CN100372858C - Method for refining oxaliplatin - Google Patents
Method for refining oxaliplatin Download PDFInfo
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- CN100372858C CN100372858C CNB2006100883077A CN200610088307A CN100372858C CN 100372858 C CN100372858 C CN 100372858C CN B2006100883077 A CNB2006100883077 A CN B2006100883077A CN 200610088307 A CN200610088307 A CN 200610088307A CN 100372858 C CN100372858 C CN 100372858C
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Abstract
The present invention relates to a method for refining oxaliplatin. The method comprises: an oxaliplatin crude product is dissolved in water of 40 to 100 DEG C, and the proportion by weight of the oxaliplatin crude product to the water is from 5 to 100; then, C1-3 alkyl alcohol of 1 to 5 times of volume amount is added into an oxaliplatin solution to extract crystals; the extracted crystals are cooled, filtered and dried to obtain an oxaliplatin refined product. The oxaliplatin which is refined by the method of the present invention has the advantages of very low oxalic acid content and high refining yield.
Description
Technical field
The present invention relates to a kind of process for purification of oxaliplatin.
Background technology
Oxaliplatin (oxaliplatin) has another name called RP-54780, is the platinum complex of new generation after cis-platinum, carboplatin.Oxaliplatin is chemical to be called [(1R, 2R)-(1,2-cyclohexanediamine-N, N ')] [oxalic acid (2-)-0,0 '] close platinum, its structural formula is:
Oxaliplatin is ratified to go on the market in France in 1997 the earliest by the exploitation of Switzerland Debiopharm company, and the clinical patient who is mainly used in through the knot after the fluorouracil in treatment failure, rectum cancer transfer can separately or unite Fluracil and use.Be very sophisticated in the treatment that is combined in metastatic colorectal cancer of its oxaliplatin+5FU+FA, clinical consumption increases swift and violent.Oxaliplatin replaces unsettled oxalate part by non-enzyme reaction in body fluid, be converted into a hydration and two hydrations 1 of biologically active, 2-diamino hexanaphthene platinum derivatives.Recent research Clin.Colorectal Cancer, 2002,2 (1): 54～58 reports, oxaliplatin acts on the Na on sensation and the motoneuron cytolemma
+Ionic channel makes Na
+Stream amplitude and action potential weaken in the ion, can be by Na in external this phenomenon
+Ionic channel resistance preparation kappa amidine piperazine antagonism.Further study Clin.CancerRes., 2004,10 (12Pt1): 4055～4061 reports, this Na
+The variation of ionic channel is that the interior metabolism product oxalate by oxaliplatin causes, causes its acute neurovirulent generation.The oxaliplatin raw material standard is all stipulated related substances oxalic acid limit≤0.1% among European Pharmacopoeia EP5.0 and the British Pharmacopoeia BP2004.Therefore, we want the content of free oxalic acid in the strict control oxaliplatin.
Patent US4169846, EP567438, EP617043, EP801070, CN1221560 disclose the method for preparing oxaliplatin and are expressed as follows with chemical equation at present:
Wherein X is Cl, 1; R is H, Ag, Na, K
Patent EP625523 discloses the method for preparing oxaliplatin and is expressed as follows with chemical equation:
According to disclosed technology, the preparation oxaliplatin is all essential to use oxalic acid or oxalate, and oxalic acid all can take in the product, and the oxaliplatin crude product mesoxalic acid content that makes is between 1.0～0.1%, so adopt effective process for purification to seem particularly important.According to the process for purification of present disclosure, all adopt aqueous solution method for recrystallizing and refining, the oxaliplatin mesoxalic acid that makes is difficult to reach related substances oxalic acid limit≤0.1% of oxaliplatin raw material standard regulation among European Pharmacopoeia EP5.0 and the British Pharmacopoeia BP2004.After aqueous solution method for recrystallizing and refining mainly adopts crude product to add the hydro-thermal dissolving, filter, cooling crystallization, but oxalic acid is difficult to remove, analytical results shows that related substances oxalic acid and oxaliplatin crude product do not have too big difference in the aqueous solution recrystallization method purified oxaliplatin.Adopt aqueous solution method for recrystallizing and refining in addition, yield has only about 65%, and mother liquor must be removed a part of water by the heating underpressure distillation could improve yield.
