WO2018171371A2 - 一种双二羧酸二氨络铂(ii)衍生物的制备方法 - Google Patents

一种双二羧酸二氨络铂(ii)衍生物的制备方法 Download PDF

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WO2018171371A2
WO2018171371A2 PCT/CN2018/076946 CN2018076946W WO2018171371A2 WO 2018171371 A2 WO2018171371 A2 WO 2018171371A2 CN 2018076946 W CN2018076946 W CN 2018076946W WO 2018171371 A2 WO2018171371 A2 WO 2018171371A2
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carboplatin
temperature
formula
platinum
product
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PCT/CN2018/076946
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French (fr)
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WO2018171371A3 (zh
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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 CN201880000700.7A priority Critical patent/CN108884119A/zh
Priority to PCT/CN2018/076946 priority patent/WO2018171371A2/zh
Publication of WO2018171371A2 publication Critical patent/WO2018171371A2/zh
Publication of WO2018171371A3 publication Critical patent/WO2018171371A3/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

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  • the present invention relates to the field of synthesis of platinum antitumor drugs, in particular, the present invention relates to a process for preparing a supramolecular platinum antitumor drug diammonium platinum dichloride (II) derivative, in particular, the present invention relates to A preparation method of a supramolecular platinum antitumor drug bicycloplatin.
  • a supramolecular platinum antitumor drug diammonium platinum dichloride (II) derivative in particular, the present invention relates to A preparation method of a supramolecular platinum antitumor drug bicycloplatin.
  • 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:
  • Bicycloplatinum is usually obtained by reacting carboplatin with 1,1-cyclobutanedicarboxylic acid.
  • the prior art discloses various preparation methods, but both have the problems of complicated preparation process and low product purity.
  • bicycloplatinum is prepared by the following method: carboplatin is dissolved in pure water at normal temperature, and then an equimolar amount of 1,1-cyclobutanedicarboxylic acid is added. After the reaction was completed, it was evaporated to dryness, washed with ethanol, and then recrystallized from distilled water. This method is cumbersome in operation due to the need for evaporation and recrystallization steps, and the yield of bicycloplatinum 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 heating and concentration in the final process makes the bicyclic platinum product exist in the higher 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 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 present invention provides an improved process for the preparation of diammonium platinum dichloride (II) derivatives.
  • the process of distillation and concentration is not required, and the diammine platinum (II) derivative of bisdicarboxylate can be directly obtained.
  • the product has high purity and no further purification treatment.
  • the product quality is stable and the production cycle is short, which is suitable for industrial scale production.
  • the process of the present invention can be environmentally friendly using only water as a solvent, resulting in a small amount of waste liquid.
  • the present invention provides a process for the preparation of a diammonium platinum dichloride (II) derivative of formula (I), which process can comprise:
  • a. dissolving a carboplatin or carboplatin analog of formula (II) and an excess of one of the dicarboxylic acids of formula (III) in a solvent at a first temperature to obtain a first solution, at a second temperature Adding a carboplatin or a carboplatin analog of the formula (II) and an excess of the dicarboxylic acid of the formula (III) to the first solution, and reacting at a third temperature to obtain a second solution;
  • the first temperature, the second temperature, and the third temperature are the same or different from each other, and are each independently 38 ° C to 92 ° C;
  • 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.
  • the method can also include:
  • the method may further comprise the preparation of a carboplatin or carboplatin analog of formula (II).
  • the preparation method of the carboplatin or carboplatin analog of the formula (II) is not particularly limited as long as the carboplatin or carboplatin analog of the formula (II) can be obtained.
  • a preparation method known in the art can be employed.
  • the carboplatin or carboplatin analog of formula (II) can be prepared by the following method:
  • the cis-dihalide ion diammine platinum (II) of the formula (IV) is reacted with silver nitrate or silver sulfate to react the resulting intermediate with the metal salt of the dicarboxylic acid of the formula (VI) to form the formula (II).
  • R 1 and R 2 are as described herein;
  • X represents a halogen
  • M represents metal
  • n 1 or 2.
  • 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 2% carboplatin and a list of its data.
  • Figure 3c is an X-ray diffraction pattern of a bicyclo platinum reference added with 3% 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 bicyclic platinum product of Example 11.
  • Figure 14 is an X-ray diffraction pattern of the bicyclic platinum product of Example 12.
  • Figure 15 is an X-ray diffraction pattern of the bicyclic platinum product of Example 13.
  • Figure 16 is an X-ray diffraction pattern of the bicyclic platinum product of Example 14.
  • Figure 18 is an X-ray diffraction pattern of the bicyclic platinum product of Example 16.
  • 21 is an X-ray diffraction pattern of a product of Comparative Example 4 and a data list thereof.
  • Figure 22 is an X-ray diffraction pattern of the product of Comparative Example 5 and a list of data thereof.
  • the present invention provides an improved process for the preparation of diammonium platinum dichloride (II) derivatives.
  • the process of distillation and concentration is not required, and the diammine platinum (II) derivative of bisdicarboxylate can be directly obtained.
  • the product has high purity and no further purification treatment.
  • the product quality is stable and the production cycle is short, which is suitable for industrial scale production.
  • the method of the present invention can use only water as a solvent, is environmentally friendly, and is easy to handle.
  • a. dissolving a carboplatin or carboplatin analog of formula (II) and an excess of one of the dicarboxylic acids of formula (III) in a solvent at a first temperature to obtain a first solution, at a second temperature Adding a carboplatin or a carboplatin analog of the formula (II) and an excess of the dicarboxylic acid of the formula (III) to the first solution, and reacting at a third temperature to obtain a second solution;
  • the first temperature, the second temperature, and the third temperature are the same or different from each other, and are each independently 38 ° C to 92 ° C;
  • 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.
  • the method can also include:
  • the method may further comprise the preparation of a carboplatin or carboplatin analog of formula (II).
  • the preparation method of the carboplatin or carboplatin analog of the formula (II) is not particularly limited as long as the carboplatin or carboplatin analog of the formula (II) can be obtained.
  • a preparation method known in the art can be employed.
  • the carboplatin or carboplatin analog of formula (II) can be prepared by the following method:
  • the cis-dihalide ion diammine platinum (II) of the formula (IV) is reacted with silver nitrate or silver sulfate to react the resulting intermediate with the metal salt of the dicarboxylic acid of the formula (VI) to form the formula (II).
  • R 1 and R 2 are as described herein;
  • X represents a halogen
  • M represents metal
  • n 1 or 2.
  • 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 carboplatin or carboplatin analog of the formula (II) may be Carboplatin, the dicarboxylic acid of formula (III) may be 1,1-cyclobutanedicarboxylic acid.
