CN1260221C - Method for preparing platinum(II) metal complex eptaplatin - Google Patents
Method for preparing platinum(II) metal complex eptaplatin Download PDFInfo
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- CN1260221C CN1260221C CN 200410014772 CN200410014772A CN1260221C CN 1260221 C CN1260221 C CN 1260221C CN 200410014772 CN200410014772 CN 200410014772 CN 200410014772 A CN200410014772 A CN 200410014772A CN 1260221 C CN1260221 C CN 1260221C
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Abstract
The present invention relates to the field of pharmaceutical chemistry, more specifically to a preparation method of anticarcinogen of eptaplatin which are platinum (II) submetallic coordination compounds. The present invention is characterized in that dihalogenated diamine platinum coordination compounds react with malonic acid mercury for obtaining eptaplatin with is platinum (II) submetallic coordination compounds. Compared with the prior art, the present invention has the advantages of low cost, simple product separation, industrialization mass production applicability, etc.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the preparation method of platinum (II) metal complexes according to platinum.
Background technology
Since 1967 it is found that cis-platinum has antitumour activity, the application of platinum (II) metal complexes cancer therapy drug and research had obtained development rapidly.In in the past nearly 40 years, the various countries scholar has synthesized several thousand new platinum series compounds and has entered screening, wherein has more than 30 compound to enter clinical study, and existing 6 compounds get the Green Light and come into the market, and also has a plurality of compounds will obtain to produce certification.At present, platinum (II) metal complexes is the antitumor drug that the world today is most widely used, in the platinum of getting permission clinical use (II) metal complexes, cis-platinum (Cisplatin), carboplatin (Carboplatin), oxaliplatin (Oxaliplatin) and S 254 (Nedaplatin) etc. have become indispensable medicine in the cancer chemotherapy.
According to platinum (Eptaplatin) is third generation platinum (II) class antitumour drug, and its chemistry is by name: suitable-[(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, 3-dioxolane] (propanedioic acid) closes platinum (II).According to platinum is the higher platinum antineoplastic medicine of a kind of therapeutic index, especially be that the 1st cancer of the stomach and the 3rd 's lung cancer curative effect is better to present domestic mortality of carcinoma, clinical quiet notes are used for the treatment of small cell lung cancer, cancer of the stomach, incidence cancer, cervical cancer and colorectal carcinoma, curative effect is similar to cis-platinum, and side effect is little than carboplatin.Began development according to platinum in 1992 by Korea S SunKyong Industries company, 1999 in Korea S's Initial Public Offering.
Platinum (II) metal complexes of formula (1) representative has several different preparation methods according to platinum:
Formula (1)
(WO 92/16539, CN1063753C): adopt silver ions to remove halide-ions in the initiator of formula (2) representative, the intermediate of acquisition formula (4) representative for method 1; By intermediate and the valent metal ion such as the sodium of formula (4) representative, the malonate of potassium or silver ions reacts again, and platinum (II) metal complexes that obtains formula (1) representative is according to platinum.
Formula (2)
Formula (4)
Method 2 (CN1339439A): adopt mercurous ion to remove halide-ions in the initiator of formula (2) representative, the intermediate of acquisition formula (4) representative; Obtain platinum (II) metal complexes that formula (1) represents according to platinum by the intermediate of formula (4) representative and propanedioic acid divalent-metal ion salt or the reaction of propanedioic acid ammonium again.
Method 3 (CN1204650A, CN1038590C): directly adopt propanedioic acid disilver salt and the initiator reaction that comprises formula (2) representative, platinum (II) metal complexes that obtains formula (1) representative is according to platinum.
Above-mentioned platinum (II) metal complexes is according to the preparation method of platinum, and aftertreatment is comparatively loaded down with trivial details: method 1 needs to adopt methods such as preparative high-performance liquid chromatographic method or anion-exchange resin column method to come reaction mixture, with product separation; Method 2 needs employings are aided with diatomite filtration and come reaction mixture; Method 3 also need adopt preparative high-performance liquid chromatographic method or anion-exchange resin column method or be aided with methods such as diatomite filtration comes reaction mixture.Therefore, be difficult to large-scale production; In addition, the price of silver salt is more expensive, is about ten times of mercury salt price, and the cost of product is higher.
Summary of the invention
The invention discloses the preparation method of a kind of platinum (II) metal complexes of new formula (1) representative according to platinum (Eptaplatin).The preparation method that the present invention adopts is similar to method 3, and different is, during according to platinum, adopts inexpensive mercury ion replacement silver ions to remove halide-ions at synthetic platinum (II) metal complexes, synthesizes according to platinum.
