WO2019161526A1 - 一锅法制备双二羧酸二氨络铂(ii)衍生物的方法 - Google Patents

一锅法制备双二羧酸二氨络铂(ii)衍生物的方法 Download PDF

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WO2019161526A1
WO2019161526A1 PCT/CN2018/076951 CN2018076951W WO2019161526A1 WO 2019161526 A1 WO2019161526 A1 WO 2019161526A1 CN 2018076951 W CN2018076951 W CN 2018076951W WO 2019161526 A1 WO2019161526 A1 WO 2019161526A1
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carboplatin
platinum
formula
dicarboxylic acid
product
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PCT/CN2018/076951
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French (fr)
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杨旭清
普绍平
丛艳伟
刘其星
王应飞
彭娟
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昆明贵研药业有限公司
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Priority to PCT/CN2018/076951 priority Critical patent/WO2019161526A1/zh
Priority to CN201880000699.8A priority patent/CN108521780B/zh
Publication of WO2019161526A1 publication Critical patent/WO2019161526A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • G01N23/2055—Analysing diffraction patterns
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • G01N23/207—Diffractometry using detectors, e.g. using a probe in a central position and one or more displaceable detectors in circumferential positions
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds

Definitions

  • the present invention relates to the field of synthesis of platinum antitumor drugs, in particular, the present invention relates to a one-pot process for preparing a supramolecular platinum antitumor drug diammonium diaminoplatinum (II) derivative, in particular, the present invention A method for preparing a supramolecular platinum antitumor drug bicycloplatin by a one-pot method.
  • the FDA approved cisplatin as an anticancer drug in 1978 the mortality rate of testicular cancer patients has been reduced from 100% to less than 10%. For patients with early detection, the cure rate can reach 100%, making cisplatin An outstanding representative of anticancer drugs.
  • the FDA approved the second-generation platinum anticancer drug carboplatin Its anticancer spectrum is similar to that of cisplatin, but it has good water solubility and light toxicity.
  • Bicycloplatinum in English is called Dicycloplatin, which is called bis(1,1-cyclobutanedicarboxylic acid) diammine platinum (II) (English name [Bis-(1,1-cyclobutane dicarboxylic acid)]diammine platinum(II) ), the structural formula is:
  • bicycloplatin requires carboplatin as a key intermediate. In the existing preparation methods, it is necessary to obtain pure carboplatin and then react it with 1,1-cyclobutanedicarboxylic acid.
  • Carboplatin is a drug that has been on the market for about 30 years. Its preparation method is very mature. It is based on cis-dihalide ion diammine platinum (II). There are two main routes, one is silver salt method (Christopher Poon, et Al, Molecular Pharmaceutics, 13 (2016), 3665-3675), the route is as follows:
  • the method is simple in operation and high in yield.
  • the disadvantage is that the product exists in an aqueous solution, and the water needs to be evaporated to obtain a solid product, so the loss of the equipment (mainly a film rotary evaporator) is large; it takes up to 48 hours.
  • the reaction time is inefficient; in addition, the crude product needs to be recrystallized to obtain pure carboplatin.
  • the yield of this method is high, and the disadvantage is that the reaction process is long, and it is necessary to use a large amount of water (the volume-to-mass ratio of water to dihalo-diammine platinum is 83:1 g/ml), and it is necessary to undergo two concentration processes to carry out the water.
  • the carboplatin solid can be obtained by evaporation, and it needs to be washed with ethanol and diethyl ether to obtain pure carboplatin.
  • CN1311183A discloses the preparation of bicycloplatinum by the following method: carboplatin is dissolved in pure water at normal temperature, and then an equimolar amount of 1,1-ring is added. Butane dicarboxylic acid was evaporated to dryness after completion of the reaction, washed with ethanol, and recrystallized from distilled water. The method needs to completely evaporate the solvent water, which increases the risk of degradation of the bicyclic platinum, and also introduces more impurities into the crude bicycloplatinum. Therefore, ethanol washing and recrystallization are required, and the operation is cumbersome, and the yield of the bicyclic platinum is low.
  • CN104693245A discloses a preparation method of bicyclo platinum, which is prepared by using carboplatin as a raw material in a ratio of 1:11 to 1,1-cyclobutanedicarboxylic acid in a molar ratio of 1:1, and is protected from light at 0-60 ° C. After -9 days, the excess water is removed by concentration under reduced pressure or freeze-drying to obtain a bicyclic platinum product.
  • the HPLC purity of the product is more than 99%, it requires a long standing process, is inefficient, and greatly increases the risk of carboplatin decomposition, especially for the process of amplification;
  • the solvent water is completely evaporated to make the bicyclic platinum product exist in a relatively high temperature aqueous solution for a long time, and the product has a high risk of degradation, and the quality stability is inevitably affected.
  • bicycloplatinum with the reported yield and purity was not obtained according to this method.
  • CN106132408A also discloses a process for the preparation of another bicyclic platinum in which carboplatin is mixed with a corresponding ratio of 1,1-cyclobutanedicarboxylic acid and a solvent to form a suspension, and the precipitated solid formed is separated from the suspension.
  • the suspension method uses a small amount of solvent, so that the product formed during the reaction is also precipitated as a solid, which is mixed with the unreacted raw material solid. This prevents the reaction from proceeding and makes the purification of the product more difficult.
  • the carboplatin can hardly be removed by purification. Therefore, the suspension method has the disadvantages of difficulty in control, poor operability, and incapability of industrial scale-up production. In fact, bicycloplatinum with the reported yield and purity cannot be obtained according to this method as well.
  • the one-pot method is a new synthesis method developed in recent years, which completes a multi-step reaction or operation in a reactor, and does not separate the intermediates, and has the advantages of high efficiency and ease of operation.
  • the reaction may be affected in the latter step.
  • the subsequent reaction may not proceed, and at the same time, the impurities Accumulation also makes it more difficult to purify in the final purification step, which is why most of the reactions require intermediate separation and purification.
  • not all reactions can be used in one-pot method. In fact, only a few reactions are currently well suited for one-pot method.
  • diammonium platinum dichloride (II) derivatives by a one-pot method.
  • the method is simple and environmentally friendly.
  • a product of high quality, excellent quality diammonium platinum dichloride (II) derivative, especially bicyclo platinum, can be obtained directly in high yield.
  • the present invention provides a one-pot process for the preparation of a diammonium bis(diamino) platinum (II) derivative, which does not include an intermediate carboplatin or carboplatin analog. Separation.
  • the method according to the present invention can directly continue the reaction with the dicarboxylic acid to obtain the bis-dicarboxyl after the reaction to form the carboplatin or the carboplatin analog without separating and purifying the pure product of carboplatin or carboplatin analog.
  • the acid diammonium platinum (II) derivative the whole process only needs to undergo a process of distillation and water removal, the overall energy consumption is low, the production cycle is short, and the single batch production cycle can be controlled within 2 days. Water alone is used as a solvent, which is environmentally friendly and produces less waste. The obtained product has high purity and does not require further purification treatment, and the product quality is stable.
  • the present invention provides a one-pot process for the preparation of a diaminocarboxylic acid diammonium platinum (II) derivative of formula (I), which process can comprise:
  • R 1 and R 2 may be the same or different from each other, and each independently represents hydrogen, a C 1-12 hydrocarbon group, a halogen, an amino group, a cyano group, a hydroxyl group, a carboxyl group, an acyl group, a phosphoryl group or a phosphorylamino group;
  • R 1 and R 2 are bonded to each other and together with the carbon atom to which they are attached form a 3-12 membered saturated or unsaturated carbocyclic ring;
  • X represents a halogen, that is, Cl, I, Br, F.
  • the method can also include:
  • the method does not include the separation of carboplatin or carboplatin analogs of formula (IV).
  • the process may further comprise the preparation of a cis-dihalide ion diammine platinum (II) of formula (II) and a dicarboxylic acid disilver salt of formula (III).
  • the preparation method is not particularly limited as long as the product can be obtained.
  • Example 1 is a nuclear magnetic resonance-hydrogen spectrum of the bicyclic platinum product of Example 1.
  • Example 2 is a nuclear magnetic resonance-carbon spectrum of the bicyclic platinum product of Example 1.
  • Example 3 is an X-ray diffraction pattern of the bicyclic platinum product of Example 1.
  • Figure 3a is an X-ray diffraction pattern of a bicycloplatin reference added with 1% carboplatin and a list of its data.
  • Figure 3b is an X-ray diffraction pattern of a bicycloplatin reference added with 1% carboplatin and a list of its data.
  • Figure 3c is an X-ray diffraction pattern of a bicycloplatin reference added with 1% carboplatin and a list of its data.
  • Example 4 is an X-ray diffraction pattern of the bicyclic platinum product of Example 2.
  • Figure 5 is an X-ray diffraction pattern of the bicyclic platinum product of Example 3.
  • Figure 7 is an X-ray diffraction pattern of the bicyclic platinum product of Example 5.
  • Figure 8 is an X-ray diffraction pattern of the bicyclic platinum product of Example 6.
  • Figure 9 is an X-ray diffraction pattern of the bicyclic platinum product of Example 7.
  • Figure 10 is an X-ray diffraction pattern of the bicyclic platinum product of Example 8.
  • Figure 11 is an X-ray diffraction pattern of the bicyclic platinum product of Example 9.
  • Figure 12 is an X-ray diffraction pattern of the bicyclic platinum product of Example 10.
  • Figure 13 is an X-ray diffraction pattern of the product of Comparative Example 1 and a list of data thereof.
  • Figure 14 is a chart showing the X-ray diffraction pattern of the product of Comparative Example 2 and its data.
  • the present invention provides a one-pot process for the preparation of a diammine platinum (II) derivative of bisdicarboxylate.
  • the method according to the present invention can directly continue the reaction with the dicarboxylic acid to obtain the bis-dicarboxyl after the reaction to form the carboplatin or the carboplatin analog without separating and purifying the pure product of carboplatin or carboplatin analog.
  • the acid diammonium platinum (II) derivative the whole process only needs to undergo a process of distillation and water removal, the overall energy consumption is low, the production cycle is short, and the single batch production cycle can be controlled within 2 days. Water alone is used as a solvent, which is environmentally friendly and produces less waste.
  • the obtained product has high purity and does not require further purification treatment, and the product quality is stable.
