CN1285603C - Synthesis of oxaliplatin - Google Patents
Synthesis of oxaliplatin Download PDFInfo
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- CN1285603C CN1285603C CN 200410079552 CN200410079552A CN1285603C CN 1285603 C CN1285603 C CN 1285603C CN 200410079552 CN200410079552 CN 200410079552 CN 200410079552 A CN200410079552 A CN 200410079552A CN 1285603 C CN1285603 C CN 1285603C
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- oxaliplatin
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Abstract
The present invention relates to a preparation method for antitumor medicament oxaliplatin C8H14N2O4Pt, which comprises the technological flow that cisform-diiodo hexamethylene diamine platinum (II) is used as a reactant; the reactant is added to a silver nitrate AgNO3 water solution of 30 DEG C to 80 DEG C under the light shielding condition to react for 4 to 10 hours; potassium oxalate K2C2O4 is added to a filtering liquid to react for 2 to 7 hours, the mol ratio of Pt(DACH)I2 to AgNO3 to K2C2O4 is equal to 1:2:1, and an oxaliplatin solid product can be obtained. The preparation method for oxaliplatin has the advantages of simple and convenient technological flow, low production cost, and high target product yield reaching more than 90 %.
Description
Technical field
The present invention relates to the synthetic preparation of antitumor drug oxaliplatin.
Background technology
Oxaliplatin belongs to platinum metal complex, is the platinum series antineoplastic medicament of new generation after cis-platinum, carboplatin.Oxaliplatin has another name called RP-54780, English name Oxaliplatin, be abbreviated as L-OHP, full name is cis-oxalic acid (trans-(-)-1, the 2-cyclohexanediamine) closes platinum (II) [cis-oxalato (trans-(1R, 2R)-(-)-1,2-diaminocyclohexane) platinum (II)], molecular weight is 397.33, chemical structural formula:
Oxaliplatin is the earliest by Switzerland Debiopharm company exploitation, is applied to clinically in that France is granted, and is mainly used in treatment transitivity cancer of colon in 1997.At present in a plurality of countries granted be applied to clinical.U.S. FDA is also approved the treatment cancer of colon.Oxaliplatin is a title complex of doing part and the formation of divalent metal platinum with oxalate and trans-(-)-1,2 hexahydroaniline (DACH).In " the synthetic and structural characterization of RP-54780 " literary composition that " precious metal " 2000 the 21st volumes the 1st periodical carries, reported the synthetic method of oxaliplatin, its synthetic route is:
Also reported the synthetic method of oxaliplatin in " Oxaliplatin " literary composition that " Drugs ofthe future " 1989 the 14th volumes the 6th periodical carries, its operational path is:
Above-mentioned two pieces of disclosed oxaliplatins of document synthetic is that to close platinum (II) with cis-dichloro cyclohexanediamine be intermediate, add the Silver Nitrate hydrolysis reaction, remove by filter the silver nitride precipitation thing then, add potassium oxalate or sodium oxalate in the mother liquor, the reaction back generates the oxaliplatin aqueous solution, and concentrating under reduced pressure gets the oxaliplatin product.This technology of preparing causes the tediously long complexity of technical process owing to adopt the multistep chemical reaction, and its product yield can reach 85%.
Summary of the invention: the oxaliplatin preparation method that provides the high production cost of a kind of product yield low is provided the object of the invention.
Oxaliplatin preparation method of the present invention, closing platinum (II) with cis-diiodo-(trans-(-)-1,2-cyclohexanediamine) is reactant, its molecular formula Pt (DACH) I
2, its structural formula is:
The Silver Nitrate AgNO that under the lucifuge condition, it is added 30 ℃ to 80 ℃
3Reacted in the aqueous solution 4～10 hours, filtering Silver iodide precipitation adds potassium oxalate K in the filtrate
2C
2O
4Reacted 2～7 hours, in the reaction process, Pt (DACH) I
2, AgNO
3And K
2C
2O
4Three's reaction mol ratio is: Pt (DACH) I
2: AgNO
3: K
2C
2O
4=1: 2: 1, obtain the oxaliplatin product.
Chemical reaction flow process of the present invention is:
In implementing process of the present invention, can improve Pt (DACH) I a little
2: AgNO
3: K
2C
2O
4=1: K in 2: 1 proportionlitys
2C
2O
4Charging capacity, promptly at [Pt (DACH) (H
2O)
2] (NO
3)
2With K
2C
2O
4Reaction relation in, K
2C
2O
4Charging capacity greater than the theory in the reaction formula (2) reaction mol ratio.