  • said X represents Cl, Br or I, preferably Cl or I.
  • said M represents Ba, Pb or Na, preferably Ba.
  • the step a may include: dissolving the carboplatin or carboplatin analog of the formula (II) in a solvent at a first temperature to obtain a first solution, and at a second temperature An excess of the dicarboxylic acid of formula (III) is added to the first solution and allowed to react at a third temperature to obtain a second solution.
  • the step a may include: dissolving an excess of the dicarboxylic acid of the formula (III) in a solvent at a first temperature to obtain a first solution, and at the second temperature, the first A carboplatin or carboplatin analog of formula (II) is added to a solution and reacted at a third temperature to obtain a second solution.
  • the solvent may be selected from the group consisting of water, tetrahydrofuran, dichloromethane, ethanol, isopropanol, ethyl acetate, dimethylformamide, 1,4-two One of alkane, acetone, toluene, isobutyl acetate, isopropyl acetate, chloroform, 2-methoxyethanol, methyl isobutyl ketone, methyl tert-butyl ether, 1,2-dichloroethane Species or more.
  • the solvent may be selected from water, or a mixed solvent of water and ethanol, isopropanol or acetone.
  • the volume ratio of water to ethanol, isopropanol or acetone in the mixed solvent may be (1 to 10): (10 to 1), preferably (1 to 5): (5 to 1), more preferably (1 to 3): (3 to 1), most preferably 1:1.
  • the solvent can be water.
  • the excess dicarboxylic acid of formula (III) in step a means that the lower molar ratio of the dicarboxylic acid of formula (III) to the carboplatin or carboplatin analog of formula (II) is It is 1.1:1.
  • the lower limit of the molar ratio of the dicarboxylic acid of the formula (III) to the carboplatin or carboplatin analog of the formula (II) may preferably be 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, 8.1: 1, 8.2: 1, 8.3: 1 8.4:1, 8.5:1, 8.6:1, 8.7:1, 8.8:1, 8.9:1, 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 upper limit of the molar ratio of the dicarboxylic acid of the formula (III) to the carboplatin or carboplatin analog of the formula (II) may be 250:1.
  • the upper limit of the molar ratio of the dicarboxylic acid of the formula (III) to the carboplatin or carboplatin analog of the formula (II) may preferably be 200:1, 180:1, 160:1, 140:1, 120:1, 100.
  • an excess of the dicarboxylic acid of formula (III) means that the molar ratio of the dicarboxylic acid of formula (III) to the carboplatin or carboplatin analog of formula (II) may range from 2:1 to 20:1;
  • an excess of the dicarboxylic acid of formula (III) means that the molar ratio of the dicarboxylic acid of formula (III) to the carboplatin or carboplatin analog of formula (II) may range from 8:1 to 15:1.
  • the volumetric mass ratio of solvent to carboplatin or carboplatin analog of formula (II) in step a may range from 15:1 ml/g to 43:1 ml/g.
  • the volumetric mass ratio of the solvent to the carboplatin or carboplatin analog of formula (II) can be 16:1 ml/g, 17:1 ml/g, 18:1 ml/g, 19:1 ml/g, 20:1 ml.
  • the volumetric mass ratio of the solvent to the carboplatin or carboplatin analog of formula (II) may be from 18:1 ml/g to 40:1 ml/g; more preferably, the solvent and carboplatin or card of formula (II)
  • the volume ratio of the platinum analog may range from 25:1 ml/g to 30:1 ml/g.
  • the first temperature, the second temperature, and the third temperature are the same or different from each other, and each independently may be 38 ° C to 92 ° C.
  • the first temperature, the second temperature, and the third temperature are the same or different from each other, and each of them may independently be 39° C., 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 50° C., 55° C. 60 ° C, 65 ° C, 70 ° C, 75 ° C, 80 ° C, 85 ° C, 86 ° C, 87 ° C, 88 ° C, 89 ° C, 90 ° C or 91 ° C.
  • the first temperature, the second temperature, and the third temperature are the same or different from each other, and each independently may be 40 ° C to 90 ° C; more preferably, the first temperature, the second temperature, and the third temperature are each independently 70 ° C ⁇ 80 ° C.
  • the mutual relationship between the first temperature, the second temperature and the third temperature is not particularly limited as long as the carboplatin or carboplatin analog of the formula (II) and the dicarboxylic acid of the formula (III) are completely dissolved in the solvent.
  • the first temperature, the second temperature, and the third temperature are the same as each other.
  • the first temperature and the second temperature are the same, and the third temperature is higher than the first temperature and the second temperature.
  • the second temperature is higher than the first temperature and the third temperature is higher than the first temperature and the second temperature.
  • the temperature is too low, the solubility of the solute is low, and the amount of the solvent needs to be increased, so that the solid product cannot be precipitated; when the temperature is too high, a large amount of side reactions occur, and the color of the reaction solution becomes dark to obtain the bis-dicarboxylate of the formula (I).
  • a diammine platinum (II) derivative is A diammine platinum (II) derivative.
  • 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 420 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, 390min or 420min.
  • the reaction time can be from 30 min to 90 min.
  • the cooling in step b means cooling to a fourth temperature, the fourth temperature being lower than the third temperature, and may be from 1 °C to 40 °C.
  • the fourth temperature may be 1 ° C, 2 ° C, 3 ° 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 25 ° C; more preferably, the fourth temperature may be 10 to 15 ° C.
  • the cooling time in step b may range from 0.5 h to 25 h.
  • the cooling time may be 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 15 h, 20 h or 25 h.
  • the cooling time may be 1 h to 20 h; more preferably, the cooling time may be 4 h to 8 h.
  • the manner of separation in the step c 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: filtration (including atmospheric filtration, pressure filtration, vacuum filtration), membrane separation, sedimentation (including centrifugation, gravity natural sedimentation) A combination of one or more, preferably by pressure filtration or reduced pressure filtration.
  • the washing in step c comprises washing the separated solids one or more times with a solvent.
  • the solvent is as described herein.
  • the drying in the step c is not particularly limited as long as the solvent 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.
  • 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 and “second solution” as used herein, unless otherwise stated, only distinguish between solutions occurring in different processes without any limitation on the solution, and not between them. Interrelationship.
  • 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 method of the present invention does not require a distillation and concentration process after the reaction, and can directly precipitate a good quality diammine platinum (II) derivative product in a high yield, and the yield of the obtained product is at least 44%.
  • the purity is as high as 98% to 102%, and it is easy to operate without further purification.