The inventor is in the process of research oxaliplatin aqueous stability, find that the oxaliplatin aqueous solution places the half an hour oxalic acid content and sharply increase (increasing to 0.425% from 0.021%) in 60 ℃ of water-baths, the visible oxaliplatin aqueous solution has part degraded generation oxalic acid under heating condition.Further studies show that, the aqueous solution in the process of water refining oxaliplatin after the oxaliplatin heat of solution is in the prolongation of process of cooling mesoxalic acid content along with storage period, the oxalic acid amount is same sharply to be increased, and finally causes oxaliplatin highly finished product mesoxalic acid content higher.
Summary of the invention
The objective of the invention is to overcome higher and yield weak point on the low side, the method for the high refining oxaliplatin of low, the refining yield of a kind of oxalic acid content is provided by above-mentioned oxaliplatin process for purification purified oxaliplatin oxalic acid content.
A kind of method of refining oxaliplatin takes following scheme to realize:
Method of the present invention is a kind of method of refining oxaliplatin, it is characterized in that the crude product oxaliplatin is dissolved in 40～100 ℃ of water, the weight proportion of oxaliplatin crude product and water is 5～100, the C1-3 alkyl alcohol crystallization that in oxaliplatin solution, adds 1～5 times of volume afterwards, cooling crystallization, filter the dry oxaliplatin highly finished product that get.Described oxaliplatin temperature soluble in water is preferably 60～90 ℃.In oxaliplatin solution, add C
1-3The alkyl alcohol volume is preferably 2～4 times.C
1-3Alkyl alcohol is a kind of in methyl alcohol, ethanol, n-propyl alcohol and the Virahol, preferred C
1-3Alkyl alcohol is an ethanol.The cooling crystallization temperature is 0～40 ℃.Drying temperature is 40～100 ℃, and be 2～12 hours time of drying.
Oxaliplatin oxalic acid content through the refining gained of the inventive method is extremely low, reaches related substances oxalic acid limit≤0.1% of oxaliplatin raw material standard regulation among European Pharmacopoeia EP5.0 and the British Pharmacopoeia BP2004; The oxaliplatin highly finished product crystal formation of gained does not change yet simultaneously, and proterties is stable; Yield also improves.
Further specify the present invention below by embodiment.Should correct understanding be: the process for purification in the embodiments of the invention is only used for the present invention is described and provides; rather than limitation of the present invention; so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Embodiment 1:
To contain oxalic acid and be 0.501% oxaliplatin 10g is dissolved in 90 ℃ of hot water of 1000g, stir the 1.6L of property adding next time ethanol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 8.6g in 6 hours, yield: 86%, fusing point is: 198～199.5 ℃, content: 99.9%.
It is 0.011% that HPLC detects related substances oxalic acid.
The HPLC detection method: the chromatographic column octadecylsilane chemically bonded silica is weighting agent (4.6mm * 150mm, 5.0 μ m), moving phase is that [the 1.36g potassium primary phosphate adds in the 10ml TBAH solution (32%) phosphate buffered saline buffer, thin up is to 1000ml, with phosphoric acid adjust pH to 6.0]-acetonitrile (80: 20); Flow velocity is 1.0ml/min, and the detection wavelength is 205nm.
Embodiment 2:
To contain oxalic acid and be 0.998% oxaliplatin 5g and be dissolved in 100 ℃ of hot water of 400g, stir the 0.8L of property adding next time ethanol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 4.1g in 6 hours, yield: 82%, and content: 99.9%.It is 0.055% that HPLC detects related substances oxalic acid,
The HPLC condition is with embodiment 1.
Embodiment 3:
To contain oxalic acid and be 0.501% oxaliplatin 5g and be dissolved in 60 ℃ of hot water of 400g, stir the 0.8L of property adding next time ethanol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 4.2g in 6 hours, yield: 84%, and content: 99.9%.It is 0.009% that HPLC detects related substances oxalic acid.
