CN103387572B - Everolimus defects inspecting reference marker and preparation method thereof - Google Patents
Everolimus defects inspecting reference marker and preparation method thereof Download PDFInfo
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- CN103387572B CN103387572B CN201310300574.6A CN201310300574A CN103387572B CN 103387572 B CN103387572 B CN 103387572B CN 201310300574 A CN201310300574 A CN 201310300574A CN 103387572 B CN103387572 B CN 103387572B
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- everolimus
- reference marker
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Abstract
The invention discloses a kind of everolimus defects inspecting reference marker and preparation method thereof, belong to a kind of everolimus defects inspecting technology, this reference marker is a kind of degraded product of everolimus, alkaline solution is adopted to dissolve everolimus solid, utilize alkali in organic acid He excessive after reacting by heating, the mixture after neutralization is condensed into mixture solid; Adopt water-containing organic solvent dissolving mixt solid, adopt water-containing organic solvent as strippant, desorb chromatography column, Fractional Collections contains the strippant of target product, concentrates and obtains everolimus defects inspecting reference marker; Everolimus defects inspecting reference marker of the present invention and preparation method thereof provide a kind of structure reference marker identical or close with the chemical derivative in everolimus impurity, synthesising by-product and degraded product and preparation method thereof, effectively improve science and the accuracy of everolimus defects inspecting.
Description
Technical field
The present invention relates to a kind of everolimus defects inspecting technology, be related specifically to a kind of everolimus defects inspecting reference marker and preparation method thereof.
Background technology
Everolimus be researched and developed by Novartis Co., Ltd of Switzerland there is certain water miscible rapamycin derivative, be mainly used to the rejection after preventing renal transplantation and heart transplant operation clinically, can be taken orally.Its mechanism of action mainly comprises immunosuppressive action, antitumor action, antivirus action and vascular protection effect, often and other immunosuppressor conbined usage such as ciclosporin to reduce toxicity.In addition, everolimus is also used for the treatment of advanced renal cell cancer.
As everyone knows, for the active pharmaceutical ingredient product of human administration, require very high to the content restriction of its impurity.Usual requirement often plants the weight ratio of foreign matter content lower than 0.15%, and the weight ratio for the uncertain foreign matter content of unconfirmed toxicity requires especially lower than 0.1%.But, comparatively extensive for its source of the impurity in active pharmaceutical ingredient, (this is relevant with the stability of product in storage process) may be produced due to the degraded of product self, also may derive from preparation method's (comprising chemosynthesis).The impurity deriving from preparation method comprises the impurity and chemical derivative, synthesising by-product and degraded product etc. that comprise in unreacted starting raw material, starting raw material.
In medicine quality analysis technical field, chemical derivative in active pharmaceutical ingredient impurity, synthesising by-product and degraded product can adopt spectrum or other physical method to differentiate, in above-mentioned impurity and color atlas there is incidence relation in peak position, therefore, can differentiate impurity according to its relative position in color atlas.Before the impurity in compound is analyzed, need to adopt purity higher and there is the material of identical or close structural as reference marker with above-mentioned impurity, adopt the compound to be checked being equivalent to pure state as reference standard thing, then, reference marker and reference standard thing are together detected, and the relative position of reference marker in color atlas is considered as the relative position of impurity in color atlas, and instruct with this defects inspecting to compound to be checked.Obviously, the selection of reference marker and preparation, the science detect foreign matter content in active pharmaceutical ingredient and accuracy have direct impact.And for the detection of everolimus foreign matter content, just need to select and to prepare a kind of structure identical with the chemical derivative in everolimus impurity, synthesising by-product and degraded product or close and have the material reference marker of higher degree, to improve science and the accuracy of everolimus defects inspecting.
Summary of the invention
For improving science and the accuracy of everolimus defects inspecting, the present invention proposes a kind of everolimus defects inspecting reference marker and preparation method thereof.
