CN101230078A - Novel method for synthesizing antineoplastic medicine carboplatin - Google Patents
Novel method for synthesizing antineoplastic medicine carboplatin Download PDFInfo
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- CN101230078A CN101230078A CNA2008100580961A CN200810058096A CN101230078A CN 101230078 A CN101230078 A CN 101230078A CN A2008100580961 A CNA2008100580961 A CN A2008100580961A CN 200810058096 A CN200810058096 A CN 200810058096A CN 101230078 A CN101230078 A CN 101230078A
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Abstract
The invention relates to a preparation method of antineoplastic medicine, namely carboplatin H12C6O4N2Pt. The technical process adopts the steps that cis form- diiododiammine platinum (2) is used as the reactant, is charged with water and stirred uniformly, heating is performed in a water bath to 50 to 60 DEG C with light prevention, Hg2(NO3)2.2H2O suspending liquid is added slowly, filtering is performed after the reaction for 6 to 8 hours, 1, 1-cyclobutyl dicarboxylic acid-Na is added for reaction for 2 to 4 hours after the filter liquor is heated to 60 DEG C, the mole ratio is Hg2(NO3)2.2H2O: Na2H6C6O4=1: 1: 1, and solid carboplatin can be obtained. The procedure of the carboplatin preparation method of the invention is short, the introduction of impurity, namely, Ag<+> is avoided, simultaneously, the solubility product of HgI is small, and is easy to be removed cleanly, and the yield rate of the target product is high, which can reach above 80 percent.
Description
Technical field the present invention relates to the synthetic preparation of antineoplastic medicament carboplatin.
The background technology carboplatin is a s-generation platinum series antineoplastic medicament after cis-platinum, by Britain Johnson Matthey company, Britain's ICR and U.S. Squibb-Bristol Myer company develop jointly, and 1986 in U.S.'s listing use, widespread use in worldwide at present.The English name of carboplatin is Carboplatin, is called for short CBP, and chemical name is a cis-1,1-cyclobutyl dicarboxylic acid-two ammino platinum (II) [Cis-1,1-cyclobutandicarboxylacid-diammine platinum (II)].Molecular weight is 371.28, and chemical structural formula is:
The characteristics of carboplatin are good water solubility (17.6mg/ml), and anti-tumor activity and cis-platinum are suitable, are mainly used in the treatment small cell lung cancer, ovarian cancer, the esophageal carcinoma, incidence cancer etc.
In patent " synthesis technique of novel platinum-containing anticancer drug carboplatin ", reported that the employing silver salt method prepares carboplatin, the productive rate of this method is higher, simple to operate, product purity height, shortcoming are that product is present in the aqueous solution, need evaporate a large amount of water and just can obtain solid phase prod, therefore bigger to the loss of equipment (mainly being the film Rotary Evaporators), its synthetic route is as follows:
Reported the synthetic method of carboplatin in " Chinese Journal of Pharmaceuticals " 1999 the 22nd the 1st phases of volume " synthesizing of carbon platinum " literary composition, its synthetic route is as follows:
The productive rate of this method is better, can reach 70%, and shortcoming is that reaction process is long, need evaporate a large amount of water equally and can obtain the carboplatin solid, has introduced heavy metal ion Ba in the reaction process simultaneously
2+, for the purification of product has increased difficulty.
Reported the synthetic method of carboplatin in " Inorg Chim Acta " 1980 the 46th volumes the 1st phase " An efficient route for the preparation ofhighly soluble platinum (II) antitumor agent " literary composition, its synthetic route is as follows:
The reaction process of this method is short, can directly obtain the carboplatin solid, and productive rate is better, and is about 75%, and shortcoming is that product purity is poor, Ag
+Generally at hundred more than the PPM, the purification difficulty is bigger.Above method exists shortcomings such as the long or product purity difference of reaction process, therefore be necessary to develop a kind of with short production cycle, productive rate height, the carboplatin preparation method that purity is good.
Summary of the invention: the object of the invention is to provide a kind of product yield height, the carboplatin preparation method that foreign matter content is little, and can solve shortcomings such as above-mentioned reaction process length or product purity difference.