In the technique scheme, at selected Silver Nitrate AgNO
3Under 30 ℃ to 80 ℃ conditions of reactant aqueous solution temperature, can obtain speed of response preferably.In selected 4～10 hours reaction times, Pt (DACH) I
2With AgNO
3Between reaction finish substantially, but exceed this reaction time range during can cause reaction not exclusively or extend manufacture cycle and do not have practical significance.Potassium oxalate K
2C
2O
4With [Pt (DACH) (H
2O)
2] (NO
3)
2The selection of reaction time range and Pt (DACH) I
2With AgNO
3The effect of reaction is basic identical.
Oxaliplatin preparation method of the present invention compares with the method for above-mentioned bibliographical information, synthetic method of the present invention can make the oxaliplatin product directly separate out from solution, and needn't pass through enrichment process, thereby has shortened the production cycle, simplified production process, made processing method easy and simple to handle.Owing to omitted enrichment process, saved production unit expensive such as Rotary Evaporators, greatly reduced production cost of the present invention.The contriver finds, adopts Pt (DACH) I
2Add AgNO
3The feeding sequence of solution, the reaction product that can avoid Silver iodide precipitation parcel silver ions and be generated makes each reactant reaction complete, obtains high transformation efficiency.Than the method for above-mentioned bibliographical information, oxaliplatin productive rate of the present invention improves more than 3～5 percentage points.After promptly adopting synthetic technology of the present invention, than the method for above-mentioned bibliographical information, every production kilogram oxaliplatin product can be increased income about 12000 yuan.In addition, adopt cis-diiodo-(trans-(-)-1,2-cyclohexanediamine) to close platinum (II) for the byproduct of reactant is Silver iodide, owing to the Silver iodide molecular particle size greater than silver chloride, its corresponding aggregate particle is also greater than silver chloride.Therefore, than silver chloride aggregate particle, very easily filter and remove Silver iodide precipitation aggregate particle.
Embodiment: reagent and material that invention is adopted
1.Pt (DACH) I
2, molecular weight is: 563.08.Employing is with K
2PtCl
4Be dissolved in the suitable quantity of water, add excessive analytical pure KI, equivalent adds DACH behind the 30min, the yellow mercury oxide that 2 hours after-filtration settle out, water, ethanol and washing with acetone respectively, 70 ℃ of dryings, Pt (DACH) I
2Product, purity 〉=98%.
2.AgNO
3, commercially available, analytical pure.
3.K
2C
2O
4, commercially available, analytical pure.
Embodiment 1:3 restrains AgNO
3Be dissolved in the appropriate amount of deionized water, temperature is controlled at about 40 ℃, adds 5 gram Pt (DACH) I
2Lucifuge stirring reaction 7 hours removes by filter the AgI precipitation then, and mother liquor adds 1.6 gram K
2C
2O
4Reacted 4 hours, and filtered white crystals water, the washing with alcohol oven dry respectively of separating out, obtain 3.14 gram oxaliplatin solid phase prods, productive rate about 90.0%.Through ultimate analysis, analysis such as infrared, structure is consistent with target compound.
Ultimate analysis: measured value is C:24.20%, H:3.59%, N:7.03%, Pt:49.07%.Theoretical value is C:24.19%, H:3.55%, N:7.05%, Pt:49.09%.Form with theoretical and coincide.
Infrared absorption spectrum: IR spectrum (KBr compressing tablet cm
-1): N-H (3212,3171,1610); C-H (3095,2932,2863,1447); C=O (1702,1664); C-O (1379); C-C (916,909); Pt-N (480); Pt-O (310).
Mass spectrum (MS): adopt the fast atom bombardment(FAB) method, measurement result sees Table 1.
Table 1
| m/e | Relative abundance | Corresponding fragment |
| 398 | 100 | Molecular ion peak |
| 353 | 7 | [Pt(DACH)CO 2] + |
| 115 | 9 | [C 6H 15N 2] + |
| 98 | 20 | [C 6H 12N] + |
| 81 | 11 | [C 6H 9] + |
Embodiment 2
3 gram AgNO
3Be dissolved in the appropriate amount of deionized water, temperature is controlled at about 70 ℃, adds 5 gram Pt (DACH) I
2Lucifuge stirring reaction 6 hours removes by filter the AgI precipitation then, and mother liquor adds 1.6 gram K
2C
2O
4Reacted 2 hours, and filtered white crystals water, the washing with alcohol oven dry respectively of separating out, obtain 3.16 gram oxaliplatin solid phase prods, productive rate about 91.0%.Through ultimate analysis, analysis such as infrared, structure is consistent with target compound.
