WO2020056582A1 - 一种双二羧酸二氨络铂(ii)衍生物的纯化方法 - Google Patents

一种双二羧酸二氨络铂(ii)衍生物的纯化方法 Download PDF

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WO2020056582A1
WO2020056582A1 PCT/CN2018/106169 CN2018106169W WO2020056582A1 WO 2020056582 A1 WO2020056582 A1 WO 2020056582A1 CN 2018106169 W CN2018106169 W CN 2018106169W WO 2020056582 A1 WO2020056582 A1 WO 2020056582A1
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formula
solution
bis
carboplatin
platinum
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PCT/CN2018/106169
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English (en)
French (fr)
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杨旭清
普绍平
丛艳伟
刘其星
王应飞
张林涛
陈红娟
彭娟
朱泽兵
栾春芳
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昆明贵研药业有限公司
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Priority to PCT/CN2018/106169 priority Critical patent/WO2020056582A1/zh
Priority to CN201880094406.7A priority patent/CN112262123B/zh
Publication of WO2020056582A1 publication Critical patent/WO2020056582A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/76—Metal complexes of amino carboxylic acids
    • 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-based antitumor drugs, and in particular, the present invention relates to a method for purifying a supramolecular platinum-based antitumor drug diaminocarboxylic acid diammonium platinum (II) derivative, and in particular, the present invention relates to Purification method of supramolecular platinum-based antitumor drug bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II).
  • the FDA approved cisplatin as an anti-cancer drug in 1978 it has reduced the mortality of testicular cancer patients from almost 100% to less than 10%. For patients detected early, the cure rate can reach 100%, making cisplatin a Outstanding Representative of Anticancer Drugs.
  • the FDA approved the second-generation platinum-based anticancer drug carboplatin Its anticancer spectrum is similar to cisplatin, but it has good water solubility and mild toxic side effects.
  • diammonium diaminoplatinum (II) derivatives based on the abnormal changes in the spatial configuration of cancer cell DNA and RNA.
  • the typical representative drug is bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II), its English name is Dicycloplatin, and its full name in English is [Bis- (1,1-cyclobutanedicarboxylic acid).
  • diammine platinum (II) the structural formula is:
  • Bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) is usually obtained by reacting carboplatin with 1,1-cyclobutanedicarboxylic acid.
  • the prior art discloses various preparation methods, such as CN1311183A , CN104693245A, CN106132408A, but all have the problems of complicated preparation process and low product purity.
  • Impure bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) product is difficult to improve purity by conventional purification methods. For example, purification of bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) cannot be performed by recrystallization.
  • Bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) in short fatty alcohols such as methanol and ethanol will produce a large amount of carboplatin due to the disproportionation reaction and remain in the product; in addition, bis (1 , 1-Cyclobutanedicarboxylic acid) diammine platinum (II) has limited solubility in water, partial hydrolysis may occur in hot water, and a large amount of carboplatin will also be generated and remain in the product. Therefore, the current preparation method is generally to directly synthesize bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) with a desired purity without purification.
  • the present invention provides a method for purifying diamino complex platinum (II) derivative.
  • the method of the present invention can purify bisaminodiaminoplatinum (II) derivatives, especially bisaminodiaminoplatinum (II) derivatives containing more free carboplatin or carboplatin analogs. And a high-quality diamino complex platinum (II) derivative is obtained in a high yield.
  • the method has simple operation, simple operation, and stable product quality, and is suitable for industrial scale-up production.
  • the method of the present invention uses only water as a solvent, is environmentally friendly, and generates a small amount of waste liquid.
  • the present invention provides a method for purifying a bis-dicarboxylic acid diammine platinum (II) derivative of the formula (I), which may include:
  • a dissolving the dicarboxylic acid of formula (III) in an appropriate amount of water to prepare a first solution having a concentration of 0.05 g / ml to 0.20 g / ml;
  • R 1 and R 2 may be the same or different from each other, and each independently represents hydrogen, C 1-12 hydrocarbyl, halogen, amino, cyano, hydroxyl, carboxyl, acyl, phosphoryl, or phosphorylamino;
  • R 1 and R 2 are connected to each other and together with the carbon atom to which they are attached form a 3-12 membered saturated or unsaturated carbocyclic ring.
  • step a includes: dissolving the dicarboxylic acid of formula (III) in an appropriate amount of water to prepare a solution having a concentration of 0.05 g / ml to 0.20 g / ml, and then adding activated carbon, and stirring Filter to obtain the first solution.
  • step b includes: heating the first solution to 60 ° C. to 85 ° C., and adding the bis dicarboxylic acid diammine platinum (II) derivative of formula (I) to be purified, Mix at 60 ° C to 85 ° C and then perform hot filtration to obtain a second solution.
  • the method may further include:
  • the method may further include the preparation of a bis-dicarboxylic acid diammine platinum (II) derivative of formula (I).
  • the method for preparing the bis-dicarboxylic acid diamino platinum (II) derivative of the formula (I) is not particularly limited as long as the bis-dicarboxylic acid diamino platinum (II) derivative of the formula (I) can be obtained Just fine.
  • a production method known in the art may be used. Specifically, the following method can be used to prepare the bis-dicarboxylic acid diammine platinum (II) derivative of formula (I):
  • Carboplatin or a carboplatin analogue of formula (II) and a dicarboxylic acid of formula (III) are reacted to form a bisdicarboxylic acid diammine platinum (II) derivative of formula (I).
  • the method may further comprise the preparation of carboplatin or a carboplatin analogue of formula (II).
  • the method for preparing carboplatin or a carboplatin analogue of formula (II) is not particularly limited as long as the carboplatin or carboplatin analogue of formula (II) can be obtained.
  • a production method known in the art may be used. Specifically, the following methods can be used to prepare carboplatin or carboplatin analogues of formula (II):
  • R 1 and R 2 are as described herein;
  • X represents halogen
  • M represents metal
  • n 1 or 2.
  • FIG. 1 is an X-ray diffraction spectrum and a data list of a bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) reference with 2% carboplatin added.
  • FIG. 2 is an X-ray diffraction spectrum and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 1.
  • FIG. 2 is an X-ray diffraction spectrum and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 1.
  • FIG. 3 is an X-ray diffraction spectrum and a data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 1.
  • FIG. 3 is an X-ray diffraction spectrum and a data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 1.
  • FIG. 4 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 2.
  • FIG. 4 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 2.
  • FIG. 5 is an X-ray diffraction pattern and a data list of a bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 2.
  • FIG. 5 is an X-ray diffraction pattern and a data list of a bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 2.
  • FIG. 6 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 3.
  • FIG. 6 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 3.
  • FIG. 7 is an X-ray diffraction pattern and data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 3.
  • FIG. 7 is an X-ray diffraction pattern and data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 3.
  • FIG. 8 is an X-ray diffraction spectrum and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 4.
  • FIG. 8 is an X-ray diffraction spectrum and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 4.
  • FIG. 9 is an X-ray diffraction pattern and data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 4.
  • FIG. 9 is an X-ray diffraction pattern and data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 4.
  • FIG. 10 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 5.
  • FIG. 10 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 5.
  • Example 11 is an X-ray diffraction spectrum and a data list of a bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 5.
  • FIG. 12 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 6.
  • FIG. 12 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 6.
  • FIG. 13 is an X-ray diffraction pattern and data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 6.
  • FIG. 13 is an X-ray diffraction pattern and data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 6.
  • Example 14 is an X-ray diffraction pattern and data list of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified in Example 7.
  • FIG. 15 is an X-ray diffraction pattern and data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 7.
  • FIG. 15 is an X-ray diffraction pattern and data list of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) product of Example 7.
  • the invention provides a method for purifying diamino complex platinum (II) derivative.
  • the method of the present invention can purify bisaminodiaminoplatinum (II) derivatives, especially bisaminodiaminoplatinum (II) derivatives containing more free carboplatin or carboplatin analogs. And a high-quality diamino complex platinum (II) derivative is obtained in a high yield.
  • the method has simple operation, simple operation, and stable product quality, and is suitable for industrial scale-up production.
  • the method of the present invention uses only water as a solvent, is environmentally friendly, and generates a small amount of waste liquid.
