CN106866791A - A kind of preparation method of high-purity daptomycin lactone hydrolysate - Google Patents
A kind of preparation method of high-purity daptomycin lactone hydrolysate Download PDFInfo
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- CN106866791A CN106866791A CN201510921002.9A CN201510921002A CN106866791A CN 106866791 A CN106866791 A CN 106866791A CN 201510921002 A CN201510921002 A CN 201510921002A CN 106866791 A CN106866791 A CN 106866791A
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Abstract
The invention discloses a kind of method for preparing high-purity daptomycin lactone hydrolysate, the method adjusts pH using Daptomycin resin chromatography liquid, it is converted into the feed liquid of the lactone hydrolysate of Daptomycin containing higher degree, again by preparative chromatography, the Daptomycin lactone hydrolysate of high-purity of the chromatographic purity more than 96% is obtained.The method is simple and easy to apply, with low cost.
Description
Technical field
The present invention relates to pharmaceutical formulating art, the preparation method of more particularly to interior ester hydrolysis Daptomycin, more particularly to one kind
Ester hydrolysis Daptomycin in high-purity is prepared using the conversion of Daptomycin resin chromatography liquid certain condition and preparative chromatography method.
Background technology
Development and the abuse of antibiotic with antibiotic, pathogen be to the drug resistance of antibiotic today's society face it is most severe
Challenge.In addition to controlling abuse of antibiotics, a kind of effective antibiotic to antimicrobial agent into this problem of solution is found at present
Optimal path, vancomycin was once considered as the last line of defense to resisting gram-positive bacteria, but now world clinical
It was found that increasing resistance to this medicine bacterium.
Daptomycin (Daptomycin) is by Lilly (gift comes) company's original research, a ring of Cubist drugmakers exploitation
Lipopeptide antibiotic.Answer active demand of the patient to new resistance antibiotic, the end of the year 2003, FDA (FDA)
Ratifying injection Daptomycin (Daptomycin) (trade name cubicin) by quick trial program is used to treat blue by some leather
Concurrency skin and skin structure infection that family name positive sensitive strain causes, such as abscess, surgery cut infection and skin ulcer.Reach
The mechanism of action of Tobramycin is different from other antibiotic, and it is by upsetting transhipment of the cell membrane to amino acid, so as to hinder bacterium thin
The biosynthesis of cell wall peptide glycan, changes the property of cytoplasma membrane；In addition, it can also make it by destroying the cell membrane of bacterium
Content leaks and reaches sterilized purpose, therefore bacterium may be relatively difficult to Daptomycin generation drug resistance.
Although Daptomycin realizes industrialized production in the U.S., in Daptomycin product often include dehydration Daptomycin,
The impurity such as isomery Daptomycin, Daptomycin lactone hydrolysate, have a strong impact on product quality, are that this can be separately separated and is purified into
Impurity in Daptomycin simultaneously carries out research and is very important.
Existing Daptomycin extracting method, such as the Daptomycin impurity ownership described by European patent 1586580A2, not
Specifically related to Daptomycin impurity separation method.
The content of the invention
It is easy to operate, with low cost and can quickly obtain high-purity daptomycin lactone hydrolysate it is an object of the invention to provide one kind
Preparation method.
According to European patent " PROCESS FOR THE PURIFICATION OF DAPTOMYCIN " (EP 1 586 580
A2 method is detected to Daptomycin disclosed in), the Daptomycin impurity ownership with reference to described by European patent 1586580A2,
To the name of Daptomycin impurity ownership and positioning scenarios as shown in figure 1, DT represents Daptomycin (retention time 38.555min) in Fig. 1,
Daptomycin lactone hydrolysate peak is located at retention time 27.250min.
The Daptomycin lactone hydrolysate preparation method that the present invention is provided, comprises the following steps：
1) by Daptomycin filtering fermentation liquor, filtrate obtains Daptomycin lactone hydrolysate resin chromatography liquid by resin chromatography；
2) by step 1) gained resin chromatography liquid regulation pH2~6,4~50 DEG C preserve 1~2 day, obtain containing chromatographic purity higher up to support
The solution of mycin lactone hydrolysate；
3) by step 2) resulting solution, by preparative chromatography column separating purification, obtains chromatographic purity>Ester hydrolysis in 90% Daptomycin
The preparation solution of thing；
4) by step 3) gained preparation solution freeze, obtain Daptomycin lactone hydrolysate.