For achieving the above object, platinum (II) metal complexes for preparing set forth in the present invention according to the method for platinum is:
The initiator dihalo-diamines of formula (2) representative is closed the propanedioic acid mercury reaction of platinum (II) title complex and formula (3) representative, obtain platinum (II) metal complexes that formula (1) represents according to platinum.
Formula (3)
Formula (2) formula (1)
Hal is a halogen atom in its Chinese style (2).
Preferred reaction conditions is: formula (2) and formula (3) under nitrogen protection, are carried out the lucifuge reaction.
The mol ratio preferred 1: 0.5～5 of formula (2) and formula (3); Further preferred 1: 1; Reaction is preferably at aqueous medium or contain in the aqueous medium of water soluble organic substance and carry out, and described medium is the mixed solvent of water or water and methyl alcohol, water and ethanol, water and acetone, water and acetonitrile.Preferred reaction medium is a water.
Formula (2) is preferably 0～100 ℃ with the temperature of reaction of formula (3), further preferred 50～70 ℃; Preferred 1 hour to 3 days of reaction times.
When concrete preparation, the valent metal ion of employing mercury ion elder generation and propanedioic acid such as sodium, sylvite reaction make the propanedioic acid mercury of formula (3) representative, and further closing the reaction of platinum (II) title complex with the initiator dihalo-diamines of formula (2) representative, platinum (II) metal complexes that obtains formula (1) representative is according to platinum.The preparation method is as follows:
Formula (3)
The first step:
Formula (3)
Second step:
Formula (2) formula (1)
The first step is that propanedioic acid is obtained propanedioic acid potassium (or sodium malonate) with potassium hydroxide (or sodium hydroxide) reaction earlier, further reacts with the mercury ion lucifuge under nitrogen protection, obtains the propanedioic acid mercury of formula (3) representative.This is reflected in the WATER AS FLOW MEDIUM and carries out, and temperature of reaction is 0～60 ℃, and the reaction times is 10 minutes～4 hours.
Second step was the propanedioic acid mercury reaction with the initiator of formula (2) representative and formula (3) representative.For guaranteeing that the mercury ion precipitation can add an amount of rare KI solution fully to remove remaining mercury ion in the reaction mixture in filtrate.
Based on same method and step, platinum (II) metal complexes of formula (1) representative also can adopt formula (3a) representative according to platinum propanedioic acid two mercurous and the initiator dihalo-diamines of formula (2) representative close platinum (II) title complex and react and make; Formula (3a) structural formula is as follows:
Formula (3a)
The present invention compared with the prior art, its advantage is:
(1) provides the preparation method of a kind of new platinum (II) metal complexes according to platinum; Solubility product (the HgI of mercury halide in aqueous solvent
2: Ksp=2.82 * 10
-29) far beyond solubility product (AgI:Ksp=8.51 * 10 of silver halide
-17) little, adopt mercury ion can remove halogen atom in the initiator of formula (2) representative easilier, react more complete, yield is improved, and contains heavy metal Hg hardly in the product, do not worry heavy metals exceeding standard; Employed mercury ion is inexpensive far beyond silver ions.
(2) preparation method's product separation of the present invention is easy and simple to handle, need not methods separation such as complicated high performance liquid chromatography or anion-exchange resin column method and obtains.After the reaction solution direct filtration of present method preparation, filtrate decompression concentrates promptly has a large amount of crystallizations to separate out, and constant product quality, yield are higher, are more suitable in industrial production.
The compound of formula (1) representative of institute of the present invention adopting process preparation is according to platinum, and ultimate analysis, infrared spectra, proton nmr spectra, carbon-13 nmr spectra and mass spectrum confirm that its structure is correct.
The present invention can further be set forth by following example, but is not restriction the present invention.
Embodiment
Embodiment 1
In water-soluble 100 milliliters of the propanedioic acid (5.2 grams, 0.05 mole), 30 milliliters of the aqueous solution of adding potassium hydroxide (5.6 grams, 0.1 mole), regulator solution pH is about 8, and stirring at room 1 hour under nitrogen protection, adds Hg (NO
3)
21/2H
2100 milliliters of the aqueous solution of O (16.68 grams, 0.05 mole), mixture lucifuge nitrogen protection stirring at room 2 hours.Filter, drying under reduced pressure gets white powder propanedioic acid mercury salt 13.6 grams, yield 89.9%, and sealing is kept in Dark Place standby.