  • a dissolving the dicarboxylic acid of formula (III) in an appropriate amount of water to prepare a first solution having a concentration of 0.05 g / ml to 0.20 g / ml;
  • R 1 and R 2 may be the same or different from each other, and each independently represents hydrogen, C 1-12 hydrocarbyl, halogen, amino, cyano, hydroxyl, carboxyl, acyl, phosphoryl, or phosphorylamino;
  • R 1 and R 2 are connected to each other and together with the carbon atom to which they are attached form a 3-12 membered saturated or unsaturated carbocyclic ring.
  • step a includes: dissolving the dicarboxylic acid of formula (III) in an appropriate amount of water to prepare a solution having a concentration of 0.05 g / ml to 0.20 g / ml, and then adding activated carbon, and stirring Filter to obtain the first solution.
  • step b includes: heating the first solution to 60 ° C. to 85 ° C., and adding the bis dicarboxylic acid diammine platinum (II) derivative of formula (I) to be purified, Mix at 60 ° C to 85 ° C and then perform hot filtration to obtain a second solution.
  • the method may further include:
  • the method may further include the preparation of a bis-dicarboxylic acid diammine platinum (II) derivative of formula (I).
  • the method for preparing the bis-dicarboxylic acid diamino platinum (II) derivative of the formula (I) is not particularly limited as long as the bis-dicarboxylic acid diamino platinum (II) derivative of the formula (I) can be obtained Just fine.
  • a production method known in the art may be used. Specifically, the following method can be used to prepare the bis-dicarboxylic acid diammine platinum (II) derivative of formula (I):
  • Carboplatin or a carboplatin analogue of formula (II) and a dicarboxylic acid of formula (III) are reacted to form a bisdicarboxylic acid diammine platinum (II) derivative of formula (I).
  • the method may further comprise the preparation of carboplatin or a carboplatin analogue of formula (II).
  • the method for preparing carboplatin or a carboplatin analogue of formula (II) is not particularly limited as long as the carboplatin or carboplatin analogue of formula (II) can be obtained.
  • a production method known in the art may be used. Specifically, the following methods can be used to prepare carboplatin or carboplatin analogues of formula (II):
  • R 1 and R 2 are as described herein;
  • X represents halogen
  • M represents metal
  • n 1 or 2.
  • R 1 and R 2 are connected to each other and together with the carbon atoms to which they are attached form a 3-12 membered saturated or unsaturated carbocyclic ring, preferably cyclopropane, cyclobutane, cyclopentane Alkane, cyclohexane or cycloheptane, more preferably cyclobutane.
  • the bisdicarboxylic acid diammine platinum (II) derivative of the formula (I) may be bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) ),
  • the dicarboxylic acid of the formula (III) may be 1,1-cyclobutanedicarboxylic acid.
  • the carboplatin or carboplatin analog of formula (II) may be carboplatin.
  • said X represents Cl, Br or I, preferably Cl or I.
  • said M represents Ba, Pb or Na, preferably Ba.
  • the bis-dicarboxylic acid diamino complex platinum (II) derivative of the formula (I) to be purified in step a is not particularly limited as long as purification is required.
  • the bis-dicarboxylic acid diammine platinum (II) derivative of formula (I) to be purified may have a color, such as yellow, light yellow, off-white, and the like.
  • the bis-dicarboxylic acid diammine platinum (II) derivative of the formula (I) to be purified may be crystalline, powder, massive or pasty.
  • the content of the bisaminodiamine platinum (II) derivative of the formula (I) to be purified is not particularly limited.
  • the carboplatin of carboplatin of formula (II) or carboplatin analog of carboplatin or carboplatin analog of formula (II) in the bisaminodiaminoplatinum platinum (II) derivative of formula (I) to be purified is determined by X-ray diffraction pattern. The content is less than about 2.0% by weight.
  • the concentration of the dicarboxylic acid of formula (III) in step a may be 0.05 g / ml to 0.20 g / ml.
  • the concentration of the dicarboxylic acid of the formula (III) may preferably be 0.05 g / ml, 0.06 g / ml, 0.07 g / ml, 0.08 g / ml, 0.09 g / ml, 0.10 g / ml, 0.11 g / ml, 0.12 g / ml, 0.13 g / ml, 0.14 g / ml, 0.15 g / ml, 0.16 g / ml, 0.17 g / ml, 0.18 g / ml, 0.19 g / ml or 0.20 g / ml.
  • the concentration of the dicarboxylic acid of the formula (III) may be 0.08 g / ml to 0.16 g / ml; more preferably, the concentration of the dicarboxylic acid of the formula (III) may be 0.11 g / ml to 0.12 g / ml .
  • the temperature at which the first solution is configured in step a may be 20 ° C to 50 ° C.
  • the temperature for preparing the first solution may be preferably 20 ° C, 21 ° C, 22 ° C, 23 ° C, 24 ° C, 25 ° C, 26 ° C, 27 ° C, 28 ° C, 29 ° C, 30 ° C, 31 ° C, 32 ° C, 33 ° C, 34 ° C, 35 ° C, 36 ° C, 37 ° C, 38 ° C, 39 ° C, 40 ° C, 41 ° C, 42 ° C, 43 ° C, 44 ° C, 45 ° C, 46 ° C, 47 ° C, 48 ° C, 49 ° C Or 50 ° C.
  • the temperature for preparing the first solution may be 25 ° C to 45 ° C; more preferably, the temperature for preparing the first solution may be 30 ° C to 40 ° C. In one embodiment, the temperature at which the first solution is formulated may be room temperature.
  • the mass ratio of the dicarboxylic acid of formula (III) to the activated carbon in step a may be 1: 0.01 to 1: 0.20.
  • the mass ratio of the dicarboxylic acid to the activated carbon of the formula (III) may preferably be 1: 0.01, 1: 0.02, 1: 0.03, 1: 0.04, 1: 0.05, 1: 0.06, 1: 0.07, 1: 0.08, 1: 0.09, 1: 0.10, 1: 0.11, 1: 0.12, 1: 0.13, 1: 0.14, 1: 0.15, 1: 0.16, 1: 0.17, 1: 0.18, 1: 0.19 or 1: 0.20.
  • the mass ratio of the dicarboxylic acid to the activated carbon of the formula (III) may be 1: 0.02 to 1: 0.08; more preferably, the mass ratio of the dicarboxylic acid to the activated carbon of the formula (III) may be 1: 0.03 to 1 : 0.06.
  • the mixing in step a is not particularly limited, and mixing methods well known to those skilled in the art may be adopted, and specifically, such as stirring, such as mechanical stirring or magnetic stirring.
  • the mass-volume ratio of the bis-dicarboxylic acid diamino complex platinum (II) derivative of the formula (I) to the first solution to be purified in step b may be 1: 5 g / ml to 1 : 20g / ml.
  • the mass-volume ratio of the bis-dicarboxylic acid diammine platinum (II) derivative of the formula (I) to be purified to the first solution may preferably be 1: 5 g / ml, 1: 6 g / ml, 1: 7 g / ml, 1: 8g / ml, 1: 9g / ml, 1: 10g / ml, 1: 11g / ml, 1: 12g / ml, 1: 13g / ml, 1: 14g / ml, 1: 15g / ml, 1: 16g / ml, 1: 17g / ml, 1: 18g / ml, 1: 19g / ml or 1: 20g / ml.
  • the mass-volume ratio of the bis-dicarboxylic acid diamino complex platinum (II) derivative of the formula (I) to the first solution to be purified may be 1: 8 g / ml to 1:16 g / ml; more preferably, The mass-volume ratio of the bis-dicarboxylic acid diammine platinum (II) derivative of the formula (I) to be purified to the first solution may be 1:10 g / ml to 1:12 g / ml.
  • the first solution may be heated to 60 ° C to 85 ° C in step b.
  • the first solution can be heated to 60 ° C, 61 ° C, 62 ° C, 63 ° C, 64 ° C, 65 ° C, 66 ° C, 67 ° C, 68 ° C, 69 ° C, 70 ° C, 71 ° C, 72 ° C, 73 C, 74C, 75C, 77C, 77C, 78C, 79C, 80C, 81C, 82C, 83C, 84C or 85C.