Preferably, above-mentioned steps 1) in filtrate through FPDA13 resin chromatographies, obtain chromatographic purity>5% (preferably>10%) reach
The resin chromatography liquid of Tobramycin lactone hydrolysate.Wherein after the upper FPDA13 resin chromatography posts of filtrate, first with 0.03N sodium chloride,
0.06N sodium acetates, the solution of acetic acid regulation pH6.5-7.0 rinse pillar, then with 0.3N sodium chloride, the sodium acetate of 0.06N, vinegar
The eluant solution of acid for adjusting pH 6.5-7.0, collects chromatographic purity>5% (preferably>10%) Daptomycin lactone hydrolysate resin bed
Analysis liquid.Above-mentioned steps 2) resin chromatography liquid is preferably adjusted into pH3~6, storage temperature is preferably 10~40 DEG C.
Above-mentioned steps 3) solution of Daptomycin lactone hydrolysate, mobile phase are further isolated and purified using preparative chromatography piece-rate system
Using methyl alcohol and the mixed liquor of trifluoroacetic acid solution, specific chromatographic condition is：
Chromatographic column：LP-C8、250×21.2mm
Wavelength：214nm
Mobile phase：Methyl alcohol, trifluoroacetic acid solution
Flow velocity：19mL/min
Column temperature：20~30 DEG C of room temperatures
Wherein, trifluoroacetic acid solution concentration is 0.01%~0.2%, preferably 0.01%~0.05%；
Mobile phase ratio is methyl alcohol:Trifluoroacetic acid solution=20:80~60:40 (volume ratios, similarly hereinafter), preferably 20:80~40:60.
In the methods of the invention, after Daptomycin zymotic fluid is through resin chromatography, destruction, the treatment of preparative chromatography piece-rate system, obtain
Daptomycin lactone hydrolysate, its chromatographic purity is more than 96%.The method is simple and easy to apply, with low cost.
Brief description of the drawings
Fig. 1 is Daptomycin HPLC detection collection of illustrative plates, which show the ownership and positioning scenarios of each impurity of Daptomycin.
Specific embodiment
The present invention, the scope of but do not limit the invention in any way are further described by the following examples.
Embodiment 1
The upper FPDA13 resin chromatographies of filtrate after Daptomycin filtering fermentation liquor, with 0.03N sodium chloride, 0.06N sodium acetates, acetic acid
The solution 2BV for adjusting pH6.5-7.0 rinses pillar, and 0.3N sodium chloride, the sodium acetate of 0.06N, acetic acid adjust the solution of pH6.5-7.0
Wash-out, collects Daptomycin lactone hydrolysate chromatographic solution of the chromatographic purity more than 10%, adjusts pH2.5, and 20 DEG C of constant temperature preserve 24h,
Obtain the Daptomycin lactone hydrolyzate solution of chromatographic purity 20%.
Through preparative chromatography, (mobile phase is methyl alcohol to Daptomycin lactone hydrolyzate solution:0.01% trifluoroacetic acid=25:75) isolate and purify,
And with efficient liquid phase tracing detection (testing conditions and European patent " PROCESS FOR THE PURIFICATION OF
Method disclosed in DAPTOMYCIN " (A2 of EP 1 586 580) is identical), collect chromatographic purity>90% Daptomycin lactone
The preparation solution of hydrolysate.
Preparation solution vacuum freeze-drying, gained solid is using high performance liquid chromatography (testing conditions and European patent " PROCESS FOR
Method disclosed in THE PURIFICATION OF DAPTOMYCIN " (A2 of EP 1 586 580) is identical) detect mould up to support
Plain lactone hydrolysate purity, its purity is 96%.
Embodiment 2
The upper FPDA13 resin chromatographies of filtrate after Daptomycin filtering fermentation liquor, 0.03N sodium chloride, 0.06N sodium acetates, acetic acid are adjusted
The solution 2BV for saving pH6.5-7.0 rinses pillar, and 0.3N sodium chloride, the sodium acetate of 0.06N, the solution of acetic acid regulation pH6.5-7.0 are washed
It is de-, Daptomycin lactone hydrolysate chromatographic solution of the chromatographic purity more than 10% is collected, pH3 is adjusted, 20 DEG C of constant temperature preserve 24h, obtain
To the Daptomycin lactone hydrolyzate solution of chromatographic purity 25%.
Through preparative chromatography, (mobile phase is methyl alcohol to Daptomycin lactone hydrolyzate solution:0.01% trifluoroacetic acid=25:75) isolate and purify,
And with efficient liquid phase tracing detection (testing conditions and European patent " PROCESS FOR THE PURIFICATION OF
Method disclosed in DAPTOMYCIN " (A2 of EP 1 586 580) is identical), collect chromatographic purity>90% Daptomycin lactone
The preparation solution of hydrolysate.