  • the present invention provides a one-pot process for the preparation of a diaminocarboxylic acid diammonium platinum (II) derivative of formula (I), which process can comprise:
  • R 1 and R 2 may be the same or different from each other, and each independently represents hydrogen, a C 1-12 hydrocarbon group, a halogen, an amino group, a cyano group, a hydroxyl group, a carboxyl group, an acyl group, a phosphoryl group or a phosphorylamino group;
  • R 1 and R 2 are bonded to each other and together with the carbon atom to which they are attached form a 3-12 membered saturated or unsaturated carbocyclic ring;
  • X represents a halogen, that is, Cl, I, Br, F.
  • the method can also include:
  • the method does not include the separation of carboplatin or carboplatin analogs of formula (IV).
  • the process may further comprise the preparation of a cis-dihalide ion diammine platinum (II) of formula (II) and a dicarboxylic acid disilver salt of formula (III).
  • the preparation method is not particularly limited as long as the product can be obtained.
  • R 1 and R 2 are bonded to each other and together with the carbon atom to which they are attached form a 3-12 membered saturated or unsaturated carbocyclic ring, preferably forming cyclopropane, cyclobutane, cyclopentane Alkane, cyclohexane or cycloheptane, more preferably forms cyclobutane.
  • the diammonium diammonium platinum (II) derivative of the formula (I) may be bicyclo platinum, and the dicarboxylic acid di silver salt of the formula (III) may be 1 , silver 1-butanedicarboxylate, the carboplatin or carboplatin analog of formula (IV) may be carboplatin, and the dicarboxylic acid of formula (V) may be 1,1-cyclobutane II carboxylic acid.
  • said X represents Cl, Br or I, preferably Cl or I.
  • the first temperature in step a may range from 20 °C to 92 °C.
  • the first temperature may be 30 ° C, 35 ° C, 40 ° C, 45 ° C, 50 ° C, 55 ° C, 60 ° C, 65 ° C, 70 ° C, 75 ° C, 80 ° C, 85 ° C, 90 ° C, 91 ° C or 92 ° C.
  • the first temperature may be from 40 ° C to 90 ° C; more preferably, the first temperature may be from 70 ° C to 80 ° C.
  • the molar ratio of the cis-dihalide ion diammine platinum (II) of the formula (II) to the dicarboxylic acid disilver salt of the formula (III) in the step a may be (1.01 to 1.05). ):1.
  • the molar ratio of the cis-dihalide ion diammine platinum (II) of the formula (II) to the dicarboxylic acid di-silver salt of the formula (III) may be 1.01:1, 1.02:1, 1.03:1. 1.04:1 or 1.05:1.
  • the volumetric mass ratio of water to cis-dihalide ion diammine platinum (II) of formula (II) in step a may range from 25: 1 g/ml to 100: 1 g/ml.
  • the volumetric mass ratio of water to cis-dihalide ion diammine platinum (II) of formula (II) may be 30:1 ml/g, 35:1 ml/g, 40:1 ml/g, 45:1 ml.
  • the volume-to-mass ratio of water to cis-dihalide ion diammine platinum (II) of formula (II) may be from 25:1 ml/g to 60:1 ml/g; more preferably, water and formula (II)
  • the volume ratio of the cis-dihalide ion diammine platinum (II) may be from 30:1 ml/g to 55:1 ml/g.
  • the reaction time of the reaction in the step a is not particularly limited as long as the reaction can be completely carried out.
  • the reaction time can range from 10 min to 360 min.
  • the reaction time can be 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, 70 min, 80 min, 90 min, 100 min, 110 min, 120 min, 150 min, 180 min, 210 min, 240 min, 270 min. , 300min, 330min or 360min.
  • the reaction time can be from 30 min to 60 min. If the reaction time is too long, the side reaction increases, the purity of the product decreases, and the economy is lowered. When the reaction time is too short, the reaction is incomplete, resulting in a decrease in product yield, and the purity of the product is also lowered due to the presence of unreacted raw materials.
  • the second temperature reached by cooling in step a may range from 10 °C to 20 °C.
  • the second temperature is too low, the resulting carboplatin or carboplatin analog of formula (IV) is precipitated and left in the filter cake, resulting in diammonium platinum dicarboxylate of formula (I) (II)
  • the yield of the derivative is lowered.
  • the second temperature is too high, the concentration of residual silver ions will rise and affect the purity of the final product. If the residual silver ions in the final product are too much, the long-term stability of the product will be deteriorated. This leads to a deeper color of the product, which in turn increases the difficulty of product storage.
  • the second temperature may be 10 ° C, 11 ° C, 12 ° C, 13 ° C, 14 ° C, 15 ° C, 16 ° C, 17 ° C, 18 ° C, 19 ° C or 20 ° C.
  • the second temperature may be 12 ° C to 18 ° C; preferably, the second temperature may be 16 ° C to 17 ° C.
  • the third temperature in step b can range from 30 °C to 92 °C.
  • the third temperature may be 30 ° C, 35 ° C, 40 ° C, 45 ° C, 50 ° C, 55 ° C, 60 ° C, 65 ° C, 70 ° C, 75 ° C, 80 ° C, 85 ° C, 90 ° C, 91 ° C or 92 ° C.
  • the third temperature may be from 40 ° C to 90 ° C; more preferably, the third temperature may be from 70 ° C to 80 ° C.
  • the lower molar ratio of the dicarboxylic acid of formula (V) in step b to the di-silver dicarboxylic acid salt of formula (III) in step a may be 1:1. Since the yield of carboplatin or carboplatin analogue of formula (IV) in step a is not 100% (according to the prior art (RC Harrison, et al, Inorganica Chimica Acta, 46 (1980), L15-L16), The yield is about 80%), so even in the case where the molar ratio of the dicarboxylic acid of the formula (V) to the dicarboxylic acid salt of the dicarboxylic acid of the formula (III) is 1:1, the formula (V) in the step b The dicarboxylic acid is still in excess compared to the carboplatin or carboplatin analog of formula (IV).
  • the lower limit of the molar ratio of the dicarboxylic acid of the formula (V) to the disilver salt of the dicarboxylic acid of the formula (III) may preferably be 1.1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5: 1, 4:1, 4.5:1, 5:1, 5.5:1,6:1, 6.5:1, 7:1, 7.5:1, 7.9:1, 8:1, 8.5:1, 9:1 9.5:1, 10:1, 10.5:1,11:1,11.5:1,12:1,12.5:1,13:1,13.5:1,14:1,14.5:1,15:1,15.5: 1, 16:1, 16.5:1, 17:1, 17.5:1, 18:1, 18.5:1, 19:1, 19.5:1 or 20:1.
  • the amount of the dicarboxylic acid of the formula (V) is not limited as long as it can be dissolved in the process.
  • the upper limit of the molar ratio of the dicarboxylic acid of the formula (V) to the di-silver salt of the dicarboxylic acid of the formula (III) may be 250:1, 200:1, 180:1, 160:1.
  • the molar ratio of the dicarboxylic acid of formula (V) to the di-silver salt of dicarboxylic acid of formula (III) may range from 2:1 to 20:1; more preferably, the dicarboxylic acid of formula (V) has the formula
  • the molar ratio of the dicarboxylic acid disilver salt of (III) may be from 10:1 to 12:1.
  • the reaction time of the reaction in the step b is not particularly limited as long as the reaction can be completely carried out.
  • the reaction time can range from 10 min to 360 min.
  • the reaction time can be 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, 70 min, 80 min, 90 min, 100 min, 110 min, 120 min, 150 min, 180 min, 210 min, 240 min, 270 min. , 300min, 330min, 360min.
  • the reaction time can be from 30 min to 60 min. If the reaction time is too long, the side reaction increases, the purity of the product decreases, and the economy is lowered. When the reaction time is too short, the reaction is incomplete and a qualified final product cannot be obtained.
  • the concentration in step c refers to the removal of at least a portion of the water in the second solution such that the third solution is cis-dihalide ion diammine platinum of formula (II) of step a
  • the upper limit of the volume-mass ratio of II may be 40:1 ml/g, and when the mass-to-mass ratio is too high, since the diammonium diammonium platinum (II) derivative of the formula (I) is dissolved in a large amount of water This results in a decrease in the amount of solids precipitated upon cooling.
  • the upper limit may be 35:1 ml/g, 30:1 ml/g, 25:1 ml/g, 20:1 ml/g, 15:1 ml/g, 10:1 ml/g, 9:1 ml/g, 8: 1 ml/g.
  • the degree of concentration is preferably such that no solid is precipitated.
  • the lower limit of the volume-to-mass ratio of the cis-dihalide ion diammine platinum (II) of the formula (II) may be 7:1 ml/g, 6:1 ml/g, 5:1 ml/g.
  • the volume to mass ratio may be from 5:1 ml/g to 40:1 ml/g, and more preferably, the volume to mass ratio may be from 5:1 ml/g to 10:1 ml/g.
  • the manner of concentration in the step c is not particularly limited as long as at least a part of water can be removed from the second solution.
  • any means of concentration known in the art can be employed.
  • the following methods may be employed, including but not limited to: a combination of one or more of vacuum distillation, dialysis concentration, thin film evaporation, multi-stage flashing, nanofiltration, preferably vacuum distillation.
  • the cooling in step d means cooling to a fourth temperature and may range from 1 °C to 40 °C.
  • the fourth temperature may be 1 ° C, 2 ° C, 3 ° C, 4 ° C, 5 ° C, 6 ° C, 7 ° C, 8 ° C, 9 ° C, 10 ° C, 11 ° C, 12 ° C, 13 ° C, 14 °C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C.
  • the fourth temperature may be 1 ° C to 20 ° C; more preferably, the fourth temperature may be 10 ° C to 15 ° C.
  • the manner of separation in the step e is not particularly limited as long as the precipitated solid can be separated from the mother liquor.
  • any separation method known in the art can be employed including, but not limited to, one or more of filtration (including atmospheric filtration, reduced pressure filtration), membrane separation, sedimentation (including centrifugation, gravity natural sedimentation). A combination of these is preferably pressure filtration or vacuum filtration.
  • the washing in step e comprises washing the separated solids one or more times with water.
  • the drying in the step e is not particularly limited as long as the water in the product can be removed.
  • any drying method known in the art can be employed. Specifically, the following methods may be employed, including but not limited to: a combination of one or more of atmospheric drying, reduced pressure drying, spray drying, microwave drying, and far infrared drying, preferably under reduced pressure, more preferably in liter Dry under reduced pressure at high temperature.