  • the method of CN1311183A requires a process of concentration by distillation, and the process of CN104693245A requires a process of distillation concentration or freeze-drying, which is troublesome in post-treatment. Further, by repeating the methods of CN104693245A and CN106132408A, the X-ray diffraction pattern of the obtained product showed that the product contained more than 3% of free carboplatin. Therefore, neither CN104693245A nor CN106132408A can directly obtain a good quality bicyclic platinum product.
  • the method of the invention has a short production cycle and remarkable efficiency.
  • the method of CN104693245A requires a standing process of up to 3-9 days with low production efficiency.
  • the method of the invention has strong controllability and repeatability, and the quality of different batches of products is similar.
  • the method of the present invention is particularly suitable for industrial scale-up production due to the above advantages. Contrary to the present invention, the methods of CN1311183A, CN104693245A and CN106132408A cannot be scaled up. Specifically, the methods of CN1311183A and CN104693245A require a process of distilling off water or freeze-drying water removal, and when performing scale-up production, the amount of water used is increased. Extending the time of distillation or freezing not only reduces production efficiency, increases production costs, but also increases the risk of bicyclic platinum deterioration.
  • CN104693245A it is expressly disclosed in CN104693245A that even if a few hundred grams of bicycloplatinum is prepared, it is necessary to wash with ethanol in a subsequent step to solve the problem of deterioration of product quality due to long-term concentration or freezing.
  • the suspension method of CN106132408A after amplification, makes the reaction process more difficult to control due to an increase in the amount of suspended solids, and in fact, a good quality bicyclic platinum product cannot be obtained. Therefore, CN1311183A, CN104693245A and CN106132408A are not scaled up in kilograms.
  • the method of the invention can not use any organic solvent when the solvent is selected from water, and the production process is environmentally friendly and the amount of waste liquid generated is small.
  • the method of the invention does not require a distillation or freeze-drying process due to its special process, and only requires simple filtration, washing and drying to obtain a product of high quality, so the production cost is low and the economy is high.
  • the obtained products were characterized by elemental analysis, negative ion electrospray mass spectrometry, nuclear magnetic resonance-hydrogen spectroscopy, nuclear magnetic resonance-carbon spectroscopy and X-ray diffraction.
  • the content of bicycloplatin was measured by high performance liquid chromatography.
  • the peak of chemical shift 1.7159-1.7793ppm is H a , the actual number of hydrogen nuclei is 2, and it is divided into 5 heavy peaks by 4 H b on both sides; the peak of chemical shift 1.8281-1.8928ppm is H c , actual hydrogen The number of nuclei is 2, which is divided into 5 heavy peaks by the influence of 4 H d on both sides; the peak of chemical shift 2.3965-2.4288ppm is H b , the actual number of hydrogen nuclei is 4, and the total number of H a unilateral is 2 Effect split into three doublet; 2.7140-2.7457ppm peak chemical shift of H d, the actual number of hydrogen nuclei is 4, a total of two affected unilateral split into 3 H c of doublet; chemical shifts of the peaks 4.0497ppm It is H e, the actual number of hydrogen nuclei 6 as broad singlet; action due to the exchange with D 2 O, and FIG peak carboxyl active hydrogen protons H f does not appear. 4. Nuclear Magnetic Reson
  • the peak of chemical shift 15.25ppm is C a ; the peak of chemical shift 15.39ppm is C h ; the peak of chemical shift 28.60ppm is C b ; the peak of chemical shift 31.02ppm is C g ; the peak of chemical shift 52.93ppm is C c ; The peak of chemical shift 56.19 ppm is C f ; the peak of chemical shift 176.11 ppm is C d ; the peak of chemical shift 181.85 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.
  • Phenylhexylsilylated silica gel as a filler eg Waters XBridgeTM Shield Phenyl 5 ⁇ m 4.6 ⁇ 250mm
  • [tetrabutylammonium hydrogen sulfate buffer take tetrabutylammonium hydrogen sulfate 8.5g, Add 80ml of water to dissolve, add 3.4ml of phosphoric acid, adjust the pH value to 7.5 ⁇ 0.05 with 10mol/L sodium hydroxide solution]]-water-acetonitrile (20:880:100) as mobile phase; detection wavelength is 220nm, column temperature 30 °C, flow rate 1.0ml / min, the complete elution time of the 1,1-cyclobutane dicarboxylic acid peak is the running time, the theoretical number of plates is not less than 3000, 1,1-cyclobutane according to the carboplatin peak The degree of separation between the dicarboxylic acid peak and the carboplatin peak The degree of separation between the di
  • 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 1 ml, as the test solution (for new use), take 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 (for new use). Accurately measure 10 ⁇ l, inject into the liquid chromatograph, record the chromatogram, and calculate the peak area of carboplatin according to the external standard method. The calculated carboplatin content was multiplied by a factor of 1.388, and the bicyclic platinum content was determined to be 99.78%.
  • 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 amount of 1,1-cyclobutanedicarboxylic acid was 7.8 g (54.17 mmol). As a result, 8.82 g of bicycloplatinum was obtained in a yield of 63.54% and a content of 98.06%.
  • Example 3 was prepared in the same manner as in Example 1 except that the amount of 1,1-cyclobutanedicarboxylic acid was 56.0 g (388.9 mmol). As a result, 9.11 g of bicycloplatinum was obtained, the yield was 65.63%, and the content was 99.12%.
  • Example 4 was prepared in the same manner as in Example 1 except that the amount of 1,1-cyclobutanedicarboxylic acid was 78.0 g (541.7 mmol). As a result, 9.19 g of bicycloplatinum was obtained, the yield was 66.21%, and the content was 98.02%.
  • Example 5 was prepared in the same manner as in Example 1 except that 400 ml of water was added and the temperature in the water bath was 40 °C. As a result, 6.02 g of bicyclo platinum was obtained, the yield was 44.52%, and the content was 101.24%.
  • Example 6 was prepared in the same manner as in Example 1, except that 330 ml of water was added, and the temperature at which the water bath was heated was 60 °C. As a result, 9.21 g of bicyclo platinum was obtained, the yield was 65.63%, and the content was 98.02%.
  • Example 7 was prepared in the same manner as in Example 1 except that 180 ml of water was added and the temperature in the water bath was 90 °C. As a result, 8.66 g of bicyclo platinum was obtained, the yield was 62.39%, and the content was 99.51%.
  • Example 8 was prepared in the same manner as in Example 1 except that the cooling temperature was 1 °C. As a result, 9.24 g of bicyclo platinum was obtained, and the yield was 66.57%, and the content was 99.89%.
  • Example 9 was prepared in the same manner as in Example 1 except that the cooling temperature was 20 °C. As a result, 6.54 g of bicyclo platinum was obtained, and the yield was 47.12%, and the content was 99.93%.
