 1) gained mixture slowly cooled to crystal separating out, under-5 DEG C of cold condition, be incubated 3h and stir, after crystal is fully separated out, filter, with the mixed solvent of 0 DEG C (this mixed solvent is identical with step 1) mixed solvent used) washing solid, 50 DEG C of oven dry, obtain the refining Roxithromycin of 94.55g.
The mass yield of the refining Roxithromycin of the present embodiment gained is 94.55%.
Embodiment 2
The process for purification of the Roxithromycin of the present embodiment, comprises the following steps:
1) 100g Roxithromycin crude product is dispersed in the mixed solvent that 50ml ethanol and 450ml acetone is mixed to form, is heated to 60 DEG C and is dissolved to clarification, obtain mixture;
2) after step 1) gained mixture slowly cooled to crystal separating out, under-20 DEG C of cold condition, be incubated 1.5h and stir, after crystal is fully separated out, filter, with the mixed solvents of 5 DEG C (this mixed solvent is identical with step 1) mixed solvent used) washing solid, 55 DEG C of oven dry, obtain the refining Roxithromycin of 85.78g.
The mass yield of the refining Roxithromycin of the present embodiment gained is 85.78%.
Embodiment 3
The process for purification of the Roxithromycin of the present embodiment, comprises the following steps:
1) 100g Roxithromycin crude product is dispersed in the mixed solvent that 900ml ethanol and 100ml acetone is mixed to form, is heated to 65 DEG C and is dissolved to clarification, obtain mixture;
2) after step 1) gained mixture slowly cooled to crystal separating out, under-10 DEG C of cold condition, be incubated 2h and stir, after crystal is fully separated out, filter, with the mixed solvents of 5 DEG C (this mixed solvent is identical with step 1) mixed solvent used) washing solid, 65 DEG C of oven dry, obtain the refining Roxithromycin of 88.74g.
The mass yield of the refining Roxithromycin of the present embodiment gained is 88.74%.
Embodiment 4
The process for purification of the Roxithromycin of the present embodiment, comprises the following steps:
1) 100g Roxithromycin crude product is dispersed in the mixed solvent that 160ml methyl alcohol and 240ml acetone is mixed to form, is heated to 55 DEG C and is dissolved to clarification, obtain mixture;
2) slowly drip the pure water of 400ml to step 1) gained mixture, dropwise rear stirring 3h, after crystal is fully separated out, filter, wash solid with pure water, 55 DEG C of oven dry, obtain the refining Roxithromycin of 98.70g.
The mass yield of the refining Roxithromycin of the present embodiment gained is 98.70%.
Embodiment 5
The process for purification of the Roxithromycin of the present embodiment, comprises the following steps:
1) 100g Roxithromycin crude product is dispersed in the mixed solvent that 360ml methyl alcohol and 240ml acetone is mixed to form, is heated to 50 DEG C and is dissolved to clarification, obtain mixture;
2) slowly drip the pure water of 600ml to step 1) gained mixture, dropwise rear stirring 3h, after crystal is fully separated out, filter, wash solid with pure water, 50 DEG C of oven dry, obtain the refining Roxithromycin of 94.78g.
The mass yield of the refining Roxithromycin of the present embodiment gained is 94.78%.
Embodiment 6
The process for purification of the Roxithromycin of the present embodiment, comprises the following steps:
1) 100g Roxithromycin crude product is dispersed in the mixed solvent that 90ml methyl alcohol and 210ml acetone is mixed to form, is heated to 60 DEG C and is dissolved to clarification, obtain mixture;
2) slowly drip the pure water of 300ml to step 1) gained mixture, dropwise rear stirring 3h, after crystal is fully separated out, filter, wash solid with pure water, 55 DEG C of oven dry, obtain the refining Roxithromycin of 91.58g.
The mass yield of the refining Roxithromycin of the present embodiment gained is 91.58%.