  • one-pot method refers to a preparation method in which the separation of the intermediate is not carried out after the end of the previous step, and the subsequent one-step reaction is carried out directly.
  • concentrate refers to the process of removing at least a portion of the water by any means.
  • cooling refers to the process of lowering the temperature by any means.
  • first temperature used to distinguish only temperatures in different processes without further explanation.
  • the temperature is any limited, and it does not represent the size relationship between them.
  • first solution “second solution”, “third solution” as used herein, unless otherwise stated, only distinguish between solutions occurring in different processes without any limitation to the solution, It does not represent the interrelationship between them.
  • hydrocarbyl refers to a straight, branched or cyclic hydrocarbon radical which may contain from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, may include Alkyl, alkenyl, alkynyl, cycloalkyl, aryl or any combination thereof.
  • hydrocarbon group may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, cyclopropyl, cyclobutyl A group, a cyclopentyl group, a cyclohexyl group, and various isomers thereof.
  • 3-12 membered saturated or unsaturated carbocyclic ring refers to a saturated or unsaturated carbocyclic ring containing from 3 to 12, preferably from 3 to 7, carbon atoms.
  • Examples of the 3-12-membered saturated or unsaturated carbocyclic ring may include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.
  • halogen denotes fluoro, chloro, bromo or iodo.
  • the content of carboplatin or cisplatin in qualified carboplatin and cisplatin products should be 98.0%-102.0%.
  • the Chinese Pharmacopoeia has not specified the quality standard of bicycloplatinum, it refers to carboplatin and cisplatin.
  • the quality standard of platinum products which is considered to be a good quality product with a bicyclic platinum content of 98% to 102%, is in line with the conventional knowledge in the field.
  • the invention adopts elemental analysis, negative ion electrospray mass spectrometry, nuclear magnetic resonance-hydrogen spectroscopy, nuclear magnetic resonance-carbon spectroscopy and X-ray diffraction to comprehensively characterize the obtained bicyclic platinum product.
  • CN104122280A clearly indicates that bicycloplatinum cannot exist as a collective form of its supramolecular hydrogen bond cluster under liquid chromatographic separation conditions, and it completely dissociates into carboplatin and cyclosuccinic acid, so it cannot pass the high-efficiency liquid.
  • the phase chromatography directly determines the content of bicycloplatinum.
  • the characteristic peak is not dominant at the 2 ⁇ angle of 11.4°-11.7°, and the peak intensity of the peak is not more than the peak intensity of the peak at the 2 ⁇ angle of 11.4°-11.7°.
  • the bicyclo platinum reference substance containing about 2.0% by weight of carboplatin can be prepared by adopting the following method: taking about 1 part by weight of the bicyclo platinum reference substance and about 0.02 part by weight of the carboplatin reference substance, accurately weighed and mixed, that is, the content is about 2.0 wt% carboplatin bicyclo platinum reference.
  • the content of the bicycloplatinum of the present invention is converted by the carboplatin content measured by a liquid chromatography liquid.
  • the characteristic curve of the carboplatin is not observed in the X-ray diffraction pattern of the product, or the product exhibits a characteristic peak at a 2 ⁇ angle of 11.4°-11.7° but the peak intensity does not exceed the peak intensity of the reference substance, the bicycloplatin which is converted at this time is obtained.
  • the content is the estimated content, and the calculated content of the bicyclic platinum is the actual content only if the product is completely free of carboplatin.
  • bicyclic platinum Although it is not necessarily the actual content of bicyclic platinum, it is close to the actual content of bicycloplatin and the error is within an acceptable range and can therefore be used to characterize the quality of the bicyclic platinum product. Studies have shown that when the content of the bicyclic platinum measured according to the above method is 98% to 102%, the obtained product is a qualified product with excellent quality. When the content of bicycloplatinum exceeds 102%, the product contains more free carboplatin and is difficult to remove in the subsequent purification step, and the product has no practical value.
  • the product shows a characteristic peak at a 2 ⁇ angle of 11.4°-11.7° and the peak intensity exceeds the peak intensity of the reference substance, the free carboplatin content in the bicyclo platinum exceeds the allowable range, and the product has no practical value.
  • the present invention cools and removes silver halide precipitates and other possible insolubles after preparing the carboplatin or carboplatin analog of formula (IV), and cools to minimize residual silver ions in the solution, thereby enabling even
  • the "one-pot method" is also able to obtain high-purity products.
  • the prior art filters at room temperature in the filtration of silver halide precipitates, which results in excessive residue of silver ions and requires a process of solvent recrystallization.
  • the "one-pot method” of the invention does not need to separate and purify the intermediate carboplatin and carboplatin analogs, and can directly obtain the diammonium platinum dichloride (II) derivative product, and the reaction process is short and the operation is simple.
  • the "one-pot method" of the present invention only needs to carry out the step of concentration and water removal, and does not need to evaporate the water, and the energy consumption is low, so the production cost can be significantly reduced.
  • the method of the present invention can directly precipitate a good quality diammonium platinum dichloride (II) derivative product in a high yield, and the yield of the obtained product is at least 39% and the purity is as high as 98% to 102%. Further purification treatment is carried out, and the operation is simple.
  • II diammonium platinum dichloride
  • the method of the invention has a short production cycle, and the single batch production cycle can be controlled within 2 days, and the efficiency is remarkable. Contrary to the present invention, the existing silver salt method for carboplatin needs to be protected from light for 2-3 days; and the method for preparing bicycloplatinum CN104693245A requires a standing process of 3-9 days, and the production efficiency is low.
  • the method of the invention has strong controllability and reproducibility, and the quality of different batches of products is similar.
  • the method of the present invention is particularly suitable for large scale production due to the above advantages.
  • the method of the present invention does not use any organic solvent, and the production process is environmentally friendly and produces a small amount of waste liquid.
  • conventional methods for the preparation of carboplatin generally require washing and/or recrystallization with an organic solvent.
  • the peak of chemical shift 1.6113-1.6269ppm is H a , the actual number of hydrogen nuclei is 2, and it is divided into 5 heavy peaks by the influence of 4 H b on both sides; the peak of chemical shift 1.8113-1.8429ppm is H c , actual hydrogen The number of nuclei is 2, which is divided into 5 peaks by the influence of 4 H d on both sides; the peak of chemical shift 2.3329-2.4873ppm is H b , the actual number of hydrogen nuclei is 4, and the total number of H a unilateral is 2
  • the influence crack is divided into three heavy peaks; the chemical shift 2.6389-2.6704ppm peak is H d , the actual hydrogen nucleus number is 4, and the unilateral total of 2 H c is split into 3 heavy peaks; the chemical shift is 4.0876ppm.
  • H e i.e. amino hydrogen nuclei
  • the actual number of hydrogen nuclei is 6
  • 12.6376ppm chemical shift peak of H f i.e., the hydroxyl hydrogen nuclei
  • the actual number of hydrogen nuclei is 2.
  • the peak of chemical shift 15.02ppm is C a ; the peak of chemical shift 15.51ppm is C h ; the peak of chemical shift 28.10ppm is C b ; the peak of chemical shift 30.35ppm is C g ; the peak of chemical shift 52.09ppm is C c ; The peak with a chemical shift of 55.55 ppm is C f ; the peak with a chemical shift of 172.73 ppm is C d ; the peak with a chemical shift of 177.56 ppm is C e .
  • Figures 3a, 3b, and 3c show the X-ray diffraction patterns of the bicycloplatin reference substance added with 1%, 2%, and 3% carboplatin, respectively, and a data list thereof, wherein the carboplatin characteristic peak is expressed at 11.6°-11.7° ( See CN104122280A), the peak intensities are 0.13, 0.39, 1.25, respectively, relative to the bicyclic platinum characteristic peak at 7.6°.
  • the test results of the bicyclic platinum product of Example 1 are shown in FIG. 3, and the obtained spectrum is consistent with that reported by CN104122280A, and the bicyclic platinum characteristic peak is exhibited at 2 ⁇ angles of 7.5°, 10.5°, and 15.1° at the 2 ⁇ angle.
  • the characteristic peak of carboplatin is not shown at 11.4°-11.7°, indicating that the content of free carboplatin in the product is below 1%, or it can be said that the product does not contain free carboplatin, and the X-ray diffraction pattern data is listed below.
  • Determination method Take the appropriate amount of bicycloplatinum, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 0.2mg per 1ml, as the test solution (for new use), take the appropriate amount of 1,1-cyclobutanedicarboxylic acid, Add mobile phase to dissolve and quantitatively dilute to make a solution containing about 0.3mg per 1ml as a positioning solution; take the appropriate amount of carboplatin reference substance and dissolve it with mobile phase and quantitatively dilute to make a solution containing about 0.2mg per 1ml as a reference solution. (Procedure new system).
  • Example 1 was repeated a plurality of times, and the obtained product was characterized, and the results were basically the same.
  • Example 2 was prepared in the same manner as in Example 1 except that the 1,1-cyclobutanedicarboxylic acid added was 2.98 g (20.7 mmol). As a result, 4.42 g of bicyclo platinum was obtained, the yield was 41.46%, and the content was 101.93%.
  • Example 3 was prepared in the same manner as in Example 1 except that the 1,1-cyclobutanedicarboxylic acid added was 59.6 g (413.9 mmol). As a result, 5.38 g of bicyclo platinum was obtained, the yield was 50.47%, and the content was 98.06%.
  • Example 4 was prepared in the same manner as in Example 1 except that the filtrate was heated to 30 ° C after the AgI residue was filtered off. As a result, 5.12 g of bicyclo platinum was obtained, the yield was 48.02%, and the content was 101.94%.
  • Example 5 was prepared in the same manner as in Example 1 except that the filtrate was heated to 90 ° C after the AgI residue was filtered off. As a result, 5.12 g of bicyclo platinum was obtained, the yield was 48.02%, and the content was 98.10%.
  • Example 6 was prepared in the same manner as in Example 1 except that 1,1-cyclobutanedicarboxylic acid was added and stirred rapidly for 10 minutes. As a result, 5.22 g of bicyclo platinum was obtained, the yield was 48.97%, and the content was 99.34%.