  • Example 10 was prepared in the same manner as in Example 1 except that the cooling temperature was 30 °C. As a result, 5.06 g of bicycloplatinum was obtained, the yield was 36.46%, and the content was 100.41%.
  • Example 11 was prepared in the same manner as in Example 1 except that the cooling time was 1 hour. As a result, 8.42 g of bicyclo platinum was obtained, the yield was 60.66%, and the content was 101.84%.
  • Example 11 was prepared in the same manner as in Example 1 except that the cooling time was 4 hours. As a result, 8.92 g of bicycloplatinum was obtained in a yield of 64.26% and a content of 100.84%.
  • Example 12 was prepared in the same manner as in Example 1 except that the cooling time was 20 hours. As a result, 8.82 g of bicycloplatinum was obtained in a yield of 63.54% and a content of 98.06%.
  • Comparative Example 1 was prepared in the same manner as in Example 1, except that the amount of 1,1-cyclobutanedicarboxylic acid was 3.88 g (26.95 mmol), that is, carboplatin and 1,1-cyclobutanedicarboxylic acid. The molar ratio is 1:1. As a result, 4.70 g of a product was obtained, and the yield was 33.86%.
  • the X-ray diffraction pattern of the obtained product is shown in Fig. 20, which has a strong carboplatin characteristic peak at a 2 ⁇ angle of 11.6° and a characteristic peak of a bicyclic platinum at a 2 ⁇ angle of 10.3°-10.7°, at 2 ⁇ .
  • the angle of 7.6° and 15.1° has a weak bicyclic platinum characteristic peak, indicating that the presence of platinum in the product is mainly free carboplatin, and only contains a small amount of bicycloplatinum.
  • Example 2 The same procedure as in Example 1 was carried out except that 450 ml of water was added and the temperature at which the water bath was heated was 35 °C. As a result, no product was precipitated after cooling at 10 ° C for 8 hours.
  • Example 2 The same procedure as in Example 1 was carried out except that 130 ml of water was added and the temperature at which the water bath was heated was 94 °C. As a result, a large number of side reactions occurred and the reaction solution turned brown.
  • Comparative Example 1 show that when the molar ratio of 1,1-cyclobutanedicarboxylic acid to carboplatin is 1:1 which is usually used in the prior art (such as CN1311183A, CN104693245A), good quality cannot be obtained.
  • a bicyclic platinum product on the contrary, the presence of platinum in the obtained product is mainly free carboplatin and contains only a small amount of bicycloplatinum.
  • Comparative Examples 2 and 3 show that when the amount of water used is too small, all of the carboplatin can be dissolved due to the need to heat to a higher temperature, resulting in the occurrence of a side reaction, which causes the reaction liquid to turn brown, and the quality is not obtained well. Double ring platinum products. On the other hand, when the amount of water used is too large, solids cannot be precipitated even after cooling, and thus a bicyclic platinum product of good quality cannot be obtained.
  • Example 17 show that the method according to the present invention can still obtain a good quality bicyclic platinum product directly in high yield after being amplified to the kilogram level.
  • the loss ratio of the bicyclic platinum product in the discharge and filtration steps is reduced, so the yield is even higher than that in the small test. 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. 21.
  • 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.
  • the X-ray diffraction spectrum is shown in Fig. 22.
  • the characteristic peak of the carboplatin is shown at a 1 ⁇ angle of 21.7°, and the peak intensity of the bicyclic platinum is 3.9° with respect to the 2 ⁇ angle.
  • the peak intensity is 3.39, 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.
  • Comparative Example 5 shows that a good quality bicyclic platinum product cannot be obtained according to the method of CN106132408A.

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Abstract

本发明提供了一种改进的双二羧酸二氨络铂(II)衍生物的制备方法。相对于现有技术，根据本发明的方法在卡铂或卡铂类似物与二羧酸反应后，无需进行蒸馏浓缩的过程，可直接获得双二羧酸二氨络铂(II)衍生物的产品，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，生产周期短，适合工业化放大生产。本发明的方法可以仅用水作为溶剂，对环境友好，废弃物处理简单。