Suitable-two iodo-[(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, the 3-dioxolane] (6.23 restrain to close platinum (II), 10 mmoles) with propanedioic acid mercury salt (3.03 grams, 10 mmoles) in 750 milliliters of the aqueous solution, 55 ℃ of suspension stirring reactions are 20 hours in the darkroom, filter out the red mercury iodide precipitation of generation.Filtrate adds 10 milliliters of rare KI solution [being dissolved in the solution that 75 ml waters are made into by 4.15 gram (25 mmole) KI], removes remaining mercury ion, stirring at room 0.5 hour, and the red mercury iodide that filters out generation precipitates, and filtrate uses millipore filtration (0.22 μ m) to filter again.Filtrate decompression has been concentrated into a large amount of white crystals and has separated out, and filters, and is drying to obtain product according to platinum 4.20 grams, yield 89.1%; Thick product HPLC assay: 98.7%.
Thick product HPLC assay: the 98.7%[chromatographic column: with the octadecylsilane chemically bonded silica is weighting agent; Moving phase: methanol-water (40: 60): 25 ℃ of column temperatures; Detect wavelength: 210nm].
Ultimate analysis: C
11H
20N
2O
6Pt
Calculated value (%): C:28.03, H:4.28, N:5.94, Pt:41.39;
Measured value (%): C:27.79, H:4.39, N:6.10, Pt:41.22.
IR(KBr)：3440、3204、3060(NH)，2969，2878，1615(C＝O)，1459，1406，1258，1163，1095cm
-1。
1H-NMR(DMSO-d
6/TMS)：δ0.87(6H，d，J＝6.84Hz，CH(CH
3)
2)，1.75(1H，m，CH(CH
3)
2)，3.26(2H，dd，J＝13.8Hz，-OOC-CH
2-COO-)，2.58(2H，m，2CHNH
2)，2.97(1H，m，CHNH
2)，3.07(1H，m，CHNH
2)，4.30(1H，m，-OCH-CH
2-)，4.56(1H，m，-OCH-CH
2-)，5.32(1H，s，NH)，5.52(3H，s，3NH)。
13C-NMR(DMSO-d
6/TMS)：δ16.68(CH
3)，16.73(CH
3)，31.53(CH(CH
3)
2)，47.90(CHNH
2)，48.11(CHNH
2)，50.50(OCCH
2CO)，78.11(OCHCH
2)，79.67(OCHCH
2)，107.09(OCHO)，174.29(COO)。
ESI-MS：m/z?493：[(C
11H
20N
2O
6 194Pt+Na)
+，79.6％]；m/z?494：[(C
11H
20N
2O
6 195Pt+Na)
+，100％]；m/z?495：[(C
11H
20N
2O
6 196Pt+Na)
+，59.5％]；m/z?497：[(C
11H
20N
2O
6 198Pt+Na)
+，25.4％]。
Embodiment 2
Suitable-two iodo-[(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, the 3-dioxolane] (6.23 restrain to close platinum (II), 10 mmoles) with embodiment 1 in the propanedioic acid mercury salt (3.03 gram, 10 mmoles) that makes in 750 milliliters of the aqueous solution, 25 ℃ of suspension stirring reactions of room temperature are 32 hours in the darkroom, filter out the Yellow mercury iodide precipitation of generation, filtrate uses millipore filtration (0.22 μ m) to filter again.Filtrate decompression has been concentrated into a large amount of white crystals and has separated out, and filters, and is drying to obtain product according to platinum 3.56 grams, yield 75.5%; Thick product HPLC assay: 93.8%.
Embodiment 3
Suitable-two iodo-[(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, the 3-dioxolane] (6.23 restrain to close platinum (II), 10 mmoles) with embodiment 1 in the propanedioic acid mercury salt (3.03 gram, 10 mmoles) that makes in 750 milliliters of the aqueous solution, 80 ℃ of suspension stirring reactions are 12 hours in the darkroom, filter out the Yellow mercury iodide precipitation of generation, filtrate uses millipore filtration (0.22 μ m) to filter again.Filtrate decompression has been concentrated into a large amount of white crystals and has separated out, and filters, and is drying to obtain product according to platinum 3.92 grams, yield 83.2%; Thick product HPLC assay: 96.7%.