  • Example 7 was prepared in the same manner as in Example 1 except that after cooling to 10 ° C, the AgI residue was filtered off, and the 1,1-cyclobutanedicarboxylic acid was added and stirred rapidly for 60 minutes. As a result, 5.36 g of bicyclo platinum was obtained, the yield was 50.28%, and the content was 99.81%.
  • Example 8 was prepared in the same manner as in Example 1 except that after cooling to 20 ° C, the AgI residue was filtered off, and 1,1-cyclobutanedicarboxylic acid was added and stirred rapidly for 240 minutes. As a result, 4.56 g of bicycloplatinum was obtained in a yield of 42.78% and a content of 98.01%.
  • Example 10 show that, after amplification according to the method of the present invention, a good quality bicyclic platinum product can still be obtained directly in high yield. Therefore, the process according to the invention is particularly suitable for the industrial scale-up production of bicycloplatinum.
  • the invention also provides the results of repeated experiments in accordance with the methods of the prior art.
  • the X-ray diffraction spectrum is shown in Fig. 13.
  • the peak intensity of this peak in the X-ray diffraction pattern of the 3% carboplatin bicyclic platinum reference is 1.25, indicating that the product contains more than 3% free carboplatin, and the free carboplatin is difficult to follow in the subsequent purification step. Removed, so the product is a non-conforming product.
  • Comparative Example 1 shows that a bicyclic platinum product of good quality cannot be obtained according to the method of CN104693245A.
  • the X-ray diffraction spectrum is shown in Fig. 14.
  • the characteristic peak of the carboplatin is shown at a 2 ⁇ angle of 11.7°, and the peak intensity is 3.39 with respect to the bicyclic platinum characteristic peak at 7.7° of the 2 ⁇ angle, which is far more than the addition of 3% card.
  • the peak intensity of this peak in the X-ray diffraction pattern of the platinum bicyclo platinum reference is 1.25, indicating that the product contains more than 3% free carboplatin, and the free carboplatin is difficult to remove in the subsequent purification step, thus The product is a non-conforming product.

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Abstract

提供一种一锅法制备双二羧酸二氨络铂(II)衍生物的方法，所述方法不包括中间体卡铂或卡铂类似的分离。相对于现有技术，该方法在反应生成卡铂或卡铂类似物后，无需处理得到卡铂或卡铂类似物的纯品，可直接继续与二羧酸反应获得双二羧酸二氨络铂(II)衍生物，整个过程只需经历一次蒸馏除水的过程，总体能耗低，生产周期短，单批次生产周期可控制在2天以内。仅用水作为溶剂，对环境友好，产生废液量少。所得产品纯度高，无需进行进一步的纯化处理，产品质量稳定。

Description

一锅法制备双二羧酸二氨络铂(II)衍生物的方法 技术领域
本发明涉及铂类抗肿瘤药物的合成领域，具体地，本发明涉及一锅法制备超分子铂类抗肿瘤药物双二羧酸二氨络铂(II)衍生物的方法，特别地，本发明涉及一锅法制备超分子铂类抗肿瘤药物双环铂的方法。
背景技术
自1978年美国FDA批准顺铂作为抗癌药物上市以来，已使睾丸癌患者的死亡率几乎从100％降到10％以下，对早期发现的患者，治愈率可达100％，使顺铂成为抗癌药物的杰出代表。1986年FDA批准第二代铂类抗癌药物卡铂上市，其抗癌谱与顺铂类似，但水溶性好，毒副反应轻。2002年FDA批准第三代铂类抗癌药物奥沙利铂进入临床治疗结直肠癌，其抗癌谱有别于顺铂，且不与顺铂产生交叉耐药性，毒副反应轻。
除上述3个产品外，另有奈达铂、舒铂、洛铂、米铂等4个产品在不同国家先后上市，均为其他国家首创。
在CN1311183A中，杨旭清等人根据癌细胞DNA、RNA的空间构型异常改变的特点，设计并制备了一类新型铂类抗肿瘤药物——双二羧酸二氨络铂(II)衍生物，其中典型的代表性药物为双环铂。双环铂英文名为Dicycloplatin，全称为双(1,1-环丁烷二羧酸)二氨合铂(II)(英文全称[Bis-(1,1-cyclobutane dicarboxylic acid)]diammine platinum(II))，结构式为：
Figure PCTCN2018076951-appb-000001
其是由卡铂同1,1-环丁烷二羧酸通过四个氢键结合而成的超分 子化合物，是中国首个自主研发的铂类抗肿瘤药物，具有广谱、低毒、高效、不产生交叉耐药及穿透性好等特点。
双环铂的制备需以卡铂作为关键中间体，现有制备方法中都需要先获得卡铂纯品，再将其与1,1-环丁烷二羧酸反应得到。
卡铂为上市约30年的药物，其制备方法非常成熟，均以顺式-二卤素离子二氨合铂(II)为原料，主要路线有两种，一为银盐法(Christopher Poon,et al,Molecular Pharmaceutics,13(2016),3665-3675)，其路线如下图：
Figure PCTCN2018076951-appb-000002
该方法操作简单、产率较高，缺点是产品存在于水溶液中，需将水蒸干才能得到固体产品，因此对设备(主要是薄膜旋转蒸发仪)的损耗较大；需要长达48小时的反应时间，效率低下；另外，需要对粗产品进行重结晶才能得到卡铂纯品。
一为钡盐法(R.C.Harrison,et al,Inorganica Chimica Acta,46(1980),L15-L16)，其路线如下图：
Figure PCTCN2018076951-appb-000003
该方法的产率较高，缺点是反应流程长，需要使用大量的水(水与二卤素二氨合铂的体积质量比为83:1g/ml)，并且需要经历两次浓缩过程将这些水蒸发掉方能得到卡铂固体，同时还需要用乙醇和乙醚洗涤才能得到卡铂纯品。
对于双环铂的制备，CN1311183A作为最早公布双环铂及其制备方法的文献，公开了通过以下方法制备双环铂：卡铂在常温下溶于纯水中，然后加入等摩尔量的1,1-环丁烷二羧酸，反应结束后蒸发至干， 加入乙醇洗涤，蒸馏水重结晶。该方法由于需要将溶剂水完全蒸干，增加了双环铂降解的风险，也将更多的杂质引入双环铂粗品中，因此需要进行乙醇洗涤和重结晶，操作繁琐，双环铂收率较低。
CN104693245A公开了一种双环铂的制备方法，以卡铂为原料，在水中与1,1-环丁烷二羧酸按摩尔比1:1的比例投料，0-60℃条件下避光放置3-9天，再通过减压浓缩或冷冻干燥，去除多余的水分，得到双环铂产品。虽然根据报道，该方法得到产品HPLC纯度可达99％以上，但是需要长时间的静置过程，效率低下，并且大大增加了卡铂分解的风险，对于放大量的工艺过程更是如此；此外，最终工序中将溶剂水完全蒸干使得双环铂产品长时间存在于较高温的水溶液内，产品发生降解风险大，质量稳定性必然受到影响。事实上，根据该方法并无法获得具有所报道的收率和纯度的双环铂。
CN106132408A还公开了另一种双环铂的制备方法，将卡铂与相应比例的1,1-环丁烷二羧酸以及溶剂混合形成悬浮液，从悬浮液中分离出形成的沉淀固体。虽然报道中声称所得产品不包含XRPD可检测量的卡铂，但悬浮法由于使用的溶剂量小，因此反应过程中生成的产物也以固体形式析出，其与未反应的原料固体混合在一起，既阻止了反应的继续进行，又使得产品的纯化难度加大，特别是在产品中包裹着卡铂的情况下，所述卡铂基本上无法通过纯化除去。因而，悬浮法存在控制困难，可操作性差的缺点，并且无法进行工业化放大生产。事实上，根据该方法并无法也获得具有所报道的收率和纯度的双环铂。
由此可见，目前尚无方法可以直接地以高收率获得一种品质良好的双环铂产品，而双环铂产品中一旦混入了过多的卡铂，其很难在后续的纯化步骤中除去。特别是，所述方法均需要先获得卡铂纯品。容易理解的是，在化学生产中，每增加一个中间体分离的工艺都会对生产效率和生产成本产生显著的影响。