Description

一种双二羧酸二氨络铂(II)衍生物的制备方法 技术领域
本发明涉及铂类抗肿瘤药物的合成领域，具体地，本发明涉及一种超分子铂类抗肿瘤药物双二羧酸二氨络铂(II)衍生物的制备方法，特别地，本发明涉及超分子铂类抗肿瘤药物双环铂的制备方法。
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 PCTCN2018076946-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。
双环铂通常由卡铂与1,1-环丁烷二羧酸反应得到，现有技术公开了多种制备方法，但均存在制备工艺复杂、产品纯度不高的问题。
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。该方法由于需要进行蒸发和重结晶步骤，因此操作繁琐，双环铂的收率较低。
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，最终工序中的加热浓缩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。
可见，现有技术的方法并不能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。因此，有必要开发一种能够简便易行、环保高 效的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的方法。
发明内容
为了克服现有技术中存在的缺陷，本发明提供了一种改进的双二羧酸二氨络铂(II)衍生物的制备方法。相对于现有技术，根据本发明的方法在卡铂或卡铂类似物与二羧酸反应后，无需进行蒸馏浓缩的过程，可直接获得双二羧酸二氨络铂(II)衍生物的产品，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，生产周期短，适合工业化放大生产。本发明的方法可以仅用水作为溶剂，对环境友好，产生废液量少。
因此，本发明提供了一种制备式(I)的双二羧酸二氨络铂(II)衍生物的方法，所述方法可包括：
Figure PCTCN2018076946-appb-000002
a.在第一温度下使式(II)的卡铂或卡铂类似物和过量的式(III)的二羧酸之一溶解于溶剂中得到第一溶液，在第二温度下向所述第一溶液中添加式(II)的卡铂或卡铂类似物和过量的式(III)的二羧酸中的另一种，在第三温度下使其反应以获得第二溶液；其中所述第一温度、第二温度和第三温度彼此相同或不同，各自独立地为38℃～92℃；
b.冷却所述第二溶液以析出固体；
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。
所述方法还可包括：
c.分离析出的固体并任选地进行洗涤和/或干燥。
在本发明的一个实施方案中，所述方法还可以包括式(II)的卡铂或卡铂类似物的制备。其中，式(II)的卡铂或卡铂类似物的制备方法没有特别限制，只要能获得所述式(II)的卡铂或卡铂类似物即可。例如，可采用本领域已知的制备方法。具体地，可采用以下方法制备式(II)的卡铂或卡铂类似物：
方法1)
Figure PCTCN2018076946-appb-000003
使式(IV)的顺式-二卤素离子二氨合铂(II)与式(V)的二羧酸二银盐反应生成式(II)的卡铂或卡铂类似物；或者
方法2)
Figure PCTCN2018076946-appb-000004
使式(IV)的顺式-二卤素离子二氨合铂(II)与硝酸银或硫酸银反应，使生成的中间体与式(VI)的二羧酸金属盐反应生成式(II)的卡铂或卡铂类似物；
其中，
R 1、R 2的定义如本文所述；
X表示卤素；
M表示金属；并且
n表示1或2。
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2％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3％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为实施例11的双环铂产品的X-射线衍射图谱。
图14为实施例12的双环铂产品的X-射线衍射图谱。
图15为实施例13的双环铂产品的X-射线衍射图谱。
图16为实施例14的双环铂产品的X-射线衍射图谱。
图17为实施例15的双环铂产品的X-射线衍射图谱。
图18为实施例16的双环铂产品的X-射线衍射图谱。
图19为实施例17的双环铂产品的X-射线衍射图谱。
图20为比较例1的产品的X-射线衍射图谱。
图21为比较例4的产品的X-射线衍射图谱及其数据列表。
图22为比较例5的产品的X-射线衍射图谱及其数据列表。
具体实施方式
本发明提供了一种改进的双二羧酸二氨络铂(II)衍生物的制备方法。相对于现有技术，根据本发明的方法在卡铂或卡铂类似物与二羧酸反应后，无需进行蒸馏浓缩的过程，可直接获得双二羧酸二氨络铂(II)衍生物的产品，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，生产周期短，适合工业化放大生产。本发明的方法可以仅用水作为溶剂，对环境友好，废弃物处理简单。
根据本发明的一个实施方案，提供了一种制备式(I)的双二羧酸二氨络铂(II)衍生物的方法，所述方法可包括：
Figure PCTCN2018076946-appb-000005
a.在第一温度下使式(II)的卡铂或卡铂类似物和过量的式(III)的二羧酸之一溶解于溶剂中得到第一溶液，在第二温度下向所述第一溶液中添加式(II)的卡铂或卡铂类似物和过量的式(III)的二羧酸中的另一种，在第三温度下使其反应以获得第二溶液；其中所述第一温度、第二温度和第三温度彼此相同或不同，各自独立地为38℃～92℃；
b.冷却所述第二溶液以析出固体；
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。
所述方法还可包括：
c.分离析出的固体并任选地进行洗涤和/或干燥。
在本发明的一个实施方案中，所述方法还可以包括式(II)的卡铂或卡铂类似物的制备。其中，式(II)的卡铂或卡铂类似物的制备方法没有特别限制，只要能获得所述式(II)的卡铂或卡铂类似物即可。例如，可采用本领域已知的制备方法。具体地，可采用以下方法制备式(II)的卡铂或卡铂类似物：
方法1)
Figure PCTCN2018076946-appb-000006
使式(IV)的顺式-二卤素离子二氨合铂(II)与式(V)的二羧酸二银盐反应生成式(II)的卡铂或卡铂类似物；或者
方法2)
Figure PCTCN2018076946-appb-000007
使式(IV)的顺式-二卤素离子二氨合铂(II)与硝酸银或硫酸银反应，使生成的中间体与式(VI)的二羧酸金属盐反应生成式(II)的卡铂或卡铂类似物；
其中，
R 1、R 2的定义如本文所述；
X表示卤素；
M表示金属；并且
n表示1或2。
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(II)的卡铂或卡铂类似物可为卡铂，所述式(III)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，所述M表示Ba、Pb或Na，优选Ba。
在本发明的一个实施方案中，所述步骤a可包括：在第一温度下使式(II)的卡铂或卡铂类似物溶解于溶剂中得到第一溶液，在第二温度下向所述第一溶液中添加过量的式(III)的二羧酸，在第三温度下使其反应以获得第二溶液。
在本发明的一个实施方案中，所述步骤a可包括：在第一温度下使过量的式(III)的二羧酸溶解于溶剂中得到第一溶液，在第二温度下向所述第一溶液中添加式(II)的卡铂或卡铂类似物，在第三温度下使其反应以获得第二溶液。
在本发明的一个实施方案中，所述溶剂可选自水、四氢呋喃、二氯甲烷、乙醇、异丙醇、乙酸乙酯、二甲基甲酰胺、1,4-二
Figure PCTCN2018076946-appb-000008
烷、丙酮、甲苯、乙酸异丁酯、乙酸异丙酯、氯仿、2-甲氧基乙醇、甲基异丁基酮、甲基叔丁基醚、1,2-二氯乙烷中的一种或更多种。
在本发明的一个实施方案中，所述溶剂可选自水、或者水与乙醇、异丙醇或丙酮的混合溶剂。
在本发明的一个实施方案中，所述混合溶剂中水与乙醇、异丙醇 或丙酮的体积比可为(1～10):(10～1)，优选(1～5):(5～1)，更优选(1～3):(3～1)，最优选1:1。
在本发明的一个实施方案中，所述溶剂可为水。
在本发明的一个实施方案中，步骤a中过量的式(III)的二羧酸是指式(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比下限可为1.1:1。式(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比的下限可优选为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、8.1:1、8.2:1、8.3:1、8.4:1、8.5:1、8.6:1、8.7:1、8.8:1、8.9:1、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(III)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(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比的上限可为250:1。式(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比的上限可优选为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(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比低于1.1:1时，析出的固体量减少且在X-射线衍射中出现明显的卡铂特征峰。优选地，过量的式(III)的二羧酸是指式(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比可为2:1～20:1；更优选地，过量的式(III)的二羧酸是指式(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比可为8:1～15:1。