  • the first solution may be heated to 65 ° C to 80 ° C; more preferably, the first solution may be heated to 70 ° C to 75 ° C.
  • the mixing may be performed at 60 ° C to 85 ° C in step b.
  • it is preferably at 60 ° C, 61 ° C, 62 ° C, 63 ° C, 64 ° C, 65 ° C, 66 ° C, 67 ° C, 68 ° C, 69 ° C, 70 ° C, 71 ° C, 72 ° C, 73 ° C, 74 ° C
  • the mixing was performed at 75 ° C, 77 ° C, 77 ° C, 78 ° C, 79 ° C, 80 ° C, 81 ° C, 82 ° C, 83 ° C, 84 ° C, or 85 ° C.
  • the mixing may be performed at 65 ° C to 80 ° C; more preferably, the mixing may be performed at 70 ° C to 75 ° C.
  • the cooling in step c comprises a process of reducing the temperature by any means.
  • the cooling in step c comprises cooling the second solution to an end temperature of crystallization.
  • the cooling in step c comprises continuously cooling the second solution to the crystallization endpoint temperature.
  • the cooling in step c comprises stepwise cooling the second solution to the crystallization endpoint temperature.
  • the crystallization endpoint temperature may be 1 ° C to 10 ° C.
  • the crystallization endpoint temperature may be preferably 1 ° C, 2 ° C, 3 ° C, 4 ° C, 5 ° C, 6 ° C, 7 ° C, 8 ° C, 9 ° C, or 10 ° C.
  • the crystallization end temperature may be 2 ° C to 8 ° C; more preferably, the crystallization end temperature may be 4 ° C to 6 ° C.
  • the time for cooling the second solution to the crystallization endpoint temperature may be 1 min to 180 min.
  • the time for cooling the second solution to the end temperature of crystallization may be preferably 1min, 5min, 10min, 15min, 20min, 25min, 30min, 35min, 40min, 45min, 50min, 55min, 60min, 65min, 70min, 75min, 80min, 85min, 90min, 95min, 100min, 105min, 110min, 115min, 120min, 125min, 130min, 135min, 140min, 145min, 150min, 155min, 160min, 165min, 170min, 175min, 180min.
  • the time for cooling the second solution to the crystallization end temperature may be 30min to 120min; more preferably, the time for cooling the second solution to the crystallization end temperature may be 60min to 90min.
  • the continuous cooling includes applying a continuous cooling environment to the second solution.
  • said continuous cooling comprises moving the second solution to an environment having a crystallization endpoint temperature.
  • the stepwise cooling includes maintaining the second solution at one or more temperatures before the crystallization end temperature for an appropriate time during the continuous cooling process.
  • the one or more temperatures refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 temperatures.
  • the temperature difference between any two adjacent temperatures may be 1 ° C to 30 ° C.
  • the temperature difference between any two adjacent temperatures may be preferably 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, 16 °C, 17 °C, 18 °C, 19 °C, 20 °C, 21 °C, 22 °C, 23 °C, 24 °C, 25 °C, 26 °C, 27 °C, 28 °C, 29 ° C or 30 ° C.
  • the temperature difference between the crystallization endpoint temperature and a temperature adjacent thereto may be any of the temperature differences defined above.
  • the time maintained at each temperature may be the same or different, and each may independently be from 1 min to 120 min. Among them, the maintaining time at each temperature may be the same or different, and each independently may be 1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min, 10min, 11min, 12min, 13min, 14min, 15min, 16min, 17min, 18min, 19min, 20min, 21min, 22min, 23min, 24min, 25min, 26min, 27min, 28min, 29min, 30min, 31min, 32min, 33min, 34min, 35min, 36min, 37min, 38min, 39min, 40min, 41min, 42min, 43min, 44min, 45min, 46min, 47min, 48min, 49min, 50min, 51min, 52min, 53min, 54min, 55min, 56min, 57min,
  • the cooling in step c further comprises maintaining the second solution to an end temperature of crystallization for an appropriate period of time.
  • the time maintained at the crystallization endpoint temperature may be from 1 min to 180 min.
  • the time maintained at the crystallization end temperature may preferably be 1min, 5min, 10min, 15min, 20min, 25min, 30min, 35min, 40min, 45min, 50min, 55min, 60min, 65min, 70min, 75min, 80min, 85min, 90min , 95min, 100min, 105min, 110min, 115min, 120min, 125min, 130min, 135min, 140min, 145min, 150min, 155min, 160min, 165min, 170min, 175min, 180min.
  • the time maintained at the crystallization end temperature may be 30 minutes to 120 minutes; more preferably, the time maintained at the crystallization end temperature may be 60 minutes to 90 minutes.
  • the manner of separation in step d 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 used, including but not limited to: filtration (including atmospheric filtration, pressure filtration, reduced pressure filtration), membrane separation, sedimentation (including centrifugal separation, gravity natural sedimentation), A combination of two or more kinds is preferred, such as pressure filtration or pressure reduction filtration.
  • the washing in step d comprises washing the separated solid one or more times with water.
  • the temperature of the washing water may be 0 ° C to 25 ° C.
  • the temperature of the washing water may be 0 ° C, 5 ° C, 10 ° C, 15 ° C, 20 ° C, or 25 ° C.
  • the washing water may be ice water.
  • the temperature of the washing water may be normal temperature.
  • the drying in step d is not particularly limited as long as the solvent in the product can be removed.
  • any drying method known in the art may be used. Specifically, the following methods can be adopted, including but not limited to one or more combinations of atmospheric pressure drying, reduced pressure drying, spray drying, microwave drying, and far infrared drying, preferably reduced pressure drying, and more preferably Dry under reduced pressure at high temperature.
  • content refers to weight content unless otherwise specified.
  • first solution and “second solution” described herein, unless otherwise specified, only distinguish between solutions appearing in different processes, and do not place any restrictions on the solutions, let alone represent between them Interrelationship.
  • hydrocarbyl refers to a straight-chain, branched-chain or cyclic hydrocarbon group which may contain 1-20 carbon atoms, preferably contains 1-10 carbon atoms, more preferably contains 1-6 carbon atoms, may include Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or any combination thereof.
  • hydrocarbon groups may include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, and various isomers thereof.
  • 3-12 membered saturated or unsaturated carbocyclic ring refers to a saturated or unsaturated carbocyclic ring containing 3-12, preferably 3-7 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 as used herein means fluorine, chlorine, bromine or iodine.
  • the content of carboplatin or cisplatin in qualified carboplatin and cisplatin products should be 98.0% to 102.0%, although bis (1,1-cyclobutanedicarboxylic acid) has not been specified in the Chinese Pharmacopoeia )
  • the quality standard of diaminoplatinum (II) but referring to the quality standards of carboplatin and cisplatin products, it is considered that the content of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) is 98% ⁇
  • the product at 102% is a qualified product of good quality, which is consistent with the conventional recognition in the art.
  • CN104122280A reports that by X-ray diffraction, the diffraction pattern is analyzed to determine whether the sample contains a double (1,1-, 2-10 angle at 10.3 ° -10.7 ° and / or a 2 ⁇ angle at 11.4 ° -11.7 °.
  • Cyclobutanedicarboxylic acid) diammine platinum (II) was determined by an external standard method.
  • CN104122280A clearly states that bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) is present in It cannot exist in the form of its supramolecular hydrogen bond cluster collective under the conditions of liquid chromatography separation, and it completely dissociates into carboplatin and cyclosuccinic acid, so it cannot be directly determined by high performance liquid chromatography. Content of carboxylic acid) diammine platinum (II).
  • the content of bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) in the product is characterized by the following method:
  • step 2) the characteristic peak is not obvious at the 2 ⁇ angle of 11.4 ° -11.7 °, and the characteristic peak is displayed but the peak intensity does not exceed the peak intensity of the peak of the reference at the 2 ⁇ angle of 11.4 ° -11.7 °.
  • the content of carboplatin was determined by high performance liquid chromatography;
  • a bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) reference containing carboplatin at about 2.0 wt% can be prepared by the following method: taking bis (1,1-cyclobutanedicarboxylate) About 1 part by weight of acid) diaminoplatinum (II) reference substance and about 0.02 parts by weight of carboplatin reference substance, precisely weighed and mixed to obtain bis (1,1-cyclobutane) containing about 2.0 wt% carboplatin Alkanedicarboxylic acid) diamine platinum (II) reference.