一锅法是近年来发展起来的一种新的合成方法，其将多步反应或操作置于一个反应器内完成，不再分离各中间体，具有高效、操作简 便的优点。然而，由于各步反应之间反应条件的差异以及前一步反应中未完全反应的原料、生成的杂质等都可能对后一步反应造成影响，严重时会导致后一步反应无法进行，同时，杂质的积累也使得在最后的纯化步骤中纯化难度增加，这也是大部分反应均需要进行中间体分离纯化的原因。换言之，并非所有的反应都可采用一锅法，事实上，目前仅有少数的反应能够很好地适用一锅法。
本申请人通过对卡铂和双环铂合成工艺的深入研究，发现通过特殊的工艺流程，可采用一锅法制备双二羧酸二氨络铂(II)衍生物，所述方法操作简便、环保高效、可直接以高收率获得品质良好的双二羧酸二氨络铂(II)衍生物特别是双环铂的产品。
发明内容
为了克服现有技术中存在的缺陷，本发明提供了一种一锅法制备双二羧酸二氨络铂(II)衍生物的方法，所述方法不包括中间体卡铂或卡铂类似物的分离。相对于现有技术，根据本发明的方法在反应生成卡铂或卡铂类似物后，无需分离纯化得到卡铂或卡铂类似物的纯品，可直接继续与二羧酸反应获得双二羧酸二氨络铂(II)衍生物，整个过程只需经历一次蒸馏除水的过程，总体能耗低，生产周期短，单批次生产周期可控制在2天以内。仅用水作为溶剂，对环境友好，产生废液量少。所得产品纯度高，无需进行进一步的纯化处理，产品质量稳定。
因此，本发明提供了一种一锅法制备式(I)的双二羧酸二氨络铂(II)衍生物的方法，所述方法可包括：
Figure PCTCN2018076951-appb-000004
a.在第一温度下使式(II)的顺式-二卤素离子二氨合铂(II)和式(III) 的二羧酸二银盐在水中反应生成式(IV)的卡铂或卡铂类似物，冷却至第二温度进行低温过滤以获得第一溶液；
b.在第三温度下使第一溶液与式(V)的二羧酸反应以获得第二溶液；
c.浓缩所述第二溶液以获得第三溶液；
d.冷却所述第三溶液以析出固体；
其中，
R 1和R 2可彼此相同或不同，并且各自独自表示氢、C 1-12烃基、卤素、氨基、氰基、羟基、羧基、酰基、磷酰基或磷酰氨基；
或者R 1与R 2相互连接并与它们相连的碳原子一起形成3-12元饱和或不饱和的碳环；
X表示卤素，即Cl，I，Br，F。
所述方法还可包括：
e.分离析出的固体并任选地进行洗涤和/或干燥。
特别地，所述方法不包括式(IV)的卡铂或卡铂类似物的分离。
在本发明的一个实施方案中，所述方法还可以包括式(II)的顺式-二卤素离子二氨合铂(II)和式(III)的二羧酸二银盐的制备。其中，所述制备方法没有特别限制，只要能获得产品即可。
附图说明
图1为实施例1的双环铂产品的核磁共振-氢谱。
图2为实施例1的双环铂产品的核磁共振-碳谱。
图3为实施例1的双环铂产品的X-射线衍射图谱。
图3a为添加有1％卡铂的双环铂对照品的X-射线衍射图谱及其数据列表。
图3b为添加有1％卡铂的双环铂对照品的X-射线衍射图谱及其数据列表。
图3c为添加有1％卡铂的双环铂对照品的X-射线衍射图谱及其数据列表。
图4为实施例2的双环铂产品的X-射线衍射图谱。
图5为实施例3的双环铂产品的X-射线衍射图谱。
图6为实施例4的双环铂产品的X-射线衍射图谱。
图7为实施例5的双环铂产品的X-射线衍射图谱。
图8为实施例6的双环铂产品的X-射线衍射图谱。
图9为实施例7的双环铂产品的X-射线衍射图谱。
图10为实施例8的双环铂产品的X-射线衍射图谱。
图11为实施例9的双环铂产品的X-射线衍射图谱。
图12为实施例10的双环铂产品的X-射线衍射图谱。
图13为比较例1的产品的X-射线衍射图谱及其数据列表。
图14为比较例2的产品的X-射线衍射图谱及其数据列表。
具体实施方式
本发明提供了一种一锅法制备双二羧酸二氨络铂(II)衍生物的方法。相对于现有技术，根据本发明的方法在反应生成卡铂或卡铂类似物后，无需分离纯化得到卡铂或卡铂类似物的纯品，可直接继续与二羧酸反应获得双二羧酸二氨络铂(II)衍生物，整个过程只需经历一次蒸馏除水的过程，总体能耗低，生产周期短，单批次生产周期可控制在2天以内。仅用水作为溶剂，对环境友好，产生废液量少。所得产品纯度高，无需进行进一步的纯化处理，产品质量稳定。
因此，本发明提供了一种一锅法制备式(I)的双二羧酸二氨络铂(II)衍生物的方法，所述方法可包括：
Figure PCTCN2018076951-appb-000005
a.在第一温度下使式(II)的顺式-二卤素离子二氨合铂(II)和式(III) 的二羧酸二银盐在水中反应生成式(IV)的卡铂或卡铂类似物，冷却至第二温度进行低温过滤以获得第一溶液；
b.在第三温度下使第一溶液与式(V)的二羧酸反应以获得第二溶液；
c.浓缩所述第二溶液以获得第三溶液；
d.冷却所述第三溶液以析出固体；
其中，
R 1和R 2可彼此相同或不同，并且各自独自表示氢、C 1-12烃基、卤素、氨基、氰基、羟基、羧基、酰基、磷酰基或磷酰氨基；
或者R 1与R 2相互连接并与它们相连的碳原子一起形成3-12元饱和或不饱和的碳环；
X表示卤素，即Cl，I，Br，F。
所述方法还可包括：
e.分离析出的固体并任选地进行洗涤和/或干燥。
特别地，所述方法不包括式(IV)的卡铂或卡铂类似物的分离。
在本发明的一个实施方案中，所述方法还可以包括式(II)的顺式-二卤素离子二氨合铂(II)和式(III)的二羧酸二银盐的制备。其中，所述制备方法没有特别限制，只要能获得产品即可。
在本发明的一个实施方案中，所述R 1与R 2相互连接并与它们相连的碳原子一起形成3-12元饱和或不饱和的碳环，优选形成环丙烷、环丁烷、环戊烷、环己烷或环庚烷，更优选形成环丁烷。
在本发明的一个实施方案中，所述式(I)的双二羧酸二氨络铂(II)衍生物可为双环铂，所述式(III)的二羧酸二银盐可为1,1-环丁烷二羧酸银，所述式(IV)的卡铂或卡铂类似物可为卡铂，所述式(V)的二羧酸可为1,1-环丁烷二羧酸。
在本发明的一个实施方案中，所述X表示Cl、Br或I，优选Cl或I。
在本发明的一个实施方案中，步骤a中的第一温度可为20℃～92℃。优选地，第一温度可为30℃、35℃、40℃、45℃、50℃、55℃、 60℃、65℃、70℃、75℃、80℃、85℃、90℃、91℃或92℃。优选地，第一温度可为40℃～90℃；更优选地，第一温度可为70℃～80℃。
在本发明的一个实施方案中，步骤a中式(II)的顺式-二卤素离子二氨合铂(II)与式(III)的二羧酸二银盐的摩尔比可为(1.01～1.05):1。优选地，式(II)的顺式-二卤素离子二氨合铂(II)与式(III)的二羧酸二银盐的摩尔比可为1.01:1、1.02:1、1.03:1、1.04:1或1.05:1。
在本发明的一个实施方案中，步骤a中水与式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比可为25:1g/ml～100:1g/ml。优选地，水与式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比可为30:1ml/g、35:1ml/g、40:1ml/g、45:1ml/g、50:1ml/g、55:1ml/g、60:1ml/g、65:1ml/g、70:1ml/g、75:1ml/g、80:1ml/g、85:1ml/g、90:1ml/g、95:1ml/g或100:1ml/g。当水与式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比过小时，在冷却时会使得所生成的式(IV)的卡铂或卡铂类似物析出并留在滤饼中，从而导致式(I)的双二羧酸二氨络铂(II)衍生物收率降低。当水与式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比过大时，一方面会导致过多的银离子残留在反应体系中，另一方面也会使得后续在浓缩时需要除去大量的水，造成经济性的下降。优选地，水与式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比可为25:1ml/g～60:1ml/g；更优选地，水与式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比可为30:1ml/g～55:1ml/g。
在本发明的一个实施方案中，步骤a所述反应的反应时间没有特别限制，只要能使反应完全进行即可。在一个实施方案中，反应时间可为10min～360min。优选地，反应时间可为10min、15min、20min、25min、30min、35min、40min、45min、50min、55min、60min、70min、80min、90min、100min、110min、120min、150min、180min、210min、240min、270min、300min、330min或360min。优选地，反应时间可为30min～60min。如果反应时间过长，则副反应增加，产品纯度下降，且经济性降低。而当反应时间过短时，反应不完全，既导致产品收率下降，且由于未反应原料的存在使得产品纯度 也下降。
在本发明的一个实施方案中，步骤a中通过冷却达到的第二温度可为10℃～20℃。当第二温度过低时，会使得所生成的式(IV)的卡铂或卡铂类似物析出并留在滤饼中，从而导致式(I)的双二羧酸二氨络铂(II)衍生物收率降低。当第二温度过高时，会导致残留银离子的浓度上升并影响到最终产品的纯度，最终产品中残留的银离子过多的话将使得产品的长期稳定性变差，在长时间放置后易导致产品颜色加深，进而增加产品储存的难度。优选地，所述第二温度可为10℃、11℃、12℃、13℃、14℃、15℃、16℃、17℃、18℃、19℃或20℃。优选地，所述第二温度可为12℃～18℃；优选地，所述第二温度可为16℃～17℃。
在本发明的一个实施方案中，步骤b中的第三温度可为30℃～92℃。优选地，第三温度可为30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃、91℃或92℃。优选地，第三温度可为40℃～90℃；更优选地，第三温度可为70℃～80℃。当此温度过低时，由于反应速率低使得反应不完全而导致所得产品的收率降低、纯度变差；当此温度过高时，发生副反应的风险变大。