在本发明的一个实施方案中，步骤a中溶剂与式(II)的卡铂或卡铂类似物的体积质量比可为15:1ml/g～43:1ml/g。优选地，溶剂与式(II)的卡铂或卡铂类似物的体积质量比可为16:1ml/g、17:1ml/g、18:1ml/g、19:1ml/g、20:1ml/g、21:1ml/g、22:1ml/g、23:1ml/g、24:1ml/g、25:1ml/g、26:1ml/g、26.5:1ml/g、27:1ml/g、27.5:1ml/g、28:1ml/g、29:1ml/g、30:1ml/g、31:1ml/g、32:1ml/g、33:1ml/g、34:1ml/g、35:1 ml/g、36:1ml/g、37:1ml/g、38:1ml/g、39:1ml/g、40:1ml/g、41:1ml/g或42:1ml/g。当溶剂与式(II)的卡铂或卡铂类似物的体积质量比过小时，需要加热至较高的温度才能将式(II)的卡铂或卡铂类似物全部溶解，结果是发生大量副反应、反应液颜色变深而不能得到式(I)的双二羧酸二氨络铂(II)衍生物。当溶剂与式(II)的卡铂或卡铂类似物的质量体积比过大时，无法析出固体产品。优选地，溶剂与式(II)的卡铂或卡铂类似物的体积质量比可为18:1ml/g～40:1ml/g；更优选地，溶剂与式(II)的卡铂或卡铂类似物的体积质量比可为25:1ml/g～30:1ml/g。
在本发明的一个实施方案中，所述第一温度、第二温度和第三温度彼此相同或不同，各自独立地可为38℃～92℃。优选地，第一温度、第二温度和第三温度彼此相同或不同，各自独立地可为39℃、40℃、41℃、42℃、43℃、44℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、86℃、87℃、88℃、89℃、90℃或91℃。优选地，第一温度、第二温度和第三温度彼此相同或不同，各自独立地可为40℃～90℃；更优选地，第一温度、第二温度和第三温度各自独立地可为70℃～80℃。其中，第一温度、第二温度和第三温度的相互大小关系没有特别限制，只要能够使得式(II)的卡铂或卡铂类似物、式(III)的二羧酸完全溶解于溶剂中即可。在一个实施方案中，第一温度、第二温度和第三温度彼此相同。在一个实施方案中，第一温度和第二温度相同，且第三温度高于第一温度和第二温度。在一个实施方案中，第二温度高于第一温度，且第三温度高于第一温度和第二温度。当温度过低时，由于溶质溶解度低而需要增加溶剂的用量，进而无法析出固体产品；当温度过高时，发生大量副反应、反应液颜色变深而不能得到式(I)的双二羧酸二氨络铂(II)衍生物。
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～420min。优选的，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、390min或420min。优选地，反应时间可为30min～90min。
在本发明的一个实施方案中，步骤b中的冷却是指冷却至第四温度，所述第四温度低于所述第三温度，且可为1℃～40℃。优选的，所述第四温度可为1℃、2℃、3℃、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)衍生物在溶剂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。优选的，所述第四温度可为1℃～25℃；更优选的，所述第四温度可为10～15℃。
在本发明的一个实施方案中，步骤b中冷却的时间可为0.5h～25h。优选的，所述冷却时间可为0.5h、1h、2h、3h、4h、5h、6h、7h、8h、9h、10h、15h、20h或25h。优选的，所述冷却时间可为1h～20h；更优选的，所述冷却时间可为4h～8h。
在本发明的一个实施方案中，步骤c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、加压过滤、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c中的洗涤包括用溶剂洗涤分离的固体一次或更多次。所述溶剂如本文中所述。
在本发明的一个实施方案中，步骤c中的干燥没有特别限制，只要能将产品中的溶剂去除即可。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“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“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”，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、本发明的方法在反应后无需进行蒸馏浓缩的过程，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44％、纯度高达98％～102％，并且无需进一步纯化，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。CN1311183A的方法需要进行蒸馏浓缩的过程，CN104693245A的方法需要进行蒸馏浓缩或冷冻干燥的过程，后处理麻烦。另外，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。
2、本发明的方法生产周期短，效率显著。与本发明相反，CN104693245A的方法需要长达3-9天的静置过程，生产效率低下。
3、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。
4、本发明的方法由于具有上述优点而特别适合于工业化放大生产。与本发明相反，CN1311183A、CN104693245A和CN106132408A的方法均无法进行放大生产，具体的，CN1311183A和CN104693245A的方法需要进行蒸馏除水或冷冻干燥除水的过程，当进行放大生产时，所用的水量增加而延长了蒸馏或冷冻的时间，不仅降低了生产效率、提高了生产成本，也增加了双环铂变质的风险。事实上，CN104693245A中明确公开了即使是制备几百克的双环铂，也需要在后续步骤中用乙醇洗涤来解决由于长时间浓缩或冷冻而导致的产品 质量变差问题。CN106132408A的悬浮方法在放大之后，由于悬浮的固体量增加而使得反应过程更加难以控制，事实上无法获得品质良好的双环铂产品。因此，CN1311183A、CN104693245A和CN106132408A均没有进行公斤级的放大生产。
5、本发明的方法在溶剂选用水的情况下，可以不使用任何有机溶剂，生产过程环保、产生废液量少。
6、本发明的方法由于其特殊的工艺过程，不需要蒸馏或冷冻干燥的过程，只需要简单的过滤、洗涤、干燥即可获得品质优良的产品，因此生产成本低、经济性高。
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。
制备实施例1：
取顺式-二碘二氨合铂(II)20.0克，加入600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14.1克，反应30分钟后，滤除AgI渣，滤液减压浓缩至剩余约50毫升，冷却至室温，过滤析出的产品，重结晶后60℃干燥即得卡铂11.26克，收率69.88％。
实施例1
取1,1-环丁烷二羧酸32.0克(222.2mmol)，加水260毫升，水浴加热至80℃。加入卡铂10.0克(26.95mmol)，快速搅拌40分钟后10℃冷却8小时，过滤析出的固体，适量纯化水洗涤滤饼，抽干洗涤水后，40℃减压干燥，得双环铂9.32克，收率67.15％，含量99.78％。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(27.96/28.40),H(3.88/4.12),N(5.44/5.55), Pt(37.86/37.78)
2、负离子电喷雾质谱：514(M-1)
3、核磁共振-氢谱(D 2O，500MHz)
测试结果如图1所示，其中各峰的归属情况如下：
Figure PCTCN2018076946-appb-000009
化学位移1.7159-1.7793ppm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1.8281-1.8928ppm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2.3965-2.4288ppm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2.7140-2.7457ppm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4.0497ppm的峰为H e，实际氢核数量为6，为宽的单峰；由于与D 2O的交换作用，图中未出现活泼氢羧基氢核H f的峰。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 PCTCN2018076946-appb-000010