Preparation solution vacuum freeze-drying, gained solid is using high performance liquid chromatography (testing conditions and European patent " PROCESS FOR
Method disclosed in THE PURIFICATION OF DAPTOMYCIN " (A2 of EP 1 586 580) is identical) detect mould up to support
Plain lactone hydrolysate purity, its purity is 96.5%.
Embodiment 3
The upper FPDA13 resin chromatographies of filtrate after Daptomycin filtering fermentation liquor, 0.03N sodium chloride, 0.06N sodium acetates, acetic acid are adjusted
The solution 2BV for saving pH6.5-7.0 rinses pillar, and 0.3N sodium chloride, the sodium acetate of 0.06N, the solution of acetic acid regulation pH6.5-7.0 are washed
It is de-, Daptomycin lactone hydrolysate chromatographic solution of the chromatographic purity more than 10% is collected, pH4 is adjusted, 20 DEG C of constant temperature preserve 24h, obtain
To the Daptomycin lactone hydrolyzate solution of chromatographic purity 37%.
Through preparative chromatography, (mobile phase is methyl alcohol to Daptomycin lactone hydrolyzate solution:0.01% trifluoroacetic acid=25:75) isolate and purify,
And with efficient liquid phase tracing detection (testing conditions and European patent " PROCESS FOR THE PURIFICATION OF
Method disclosed in DAPTOMYCIN " (A2 of EP 1 586 580) is identical), collect chromatographic purity>90% Daptomycin lactone
The preparation solution of hydrolysate.
Preparation solution vacuum freeze-drying, gained solid is using high performance liquid chromatography (testing conditions and European patent " PROCESS FOR
Method disclosed in THE PURIFICATION OF DAPTOMYCIN " (A2 of EP 1 586 580) is identical) detect mould up to support
Plain lactone hydrolysate purity, its purity is 96.3%.
Embodiment 4
The upper FPDA13 resin chromatographies of filtrate after Daptomycin filtering fermentation liquor, 0.03N sodium chloride, 0.06N sodium acetates, acetic acid are adjusted
The solution 2BV for saving pH6.5-7.0 rinses pillar, and 0.3N sodium chloride, the sodium acetate of 0.06N, the solution of acetic acid regulation pH6.5-7.0 are washed
It is de-, Daptomycin lactone hydrolysate chromatographic solution of the chromatographic purity more than 10% is collected, pH5 is adjusted, 20 DEG C of constant temperature preserve 24h, obtain
To the Daptomycin lactone hydrolyzate solution of chromatographic purity 25%.
Through preparative chromatography, (mobile phase is methyl alcohol to Daptomycin lactone hydrolyzate solution:0.01% trifluoroacetic acid=25:75) isolate and purify,
And with efficient liquid phase tracing detection (testing conditions and European patent " PROCESS FOR THE PURIFICATION OF
Method disclosed in DAPTOMYCIN " (A2 of EP 1 586 580) is identical), collect chromatographic purity>90% Daptomycin lactone
The preparation solution of hydrolysate.
Preparation solution vacuum freeze-drying, gained solid is using high performance liquid chromatography (testing conditions and European patent " PROCESS FOR
Method disclosed in THE PURIFICATION OF DAPTOMYCIN " (A2 of EP 1 586 580) is identical) detect mould up to support
The purity of plain lactone hydrolysate, its purity is 97%.
Embodiment 5
The upper FPDA13 resin chromatographies of filtrate after Daptomycin filtering fermentation liquor, 0.03N sodium chloride, 0.06N sodium acetates, acetic acid are adjusted
The solution 2BV for saving pH6.5-7.0 rinses pillar, and 0.3N sodium chloride, the sodium acetate of 0.06N, the solution of acetic acid regulation pH6.5-7.0 are washed
It is de-, Daptomycin lactone hydrolysate chromatographic solution of the chromatographic purity more than 10% is collected, pH4.5 is adjusted, 30 DEG C of climatic chambers are preserved
24h, obtains the Daptomycin lactone hydrolyzate solution of chromatographic purity 30%.
Through preparative chromatography, (mobile phase is methyl alcohol to Daptomycin lactone hydrolyzate solution:0.01% trifluoroacetic acid=25:75) isolate and purify,
And with efficient liquid phase tracing detection (testing conditions and European patent " PROCESS FOR THE PURIFICATION OF
Method disclosed in DAPTOMYCIN " (A2 of EP 1 586 580) is identical), collect chromatographic purity>90% Daptomycin lactone
The preparation solution of hydrolysate.