Experimental example
This experimental example adopts HPLC(high performance liquid chromatography) the refining Roxithromycin of embodiment 1～6 gained is detected, result is as shown in table 1.Detection method is specifically referring to " European Pharmacopoeia 6.3 " (EP6.3) 2842nd～2843 pages of versions.The model of the high performance liquid chromatograph that this experiment adopts is waters2695-2489, and testing conditions is: taking octadecylsilane chemically bonded silica as weighting agent; With 0.067mol/L ammonium dihydrogen phosphate (regulating pH to 6.5 taking triethylamine) ,-acetonitrile (65:35) is as moving phase; Detection wavelength is 210nm.Get Roxithromycin reference substance and erythromycin standard substance are appropriate, dissolve and be diluted in every 1ml respectively approximately containing the mixing solutions of 1mg by moving phase, get 20 μ L injection liquid chromatographies.The retention time of Roxithromycin is about 14 minutes, the resolution at itself and erythromycin peak should not be less than 15.0, Roxithromycin and relative retention time are about 0.95 place's impurity peaks resolution should be not less than 1.0, and the resolution that is about 1.2 place's impurity peaks with relative retention time should be not less than 2.0; Theoretical version number calculates and is not less than 2500 by Roxithromycin.
Table 1 embodiment 1～6 gained is refined Roxithromycin detected result
Note: in table, " other " refer to other uncertain impurity.
Claims (10)
1. a process for purification for Roxithromycin, is characterized in that: comprise the following steps:
1) Roxithromycin crude product is dispersed in the mixed solvent that lower alcohol and acetone is mixed to form, is heated to clarification, obtain mixture;
2) after step 1) gained mixture is cooled to crystal separates out, under cold condition, be incubated and stir or drip polar solvent and stir, after crystal is fully separated out, filtering, wash and dry, obtaining refining Roxithromycin.
2. the process for purification of Roxithromycin according to claim 1, is characterized in that: in described mixed solvent, the volume ratio of lower alcohol and acetone is 10:90～90:10.
3. the process for purification of Roxithromycin according to claim 1 and 2, is characterized in that: described lower alcohol is that carbonatoms is 1～4 alcohol.
4. the process for purification of Roxithromycin according to claim 3, is characterized in that: described lower alcohol is methyl alcohol or ethanol.
5. the process for purification of Roxithromycin according to claim 1, is characterized in that: the amount of every Crow erythromycin crude product mixed solvent used is 1～10ml.
6. the process for purification of Roxithromycin according to claim 1, is characterized in that: the temperature heating described in step 1) is 50～60 DEG C; Step 2) described in bake out temperature be 50～55 DEG C.
7. the process for purification of Roxithromycin according to claim 1, is characterized in that: step 2) described in low temperature be-20～-5 DEG C, soaking time is 1.5～3h.
8. the process for purification of Roxithromycin according to claim 1, is characterized in that: step 2) described in polar solvent be water, methane amide or acetonitrile.
9. according to the process for purification of the Roxithromycin described in claim 1 or 8, it is characterized in that: step 2) described in the add-on of polar solvent equate with the usage quantity of mixed solvent described in step 1).
10. the process for purification of Roxithromycin according to claim 1, is characterized in that: step 2) described in washing be with the mixed solvent of 0～5 DEG C, the solid after filtering to be washed, or the solid after to filtration washs with polar solvent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106589022A (en) * | 2016-11-16 | 2017-04-26 | 山东裕欣药业有限公司 | Roxithromycin compound as well as preparation method and pharmaceutical composition thereof |
| CN112094183A (en) * | 2020-08-24 | 2020-12-18 | 安徽佳先功能助剂股份有限公司 | Novel efficient dibenzoyl methane crystallization method |
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| US6204368B1 (en) * | 1998-09-10 | 2001-03-20 | Hovione Inter Ltd. | Process for the purification of roxithromycin |
| EP1435359A1 (en) * | 2002-12-31 | 2004-07-07 | Alembic Limited | A process for the purification of roxithromycin |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106589022A (en) * | 2016-11-16 | 2017-04-26 | 山东裕欣药业有限公司 | Roxithromycin compound as well as preparation method and pharmaceutical composition thereof |
| CN106589022B (en) * | 2016-11-16 | 2019-06-18 | 山东裕欣药业有限公司 | A kind of roxithromycin compound and preparation method thereof, pharmaceutical composition |
| CN112094183A (en) * | 2020-08-24 | 2020-12-18 | 安徽佳先功能助剂股份有限公司 | Novel efficient dibenzoyl methane crystallization method |
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Application publication date: 20141126 |