  • the content of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) according to the present invention is converted by the carboplatin content measured by liquid chromatography.
  • the converted double (( The content of 1,1-cyclobutanedicarboxylic acid) diammine platinum (II) is an estimated content, and the calculated bis (1,1-cyclobutane) is only obtained if the carboplatin is not contained in the product at all.
  • the content of alkanedicarboxylic acid) diammine platinum (II) is its actual content. Although it is not necessarily the actual content of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II), The actual content of II) is close, and the error is within an acceptable range, so it can still be used to characterize the quality of bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) products. Studies have shown that when the content of bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) measured according to the above method is 98% to 102%, the obtained product is a qualified product with good quality.
  • the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) The content of free carboplatin exceeds the allowable range, and the product has no practical value. However, carboplatin content can still be determined by high performance liquid chromatography. The measured carboplatin content is multiplied by 1.388 to obtain the bis (1,1-cyclobutanedicarboxylic acid) diamine compound converted from the carboplatin content.
  • the platinum (II) content is a rough estimate of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) and carboplatin content in the product.
  • the bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) purified according to the method of the present invention has a noticeable change in the appearance of the product, and the color changes from yellow, light yellow, off-white, etc. to white, and / Or morphology changed from powder to crystal.
  • a dark, powdery bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) can be purified into white crystals. The improvement in color and / or morphology indicates a significant improvement in product quality.
  • the X-ray diffraction pattern shows that the product does not decompose like the prior art recrystallization method after purification according to the method of the present invention.
  • Carboplatin impurities appear. That is, the method according to the present invention can be used for bis (1,1) without causing a decrease in the content of bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) and the occurrence of a large amount of carboplatin. -Cyclobutanedicarboxylic acid) diamine platinum (II) content and / or carboplatin content qualified products for further purification.
  • the purification method according to the present invention can be implemented under various conditions, and can obtain bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) of good quality as white crystals in a high yield. It can also be used to purify large batches of substandard bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II).
  • the method of the present invention uses only water as a solvent, and does not use any organic solvent.
  • the production process is environmentally friendly and the amount of waste liquid generated is small.
  • the method has simple operation, simple operation, and stable product quality, and is suitable for industrial scale-up production.
  • Examples 2-6 were performed in the same manner as in Example 1, and Examples 1-6 are summarized in Table 1 below.
  • Phenylhexyl silanized silica gel as a filler for example, Waters XBridgeTM Shield Phenyl 5 ⁇ m 4.6 ⁇ 250mm
  • [tetrabutylammonium hydrogen sulfate buffer solution take 8.5g of tetrabutylammonium hydrogen sulfate, Add 80ml of water to dissolve, add 3.4ml of phosphoric acid, and adjust the pH value to 7.5 ⁇ 0.05 with 10mol / L sodium hydroxide solution]]-water-acetonitrile (20: 880: 100) as the mobile phase
  • detection wavelength is 220nm, column temperature 30 °C, flow rate 1.0ml / min, with the elution of 1,1-cyclobutanedicarboxylic acid peak as the cut-off time.
  • the number of theoretical plates calculated from the carboplatin peak is not less than 3000,1,1-cyclobutane
  • Assay method Take an appropriate amount of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) product, add mobile phase to dissolve and quantitatively dilute it to make a solution containing about 0.2mg per 1ml, as a test solution ( Use a new system), take an appropriate amount of 1,1-cyclobutanedicarboxylic acid, add the mobile phase to dissolve and quantitatively dilute it to make a solution containing about 0.3mg per 1ml, as a positioning solution; take an appropriate amount of carboplatin reference substance to dissolve in mobile phase And quantitatively diluted to make a solution containing about 0.2mg per 1ml, as a reference solution (provisional new).
  • test results show that the purification method according to the present invention can effectively improve the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) content with unqualified content. ) The quality of diamine platinum (II) products.
  • Figure 1 is bis (1,1-cyclobutanedicarboxylic acid) with 2% carboplatin added X-ray diffraction pattern of diammonium platinum (II) reference and its data list.
  • the characteristic platinum peak of the graphics card at 11.4 ° -11.7 ° see CN104122280A
  • -Cyclobutanedicarboxylic acid) diamino platinum (II) characteristic peak with a peak intensity of 0.65.
  • Figure 2 Figure 4, Figure 6, Figure 8, Figure 10, and Figure 12 are X-ray diffraction patterns and data of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified
  • the stronger carboplatin characteristic peaks of the reference relative to the bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) characteristic peak at 7.4 ° -7.8 °
  • suggest that these bis The content of carboplatin in 1,1-cyclobutanedicarboxylic acid) diammine platinum (II) is not qualified.
  • the characteristic carboplatin peak at 11.4 ° -11.7 ° in the obtained purified bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) substantially disappeared, compared to
  • the peak intensity of the characteristic peak of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) at 7.4 ° -7.8 ° is reduced to below 0.65, as shown in Fig. 3, Fig. 5, Fig. 7, Fig. 9, Figure 11 and Figure 13. This indicates that the carboplatin content in bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) is reduced to an acceptable range after purification according to the method of the present invention.
  • the bis (1,1-cyclobutanedicarboxylic acid) diamine in Examples 1-3 and 5-6 The content of platinum (II) is lower than 98%, or higher than 102%, and the content of the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) is unqualified. After purification according to the method of the present invention, the contents all fall within the acceptable range of 98% to 102%. This indicates that after purification according to the method of the present invention, the content of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) can be changed from apparently unacceptable to acceptable.
  • the bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum to be purified in Examples 1-6 has a yellow, pale yellow, off-white or white powdery appearance, and after purification according to the method of the present invention, the resulting purified bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) is obtained Both have a white crystalline appearance, which means a significant improvement in product quality. This indicates that the product quality of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) can be improved after purification according to the method of the present invention.
  • Example 4 Although the content of bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) in Example 4 is acceptable, it can still be further purified by the method according to the present invention, such as reducing the content of carboplatin and improving Product appearance, which is further illustrated by the following Examples 7-11.
  • Examples 7-11 were carried out in the same manner as in Example 1, except that the bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified was different. Examples 7-11 are summarized below In Table 2. In addition, as a representative, the bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) to be purified used in Example 7 and the purified bis (1,1-cyclobutanedicarboxylic acid) obtained The X-ray diffraction pattern of the acid) diammonium platinum (II) and its data list are shown in Figs. 14 and 15, respectively.
  • test results show that the purification method according to the present invention can also effectively improve the overall quality of bis (1,1-cyclobutanedicarboxylic acid) diaminoplatinum (II) products with qualified content.
  • FIG. 14 shows that Carboplatin is included, but, from its appearance, the bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II) crystal has a pale yellow color, indicating that it may also contain certain impurities.
  • Examples 12-13 are summarized in Table 3 below.
  • Example 15 was carried out in the same manner as in Example 14. The difference was that the filtrate was directly moved into a 5 ° C environment after passing nitrogen gas, and slowly crystallized, filtered after 20 minutes, rinsed once with 10 ml of ice water, dried, and the cake was dried at 40 ° C to Constant weight.
  • Example 16 was carried out in the same manner as in Example 14, except that the filtrate was vented to nitrogen and moved to room temperature for 15 minutes and then cooled to 5 ° C. The mixture was slowly stirred for crystallization, filtered after 120 minutes, washed with 10 ml of ice water, and drained. The cake was dried to constant weight at 40 ° C.
  • the filtrate was purged with nitrogen and cooled to 35 ° C for 5min, then cooled to 25 ° C for 10min, then moved to 15 ° C for 10min, and finally moved to 5 ° C and stopped nitrogen flow, cooled for 60min, and slowly at this temperature After stirring for 60 minutes, the solution was filtered, washed once with 20 ml of ice water, dried, and the filter cake was dried at 40 ° C to constant weight.