在本发明的一个实施方案中，步骤b中式(V)的二羧酸与步骤a中式(III)的二羧酸二银盐的摩尔比下限可为1:1。由于步骤a中式(IV)的卡铂或卡铂类似物的收率不为100％(按照现有技术(R.C.Harrison,et al,Inorganica Chimica Acta,46(1980),L15-L16)的记载，收率为80％左右)，因此即使是在式(V)的二羧酸与式(III)的二羧酸二银盐的摩尔比为1:1的情况下，步骤b中式(V)的二羧酸与式(IV)的卡铂或卡铂类似物相比仍是过量的。式(V)的二羧酸与式(III)的二羧酸二银盐的摩尔比的下限可优选为1.1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4:1、4.5:1、5:1、5.5:1、6:1、6.5:1、7:1、7.5:1、7.9:1、8:1、8.5:1、9:1、9.5:1、10:1、10.5:1、11:1、11.5:1、12:1、12.5:1、13:1、13.5:1、14:1、14.5:1、15:1、15.5:1、16:1、16.5:1、17:1、17.5:1、18:1、18.5:1、19:1、19.5:1或20:1。其中，式(V)的二羧酸的用量没有上限，只要在 工艺过程中能够溶解即可。但是，考虑到经济性，式(V)的二羧酸与式(III)的二羧酸二银盐的摩尔比的上限可为250:1、200:1、180:1、160:1、140:1、120:1、100:1、90:1、89:1、88:1、87:1、86:1、85:1、84:1、83:1、82:1、81:1、80:1、79:1、78:1、76:1、74:1、70:1、65:1、60:1、55:1、50:1、45:1、40:1、35:1、30:1、25:1或20:1。当式(V)的二羧酸与式(III)的二羧酸二银盐的摩尔比过低时，析出的固体量减少且产品中含有未反应完全的游离卡铂，在X-射线衍射图谱中出现明显的卡铂特征峰。优选地，式(V)的二羧酸与式(III)的二羧酸二银盐的摩尔比可为2:1～20:1；更优选地，式(V)的二羧酸与式(III)的二羧酸二银盐的摩尔比可为10:1～12:1。
在本发明的一个实施方案中，步骤b所述反应的反应时间没有特别限制，只要能够使得反应完全进行即可。在一个实施方案中，反应时间可为10min～360min。优选地，反应时间可为10min、15min、20min、25min、30min、35min、40min、45min、50min、55min、60min、70min、80min、90min、100min、110min、120min、150min、180min、210min、240min、270min、300min、330min、360min。优选地，反应时间可为30min～60min。如果反应时间过长，则副反应增加，产品纯度下降，且经济性降低。而当反应时间过短时，反应不完全，无法得到合格的最终产品。
在本发明的一个实施方案中，步骤c所述浓缩是指除去第二溶液中的至少一部分水以使得第三溶液与步骤a的式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比的上限可为40:1ml/g，当所述体积质量比过高时，由于式(I)的双二羧酸二氨络铂(II)衍生物溶解于大量水中而导致冷却时析出的固体量减少。优选地，所述上限可为35:1ml/g、30:1ml/g、25:1ml/g、20:1ml/g、15:1ml/g、10:1ml/g、9:1ml/g、8:1ml/g。浓缩的程度以不析出固体为宜。优选地，式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比的下限可为7:1ml/g、6:1ml/g、5:1ml/g。优选地，所述体积质量比可为5:1ml/g～40:1ml/g，更优选地，所述体积质量比可为5:1ml/g～10:1ml/g。
在本发明的一个实施方案中，步骤c所述浓缩的方式没有特别限制，只要能从第二溶液中除去至少一部分水即可。例如，可采用本领域中已知的任何浓缩方式。具体地，可采用以下方法，包括但不限于：减压蒸馏、透析浓缩、薄膜蒸发、多级闪蒸、纳滤中的一种或更多种的组合，优选减压蒸馏。
在本发明的一个实施方案中，步骤d中的冷却是指冷却至第四温度，且可为1℃～40℃。优选地，所述第四温度可为1℃、2℃、3℃、4℃、5℃、6℃、7℃、8℃、9℃、10℃、11℃、12℃、13℃、14℃、15℃、20℃、25℃、30℃、35℃或40℃。当该温度过高时，由于式(I)的双二羧酸二氨络铂(II)衍生物在水中仍然具有较高的溶解度而不能很好地析出，导致收率降低。优选地，所述第四温度可为1℃～20℃；更优选地，所述第四温度可为10℃～15℃。
在本发明的一个实施方案中，步骤e中分离的方式没有特别限制，只要能将析出的固体与母液分开即可。例如，可采用本领域中已知的任何分离方法，包括但不限于：过滤(包括常压过滤、减压过滤)、膜分离、沉降(包括离心分离、重力自然沉降)的一种或更多种的组合，优选加压过滤或减压过滤。
在本发明的一个实施方案中，步骤e中的洗涤包括用水洗涤分离的固体一次或更多次。
在本发明的一个实施方案中，步骤e中的干燥没有特别限制，只要能将产品中的水去除即可。例如，可采用本领域中已知的任何干燥方法。具体地，可采用以下方法，包括但不限于：常压干燥、减压干燥、喷雾干燥、微波干燥和远红外干燥中的一种或更多种的组合，优选减压干燥，更优选在升高的温度下减压干燥。
定义
本文所述的术语“一锅法”是指在前一步反应结束之后不进行中间体的分离，直接进行后一步反应的制备方法。
本文所述的术语“含量”，在没有其他说明的情况下，均指重量含量。
本文所述的术语“浓缩”是指通过任何方式除去至少一部分水的过程。
本文所述的术语“冷却”是指通过任何方式使温度降低的过程。
本文所述的术语“第一温度”、“第二温度”、“第三温度”、“第四温度”，在没有其他说明的情况下，仅区分不同工艺过程中的温度，而不对所述温度进行任何限定，更不代表它们之间的大小关系。
本文所述的术语“第一溶液”、“第二溶液”、“第三溶液”，在没有其他说明的情况下，仅区分不同工艺过程中出现的溶液，而不对所述溶液进行任何限定，更不代表它们之间的相互关系。
本文所述的术语“烃基”是指可包含1-20个碳原子的直链、支链或环状烃基，优选包含1-10个碳原子，更优选包含1-6个碳原子，可包括烷基、烯基、炔基、环烷基、芳基或其任意组合。烃基的实例可包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、戊基、己基、环丙基、环丁基、环戊基、环己基，及它们的各种异构体等。
本文所述的术语“3-12元饱和或不饱和的碳环”是指包含3-12个、优选3-7个碳原子的饱和或不饱和的碳环。3-12元饱和或不饱和的碳环的实例可包括但不限于：环丙烷、环丁烷、环戊烷、环己烷、环庚烷等。
本文所述的术语“卤素”表示氟、氯、溴或碘。
表征和含量测定
根据中国药典2010年版第二部，合格的卡铂和顺铂产品中卡铂或顺铂的含量应为98.0％～102.0％，虽然中国药典尚未规定双环铂的质量标准，但是参照卡铂和顺铂产品的质量标准，认为双环铂含量在98％～102％时的产品为品质优良的合格产品符合本领域的常规认知。
而本领域已知式(I)的双二羧酸二氨络铂(II)衍生物特别是双环铂的表征和含量的测定较为困难，原因在于由于双环铂的特殊结构，导致难以将双环铂与卡铂和1,1-环丁烷二羧酸的物理混合物区分开。CN104122280A报道了通过X-射线衍射，分析衍射图谱中2θ角为 10.3°-10.7°处和/或2θ角为11.4°-11.7°处是否具有衍射峰来表征样品中是否含有双环铂，并且通过外标法确定杂质卡铂的大致含量范围。
本发明采用元素分析、负离子电喷雾质谱、核磁共振-氢谱、核磁共振-碳谱、X-射线衍射，对所获得的双环铂产品进行全面表征。
关于双环铂的含量，CN104122280A中明确指出了双环铂在液相色谱分离条件下无法以其超分子氢键簇集体形式存在，其完全解离成卡铂与环丁二酸，因此无法通过高效液相色谱直接确定双环铂的含量。
本发明通过如下方法表征产品中双环铂的含量：
1)获得含约2.0wt％卡铂的双环铂对照品的X-射线衍射图谱；
2)测定产品的X-射线衍射，确定产品在2θ角为11.4°-11.7°处是否显特征峰；
3)对于步骤2)中在2θ角为11.4°-11.7°处不显特征峰，以及显特征峰但其峰强度不超过对照品在2θ角为11.4°-11.7°处的峰的峰强度的产品，采用高效液相色谱测定卡铂含量；
4)将步骤3)测得的卡铂含量乘以1.388得到双环铂的含量。
其中，含约2.0wt％卡铂的双环铂对照品可通过如下方法制备：取双环铂对照品约1重量份与卡铂对照品约0.02重量份，精密称定，混匀，即得含约2.0wt％卡铂的双环铂对照品。
本发明所述双环铂的含量是通过液相色谱液测定的卡铂含量来换算的。当产品的X-射线衍射图谱中不显卡铂特征峰时，或产品在2θ角为11.4°-11.7°处显特征峰但峰强度不超过对照品的峰强度时，此时换算得到的双环铂的含量为估算的含量，只有在产品中完全不含卡铂的情况下，所计算得到的双环铂的含量才是其实际含量。虽然其并不一定是双环铂的实际含量，但与双环铂的实际含量接近，且误差在可接受的范围内，因此仍可用于表征双环铂产品的质量。研究表明，按照上述方法测得的双环铂含量在98％～102％时，所得产品为品质优良的合格产品。当双环铂含量超过102％时，产品中含有较多的游离卡铂，且很难在后续的纯化步骤中除去，该产品不具有实用价值。
当产品在2θ角为11.4°-11.7°处显特征峰且峰强度超过对照品的峰强度时，此时双环铂中的游离卡铂含量超过允许范围，该产品不具有实用价值。
有益效果
本发明的方法具有以下突出的效果：
1、本发明在制备式(IV)的卡铂或卡铂类似物后冷却过滤除去了卤化银沉淀和其他可能的不溶物，通过冷却以最小化溶液中残留的银离子，从而使得即使是采用“一锅法”也能够获得高纯度的产品。与本发明相反，现有技术在过滤卤化银沉淀时均是在常温下过滤，这导致了银离子的过多残留进而需要进行溶剂重结晶的过程。
2、本发明的“一锅法”无需将中间体卡铂及卡铂类似物分离纯化，可直接获得双二羧酸二氨络铂(II)衍生物产品，反应流程短、操作简便。
3、本发明的“一锅法”只需进行一次浓缩除水的步骤，且无需将水蒸干，能耗较低，因此可明显降低生产成本。
4、本发明的方法可直接以高收率析出品质良好的双二羧酸二氨络铂(II)衍生物产品，所得产品的收率至少为39％、纯度高达98％～102％，无需进行进一步的纯化处理，操作简便。
与本发明相反，已有的双环铂制备方法均不能具备本发明的上述优点。经重复CN104693245A和CN106132408A的方法，所获得的产品的X-射线衍射图谱表明产品中均含有3％以上的游离卡铂。因此，CN104693245A和CN106132408A均无法直接获得品质良好的双环铂产品。
5、本发明的方法生产周期短，单批次生产周期可控制在2天以内，效率显著。与本发明相反，现有银盐法制卡铂需要避光2-3天；而制备双环铂的CN104693245A的方法需要长达3-9天的静置过程，生产效率低下。
6、本发明的方法可控性、可重复性强，不同批次的产品之间质 量相近。
7、本发明的方法由于具有上述优点而特别适合于规模化生产。