Preparation solution vacuum freeze-drying, gained solid is using high performance liquid chromatography (testing conditions and European patent " PROCESS FOR
Method disclosed in THE PURIFICATION OF DAPTOMYCIN " (A2 of EP 1 586 580) is identical) detection lactone water
Solution Daptomycin purity, its purity is 97%.
Embodiment 6
The upper FPDA13 resin chromatographies of filtrate after Daptomycin filtering fermentation liquor, 0.03N sodium chloride, 0.06N sodium acetates, acetic acid are adjusted
The solution 2BV for saving pH6.5-7.0 rinses pillar, and 0.3N sodium chloride, the sodium acetate of 0.06N, the solution of acetic acid regulation pH6.5-7.0 are washed
It is de-, Daptomycin lactone hydrolysate chromatographic solution of the chromatographic purity more than 10% is collected, pH4.5 is adjusted, 40 DEG C of constant temperature preserve 24h,
Obtain the Daptomycin lactone hydrolyzate solution of chromatographic purity 18%.
Through preparative chromatography, (mobile phase is methyl alcohol to Daptomycin lactone hydrolyzate solution:0.01% trifluoroacetic acid=25:75) isolate and purify,
And with efficient liquid phase tracing detection (testing conditions and European patent " PROCESS FOR THE PURIFICATION OF
Method disclosed in DAPTOMYCIN " (A2 of EP 1 586 580) is identical), collect chromatographic purity>90% Daptomycin lactone
The preparation solution of hydrolysate.
Preparation solution vacuum freeze-drying, gained solid is using high performance liquid chromatography (testing conditions and European patent " PROCESS FOR
Method disclosed in THE PURIFICATION OF DAPTOMYCIN " (A2 of EP 1 586 580) is identical) detect mould up to support
Plain lactone hydrolysate purity, its purity is 96%.
Embodiment 7
The upper FPDA13 resin chromatographies of filtrate after Daptomycin filtering fermentation liquor, 0.03N sodium chloride, 0.06N sodium acetates, acetic acid are adjusted
The solution 2BV for saving pH6.5-7.0 rinses pillar, and 0.3N sodium chloride, the sodium acetate of 0.06N, the solution of acetic acid regulation pH6.5-7.0 are washed
It is de-, Daptomycin lactone hydrolysate chromatographic solution of the chromatographic purity more than 10% is collected, pH4.5 is adjusted, 20 DEG C of constant temperature preserve 24h,
Obtain the Daptomycin lactone hydrolyzate solution of chromatographic purity 27%.
Through preparative chromatography, (mobile phase is methyl alcohol to Daptomycin lactone hydrolyzate solution:0.01% trifluoroacetic acid=30:70) isolate and purify,
And with efficient liquid phase tracing detection (testing conditions and European patent " PROCESS FOR THE PURIFICATION OF
Method disclosed in DAPTOMYCIN " (A2 of EP 1 586 580) is identical), collect chromatographic purity>90% Daptomycin lactone
The preparation solution of hydrolysate.
Preparation solution vacuum freeze-drying, gained solid is using high performance liquid chromatography (testing conditions and European patent " PROCESS FOR
Method disclosed in THE PURIFICATION OF DAPTOMYCIN " (A2 of EP 1 586 580) is identical) detect mould up to support
Plain lactone hydrolysate purity, its purity is 99%.
Embodiment 8
The upper FPDA13 resin chromatographies of filtrate after Daptomycin filtering fermentation liquor, 0.03N sodium chloride, 0.06N sodium acetates, acetic acid are adjusted
The solution 2BV for saving pH6.5-7.0 rinses pillar, and 0.3N sodium chloride, the sodium acetate of 0.06N, the solution of acetic acid regulation pH6.5-7.0 are washed
It is de-, Daptomycin lactone hydrolysate chromatographic solution of the chromatographic purity more than 10% is collected, pH4.5 is adjusted, 20 DEG C of constant temperature preserve 24h,
Obtain the Daptomycin lactone hydrolyzate solution of chromatographic purity 27%.
Through preparative chromatography, (mobile phase is methyl alcohol to Daptomycin lactone hydrolyzate solution:0.01% trifluoroacetic acid=33:77) isolate and purify,
And with efficient liquid phase tracing detection (testing conditions and European patent " PROCESS FOR THE PURIFICATION OF
Method disclosed in DAPTOMYCIN " (A2 of EP 1 586 580) is identical), collect chromatographic purity>90% Daptomycin lactone
The preparation solution of hydrolysate.