  • Example 20 was carried out in the same manner as in Example 19, except that the filtrate was blown into nitrogen and then cooled to 35 ° C for 20min, then cooled to 25 ° C for 20min, then to 15 ° C for 20min, and finally to 5 °C and stop the nitrogen flow, cool for 60min, stir slowly at this temperature for 60min, then filter, 20ml ice water once, suck dry, and dry the filter cake to constant weight at 40 °C.
  • test results of Examples 12-25 show that the purification method according to the present invention can be implemented under various conditions, and can obtain bis (1,1-cyclobutanedicarboxylic acid) diamine in the form of white crystals in a higher yield.
  • Platinum (II) products and can also be used to purify large batches of substandard bis (1,1-cyclobutanedicarboxylic acid) diamine platinum (II).

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Abstract

双二羧酸二氨络铂衍生物的纯化方法以及由该方法获得的产品，纯化方法包括：将二羧酸溶于水中获得第一溶液，加热，加入待纯化的双二羧酸二氨络铂衍生物，然后热过滤获得第二溶液，冷却第二溶液，析出固体。

Description

一种双二羧酸二氨络铂(II)衍生物的纯化方法 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)衍生物的纯化方法，特别地，本发明涉及超分子铂类抗肿瘤药物双(1,1-环丁烷二羧酸)二氨合铂(II)的纯化方法。
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(1,1-环丁烷二羧酸)二氨合铂(II)，其英文名为Dicycloplatin，英文全称为[Bis-(1,1-cyclobutane dicarboxylic acid)]diammine platinum(II)，结构式为：
Figure PCTCN2018106169-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(1,1-环丁烷二羧酸)二氨合铂(II)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，例如CN1311183A、CN104693245A、CN106132408A，但均存在制备工艺复杂、产品纯度不高的问题。而不纯的双(1,1-环丁烷二羧酸)二氨合铂(II)产品难以通过常规纯化方法提高纯度。例如，双(1,1-环丁烷二羧酸)二氨合铂(II)的纯化无法通过重结晶进行。双(1,1-环丁烷二羧酸)二氨合铂(II)在较短脂肪醇如甲醇、乙醇中会由于歧化反应而产生大量卡铂并留在产物中；另外，双(1,1-环丁烷二羧酸)二氨合铂(II)在水中溶解度有限，在热水中则可能会发生部分水解，同样也会产生大量卡铂并留在产物中。因此，目前的制备方法通常是不经纯化地直接合成得到具有所需纯度的双(1,1-环丁烷二羧酸)二氨合铂(II)。
而这存在一个严重的问题，如果直接合成得到的双(1,1-环丁烷二羧酸)二氨合铂(II)中卡铂含量超标，则该批次的双(1,1-环丁烷二羧酸)二氨合铂(II)不能通过纯化获得合格的双(1,1-环丁烷二羧酸)二氨合铂(II)产品，只能舍弃。这导致了双(1,1-环丁烷二羧酸)二氨合铂(II)获取成本的增加，也造成极大的浪费。
因此，有必要开发一种能够简便易行、环保高效的可对双二羧酸二氨络铂(II)衍生物，例如游离卡铂或卡铂类似物含量过高的粗二羧酸二氨络铂(II)衍生物产品进行纯化的方法。
发明内容
为了克服现有技术中存在的缺陷，本发明提供了一种双二羧酸二氨络铂(II)衍生物的纯化方法。本发明的方法能够对双二羧酸二氨络铂(II)衍生物，特别是包含较多游离卡铂或卡铂类似物的双二羧酸二氨络铂(II)衍生物进行纯化，并以高收率获得品质良好的双二羧酸二氨络铂(II)衍生物。所述方法操作简单、简便易行，产品质量稳定，适合工业化放大生产。本发明的方法仅用水作为溶剂，对环境 友好，产生废液量少。
因此，本发明提供了一种式(I)的双二羧酸二氨络铂(II)衍生物的纯化方法，所述方法可包括：
a.将式(III)的二羧酸溶解于适量的水中，配制成浓度为0.05g/ml～0.20g/ml的第一溶液；
b.将所述第一溶液加热至60℃～85℃，加入待纯化的式(I)的双二羧酸二氨络铂(II)衍生物，然后进行热过滤以获得第二溶液；
c.冷却所述第二溶液以析出固体；
Figure PCTCN2018106169-appb-000002
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。
在本发明的一个实施方案中，步骤a包括：将式(III)的二羧酸溶解于适量的水中，配制成浓度为0.05g/ml～0.20g/ml的溶液，然后加入活性炭，搅拌后过滤以获得第一溶液。
在本发明的一个实施方案中，步骤b包括：将所述第一溶液加热至60℃～85℃，加入待纯化的式(I)的双二羧酸二氨络铂(II)衍生物，在60℃～85℃下混合，然后进行热过滤以获得第二溶液。
所述方法还可包括：
d.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(I)的双二羧酸二氨络铂(II)衍生物的制备。其中，式(I)的双二羧酸二氨络铂(II)衍生物的制备方法没有特别限制，只要能获得所述式(I)的双二羧酸 二氨络铂(II)衍生物即可。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(I)的双二羧酸二氨络铂(II)衍生物：
Figure PCTCN2018106169-appb-000003
使式(II)的卡铂或卡铂类似物和式(III)的二羧酸反应以生成式(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，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 PCTCN2018106169-appb-000004
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 PCTCN2018106169-appb-000005
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为添加有2％卡铂的双(1,1-环丁烷二羧酸)二氨合铂(II)对照品的X-射线衍射图谱及其数据列表。
图2为实施例1中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的X-射线衍射图谱及其数据列表。
图3为实施例1的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的X-射线衍射图谱及其数据列表。
图4为实施例2中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的X-射线衍射图谱及其数据列表。
图5为实施例2的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的X-射线衍射图谱及其数据列表。
图6为实施例3中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的 X-射线衍射图谱及其数据列表。
图7为实施例3的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的X-射线衍射图谱及其数据列表。
图8为实施例4中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的X-射线衍射图谱及其数据列表。
图9为实施例4的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的X-射线衍射图谱及其数据列表。
图10为实施例5中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的X-射线衍射图谱及其数据列表。
图11为实施例5的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的X-射线衍射图谱及其数据列表。
图12为实施例6中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的X-射线衍射图谱及其数据列表。
图13为实施例6的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的X-射线衍射图谱及其数据列表。
图14为实施例7中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的X-射线衍射图谱及其数据列表。
图15为实施例7的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的X-射线衍射图谱及其数据列表。
具体实施方式