Everolimus defects inspecting reference marker of the present invention is a kind of degraded product of everolimus, and its structure is:
Everolimus defects inspecting reference marker preparation method of the present invention adopts alkaline solution to dissolve everolimus solid, utilizes alkali in organic acid He excessive after reacting by heating, and the mixture after neutralization is condensed into mixture solid; Adopt water-containing organic solvent dissolving mixt solid, adopt water-containing organic solvent as strippant, desorb chromatography column, Fractional Collections contains the strippant of target product, concentrates and obtains everolimus defects inspecting reference marker; Wherein,
Described alkaline solution is the one in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
Described reacting by heating temperature is 20 to 90 DEG C;
Described organic acid is the one in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
Described thickening temperature is 30 to 60 DEG C, and adopts rotatory evaporator to concentrate;
Described water-containing organic solvent is the one in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
Described silicagel column is the one in C1, C4, C8 and C18 reverse phase silica gel;
Described strippant is the one of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction.
Further, everolimus defects inspecting reference marker preparation method of the present invention, comprises the following steps:
S1, employing alkaline solution dissolve everolimus solid, and described alkaline solution is the one in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
S2, reacting by heating, its reacting by heating temperature is 20 to 90 DEG C;
S3, adopt in organic acid and above-mentioned everolimus solution, its organic acid is the one in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
S4, enriched mixture, adopt rotatory evaporator to concentrate at 30 to 60 DEG C, make mixture solid;
S5, the mixture solid adopting water-containing organic solvent dissolving step S4 to make, its water-containing organic solvent is the one in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
S6, desorb chromatography column, the silicagel column of employing is the one in C1, C4, C8 and C18 reverse phase silica gel, and strippant is the one of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction;
S7, the strippant of collection containing target product;
S8, the concentrated strippant containing target product obtain everolimus defects inspecting reference marker.
Everolimus defects inspecting reference marker of the present invention and preparation method thereof provide a kind of structure reference marker identical or close with the chemical derivative in everolimus impurity, synthesising by-product and degraded product and preparation method thereof, effectively improve science and the accuracy of everolimus defects inspecting.
Accompanying drawing explanation
Accompanying drawing 1 is the schematic flow sheet of everolimus defects inspecting reference marker preparation method of the present invention.
Below in conjunction with the drawings and specific embodiments, everolimus defects inspecting reference marker of the present invention and preparation method thereof is further described.
Embodiment
Accompanying drawing 1 is the schematic flow sheet of everolimus defects inspecting reference marker preparation method of the present invention, and as seen from the figure, everolimus defects inspecting reference marker of the present invention is a kind of degraded product of everolimus, and its structure is:
Everolimus defects inspecting reference marker preparation method of the present invention adopts alkaline solution to dissolve everolimus solid, utilizes alkali in organic acid He excessive after reacting by heating, and the mixture after neutralization is condensed into mixture solid; Adopt water-containing organic solvent dissolving mixt solid, adopt water-containing organic solvent as strippant, desorb chromatography column, Fractional Collections contains the strippant of target product, concentrates and obtains everolimus defects inspecting reference marker; Wherein,
Described alkaline solution is the one in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
Described reacting by heating temperature is 20 to 90 DEG C;
Described organic acid is the one in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
Described thickening temperature is 30 to 60 DEG C, and adopts rotatory evaporator to concentrate;
Described water-containing organic solvent is the one in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
Described silicagel column is the one in C1, C4, C8 and C18 reverse phase silica gel;
Described strippant is the one of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction.
Everolimus defects inspecting reference marker preparation method of the present invention, comprises the following steps:
S1, employing alkaline solution dissolve everolimus solid, and described alkaline solution is the one in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
S2, reacting by heating, its reacting by heating temperature is 20 to 90 DEG C;
S3, adopt in organic acid and above-mentioned everolimus solution, its organic acid is the one in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
S4, enriched mixture, adopt rotatory evaporator to concentrate at 30 to 60 DEG C, make mixture solid;
S5, the mixture solid adopting water-containing organic solvent dissolving step S4 to make, its water-containing organic solvent is the one in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
S6, desorb chromatography column, the silicagel column of employing is the one in C1, C4, C8 and C18 reverse phase silica gel, and strippant is the one of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction;
S7, the strippant of collection containing target product;
S8, the concentrated strippant containing target product obtain everolimus defects inspecting reference marker.