Embodiment 4:
To contain oxalic acid and be 0.501% oxaliplatin 2g and be dissolved in 40 ℃ the water of 160g, stir the 320mL of property adding next time ethanol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 1.5g in 6 hours, yield: 75%, and content: 100%.It is 0.007% that HPLC detects related substances oxalic acid.
Embodiment 5:
To contain oxalic acid and be 0.102% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 160mL of property adding next time ethanol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 1.4g in 6 hours, yield: 70%, and content: 99.9%.It is 0.010% that HPLC detects related substances oxalic acid.
Embodiment 6:
To contain oxalic acid and be 0.501% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 640mL of property adding next time ethanol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 1.7g in 6 hours, yield: 85%, and content: 99.8%.It is 0.013% that HPLC detects related substances oxalic acid.
Embodiment 7:
To contain oxalic acid and be 0.501% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 800mL of property adding next time ethanol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 1.7g in 6 hours, yield: 85%, and content: 99.6%.It is 0.035% that HPLC detects related substances oxalic acid.
Embodiment 8:
To contain oxalic acid and be 0.501% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 320mL of property adding next time methyl alcohol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 1.3g in 6 hours, yield: 65%, and content: 99.9%.It is 0.006% that HPLC detects related substances oxalic acid.
Embodiment 9:
To contain oxalic acid and be 0.501% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 320mL of property adding next time n-propyl alcohol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 1.7g in 6 hours, yield: 85%, and content: 99.8%.It is 0.042% that HPLC detects related substances oxalic acid.
Embodiment 10:
To contain oxalic acid and be 0.501% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 320mL of property adding next time Virahol, be cooled to 15 ℃, the solid that filtration is separated out, 60 ℃ of dryings got oxaliplatin highly finished product 1.5g in 6 hours, yield: 75%, and content: 99.7%.It is 0.053% that HPLC detects related substances oxalic acid.
Embodiment 11:
To contain oxalic acid and be 0.335% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 320mL of property adding next time ethanol, be cooled to 5 ℃, the solid that filtration is separated out, 100 ℃ of dryings got oxaliplatin highly finished product 1.7g in 2 hours, yield: 85%, and content: 99.2%.It is 0.035% that HPLC detects related substances oxalic acid.
Embodiment 12:
To contain oxalic acid and be 0.335% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 320mL of property adding next time ethanol, be cooled to 40 ℃, the solid that filtration is separated out, 80 ℃ of dryings got oxaliplatin highly finished product 1.3g in 4 hours, yield: 65%, and content: 99.5%.It is 0.004% that HPLC detects related substances oxalic acid.
Embodiment 13:
To contain oxalic acid and be 0.721% oxaliplatin 2g and be dissolved in 80 ℃ the water of 160g, stir the 320mL of property adding next time ethanol, be cooled to 15 ℃, the solid that filtration is separated out, 40 ℃ of dryings got oxaliplatin highly finished product 1.7g in 12 hours, yield: 85%, and content: 99.1%.It is 0.044% that HPLC detects related substances oxalic acid.
Embodiment 14:
To contain oxalic acid and be 0.223% oxaliplatin 2g and be dissolved in 100 ℃ the water of 10g, stir the 20mL of property adding next time ethanol, be cooled to 30 ℃, the solid that filtration is separated out, 50 ℃ of dryings got oxaliplatin highly finished product 1.3g in 8 hours, yield: 65%, and content: 99.4%.It is 0.032% that HPLC detects related substances oxalic acid.
Embodiment 15:
To contain oxalic acid and be 0.721% oxaliplatin 10g and be dissolved in 80 ℃ of hot water of 800g, stir the 1.6L of property adding next time ethanol, be cooled to 0 ℃, filter the solid of separating out, 60 ℃ of dryings 6 hours oxaliplatin highly finished product A.It is 0.011% that HPLC detects related substances oxalic acid.
It is that 0.352% oxaliplatin 2g is dissolved in 80 ℃ of hot water of 160mL that the purification techniques that discloses according to patent EP617043 will contain oxalic acid, is cooled to 15 ℃, filters the solid of separating out, 60 ℃ of dryings 6 hours oxaliplatin highly finished product B.It is 0.295% that HPLC detects related substances oxalic acid.