本发明提供了一种双二羧酸二氨络铂(II)衍生物的纯化方法。本发明的方法能够对双二羧酸二氨络铂(II)衍生物，特别是包含较多游离卡铂或卡铂类似物的双二羧酸二氨络铂(II)衍生物进行纯化，并以高收率获得品质良好的双二羧酸二氨络铂(II)衍生物。所述方法操作简单、简便易行，产品质量稳定，适合工业化放大生产。本发明的方法仅用水作为溶剂，对环境友好，产生废液量少。
根据本发明的一个实施方案，提供了一种式(I)的双二羧酸二氨络铂(II)衍生物的纯化方法，所述方法可包括：
a.将式(III)的二羧酸溶解于适量的水中，配制成浓度为0.05g/ml～0.20g/ml的第一溶液；
b.将所述第一溶液加热至60℃～85℃，加入待纯化的式(I)的双二羧酸二氨络铂(II)衍生物，然后进行热过滤以获得第二溶液；
c.冷却所述第二溶液以析出固体；
Figure PCTCN2018106169-appb-000006
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。
在本发明的一个实施方案中，步骤a包括：将式(III)的二羧酸溶解于适量的水中，配制成浓度为0.05g/ml～0.20g/ml的溶液，然后加入活性炭，搅拌后过滤以获得第一溶液。
在本发明的一个实施方案中，步骤b包括：将所述第一溶液加热至60℃～85℃，加入待纯化的式(I)的双二羧酸二氨络铂(II)衍生物，在60℃～85℃下混合，然后进行热过滤以获得第二溶液。
所述方法还可包括：
d.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(I)的双二羧酸二氨络铂(II)衍生物的制备。其中，式(I)的双二羧酸二氨络铂(II)衍生物的制备方法没有特别限制，只要能获得所述式(I)的双二羧酸二氨络铂(II)衍生物即可。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(I)的双二羧酸二氨络铂(II)衍生物：
Figure PCTCN2018106169-appb-000007
使式(II)的卡铂或卡铂类似物和式(III)的二羧酸反应以生成式(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，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 PCTCN2018106169-appb-000008
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 PCTCN2018106169-appb-000009
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(1,1-环丁烷二羧酸)二氨合铂(II)，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，所述式(II)的卡铂或卡铂类似物可为卡铂。
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，步骤a中待纯化的式(I)的双二羧酸二氨络铂(II)衍生物没有特别限制，只要有需要进行纯化即可。在一个实施方案中，待纯化的式(I)的双二羧酸二氨络铂(II)衍生物可具有颜色，如黄色、浅黄色、灰白色等。在一个实施方案中，待纯化的式(I)的双二羧酸二氨络铂(II)衍生物可为晶体、粉末、块状或者糊状。在一个实施方案中，待纯化的式(I)的双二羧酸二氨络铂(II)衍生物中式(I)的双二羧酸二氨络铂(II)衍生物的含量没有特别限制，可为低于98％、98％～102％或者高于102％。在一个实施方案中，待纯化的式(I)的双二羧酸二氨络铂(II)衍生物中由X-射线衍射图谱测得的式(II) 的卡铂或卡铂类似物的含量小于约2.0wt％。在一个实施方案中，待纯化的式(I)的双二羧酸二氨络铂(II)衍生物的X-射线衍射图谱中，相对于式(I)的双二羧酸二氨络铂(II)衍生物的特征峰的式(II)的卡铂或卡铂类似物的特征峰强度小于含2.0wt％的式(II)的卡铂或卡铂类似物的式(I)的双(1,1-环丁烷二羧酸)二氨合铂(II)对照品的所述强度。在本发明的一个实施方案中，步骤a中式(III)的二羧酸的浓度可为0.05g/ml～0.20g/ml。其中，式(III)的二羧酸的浓度可优选为0.05g/ml、0.06g/ml、0.07g/ml、0.08g/ml、0.09g/ml、0.10g/ml、0.11g/ml、0.12g/ml、0.13g/ml、0.14g/ml、0.15g/ml、0.16g/ml、0.17g/ml、0.18g/ml、0.19g/ml或0.20g/ml。优选地，式(III)的二羧酸的浓度可为0.08g/ml～0.16g/ml；更优选地，式(III)的二羧酸的浓度可为0.11g/ml～0.12g/ml。
在本发明的一个实施方案中，步骤a中配置第一溶液的温度可为20℃～50℃。其中，配制第一溶液的温度可优选为20℃、21℃、22℃、23℃、24℃、25℃、26℃、27℃、28℃、29℃、30℃、31℃、32℃、33℃、34℃、35℃、36℃、37℃、38℃、39℃、40℃、41℃、42℃、43℃、44℃、45℃、46℃、47℃、48℃、49℃或50℃。优选地，配制第一溶液的温度可为25℃～45℃；更优选地，配制第一溶液的温度可为30℃～40℃。在一个实施方案中，配制第一溶液的温度可为室温。
在本发明的一个实施方案中，在使用活性炭的情况下，步骤a中式(III)的二羧酸与活性炭的质量比可为1:0.01～1:0.20。其中，式(III)的二羧酸与活性炭的质量比可优选为1:0.01、1:0.02、1:0.03、1:0.04、1:0.05、1:0.06、1:0.07、1:0.08、1:0.09、1:0.10、1:0.11、1:0.12、1:0.13、1:0.14、1:0.15、1:0.16、1:0.17、1:0.18、1:0.19或1:0.20。优选地，式(III)的二羧酸与活性炭的质量比可为1:0.02～1:0.08；更优选地，式(III)的二羧酸与活性炭的质量比可为1:0.03～1:0.06。
在本发明的一个实施方案中，步骤a的混合没有特别限制，可 采用本领域技术人员熟知的混合方式，具体的，如搅拌，诸如机械搅拌或磁力搅拌。
在本发明的一个实施方案中，步骤b中待纯化的式(I)的双二羧酸二氨络铂(II)衍生物与第一溶液的质量体积比可为1:5g/ml～1:20g/ml。其中，待纯化的式(I)的双二羧酸二氨络铂(II)衍生物与第一溶液的质量体积比可优选为1:5g/ml、1:6g/ml、1:7g/ml、1:8g/ml、1:9g/ml、1:10g/ml、1:11g/ml、1:12g/ml、1:13g/ml、1:14g/ml、1:15g/ml、1:16g/ml、1:17g/ml、1:18g/ml、1:19g/ml或1:20g/ml。优选地，待纯化的式(I)的双二羧酸二氨络铂(II)衍生物与第一溶液的质量体积比可为1:8g/ml～1:16g/ml；更优选地，待纯化的式(I)的双二羧酸二氨络铂(II)衍生物与第一溶液的质量体积比可为1:10g/ml～1:12g/ml。
在本发明的一个实施方案中，步骤b中可将第一溶液加热至60℃～85℃。其中，优选可将第一溶液加热至60℃、61℃、62℃、63℃、64℃、65℃、66℃、67℃、68℃、69℃、70℃、71℃、72℃、73℃、74℃、75℃、77℃、77℃、78℃、79℃、80℃、81℃、82℃、83℃、84℃或85℃。优选地，可将第一溶液加热至65℃～80℃；更优选地，可将第一溶液加热至70℃～75℃。
在本发明的一个实施方案中，步骤b中可在60℃～85℃下进行所述混合。其中，优选可在60℃、61℃、62℃、63℃、64℃、65℃、66℃、67℃、68℃、69℃、70℃、71℃、72℃、73℃、74℃、75℃、77℃、77℃、78℃、79℃、80℃、81℃、82℃、83℃、84℃或85℃下进行所述混合。优选地，可在65℃～80℃下进行所述混合；更优选地，可在70℃～75℃下进行所述混合。
在本发明的一个实施方案中，步骤c中的冷却包括通过任何方式使温度降低的过程。在一个实施方案中，步骤c中的冷却包括使第二溶液冷却至结晶终点温度。在一个实施方案中，步骤c中的冷却包括将第二溶液连续冷却至结晶终点温度。在一个实施方案中，步骤c中的冷却包括将第二溶液逐级冷却至结晶终点温度。
在本发明的一个实施方案中，所述结晶终点温度可为1℃～10℃。其中，所述结晶终点温度可优选为1℃、2℃、3℃、4℃、5℃、6℃、7℃、8℃、9℃或10℃。优选地，所述结晶终点温度可为2℃～8℃；更优选地，所述结晶终点温度可为4℃～6℃。
在本发明的一个实施方案中，使第二溶液冷却至结晶终点温度的时间可为1min～180min。其中，使第二溶液冷却至结晶终点温度的时间可优选为1min、5min、10min、15min、20min、25min、30min、35min、40min、45min、50min、55min、60min、65min、70min、75min、80min、85min、90min、95min、100min、105min、110min、115min、120min、125min、130min、135min、140min、145min、150min、155min、160min、165min、170min、175min、180min。优选地，使第二溶液冷却至结晶终点温度的时间可为30min～120min；更优选地，使第二溶液冷却至结晶终点温度的时间可为60min～90min。
在本发明的一个实施方案中，所述连续冷却包括对第二溶液施加连续降温的环境。在本发明的一个实施方案中，所述连续冷却包括将第二溶液移至具有结晶终点温度的环境。