化学位移15.25ppm的峰为C a；化学位移15.39ppm的峰为C h；化学位移28.60ppm的峰为C b；化学位移31.02ppm的峰为C g；化学位移52.93ppm的峰为C c；化学位移56.19ppm的峰为C f；化学位移176.11ppm的峰为C d；化学位移181.85ppm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。
Figure PCTCN2018076946-appb-000011
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1 ml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99.78％。
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，1,1-环丁烷二羧酸的量为7.8克(54.17mmol)。结果得到双环铂8.82克，收率63.54％，含量98.06％。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，1,1-环丁烷二羧酸的量为56.0克(388.9mmol)。结果得到双环铂9.11克，收率65.63％，含量99.12％。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，1,1-环丁烷二羧酸的量为78.0克(541.7mmol)。结果得到双环铂9.19克，收率66.21％，含量98.02％。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，加水400毫升，水浴加热的温度为40℃。结果得到双环铂6.02克，收率44.52％， 含量101.24％。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，加水330毫升，水浴加热的温度为60℃。结果得到双环铂9.21克，收率65.63％，含量98.02％。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，加水180毫升，水浴加热的温度为90℃。结果得到双环铂8.66克，收率62.39％，含量99.51％。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，冷却温度为1℃。结果得到双环铂9.24克，收率66.57％，含量99.89％。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
按照实施例1相同的方法制备实施例9，区别在于，冷却温度为20℃。结果得到双环铂6.54克，收率47.12％，含量99.93％。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
按照实施例1相同的方法制备实施例10，区别在于，冷却温度为30℃。结果得到双环铂5.06克，收率36.46％，含量100.41％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图12所示。
实施例11
按照实施例1相同的方法制备实施例11，区别在于，冷却时间为1小时。结果得到双环铂8.42克，收率60.66％，含量101.84％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图13所示。
实施例12
按照实施例1相同的方法制备实施例11，区别在于，冷却时间为4小时。结果得到双环铂8.92克，收率64.26％，含量100.84％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图14所示。
实施例13
按照实施例1相同的方法制备实施例12，区别在于，冷却时间为20小时。结果得到双环铂8.82克，收率63.54％，含量98.06％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图15所示。
实施例14
取卡铂10.0克，加水280毫升，水浴加热至80℃。加入1,1-环丁烷二羧酸32.0克，快速搅拌40分钟后10℃冷却8小时，过滤析出的固体，适量纯化水洗涤滤饼，抽干洗涤水后，40℃减压干燥，得双环铂8.76克，收率63.11％，含量100.14％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图16所示。
实施例15
取卡铂10.0克，加水300毫升，水浴加热至80℃。加入1,1-环丁烷二羧酸32.0克，快速搅拌40分钟后10℃冷却4小时，过滤析出的固体，适量纯化水洗涤滤饼，抽干洗涤水后，40℃减压干燥，得双环铂9.04克，收率65.13％，含量99.62％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图17所示。
实施例16
取卡铂10.0克，加水300毫升，水浴加热至70℃。加入1,1-环丁烷二羧酸32.0克，快速搅拌40分钟后10℃冷却5小时，过滤析出的固体，适量纯化水洗涤滤饼，抽干洗涤水后，40℃减压干燥，得双环铂9.19克，收率66.21％，含量100.06％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图18所示。
实施例17
取1,1-环丁烷二羧酸4080.0克，加水33000毫升，水浴加热至80℃。加入卡铂1200.0克，快速搅拌80分钟后10℃冷却6小时，过滤析出的固体，适量纯化水洗涤滤饼，抽干洗涤水后，40℃减压干燥，得双环铂1170.8克，收率70.29％，含量99.93％。负离子电喷雾质谱：514(M-1)；X-射线衍射图谱如图19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18
取顺-二氨-1,1-环戊烷二羧酸合铂(II)10.0克(25.97mmol)，加水260毫升，水浴加热至80℃。加入1,1-环戊二羧酸35.1克(222.2mmol)，快速搅拌40分钟后10℃冷却8小时，过滤析出的固体，适量纯化水洗涤滤饼，抽干洗涤水后，40℃减压干燥，得双(1,1-环戊烷二羧酸)二氨合铂(II)7.06克，收率50.07％，含量98.71％。负离子电喷雾质谱：542(M-1)。 1H-NMR(D 2O，500MHz)δ：1.7238-1.7603(5重峰，4H)；1.8792-1.9078(5重峰，4H)；2.3202-2.3512(3重峰，4H)；2.7282-2.7632(3重峰，4H)；4.7686(单峰，6H)。
实施例19
取顺-二氨-1,1-环己烷二羧酸合铂(II)10.0克(25.06mmol)，加水 260毫升，水浴加热至80℃。加入1,1-环己二羧酸38.2克(222.2mmol)，快速搅拌40分钟后10℃冷却8小时，过滤析出的晶体，适量纯化水洗涤滤饼，抽干洗涤水后，40℃减压干燥，得双(1,1-环己烷二羧酸)二氨合铂(II)6.80克，收率47.52％，含量98.44％。负离子电喷雾质谱：570(M-1)。 1H-NMR(D 2O，500MHz)δ：1.7133-1.7467(5重峰，2H)；1.8022-1.8329(5重峰，2H)；1.8933-1.9245(5重峰，4H)；2.0221-2.0352(5重峰，4H)；2.4382-2.4804(3重峰，4H)；2.6248-2.6565(3重峰，4H)；4.2668(单峰，6H)。
比较例1
按照实施例1相同的方法制备比较例1，区别在于，1,1-环丁烷二羧酸的量为3.88克(26.95mmol)，即卡铂与1,1-环丁烷二羧酸的摩尔比为1:1。结果得到产品4.70克，收率33.86％。所得产品的X-射线衍射图谱如图20所示，其在2θ角为11.6°处具有强的卡铂特征峰，在2θ角为10.3°-10.7°处不具有双环铂的特征峰，在2θ角为7.6°、15.1°处具有微弱的双环铂特征峰，表明产品中铂的存在以游离卡铂为主，仅含有少量的双环铂。
比较例2
按照实施例1相同的方法，区别在于，加水450毫升，水浴加热的温度为35℃。结果在10℃冷却8小时之后没有产品析出。
比较例3
按照实施例1相同的方法，区别在于，加水130毫升，水浴加热的温度为94℃。结果发生了大量副反应，反应液变成棕色。
通过以上实施例和比较例，进一步突显了本发明的优点：
1.实施例1-4的实验结果表明，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63％。其中，优选的条件是1,1-环丁烷二羧酸与卡铂的摩尔比为8.2:1。
比较例1的实验结果表明，当1,1-环丁烷二羧酸与卡铂的摩尔比为现有技术(如CN1311183A、CN104693245A)中通常使用的1:1时，并不能获得品质良好的双环铂产品，相反，所得到的产品中铂的存在以游离卡铂为主，仅含有少量的双环铂。
2.实施例1，5-7的实验结果表明，当卡铂与水的质量体积比和加热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44％。其中，优选的条件是卡铂与水的质量体积比为26ml/g，加热温度为60℃。