Embodiment 1
The sodium dihydrogen phosphate utilizing 50ml concentration to be 0.5mol/L 10.00g everolimus dissolves, and is heated to 35 DEG C, after heating 30min, utilizes acetic acid to adjust pH value to neutral, utilizes rotatory evaporator to concentrate at 40 DEG C, obtain 10.23g mixture solid.
Embodiment 2
The disodium phosphate soln utilizing 60ml concentration to be 0.6mol/L 12.00g everolimus dissolves, and is heated to 40 DEG C, after heating 45min, utilizes acetic acid to adjust pH value to neutral, utilizes rotatory evaporator to concentrate at 45 DEG C, obtain 12.13g mixture solid.
Embodiment 3
The disodium phosphate soln utilizing 50ml concentration to be 0.5mol/L 10.00g everolimus dissolves, and is heated to 40 DEG C, after heating 40min, utilizes formic acid to adjust pH value to neutral, utilizes rotatory evaporator to concentrate at 45 DEG C, obtain 10.17g mixture solid.
Embodiment 4
(its everolimus defects inspecting reference marker content is 35.77% to the mixture solid obtained after being concentrated by 5g, high performance liquid chromatography area normalization method is adopted to detect), 100ml concentration is utilized to be the acetone solution of 60% weight ratio, the anti-phase C4 silica gel column chromatography of upper 1000ml, concentration is utilized to be that the acetone of 73% weight ratio makes strippant, desorb chromatography column, Fractional Collections, liquid phase is monitored, merge to concentrate and obtain everolimus defects inspecting reference marker 1.6g, its everolimus defects inspecting reference marker content is 95.33%, everolimus content is 2.31%, other foreign matter contents are 2.36%.
Embodiment 5
(its everolimus defects inspecting reference marker content is 44.28% to the mixture solid obtained after being concentrated by 3g, high performance liquid chromatography area normalization method is adopted to detect), utilize 100ml concentration be 65% weight ratio Virahol dissolve, the anti-phase C8 silica gel column chromatography of upper 1000ml, concentration is utilized to be that the Virahol of 76% weight ratio makes strippant, desorb chromatography column, Fractional Collections, liquid phase is monitored, merging is concentrated dry obtains everolimus defects inspecting reference marker 0.83g, its everolimus defects inspecting reference marker content is 96.18%, everolimus content is 2.17%, other foreign matter contents are 1.65%.
Embodiment 6
(its everolimus defects inspecting reference marker content is 48.97% to the mixture solid obtained after being concentrated by 5g, high performance liquid chromatography area normalization method is adopted to detect), utilize 100ml concentration be 45% weight ratio acetonitrile dissolve, the anti-phase C8 silica gel column chromatography of upper 1000ml, concentration is utilized to be that the acetonitrile of 58% weight ratio makes strippant, desorb chromatography column, Fractional Collections, liquid phase is monitored, merging is concentrated dry obtains everolimus defects inspecting reference marker 1.34g, its everolimus defects inspecting reference marker content is 97.02%, everolimus content is 1.31%, other foreign matter contents are 1.67%.
As can be seen from above-described embodiment, everolimus defects inspecting reference marker of the present invention is a kind of degraded product of everolimus, its structure is identical with the chemical derivative in everolimus impurity, synthesising by-product and degraded product or close, effectively can improve science and the accuracy of everolimus defects inspecting.