Carboplatin preparation method of the present invention is a reactant with cis-diiodo-two ammino platinum (II), and its molecular formula is Pt (NH
3)
2I
2, structural formula is as follows:
Add a certain amount of deionized water and stirring evenly after, under the lucifuge condition, add Hg
2(NO
3)
22 H
2The O suspension liquid, 60 ℃ were reacted 8～10 hours down, and the filtering Yellow mercury iodide adds 1 after filtrate is warming up to 60 ℃, and 1-cyclobutyl dicarboxylic acid sodium reacted 3～5 hours, Pt (NH in the reaction process
3)
2I
2: Hg
2(NO
3)
22 H
2O: Na
2CBDCA three's mol ratio is 1: 1: 1, obtains the carboplatin product.
Reaction process of the present invention is:
Carboplatin preparation method of the present invention compares with the method for above-mentioned bibliographical information, and method of the present invention can directly make the carboplatin product separate out from solution, needn't pass through enrichment process, thereby shorten preparation cycle, has simplified production process, makes processing method easy and simple to handle.Simultaneously owing to avoided impurity A g in the reaction process
+Introducing, the by product HgI solubility product that reaction generates is little, particle is big, filters easily to eliminate, and makes product purity better.
Embodiment
Reagent and material that invention is adopted
1.Pt (NH
3)
2I
2(cis-diiodo-two ammino platinum (II)), self-control,＞98%.
2.Hg
2(NO
3)
22H
2O, commercially available, analytical pure.
3.1,1-CBDCA, commercially available, analytical pure.
4.NaOH commercially available, analytical pure.
Embodiment 1:3 gram 1,1-CBDCA, 1.6 gram NaOH add the suitable quantity of water back that stirs respectively and mix, and regulate pH value to neutral, and reaction solution is concentrated into dried white product, filters, wash respectively with water, dehydrated alcohol, oven dry, Na
2(1,1-CBDCA) 2.53 grams, productive rate 96.93%.
5 gram Pt (NH
3)
2I
2Add that suitable quantity of water stirs and temperature is controlled at about 50 ℃, add Hg
2(NO
3)
22H
2O 5.2 grams, 50 ℃ of following lucifuges were reacted 8 hours, removed by filter the HgI precipitation, and filtrate is warming up to about 60 ℃, adds 2 gram Na
2(1,1-CBDCA), react 4 hours postcooling, filter white crystals difference water, the absolute ethanol washing of separating out, oven dry obtains 3.32 gram calorie platinum solid phase prods, and productive rate is 86.46%.It is consistent with target compound to analyze structure through ultimate analysis, infrared, mass spectrum etc.
Ultimate analysis: measured value is C:19.36%, H:3.26%, N:7.51%, Pt:52.58%.Theoretical value is C:18.89%, H:3.23%, N:7.55%, Pt:52.56%.Form with theoretical and coincide.
Infrared absorption spectrum: IR spectrum (KBr compressing tablet cm
-1): N-H (3269,1609); C-H (2995,2957,2861,1465); C=O (1648); C-O (1381); C-C (940,902); Pt-N (475); Pt-O (316).
Mass spectrum (MS): adopt the fast atom bombardment(FAB) method, measurement result sees Table 1.
Table 1: embodiment 1 measurement result
| m/e | Relative abundance | Corresponding fragment |
| 372 | 100 | Molecular ion peak |
| 110 | 22 | [(C 3O 3H 8)OH 2] + |
| 450 | 26 | [Pt(CBDCA)(NH 3) 2(C 2H 5O 2)OH 2] + |
| 743 | 12 | [Pt(CBDCA)(NH 3) 2] 2H + |
Embodiment 2:3 gram 1,1-CBDCA, 1.6 gram NaOH add the suitable quantity of water back that stirs respectively and mix, and regulate pH value to neutral, and reaction solution is concentrated into dried white product, filters, wash respectively with water, dehydrated alcohol, oven dry, Na
2(1,1-CBDCA) 2.58 grams, productive rate 98.84%.