Ultimate analysis: measured value is C:24.24%, H:3.57%, N:7.08%, Pt:49.08%.Theoretical value is C:24.19%, H:3.55%, N:7.05%, Pt:49.09%.Form with theoretical and coincide.
Infrared absorption spectrum: IR spectrum (KBr compressing tablet cm
-1): N-H (3216,3176,1615); C-H (3099,2932,2865,1450); C=O (1710,1670); C-O (1381); C-C (917,914); Pt-N (481); Pt-O (310).
Mass spectrum (MS): adopt the fast atom bombardment(FAB) method, measurement result sees Table 1.
Table 1
| m/e | Relative abundance | Corresponding fragment |
| 398 | 100 | Molecular ion peak |
| 115 | 6 | [C 6H 15N 2] + |
| 98 | 27 | [C 6H 12N] + |
| 81 | 17 | [C 6H 9] + |
Embodiment 3
3 gram AgNO
3Be dissolved in the appropriate amount of deionized water, temperature is controlled at about 60 ℃, adds 5 gram Pt (DACH) I
2Lucifuge stirring reaction 5 hours, operation afterwards obtain 3.19 gram oxaliplatin solid phase prods with embodiment 1, and structure is consistent with target compound, productive rate about 92.0%.
Embodiment 4
5.4 gram AgNO
3Be dissolved in the appropriate amount of deionized water, temperature is controlled at about 50 ℃, adds 9 gram Pt (DACH) I
2Lucifuge stirring reaction 7 hours, operation afterwards obtain 5.68 gram oxaliplatin solid phase prods with embodiment 1, and structure is consistent with target compound, productive rate about 91.0%.
Embodiment 5
5.4 gram AgNO
3Be dissolved in the appropriate amount of deionized water, temperature is controlled at about 70 ℃, adds 9 gram Pt (DACH) I
2Lucifuge stirring reaction 5 hours, operation afterwards obtain 5.47 gram oxaliplatin solid phase prods with embodiment 1, and structure is consistent with target compound, productive rate about 88.0%.
Embodiment 6
5.4 gram AgNO
3Be dissolved in the appropriate amount of deionized water, temperature is controlled at about 55 ℃, adds 9 gram Pt (DACH) I
2Lucifuge stirring reaction 6 hours, operation afterwards obtain 5.55 gram oxaliplatin solid phase prods with embodiment 1, and structure is consistent with target compound, productive rate about 89.0%.
Claims (1)
1. the preparation method of antitumor drug oxaliplatin, its structural formula is as follows:
It is characterized in that adopting cis-diiodo-(trans-(-)-1,2-cyclohexanediamine) to close platinum (II) is reactant, its molecular formula Pt (DACH) I
2, its structural formula is:
Under the lucifuge condition, it is added 30 ℃～80 ℃ AgNO
3React in the aqueous solution after 4～10 hours mother liquor, add K in the mother liquor
2C
2O
4Reacted mol ratio Pt (DACH) I 2～7 hours
2: AgNO
3: K
2C
2O
4=1: 2: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410079552 CN1285603C (en) | 2004-11-08 | 2004-11-08 | Synthesis of oxaliplatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410079552 CN1285603C (en) | 2004-11-08 | 2004-11-08 | Synthesis of oxaliplatin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1634945A CN1634945A (en) | 2005-07-06 |
| CN1285603C true CN1285603C (en) | 2006-11-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410079552 Expired - Fee Related CN1285603C (en) | 2004-11-08 | 2004-11-08 | Synthesis of oxaliplatin |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100398550C (en) * | 2006-04-18 | 2008-07-02 | 昆明贵研药业有限公司 | Novel process for synthesis of oxaliplatin as anticancer medicine |
| CN100372858C (en) * | 2006-07-10 | 2008-03-05 | 江苏奥赛康药业有限公司 | Method for refining oxaliplatin |
| CN101891771B (en) * | 2010-07-30 | 2012-12-12 | 重庆泰濠制药有限公司 | Method for preparing oxaliplatin |
| CN103232494A (en) * | 2012-05-22 | 2013-08-07 | 湖北一半天制药有限公司 | Oxaliplatin preparation method |
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