Embodiment 4
In water-soluble 100 milliliters of the propanedioic acid (5.2 grams, 0.05 mole), 30 milliliters of the aqueous solution of adding potassium hydroxide (5.6 grams, 0.1 mole), the pH value of control reaction soln is about 8, and stirring at room 1 hour under nitrogen protection, adds Hg
2(NO
3)
22H
2300 milliliters of the aqueous solution of O (28.1 grams, 0.05 mole), stirring at room is 2 hours under mixture lucifuge, the nitrogen protection.Filter, the filter cake washing, washing with alcohol, drying under reduced pressure gets pale powder shape propanedioic acid two mercurous salts 21.5 grams, yield 85.5%, sealing is kept in Dark Place standby.
Suitable-two iodo-[(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, the 3-dioxolane] (6.23 restrain to close platinum (II), 10 mmoles) with propanedioic acid two mercurous salts (5.03 grams, 10 mmoles) in 750 milliliters of the aqueous solution, 60 ℃ of suspension stirring reactions are 20 hours in the darkroom, filter out the Yellow mercury iodide precipitation of generation.Filtrate adds 10 milliliters of rare liquor kalii iodides [by potassiumiodide (4.15 grams, 25 mmoles) be dissolved in the solution that 75 ml waters are made into], remove remaining mercurous ion, stirring at room 0.5 hour, filter out the Yellow mercury iodide precipitation of generation, filtrate uses millipore filtration (0.22 μ m) to filter again.Filtrate decompression has been concentrated into a large amount of white crystals and has separated out, and filters, and is drying to obtain product according to platinum 3.68 grams, yield 78.1%.
Embodiment 5
Suitable-two iodo-[(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, the 3-dioxolane] (6.23 restrain to close platinum (II), 10 mmoles) with embodiment 4 in propanedioic acid two mercurous salts (5.03 gram, 10 mmoles) that make in 750 milliliters of the aqueous solution, 20 ℃ of suspension stirring reactions of room temperature are 32 hours in the darkroom, filter out the Yellow mercury iodide precipitation of generation, filtrate uses millipore filtration (0.22 μ m) to filter again.Filtrate decompression has been concentrated into a large amount of white crystals and has separated out, and filters, and is drying to obtain product according to platinum 3.35 grams, yield 71.1%; Thick product HPLC assay: 90.4%.
Embodiment 6
Suitable-two iodo-[(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, the 3-dioxolane] (6.23 restrain to close platinum (II), 10 mmoles) with embodiment 4 in propanedioic acid two mercurous salts (5.03 gram, 10 mmoles) that make in 750 milliliters of the aqueous solution, 80 ℃ of suspension stirring reactions are 12 hours in the darkroom, filter out the Yellow mercury iodide precipitation of generation, filtrate uses millipore filtration (0.22 μ m) to filter again.Filtrate decompression has been concentrated into a large amount of white crystals and has separated out, and filters, and is drying to obtain product according to platinum 3.62 grams, yield 76.8%; Thick product HPLC assay: 95.9%.
Crude product refining:
Get crude product in the present embodiment according to platinum, add the distilled water of 100ml, be heated to little boiling, make the solid dissolving by every gram crude product.Cold slightly, add gac and stir decolouring 20 minutes, filtered while hot in right amount.Filtrate decompression has been concentrated into a large amount of white solids and has separated out, cooling crystallization.Filter, drying under reduced pressure gets elaboration according to platinum, is white crystalline powder.The recrystallization yield is about 80%, elaboration HPLC assay:＞99.0%.
Claims (6)
1, platinum (II) metal complexes of preparation formula (1) representative is according to the method for platinum,
Formula (1)
It is characterized in that:
The initiator dihalo-diamines of formula (2) representative is closed the propanedioic acid mercury reaction of platinum (II) title complex and formula (3) representative, obtains platinum (II) metal complexes that formula (1) represents according to platinum,
Formula (3)
Formula (2) formula (1)
Hal is a halogen atom in its Chinese style (2).
2, the method for claim 1 is characterized in that: formula (2) and formula (3) under nitrogen protection, are carried out the lucifuge reaction.
3, claim 1 or 2 method is characterized in that: formula (2) is 1: 0.5～5 with the mol ratio of formula (3); Be reflected at aqueous medium or contain in the aqueous medium of water soluble organic substance and carry out, described medium is the mixed solvent of water or water and methyl alcohol, water and ethanol, water and acetone, water and acetonitrile.
4, the method for claim 3 is characterized in that: formula (2) is 1: 1 with the mol ratio of formula (3), and reaction medium is a water.
5, the method for claim 1 is characterized in that: formula (2) is 0～100 ℃ with the temperature of reaction of formula (3), and the reaction times is 1 hour to 3 days.
6, the method for claim 5 is characterized in that: formula (2) is 50～70 ℃ with the temperature of reaction of formula (3).
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