在本发明的一个实施方案中，所述逐级冷却包括在连续冷却的过程中，使第二溶液在结晶终点温度前的一个或更多个温度下各维持适当的时间。在一个实施方案中，所述一个或更多个温度是指1、2、3、4、5、6、7、8、9或10个温度。在一个实施方案中，任意两个相邻的温度之间的温差可为1℃～30℃。其中，任意两个相邻的温度之间的温差可优选为1℃、2℃、3℃、4℃、5℃、6℃、7℃、8℃、9℃、10℃、11℃、12℃、13℃、14℃、15℃、16℃、17℃、18℃、19℃、20℃、21℃、22℃、23℃、24℃、25℃、26℃、27℃、28℃、29℃或30℃。在一个实施方案中，结晶终点温度和与其相邻的温度之间的温差可为以上定义的温差中的任一个。在一个实施方案中，在各个温度下维持的时间可以相同或不同，并且各自独立地可为1min～120min。其中，在各个温度下维持的时间可以 相同或不同，并且各自独立地可为1min、2min、3min、4min、5min、6min、7min、8min、9min、10min、11min、12min、13min、14min、15min、16min、17min、18min、19min、20min、21min、22min、23min、24min、25min、26min、27min、28min、29min、30min、31min、32min、33min、34min、35min、36min、37min、38min、39min、40min、41min、42min、43min、44min、45min、46min、47min、48min、49min、50min、51min、52min、53min、54min、55min、56min、57min、58min、59min、60min、65min、70min、75min、80min、85min、90min、95min、100min、105min、110min、115min或120min。
在本发明的一个实施方案中，步骤c中的冷却还包括在使第二溶液冷却至结晶终点温度后继续维持适当的时间。在一个实施方案中，在结晶终点温度下维持的时间可以为1min～180min。其中，在结晶终点温度下维持的时间可优选为1min、5min、10min、15min、20min、25min、30min、35min、40min、45min、50min、55min、60min、65min、70min、75min、80min、85min、90min、95min、100min、105min、110min、115min、120min、125min、130min、135min、140min、145min、150min、155min、160min、165min、170min、175min、180min。优选地，在结晶终点温度下维持的时间可为30min～120min；更优选地，在结晶终点温度下维持的时间可为60min～90min。
在本发明的一个实施方案中，步骤d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d中的洗涤包括用水洗涤分离的固体一次或更多次。在一个实施方案，所述洗涤用水的温度可为0℃～25℃，优选地，所述洗涤用水的温度可为0℃、5℃、 10℃、15℃、20℃或25℃。在一个实施方案，所述洗涤用水可为冰水。在一个实施方案，所述洗涤用水的温度可为常温。
在本发明的一个实施方案中，步骤d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“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(1,1- 环丁烷二羧酸)二氨合铂(II)的质量标准，但是参照卡铂和顺铂产品的质量标准，认为双(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)的表征和含量的测定较为困难，原因在于由于双(1,1-环丁烷二羧酸)二氨合铂(II)的特殊结构，导致难以将双(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)，并且通过外标法确定杂质卡铂的大致含量范围。
关于双(1,1-环丁烷二羧酸)二氨合铂(II)的含量，CN104122280A中明确指出了双(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)的含量。
本发明通过如下方法表征产品中双(1,1-环丁烷二羧酸)二氨合铂(II)的含量：
1)获得含约2.0wt％卡铂的双(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)的含量。
其中，含约2.0wt％卡铂的双(1,1-环丁烷二羧酸)二氨合铂(II)对照品可通过如下方法制备：取双(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)对照品。
本发明所述双(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)的含量才是其实际含量。虽然其并不一定是双(1,1-环丁烷二羧酸)二氨合铂(II)的实际含量，但与双(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)产品的质量。研究表明，按照上述方法测得的双(1,1-环丁烷二羧酸)二氨合铂(II)含量在98％～102％时，所得产品为品质优良的合格产品。当双(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)中的游离卡铂含量超过允许范围，该产品不具有实用价值。但是，仍然可以采用高效液相色谱测定卡铂含量，将测得的卡铂含量乘以1.388以得到由卡铂含量换算而来的双(1,1-环丁烷二羧酸)二氨合铂(II)含量，以对产品中的双(1,1-环丁烷二羧酸)二氨合铂(II)和卡铂含量进行粗略估算。
有益效果
本发明的方法具有以下突出的效果：
1、在普遍的药品质量标准中，外观为首个检验项，是判断产品是否合格的重要依据。根据本发明的方法纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)，其产品外观有明显变化，颜色由黄色、浅黄色、灰白色等变为白色，和/或形态由粉末状变为晶体。换言之，根据本发 明的方法可将颜色深的、粉末状的双(1,1-环丁烷二羧酸)二氨合铂(II)纯化为白色晶体。所述颜色和/或形态的改善表明了产品质量的显著提升。
2、当双(1,1-环丁烷二羧酸)二氨合铂(II)中包含较多卡铂时，按照常规纯化方法无法将卡铂去除。然而，根据本发明的方法可以除掉绝大部分的卡铂，使得卡铂含量下降至2％以内，从而可获得基本不含卡铂的品质良好的双(1,1-环丁烷二羧酸)二氨合铂(II)。
3、在双(1,1-环丁烷二羧酸)二氨合铂(II)含量不合格的情况下，无论是双(1,1-环丁烷二羧酸)二氨合铂(II)含量过低或者过高(即卡铂含量过高)，根据本发明的方法都可以将双(1,1-环丁烷二羧酸)二氨合铂(II)纯化至其卡铂含量和双(1,1-环丁烷二羧酸)二氨合铂(II)含量达到合格的程度，也就是产品的X-射线衍射图谱示出其中卡铂含量低于2％，而且高效液相色谱法测定的双(1,1-环丁烷二羧酸)二氨合铂(II)含量为98％～102％。因此，根据本发明的方法保证了不同工艺所得的不合格双(1,1-环丁烷二羧酸)二氨合铂(II)产品有补救措施，可将损失降至最低。
4、对于双(1,1-环丁烷二羧酸)二氨合铂(II)含量和/或卡铂含量已合格，但由于杂质的存在而导致颜色和/或形态不佳的双(1,1-环丁烷二羧酸)二氨合铂(II)原料，在按照本发明的方法纯化后，虽然双(1,1-环丁烷二羧酸)二氨合铂(II)的含量没有明显变化，但颜色和/或形态得到明显改善，更重要的是，X-射线衍射图谱表明在按照本发明的方法纯化后，产品不会如现有技术的重结晶方法那样发生分解进而出现卡铂杂质。也就是说，根据本发明的方法能够在不造成双(1,1-环丁烷二羧酸)二氨合铂(II)含量下降、大量卡铂出现的情况下，对双(1,1-环丁烷二羧酸)二氨合铂(II)含量和/或卡铂含量合格的产品进行进一步的纯化。这意味着当双(1,1-环丁烷二羧酸)二氨合铂(II)含量和/或卡铂含量合格的双(1,1-环丁烷二羧酸)二氨合铂(II)产品为普通环境生产，在需要提高产品洁净度、控制产品微生物含量时，可采用根据本发明的方法在结晶环境中对产品进行纯化。
5、根据本发明的纯化方法可在各条件下实施，能够以较高的收率获得白色晶体状的品质良好的双(1,1-环丁烷二羧酸)二氨合铂(II)产品，并且还能够用于纯化较大批量的质量不合格的双(1,1-环丁烷二羧酸)二氨合铂(II)。
6、本发明的方法仅用水作为溶剂，未使用任何有机溶剂，生产过程环保、产生废液量少。所述方法操作简单、简便易行，产品质量稳定，适合工业化放大生产。
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1-6
配制0.115g/ml的1,1-环丁烷二羧酸溶液100ml，加入0.557g活性炭，搅拌10-20min，过滤除活性炭备用。
取上述1,1-环丁烷二羧酸溶液55ml，加热至70℃-75℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)5.5g，快速搅拌溶解，热过滤。滤液移至50℃水浴中，缓慢搅拌结晶，在60min内将水浴温度降至5℃，过滤，抽干，滤饼40℃干燥至恒重，得产品3.784g，收率68.80％。
按照实施例1相同的方法进行实施例2-6，将实施例1-6总结于以下表1中。
表1：
Figure PCTCN2018106169-appb-000010
Figure PCTCN2018106169-appb-000011
其中，双(1,1-环丁烷二羧酸)二氨合铂(II)的含量通过高效液相色谱法测定，具体条件和方法如下：
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/min，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(1,1-环丁烷二羧酸)二氨合铂(II)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(1,1-环丁烷二羧酸)二氨合铂(II)含量。
试验结果表明，根据本发明的纯化方法能够有效地改善双(1,1-环丁烷二羧酸)二氨合铂(II)含量不合格的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的质量。