8、本发明的方法不使用任何有机溶剂，生产过程环保、产生废液量少。与本发明相反，现有卡铂的制备方法中一般都需要用有机溶剂进行洗涤和/或重结晶。
实施例
以下实施例为进一步说明本发明内容，而非限制本发明。
实施例1
取顺式-二碘二氨合铂(II)10.0克(20.7mmol)，加入350毫升纯化水，搅拌均匀并水浴加热至80℃后加入1,1-环丁烷二羧酸银7.2克(20.1mmol)，反应30分钟后，冷却至16℃后滤除AgI渣，滤液水浴加热至70℃。加入1,1-环丁烷二羧酸32.0克(222.2mmol)，快速搅拌30分钟后减压浓缩至剩余液体量约70毫升，冷却至10℃，过滤析出的固体，60℃干燥，得产品5.43克，收率50.94％，含量100.18％。采用元素分析、负离子电喷雾质谱、核磁共振-氢谱、核磁共振-碳谱、X-射线衍射对所获得的产品进行表征，采用高效液相色谱法测量双环铂的含量。
结果如下：
1、元素分析
理论值/实测值：C(27.96/28.27),H(3.88/4.00),N(5.44/5.33),Pt(37.86/37.56)
2、负离子电喷雾质谱：514(M-1)
3、核磁共振-氢谱(DMSO，500MHz)
测试结果如图1所示，其中各峰的归属情况如下：
Figure PCTCN2018076951-appb-000006
化学位移1.6113-1.6269ppm的峰为H a，实际氢核数量为2，受到两侧共4个H b的影响裂分为5重峰；化学位移1.8113-1.8429ppm的峰为H c，实际氢核数量为2，受到两侧共4个H d的影响裂分为5重峰；化学位移2.3329-2.4873ppm的峰为H b，实际氢核数量为4，受到单侧共2个H a的影响裂分为3重峰；化学位移2.6389-2.6704ppm的峰为H d，实际氢核数量为4，受到单侧共2个H c的影响裂分为3重峰；化学位移4.0876ppm的峰为H e，即氨基氢核，实际氢核数量为6；化学位移12.6376ppm的峰为H f，即羟基氢核，实际氢核数量为2。
4、核磁共振-碳谱(D 2O，500MHz)
测试结果如图2所示，其中各峰的归属情况如下：
Figure PCTCN2018076951-appb-000007
化学位移15.02ppm的峰为C a；化学位移15.51ppm的峰为C h；化学位移28.10ppm的峰为C b；化学位移30.35ppm的峰为C g；化学位移52.09ppm的峰为C c；化学位移55.55ppm的峰为C f；化学位移172.93ppm的峰为C d；化学位移177.56ppm的峰为C e。
5、X-射线衍射
图3a、3b、3c分别示出了添加有1％、2％和3％卡铂的双环铂对照品的X-射线衍射图谱及其数据列表，其中11.6°-11.7°处显卡铂特征峰(参见CN104122280A)，相对于7.6°处的双环铂特征峰，峰强度分别为0.13、0.39、1.25。而实施例1的双环铂产品的测试结果如图3所示，所获得的图谱与CN104122280A报道的一致，并且在2θ角为7.5°、10.5°、15.1°处显双环铂特征峰，在2θ角为11.4°-11.7°处不显卡铂特征峰，说明产品中游离卡铂的含量在1％以下，或者可以说，产品中基本不含有游离卡铂，X-射线衍射图谱数据列表如下。
[根据细则26改正04.04.2018]　
Figure WO-DOC-FIGURE-a
6、高效液相色谱法
色谱条件与系统适用性试验以苯基己基硅烷化硅胶为填充剂(例如Waters XBridgeTM Shield Phenyl 5μm 4.6×250mm)，以[四丁基硫酸氢铵缓冲液(取四丁基硫酸氢铵8.5g，加水80ml使溶解，加磷酸3.4ml，用10mol/L氢氧化钠溶液调节pH值至7.5±0.05)]-水-乙腈(20:880:100)为流动相；检测波长为220nm，柱温30℃，流速1.0ml/分钟，以1,1-环丁烷二羧酸峰完全洗脱出来截止时间为运行时间，理论板数按卡铂峰计算不低于3000，1,1-环丁烷二羧酸峰与卡铂峰之间的分离度应大于2.5。
测定法 取双环铂产品适量，加流动相溶解并定量稀释制成每1ml约含0.2mg的溶液，作为供试品溶液(临用新制)，取1,1-环丁烷二羧酸适量，加流动相溶解并定量稀释制成每1ml约含0.3mg的溶液，作为定位溶液；取卡铂对照品适量用流动相溶解并定量稀释制成每1ml约含0.2mg的溶液，作为对照品溶液(临用新制)。精密量取10μl，注入液相色谱仪，记录色谱图，按外标法以卡铂峰面积计算。将计算得到的卡铂含量乘以系数1.388，测得双环铂含量为100.18％。
此外，多次重复实施例1，对所得产品进行表征，结果基本相同。
实施例2
按照实施例1相同的方法制备实施例2，区别在于，加入的1,1-环丁烷二羧酸为2.98克(20.7mmol)。结果得到双环铂4.42克，收率41.46％，含量101.93％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图4所示。
实施例3
按照实施例1相同的方法制备实施例3，区别在于，加入的1,1-环丁烷二羧酸为59.6克(413.9mmol)。结果得到双环铂5.38克，收率50.47％，含量98.06％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图5所示。
实施例4
按照实施例1相同的方法制备实施例4，区别在于，滤除AgI渣后滤液水浴加热至30℃。结果得到双环铂5.12克，收率48.02％，含量101.94％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图6所示。
实施例5
按照实施例1相同的方法制备实施例5，区别在于，滤除AgI渣后滤液水浴加热至90℃。结果得到双环铂5.12克，收率48.02％，含量98.10％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图7所示。
实施例6
按照实施例1相同的方法制备实施例6，区别在于，加入1,1-环丁烷二羧酸后快速搅拌10分钟。结果得到双环铂5.22克，收率48.97％，含量99.34％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图8所示。
实施例7
按照实施例1相同的方法制备实施例7，区别在于，冷却至10℃后滤除AgI渣，并且加入1,1-环丁烷二羧酸后快速搅拌60分钟。结果得到双环铂5.36克，收率50.28％，含量99.81％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图9所示。
实施例8
按照实施例1相同的方法制备实施例8，区别在于，冷却至20℃后滤除AgI渣，并且加入1,1-环丁烷二羧酸后快速搅拌240分钟。结果得到双环铂4.56克，收率42.78％，含量98.01％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图10所示。
实施例9
取顺式-二氯二氨合铂(II)10.0克(33.3mmol)，加入550毫升纯化水，搅拌均匀并水浴至80℃后加入1,1-环丁烷二羧酸银11.5克(32.1mmol)，反应40分钟后，冷却至16℃滤除AgCl渣，滤液水浴加热至40℃。加入1,1-环丁烷二羧酸48.3克(335.1mmol)，快速搅拌40分钟后减压浓缩至剩余液体量约80毫升，冷却至10℃，过滤析出的固体，60℃干燥，得产品9.77克，收率56.94％，含量99.38％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图11所示。
实施例10
取顺式-二碘二氨合铂(II)100.0克(207.1mmol)，加入3000毫升纯化水，搅拌均匀并水浴至80℃后加入1,1-环丁烷二羧酸银73.0克(204.0mmol)，反应1小时后，冷却至16℃滤除AgI渣，滤液水浴加热至80℃。加入1,1-环丁烷二羧酸300.0克(2.08mol)，快速搅拌60分钟后减压浓缩至剩余液体量约800毫升，冷却至10℃，过滤析出的固体，60℃干燥，得产品64.73克，收率60.72％，含量99.84％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图12所示。
按照类似的方法制备双(1,1-环戊烷二羧酸)二氨合铂(II)和双(1,1-环己烷二羧酸)二氨合铂(II)：
实施例11
取顺式-二碘二氨合铂(II)10.0克(20.7mmol)，加入350毫升纯化水，搅拌均匀并水浴至80℃后加入1,1-环戊烷二羧酸银7.48克(20.1mmol)，反应30分钟后，冷却至16℃滤除AgI渣，滤液水浴加热至70℃。加入1,1-环戊烷二羧酸35.1克(222.2mmol)，快速搅拌30分钟后减压浓缩至剩余液体量约70毫升，冷却至10℃，过滤析出的固体，60℃干燥，得双(1,1-环戊烷二羧酸)二氨合铂(II)4.54克，收率40.39％，含量98.32％。负离子电喷雾质谱：542(M-1)。 1H-NMR(D 2O，500MHz)δ：1.9013-1.9776(5重峰，4H)；1.9013-1.9776(5重峰，4H)；2.3502-2.3812(3重峰，4H)；2.7028-2.7413(3重峰，4H)；4.3706(单峰，6H)。
实施例12
取顺式-二碘二氨合铂(II)10.0克(20.7mmol)，加入350毫升纯化水，搅拌均匀并水浴至80℃后加入1,1-环己烷二羧酸银7.76克(20.1mmol)，反应30分钟后，冷却至16℃滤除AgI渣，滤液水浴加热至70℃。加入1,1-环己烷二羧酸38.2克(222.2mmol)，快速搅拌30分钟后减压浓缩至剩余液体量约70毫升，冷却至10℃，过滤析出的固体，60℃干燥，得双(1,1-环己烷二羧酸)二氨合铂(II)4.65克，收率39.34％，含量101.80％。负离子电喷雾质谱：570(M-1)。 1H-NMR(D 2O，500MHz)δ：1.7406-1.7812(5重峰，2H)；1.8313-1.8676(5重峰，2H)；1.9313-1.9766(5重峰，4H)；2.1212-2.1612(5重峰，4H)；2.7638-2.8012(3重峰，4H)；2.9083-2.9425(3重峰，4H)；4.2786(单峰，6H)。
通过以上实施例，进一步突显了本发明的优点：
1.实施例1-3的实验结果表明，步骤b中当1,1-环丁烷二羧酸以过量的方式与卡铂反应时，根据本发明的方法能够直接获得双环铂含量为98％～102％的品质良好的双环铂产品，且产率超过41％。其中，优选的条件是1,1-环丁烷二羧酸与1,1-环丁烷二羧酸银的摩尔比为11:1。