Highly finished product A and highly finished product B the results are shown in Table 1 through the X-ray powder diffraction analysis.
Instrument model: rotation sun level X-ray diffractometer D/max-YA Rigaku (day)
Test condition; Cu/ graphite 40KV30mA 4.00～50.00 (Deg) 10.00Deg/min
Measuring unit: Nanjing University modern analysis center
Table 1 oxaliplatin x ray powder diffraction determination data
| Crystal face is apart from () | |
| Oxaliplatin highly finished product A | Oxaliplatin highly finished product B |
| 16.944 8.404 5.618 4.214 3.839 2.401 | 16.944 8.404 5.618 4.214 3.828 2.401 |
Claims (7)
1. the method for a refining oxaliplatin is characterized in that the crude product oxaliplatin is dissolved in 40～100 ℃ of water, and the weight proportion of oxaliplatin crude product and water is 5～100, adds the C of 1～5 times of volume afterwards in oxaliplatin solution
1-3The alkyl alcohol crystallization, cooling crystallization filters, the dry oxaliplatin highly finished product that get.
2. the method for refining oxaliplatin according to claim 1 is characterized in that oxaliplatin temperature soluble in water is 60～90 ℃.
3. the method for refining oxaliplatin in according to claim 1 is characterized in that adding C in oxaliplatin solution
1-3The alkyl alcohol volume is 2～4 times.
4. the method for a kind of refining oxaliplatin according to claim 1 is characterized in that C
1-3Alkyl alcohol is a kind of in methyl alcohol, ethanol, n-propyl alcohol and the Virahol.
5. the method for a kind of refining oxaliplatin according to claim 4 is characterized in that C
1-3Alkyl alcohol is an ethanol.
6. the method for a kind of refining oxaliplatin according to claim 1 is characterized in that the cooling crystallization temperature is 0～40 ℃.
7. the method for a kind of refining oxaliplatin according to claim 1 is characterized in that drying temperature is 40～100 ℃, and be 2～12 hours time of drying.
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| CNB2006100883077A CN100372858C (en) | 2006-07-10 | 2006-07-10 | Method for refining oxaliplatin |
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| CNB2006100883077A CN100372858C (en) | 2006-07-10 | 2006-07-10 | Method for refining oxaliplatin |
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| CN100372858C true CN100372858C (en) | 2008-03-05 |
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| CN101723982B (en) * | 2008-10-31 | 2013-01-02 | 齐鲁制药有限公司 | Platinum complex compound with antitumor activity and synthesis method thereof |
| CN101723988B (en) * | 2009-12-16 | 2012-07-04 | 南京东捷药业有限公司 | Method for preparing oxaliplatin with very low content of impurities |
| CN104945443A (en) * | 2015-07-23 | 2015-09-30 | 青岛蓝盛洋医药生物科技有限责任公司 | Drug, namely oxaliplatin compound, for treating cancer |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1460683A (en) * | 2003-06-06 | 2003-12-10 | 昆明贵金属研究所 | Oxalibo purification |
| US20040186172A1 (en) * | 2001-07-02 | 2004-09-23 | Houssam Ibrahim | Oxaliplatin active substance with a very low content of oxalic acid |
| CN1634945A (en) * | 2004-11-08 | 2005-07-06 | 昆明贵金属研究所 | Synthesis of oxaliplatin |
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- 2006-07-10 CN CNB2006100883077A patent/CN100372858C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040186172A1 (en) * | 2001-07-02 | 2004-09-23 | Houssam Ibrahim | Oxaliplatin active substance with a very low content of oxalic acid |
| CN1460683A (en) * | 2003-06-06 | 2003-12-10 | 昆明贵金属研究所 | Oxalibo purification |
| CN1634945A (en) * | 2004-11-08 | 2005-07-06 | 昆明贵金属研究所 | Synthesis of oxaliplatin |
Non-Patent Citations (1)
| Title |
|---|
| 抗癌药物奥沙利铂的合成研究进展. 乔东宇，尹先清.精细化工中间体，第36卷第1期. 2006 * |
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Address after: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699 Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699 Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |
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