Obviously, everolimus defects inspecting reference marker of the present invention and preparation method thereof provide a kind of structure reference marker identical or close with the chemical derivative in everolimus impurity, synthesising by-product and degraded product and preparation method thereof, effectively improve science and the accuracy of everolimus defects inspecting.
Claims (2)
1. an everolimus defects inspecting reference marker, is characterized in that, this reference marker is a kind of degraded product of everolimus, and its structure is:
2. everolimus defects inspecting reference marker preparation method described in a claim 1, it is characterized in that, adopt alkaline solution to dissolve everolimus solid, after reacting by heating, utilize alkali in organic acid He excessive, the mixture after neutralization is condensed into mixture solid; Adopt water-containing organic solvent dissolving mixt solid, adopt water-containing organic solvent as strippant, desorb chromatography column, Fractional Collections contains the strippant of target product, concentrates and obtains everolimus defects inspecting reference marker; Wherein,
Described alkaline solution is the one in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
Described reacting by heating temperature is 20 to 90 DEG C;
Described organic acid is the one in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
Described thickening temperature is 30 to 60 DEG C, and adopts rotatory evaporator to concentrate;
Described water-containing organic solvent is the one in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
Described silicagel column is the one in C1, C4, C8 and C18 reverse phase silica gel;
Described strippant is the one of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction.
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| WO2023213731A1 (en) * | 2022-05-02 | 2023-11-09 | Roche Diagnostics Gmbh | Hemolysis and derivatization reagents and methods for determining lactone analytes |
| CN115716839A (en) * | 2022-11-15 | 2023-02-28 | 无锡福祈制药有限公司 | Synthesis method of everolimus impurity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1694736A (en) * | 2002-09-06 | 2005-11-09 | 艾博特公司 | Medical devices containing rapamycin analogs |
| CN102215682A (en) * | 2008-03-11 | 2011-10-12 | 万能医药公司 | Macrocyclic lactone compounds and methods for their use |
| CN102268015A (en) * | 2011-08-30 | 2011-12-07 | 成都摩尔生物医药有限公司 | Synthesis method of everolimus |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2673296C (en) * | 2006-12-29 | 2012-10-16 | Abbott Laboratories | Improved assay for immunosuppressant drugs |
| WO2008082979A2 (en) * | 2006-12-29 | 2008-07-10 | Abbott Laboratories | Diagnostic test for the detection of a molecule or drug in whole blood |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1694736A (en) * | 2002-09-06 | 2005-11-09 | 艾博特公司 | Medical devices containing rapamycin analogs |
| CN102215682A (en) * | 2008-03-11 | 2011-10-12 | 万能医药公司 | Macrocyclic lactone compounds and methods for their use |
| CN102268015A (en) * | 2011-08-30 | 2011-12-07 | 成都摩尔生物医药有限公司 | Synthesis method of everolimus |
Non-Patent Citations (2)
| Title |
|---|
| Juan I. Luengo 等.Studies on the Chemistry of Rapamycin:Novel Transformations under Lewis-Acid Catalysis.《Tetrahedron Letters》.1993,第34卷(第6期),第991-994页. * |
| Vidal, Christian;Kirchner, Gabriele I.;Sewing, Karl-Friedrich.Structural Elucidation by Electrospray Mass Spectrometry: An Approach to the In Vitro Metabolism of the Macrolide Immunosuppressant SDZ RAD.《Journal of the American Society for Mass Spectrometry》.1998,第9卷(第12期),第1267-1274页. * |
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Denomination of invention: Reference marker for everolimus impurity detection and preparation method thereof Effective date of registration: 20190425 Granted publication date: 20150930 Pledgee: Chengdu technical transformation incubator management Co., Ltd. Pledgor: Chengdu Yatu Biotechnology Co., Ltd. Registration number: 2019510000049 |
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Date of cancellation: 20200708 Granted publication date: 20150930 Pledgee: Chengdu technical transformation incubator management Co.,Ltd. Pledgor: YACHT BIOTECHNOLOGY Co. Registration number: 2019510000049 |