5 gram Pt (NH
3)
2I
2Add that suitable quantity of water stirs and temperature is controlled at about 50 ℃, add Hg
2(NO
3)
22H
2O 5.3 grams, 60 ℃ of following lucifuges were reacted 10 hours, removed by filter the HgI precipitation, and filtrate is warming up to about 60 ℃, adds 2 gram Na
2(1,1-CBDCA), react 5 hours postcooling, filter white crystals difference water, the absolute ethanol washing of separating out, oven dry obtains 3.30 gram calorie platinum solid phase prods, and productive rate is 85.94%.It is consistent with target compound to analyze structure through ultimate analysis, infrared, mass spectrum etc.
Ultimate analysis: measured value is C:19.34%, H:3.27%, N:7.52%, Pt:52.55%.Theoretical value is C:18.89%, H:3.23%, N:7.55%, Pt:52.56%.Form with theoretical and coincide.
Infrared absorption spectrum: IR spectrum (KBr compressing tablet cm
-1): N-H (3271,1604); C-H (2992,2959,2853,1458); C=O (1644); C-O (1381); C-C (942,903); Pt-N (473); Pt-O (313).
Mass spectrum (MS): adopt the fast atom bombardment(FAB) method, measurement result sees Table 2.
Table 2: embodiment 2 measurement results
| m/e | Relative abundance | Corresponding fragment |
| 372 | 100 | Molecular ion peak |
| 110 | 22 | [(C 3O 3H 8)OH 2] + |
| 356 | 8 | [Pt(NH 3) 2(C 6H 6O 3)]H + |
| 450 | 26 | [Pt(CBDCA)(NH 3) 2(C 2H 5O 2)OH 2] + |
| 743 | 12 | [Pt(CBDCA)(NH 3) 2] 2H + |
Claims (4)
1. the preparation method of antineoplastic medicament carboplatin is characterized in that with cis-diiodo-two ammino platinum (II) be reactant, and its molecular formula is Pt (NH
3)
2I
2, after the adding deionized water and stirring is even, under the lucifuge condition, add Hg
2(NO
3)
22 H
2The reaction of O suspension liquid, the filtering Yellow mercury iodide adds 1 after filtrate is heated up, and the reaction of 1-cyclobutyl dicarboxylic acid sodium obtains the carboplatin product,
Its reaction process is:
2. according to the preparation method of the described antineoplastic medicament carboplatin of claim 1, it is characterized in that Pt (NH in the described reaction process
3)
2I
2: Hg
2(NO
3)
22H
2O: Na
2CBDCA three's mol ratio is 1: 1: 1.
3. according to the preparation method of the described antineoplastic medicament carboplatin of claim 1, it is characterized in that describedly under the lucifuge condition, adding Hg
2(NO
3)
22H
2The temperature of O suspension liquid reaction is 50 ℃～60 ℃, and the time is 8～10 hours.
4. according to the preparation method of the described antineoplastic medicament carboplatin of claim 1, it is characterized in that adding 1 after described filtrate is heated up, the reaction of 1-cyclobutyl dicarboxylic acid sodium is meant after filtrate is warming up to 60 ℃ and adds 1 that 1-cyclobutyl dicarboxylic acid sodium reacted 3～5 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810058096A CN100582115C (en) | 2008-02-05 | 2008-02-05 | Novel method for synthesizing antineoplastic medicine carboplatin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810058096A CN100582115C (en) | 2008-02-05 | 2008-02-05 | Novel method for synthesizing antineoplastic medicine carboplatin |
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| Publication Number | Publication Date |
|---|---|
| CN101230078A true CN101230078A (en) | 2008-07-30 |
| CN100582115C CN100582115C (en) | 2010-01-20 |
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ID=39896937
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103739631A (en) * | 2014-01-22 | 2014-04-23 | 上海金和生物技术有限公司 | Method for preparing antitumor drug carboplatin |
| EP2913336A1 (en) * | 2014-02-28 | 2015-09-02 | Umicore AG & Co. KG | Process for the preparation of carboplatin |
-
2008
- 2008-02-05 CN CN200810058096A patent/CN100582115C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103739631A (en) * | 2014-01-22 | 2014-04-23 | 上海金和生物技术有限公司 | Method for preparing antitumor drug carboplatin |
| EP2913336A1 (en) * | 2014-02-28 | 2015-09-02 | Umicore AG & Co. KG | Process for the preparation of carboplatin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100582115C (en) | 2010-01-20 |
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