Preparation solution vacuum freeze-drying, gained solid is using high performance liquid chromatography (testing conditions and European patent " PROCESS FOR
Method disclosed in THE PURIFICATION OF DAPTOMYCIN " (A2 of EP 1 586 580) is identical) detect mould up to support
Plain lactone hydrolysate purity, its purity is 96%.
The present invention provides ester hydrolysis in a kind of fast and convenient, with low cost preparation high-purity daptomycin using preparative chromatography technology
The technology of thing.Methyl alcohol and trifluoro second wherein in the destruction pH and temperature of Daptomycin lactone hydrolysate and preparation mobile phase
Acid solution ratio and trifluoroacetic acid concentration are even more the critical process control point of high-purity lactone hydrolysate Daptomycin preparation.Although this
Text to this invention as described description in detail, it is to be understood that, on the basis of without prejudice to spirit of the invention and essence, this
Art personnel can be modified or change, and these modifications or variation are within the scope of protection of present invention.
Claims (10)
1. a kind of preparation method of Daptomycin lactone hydrolysate, comprises the following steps：
1) by Daptomycin filtering fermentation liquor, filtrate obtains the resin chromatography liquid of Daptomycin lactone hydrolysate by resin chromatography；
2) by step 1) gained resin chromatography liquid regulation pH2~6,4~50 DEG C preserve 1~2 day, obtain being reached containing chromatographic purity higher
The solution of Tobramycin lactone hydrolysate；
3) by step 2) resulting solution, by preparative chromatography column separating purification, obtains chromatographic purity>Ester hydrolysis in 90% Daptomycin
The preparation solution of thing；
4) by step 3) gained preparation solution freeze, obtain Daptomycin lactone hydrolysate.
2. preparation method as claimed in claim 1, it is characterised in that step 1) FPDA13 resin chromatographies are used, obtain chromatogram
Purity>The resin chromatography liquid of 5% Daptomycin lactone hydrolysate.
3. preparation method as claimed in claim 1, it is characterised in that step 1) in filtrate through FPDA13 resin chromatography posts after,
The solution for first adjusting pH6.5-7.0 with 0.03N sodium chloride, 0.06N sodium acetates, acetic acid rinses pillar, then uses 0.3N chlorine
Change the eluant solution that sodium, the sodium acetate of 0.06N, acetic acid adjust pH6.5-7.0, collect chromatographic purity>5% Daptomycin
Lactone hydrolysate resin chromatography liquid.
4. preparation method as claimed in claim 1, it is characterised in that step 2) resin chromatography liquid is adjusted into pH3~6, preserve temperature
Spend is 10~40 DEG C.
5. preparation method as claimed in claim 1, it is characterised in that step 3) preparative chromatography column separating purification in, mobile phase
Using methyl alcohol and the mixed liquor of trifluoroacetic acid solution.
6. preparation method as claimed in claim 5, it is characterised in that the trifluoroacetic acid solution concentration is 0.01%~0.2%.
7. preparation method as claimed in claim 6, it is characterised in that the trifluoroacetic acid solution concentration is 0.01%~0.05%.
8. preparation method as claimed in claim 1, it is characterised in that step 3) preparative chromatography column separating purification in, mobile phase
Methyl alcohol:The volume ratio of trifluoroacetic acid solution is 20:80~60:40.
9. preparation method as claimed in claim 8, it is characterised in that the methyl alcohol of mobile phase:The volume ratio of trifluoroacetic acid solution is
20:80~40:60.
10. the preparation method as described in claim 5~9 is any, it is characterised in that step 3) chromatographic condition of preparative chromatography is：
Chromatographic column：LP-C8、250×21.2mm；
Wavelength：214nm；
Mobile phase：The mixed liquor of methyl alcohol and trifluoroacetic acid solution；
Flow velocity：19mL/min；
Column temperature：20~30 DEG C.
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Cited By (2)
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| CN113929747A (en) * | 2020-06-29 | 2022-01-14 | 鲁南制药集团股份有限公司 | Method for preparing daptomycin impurity RS-7a |
| CN114685610A (en) * | 2020-12-28 | 2022-07-01 | 杭州中美华东制药有限公司 | Lactone hydrolysate of daptomycin RS-8a impurity and preparation method thereof |
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| CN114685610A (en) * | 2020-12-28 | 2022-07-01 | 杭州中美华东制药有限公司 | Lactone hydrolysate of daptomycin RS-8a impurity and preparation method thereof |
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Application publication date: 20170620 |