比较例2和3的实验结果表明，当水的用量过少时，由于需要加热至较高的温度才能将卡铂全部溶解，导致副反应的发生而使得反应液变成棕色，无法得到品质良好的双环铂产品。而当水的用量过多时，即使经过冷却也无法析出固体，因而同样无法得到品质良好的双环铂产品。
3.实施例1，8-10的实验结果表明，降低冷却的温度有助于提高双环铂的收率，但是，降温至一定程度后达到极限，再降低温度只会增加生产时的能耗，增加生产成本。当卡铂与水的质量体积比为26ml/g，优选的结晶温度是10℃。
4.实施例1，11-13的实验结果表明，合适的冷却时间有助于直接获得双环铂含量为98％～102％的品质良好的双环铂产品。然而，过度延长冷却时间并不必然能够增加双环铂产品的收率和含量。其中，优选的条件是冷却8小时。
5.实施例14-16的实验结果表明，对于本发明的制备方法而言，卡铂和1,1-环丁烷二羧酸的加料顺序对于双环铂产品的收率和含量的影响较小。不管是先将卡铂溶解于水中再添加1,1-环丁烷二羧酸，还是先将1,1-环丁烷二羧酸溶解地水中再添加卡铂，均能够以满意的收率直接获得双环铂含量为98％～102％的品质良好的双环铂产品。
6.实施例17的实验结果表明，根据本发明的方法在放大至公斤级以后，仍然能够直接以高收率获得品质良好的双环铂产品。另外，在放大后，双环铂产品在出料、过滤环节的损失比例降低，因此收率甚至比小试时更高。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。
7.实施例18和19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4
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％。
其X-射线衍射图谱如图21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4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5
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22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5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 (30)

  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 PCTCN2018076946-appb-100001
    a.在第一温度下使式(II)的卡铂或卡铂类似物和过量的式(III)的二羧酸之一溶解于溶剂中得到第一溶液，在第二温度下向所述第一溶液中添加式(II)的卡铂或卡铂类似物和过量的式(III)的二羧酸中的另一种，在第三温度下使其反应以获得第二溶液；所述第一温度、第二温度和第三温度彼此相同或不同，各自独立地为38℃～92℃；
    b.冷却所述第二溶液以析出固体；
    其中，
    R 1和R 2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。
  2. 根据权利要求1所述的方法，所述方法还包括：
    c.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或2所述的方法，所述方法还包括按照以下方法制备式(II)的卡铂或卡铂类似物：
    方法1)
    Figure PCTCN2018076946-appb-100002
    使式(IV)的顺式-二卤素离子二氨合铂(II)与式(V)的二羧酸二银盐反应生成式(II)的卡铂或卡铂类似物；或者
    方法2)
    Figure PCTCN2018076946-appb-100003
    使式(IV)的顺式-二卤素离子二氨合铂(II)与硝酸银或硫酸银反应，使生成的中间体与式(VI)的二羧酸金属盐反应生成式(II)的卡铂或卡铂类似物；
    其中，
    R 1、R 2的定义如权利要求1中所定义；
    X表示卤素阴离子，优选Cl、Br或I，更优选I；
    M表示金属，优选Ba、Pb或Na，更优选Ba；并且
    n表示1或2。
  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。
  5. 根据权利要求1-4中任一项所述的方法，其特征在于，所述式 (I)的双二羧酸二氨络铂(II)衍生物为双环铂，所述式(II)的卡铂或卡铂类似物为卡铂，并且所述式(III)的二羧酸为1,1-环丁烷二羧酸。
  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包括：在第一温度下将式(II)的卡铂或卡铂类似物溶解于溶剂中得到第一溶液，在第二温度下向所述第一溶液中添加过量的式(III)的二羧酸，在第三温度下使其反应以获得第二溶液。
  7. 根据权利要求1-5中任一项所述的方法，其特征在于，在第一温度下将过量的式(III)的二羧酸溶解于溶剂中得到第一溶液，在第二温度下向所述第一溶液中添加式(II)的卡铂或卡铂类似物，在第三温度下使其反应以获得第二溶液。
  8. 根据权利要求1-7中任一项所述的方法，其特征在于，第一温度、第二温度和第三温度彼此相同或不同，各自独立地为40℃～90℃；优选地，第一温度、第二温度和第三温度彼此相同或不同，各自独立地为70℃～80℃。
  9. 根据权利要求8所述的方法，其特征在于，所述第一温度、第二温度和第三温度彼此相同。
  10. 根据权利要求8所述的方法，其特征在于，所述第一温度和所述第二温度相同，且所述第三温度高于所述第一温度和所述第二温度。
  11. 根据权利要求8所述的方法，其特征在于，所述第二温度高于所述第一温度，且所述第三温度高于所述第一温度和所述第二温度。
  12. 根据权利要求1-11中任一项所述的方法，其特征在于，所述溶剂选自水、四氢呋喃、二氯甲烷、乙醇、异丙醇、乙酸乙酯、二甲基甲酰胺、1,4-二
    Figure PCTCN2018076946-appb-100004
    烷、丙酮、甲苯、乙酸异丁酯、乙酸异丙酯、氯仿、2-甲氧基乙醇、甲基异丁基酮、甲基叔丁基醚、1,2-二氯乙烷中的一种或更多种。
  13. 根据权利要求12所述的方法，其特征在于，所述溶剂选自水、或者水与乙醇、异丙醇或丙酮的混合溶剂。
  14. 根据权利要求13所述的方法，其特征在于，所述混合溶剂中水与乙醇、异丙醇或丙酮的体积比为(1～10):(10～1)。
  15. 根据权利要求12所述的方法，其特征在于，所述溶剂为水。
  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a中过量的式(III)的二羧酸是指式(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比下限为1.1:1。
  17. 根据权利要求16所述的方法，其特征在于，步骤a中过量的式(III)的二羧酸是指式(III)的二羧酸与式(II)的卡铂或卡铂类似物的摩尔比为2:1～20:1，优选8:1～15:1。
  18. 根据权利要求1-17中任一项所述的方法，其特征在于，步骤a中式(II)卡铂或卡铂类似物与溶剂的质量体积比为15:1ml/g～43:1ml/g，优选18:1ml/g～40:1ml/g，更优选25:1ml/g～30:1ml/g。
  19. 根据权利要求1-18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30min～90min。
  20. 根据权利要求1-19中任一项所述的方法，其特征在于，步骤b中的冷却是指冷却至第四温度，所述第四温度低于所述第三温度，且为1℃～40℃，优选1℃～25℃，更优选10℃～15℃。
  21. 根据权利要求1-20中任一项所述的方法，其特征在于，步骤b中冷却的时间为0.5h～25h，优选1～20h，更优选4～8h。
  22. 根据权利要求2-21中任一项所述的方法，其特征在于，步骤c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。
  23. 根据权利要求2-22中任一项所述的方法，其特征在于，步骤c中所述的洗涤包括用溶剂洗涤分离的固体一次或更多次。
  24. 根据权利要求2-23中任一项所述的方法，其特征在于，步骤c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。
  25. 根据权利要求1-24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。
  26. 根据权利要求1-25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。
  27. 根据权利要求25或26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。
  28. 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。
  29. 根据权利要求28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。
  30. 一种根据权利要求1-27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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