2.实施例1，4-5的实验结果表明，当卡铂与1,1-环丁烷二羧酸的反应温度落入本发明所述的范围内时，根据本发明的方法能够直接获得双环铂含量为98％～102％的品质良好的双环铂产品，且产率超过48％。其中，优选的条件是反应温度为70℃。
3.实施例1，6-8的实验结果表明，当卡铂与1,1-环丁烷二羧酸的反应时间落入本发明所述的范围内时，根据本发明的方法能够直接获得双环铂含量为98％～102％的品质良好的双环铂产品，且产率超过42％。其中，优选的条件是反应时间为30分钟。
4、实施例1和9的实验结果表明，根据本发明的方法可使用的顺式-二碘二氨合铂(II)作为起始原料，也可使用顺式-二氯二氨合铂(II)作为起始原料。
5.实施例10的实验结果表明，根据本发明的方法在放大后，仍然能够直接以高收率获得品质良好的双环铂产品。因此，根据本发明的方法特别适合于双环铂的工业化放大生产。
6.实施例11和12的实验结果表明，按照本发明的方法不仅可以用来制备双环铂，并且也可以以高收率、高含量地制备其他双二羧酸二氨络铂(II)衍生物，例如双(1,1-环戊烷二羧酸)二氨合铂(II)和双(1,1-环己烷二羧酸)二氨合铂(II)。
最后，为了进一步验证本发明方法的优越性，本发明还提供了按照现有技术的方法重复试验的结果。
参照CN104693245A进行以下试验：
比较例1
将10.0克(26.95mmol)卡铂和3.88克(26.95mmol)1,1-环丁烷二羧酸加入到500毫升(50倍量)注射用水中，室温(25℃左右) 下搅拌约1小时至固体全部溶解，然后在室温下避光静置7天；40℃减压浓缩，干燥后得到13.86克的产品，收率99.86％。采用X-射线衍射和高效液相色谱对所得产品进行表征。
其X-射线衍射图谱如图13所示，在2θ角为11.8°处显卡铂特征峰，相对于2θ角为7.8°处的双环铂特征峰，峰强度为1.78/76.47＝2.32，远超过添加有3％卡铂的双环铂对照品的X-射线衍射图谱中该峰的峰强度1.25，表明产品中含有大于3％的游离卡铂，并且所述游离卡铂很难在后续的纯化步骤中除去，因此所述产品为不合格产品。
可见，比较例1的实验结果表明，按照CN104693245A的方法并不能获得品质良好的双环铂产品。
参照CN106132408A进行以下试验：
比较例2
将5.0g卡铂(13.47mmol)与2.232g 1,1-环丁烷二羧酸(15.50mmol)加入20mL的玻璃小瓶中。在上述玻璃小瓶中加入12.5mL去离子水，并在室温下搅拌该混合物以形成均匀的悬浮液，同时保持小瓶远离光源。以0.33℃/min的速度冷却混合物至5℃，并在5℃恒温20小时以形成沉淀。真空过滤，并用5mL去离子水清洗滤饼，然后真空干燥。
其X-射线衍射图谱如图14所示，在2θ角为11.7°处显卡铂特征峰，相对于2θ角为7.7°处的双环铂特征峰，峰强度为3.39，远超过添加有3％卡铂的双环铂对照品的X-射线衍射图谱中该峰的峰强度1.25，表明产品中含有大于3％的游离卡铂，并且所述游离卡铂很难在后续的纯化步骤中除去，因此所述产品为不合格产品。
可见，比较例2的实验结果表明，按照CN106132408A的方法并不能获得品质良好的双环铂产品。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载 的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。

Claims (25)

  1. 一种制备式(I)的双二羧酸二氨络铂(II)衍生物的方法，所述方法包括：
    Figure PCTCN2018076951-appb-100001
    a.在第一温度下使式(II)的顺式-二卤素离子二氨合铂(II)和式(III)的二羧酸二银盐在水中反应生成式(IV)的卡铂或卡铂类似物，冷却至第二温度进行低温过滤以获得第一溶液；
    b.在第三温度下使第一溶液与式(V)的二羧酸反应以获得第二溶液；
    c.浓缩所述第二溶液以获得第三溶液；
    d.冷却所述第三溶液以析出固体；
    其中，
    R 1和R 2可彼此相同或不同，并且各自独自表示氢、C 1-12烃基、卤素、氨基、氰基、羟基、羧基、酰基、磷酰基或磷酰氨基；
    或者R 1与R 2相互连接并与它们相连的碳原子一起形成3-12元饱和或不饱和的碳环；
    X表示卤素。
  2. 根据权利要求1所述的方法，所述方法还包括：
    e.分离析出的固体并任选地进行洗涤和/或干燥。
  3. 根据权利要求1-2中任一项所述的方法，其特征在于，所述R 1与R 2相互连接并与它们相连的碳原子一起形成3-12元饱和或不饱和的碳环，优选形成环丙烷、环丁烷、环戊烷、环己烷或环庚烷，更优选形成环丁烷。
  4. 根据权利要求1-3中任一项所述的方法，其特征在于，所述式(I)的双二羧酸二氨络铂(II)衍生物为双环铂，所述式(III)的二羧酸二银 盐为1,1-环丁烷二羧酸银，所述式(IV)的卡铂或卡铂类似物为卡铂，所述式(V)的二羧酸为1,1-环丁烷二羧酸。
  5. 根据权利要求1-4中任一项所述的方法，其特征在于，所述X表示Cl、Br或I，优选Cl或I。
  6. 根据权利要求1-5中任一项所述的方法，其特征在于，所述步骤a中的第一温度为20℃～92℃，优选为40℃～90℃，更优选为70℃～80℃。
  7. 根据权利要求1-6中任一项所述的方法，其特征在于，所述步骤a中式(II)的顺式-二卤素离子二氨合铂(II)与式(III)的二羧酸二银盐的摩尔比为(1.01～1.05):1，优选为1.01:1、1.02:1、1.03:1、1.04:1、1.05:1。
  8. 根据权利要求1-7中任一项所述的方法，其特征在于，所述步骤a中水与式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比为25:1ml/g～200:1ml/g，优选为25:1ml/g～60:1ml/g，更优选为30:1ml/g～55:1ml/g。
  9. 根据权利要求1-8中任一项所述的方法，其特征在于，所述步骤a中的第二温度为10℃～20℃，优选为12℃～18℃，更优选为16℃～17℃。
  10. 根据权利要求1-9中任一项所述的方法，其特征在于，步骤a所述反应的反应时间为10min～360min，优选为30min～60min。
  11. 根据权利要求1-10中任一项所述的方法，其特征在于，所述步骤b中的第三温度为30℃～92℃，优选为30℃～90℃，更优选为40℃～90℃，最优选为70℃～80℃。
  12. 根据权利要求1-11中任一项所述的方法，其特征在于，所述步骤b中式(V)的二羧酸与步骤a中式(III)的二羧酸二银盐的摩尔比下限为1:1，优选地，式(V)的二羧酸与式(III)的二羧酸二银盐的摩尔比为2:1～20:1；更优选地，式(V)的二羧酸与式(III)的二羧酸二银盐的摩尔比为10:1～12:1。
  13. 根据权利要求1-12中任一项所述的方法，其特征在于，步骤 b所述反应的反应时间为10min～360min，优选为30min～60min。
  14. 根据权利要求1-13中任一项所述的方法，其特征在于，步骤c所述浓缩是指除去第二溶液中的至少一部分水以使得所述第三溶液与步骤a的式(II)的顺式-二卤素离子二氨合铂(II)的体积质量比的上限为40:1ml/g，优选地，所述体积质量比为5:1ml/g～40:1ml/g。
  15. 根据权利要求1-14中任一项所述的方法，其特征在于，步骤c中所述的浓缩包括但不限于：减压蒸馏、透析浓缩、薄膜蒸发、多级闪蒸、纳滤中的一种或更多种的组合，优选减压蒸馏。
  16. 根据权利要求1-15中任一项所述的方法，其特征在于，步骤d中的冷却是指冷却至第四温度，且所述第四温度为1℃～40℃，优选为1℃～20℃，更优选为10℃～15℃。
  17. 根据权利要求2-16中任一项所述的方法，其特征在于，步骤e中所述的分离包括但不限于：过滤或离心，优选过滤，更优选减压过滤。
  18. 根据权利要求2-17中任一项所述的方法，其特征在于，步骤e中所述的步骤e中的洗涤包括用水洗涤分离的固体一次或更多次。
  19. 根据权利要求2-18中任一项所述的方法，其特征在于，步骤e中所述的干燥包括但不限于：常压干燥、减压干燥、喷雾干燥、微波干燥和远红外干燥中的一种或更多种的组合，优选减压干燥，更优选在升高的温度下减压干燥。
  20. 根据权利要求1-19中任一项所述的方法，其特征在于，当式(I)的双二羧酸二氨络铂(II)衍生物为双环铂时，所述方法所获得的产品的X-射线衍射在2θ角为11.4°-11.7°处不显特征峰；或者显特征峰但其峰强度低于含约2.0wt％卡铂的双环铂对照品在11.4°-11.7°处的峰的峰强度。
  21. 根据权利要求1-20中任一项所述的方法，其特征在于，当式(I)的双二羧酸二氨络铂(II)衍生物为双环铂时，所述方法所获得的产品具有98％～102％的按照以下方法获得的双环铂含量：
    1)获得含约2.0wt％卡铂的双环铂对照品的X-射线衍射图谱；
    2)测定所述产品的X-射线衍射，确定所述产品在2θ角为11.4°-11.7°处是否显特征峰；
    3)对于步骤2)中在2θ角为11.4°-11.7°处不显特征峰，以及显特征峰但其峰强度不超过所述对照品在2θ角为11.4°-11.7°处的峰的峰强度的产品，采用高效液相色谱测定卡铂含量；
    4)将步骤3)测得的卡铂含量乘以1.388得到双环铂的含量。
  22. 根据权利要求20或21所述的方法，其特征在于，所述含约2.0wt％卡铂的双环铂对照品通过如下方法制备：
    取双环铂对照品约1重量份与卡铂对照品约0.02重量份，精密称定，混匀，即得含约2.0wt％卡铂的双环铂对照品。
  23. 一种双环铂产品中双环铂含量的测定方法，其包括以下步骤：
    1)获得含约2.0wt％卡铂的双环铂对照品的X-射线衍射图谱；
    2)测定所述产品的X-射线衍射，确定所述产品在2θ角为11.4°-11.7°处是否显特征峰；
    3)对于步骤2)中在2θ角为11.4°-11.7°处不显特征峰，以及显特征峰但其峰强度不超过所述对照品在2θ角为11.4°-11.7°处的峰的峰强度的产品，采用高效液相色谱测定卡铂含量；
    4)将步骤3)测得的卡铂含量乘以1.388得到双环铂的含量。
  24. 根据权利要求23所述的方法，其特征在于，所述含约2.0wt％卡铂的双环铂对照品通过如下方法制备：
    取双环铂对照品约1重量份与卡铂对照品约0.02重量份，精密称定，混匀，即得含约2.0wt％卡铂的双环铂对照品。
  25. 一种根据权利要求1-22中任一项所述的方法制备的式(I)的双二羧酸二氨络铂(II)衍生物。
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