对于双(1,1-环丁烷二羧酸)二氨合铂(II)中的游离卡铂，图1为添加有2％卡铂的双(1,1-环丁烷二羧酸)二氨合铂(II)对照品的X-射线衍射图谱及其数据列表，其中11.4°-11.7°处显卡铂特征峰(参见CN104122280A)，相对于7.4°-7.8°处的双(1,1-环丁烷二羧酸)二氨合铂(II)特征峰，峰强度为0.65。图2、图4、图6、图8、图10、图12为待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的X-射线衍射图谱及其数据列表，其显示这些待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)具有比双(1,1-环丁烷二羧酸)二氨合铂(II)对照品更强的卡铂特征峰(相对于7.4°-7.8°处的双(1,1-环丁烷二羧酸)二氨合铂(II)特征峰)，提示这些待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)中卡铂含量不含格。而在按照本发明的方法纯化后，所得纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)中11.4°-11.7°处的卡铂特征峰基本消失，相对于7.4°-7.8°处的双(1,1-环丁烷二羧酸)二氨合铂(II)特征峰的峰强降低至0.65以下，如图3、图5、图7、图9、图11、图13所示。这表明在 按照本发明的方法纯化后，双(1,1-环丁烷二羧酸)二氨合铂(II)中的卡铂含量降低至可接受的范围。
对于双(1,1-环丁烷二羧酸)二氨合铂(II)的含量，实施例1-3、5-6中双(1,1-环丁烷二羧酸)二氨合铂(II)的含量低于98％，或高于102％，所述双(1,1-环丁烷二羧酸)二氨合铂(II)的含量不合格。而在按照本发明的方法纯化后，所述含量均落在98％～102％的合格范围内。这表明在按照本发明的方法纯化后，双(1,1-环丁烷二羧酸)二氨合铂(II)的含量可以从明显不合格变为合格。
对于双(1,1-环丁烷二羧酸)二氨合铂(II)的外观，实施例1-6中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)具有黄色、浅黄色、灰白色或白色粉状外观，而在按照根据本发明的方法纯化后，所得纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)均具有白色晶体状外观，其意味着产品质量的显著提升。这表明在按照本发明的方法纯化后，双(1,1-环丁烷二羧酸)二氨合铂(II)的产品质量可得到改善。
此外，实施例4中双(1,1-环丁烷二羧酸)二氨合铂(II)的含量虽然合格，但是仍可以通过根据本发明的方法进一步纯化，例如降低卡铂含量以及改善产品外观，这通过以下实施例7-11进一步示出。
实施例7-11
按照实施例1相同的方法进行实施例7-11，区别在于待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)不同，将实施例7-11总结于以下表2中。此外，作为代表，实施例7所用的待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)以及所获得的纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的X-射线衍射图谱及其数据列表分别如图14和15所示。
表2：
Figure PCTCN2018106169-appb-000012
Figure PCTCN2018106169-appb-000013
试验结果表明，根据本发明的纯化方法还能够有效地改善含量合格的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的整体质量。
对于双(1,1-环丁烷二羧酸)二氨合铂(II)中的游离卡铂，图14和15中均不包含11.4°-11.7°处的卡铂特征峰，表明纯化前后的双(1,1-环丁烷二羧酸)二氨合铂(II)中均不包含游离卡铂。
虽然实施例7-11中待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)的含量均落在98％～102％的合格范围内，图14显示其中不包含卡铂，但是，从其外观上看，所述双(1,1-环丁烷二羧酸)二氨合铂(II)晶体具有淡黄色，表明其可能还含有一定杂质。而在按照本发明的方法纯化后，纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)产品的含量没有 发生太大变化，仍落在98％～102％的合格范围内，也就是含量没有“质的改变”，图15显示11.4°-11.7°处没有出现新的卡铂特征峰，表明在按照本发明的方法纯化后产品不会分解进而出现卡铂杂质。然而，双(1,1-环丁烷二羧酸)二氨合铂(II)的颜色去从淡黄色变为白色，提示了产品质量的提升。因此，即使是双(1,1-环丁烷二羧酸)二氨合铂(II)含量和/或卡铂含量合格的双(1,1-环丁烷二羧酸)二氨合铂(II)产品，在有需要时例如在需要提高产品洁净度、控制产品微生物含量时，也可采用根据本发明的方法在结晶环境中对产品进行进一步纯化。
实施例12
取1,1-环丁烷二羧酸16.00g，活性炭0.80g，加入纯化水200ml，40℃下搅拌10min，过滤除活性炭备用。
取上述1,1-环丁烷二羧酸溶液30ml，加热至85℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)4.0g，85℃下快速搅拌溶解，热过滤。滤液通入氮气并移至5℃环境，缓慢搅拌结晶，40min后过滤，10ml冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例13
取1,1-环丁烷二羧酸16.00g，活性炭0.80g，加入纯化水200ml，40℃下搅拌10min，过滤除活性炭备用。
取上述1,1-环丁烷二羧酸溶液45ml，加热至62℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)4.0g，64℃下搅拌3min并补加15ml上述1,1-环丁烷二羧酸溶液才基本溶清，热过滤。滤液通入氮气并移至5℃环境，缓慢搅拌结晶，40min后过滤，10毫升冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
将实施例12-13总结于以下表3中。
表3：
Figure PCTCN2018106169-appb-000014
Figure PCTCN2018106169-appb-000015
实施例14
取1,1-环丁烷二羧酸16.00g，活性炭0.80g，加入纯化水200ml，40℃下搅拌10min，过滤除活性炭备用。
取上述1,1-环丁烷二羧酸溶液40ml，加热至70℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)4.0g，73℃下搅拌2min溶解，热过滤。滤液通入氮气并移至室温冷却20min后再移入5℃环境，缓慢搅拌结晶，30min后过滤，10ml冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例15
按照实施例14相同的方法进行实施例15，区别在于将滤液通入氮气后直接移入5℃环境，缓慢搅拌结晶，20min后过滤，10ml冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例16
按照实施例14相同的方法进行实施例16，区别在于将滤液通入氮气后移至室温冷却15min后再移入5℃环境，缓慢搅拌结晶，120min后过滤，10ml冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
将实施例14-16总结于以下表4中。
表4：
Figure PCTCN2018106169-appb-000016
Figure PCTCN2018106169-appb-000017
实施例17
取1,1-环丁烷二羧酸8.00g，活性炭0.40g，加入纯化水100ml，40℃下搅拌10min，过滤除活性炭备用。
取上述1,1-环丁烷二羧酸溶液30ml，加热至80℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)4.0g，85℃下搅拌2min溶解，热过滤。滤液通入氮气并移至室温冷却7min后再移入5℃环境，缓慢搅拌结晶，120min后过滤，10ml冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例18
取1,1-环丁烷二羧酸8.00g，活性炭0.40g，加入纯化水100ml，40℃下搅拌10min，过滤除活性炭备用。
取上述1,1-环丁烷二羧酸溶液50ml，加热至60℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)4.0g，63℃下搅拌3min并补加5ml上述1,1-环丁烷二羧酸溶液再搅拌2min才基本溶清，热过滤。滤液通入氮气并移至室温冷却20min后再移入5℃环境，缓慢搅拌结晶，120min后过滤，10ml冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
将实施例17-18总结于以下表5中。
表5：
Figure PCTCN2018106169-appb-000018
Figure PCTCN2018106169-appb-000019
实施例19
取1,1-环丁烷二羧酸40.00g，活性炭2.00g，加入纯化水350ml，40℃下搅拌10min，过滤除活性炭备用。
取上述1,1-环丁烷二羧酸溶液100ml，加热至75℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)10.0g，71℃下搅拌3min溶解，热过滤。滤液通入氮气并移至35℃下冷却5min后，移至25℃下冷却10min，再移至15℃下冷却10min，最后移至5℃并停止氮气通入，冷却60min，在此温度下缓慢搅拌60min后过滤，20ml冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例20
按照实施例19相同的方法进行实施例20，区别在于将滤液通入氮气后移至35℃下冷却20min后，移至25℃下冷却20min，再移至15℃下冷却20min，最后移至5℃并停止氮气通入，冷却60min，在此温度下缓慢搅拌60min后过滤，20ml冰水搅洗一次，抽干，滤饼40℃干燥至恒重。
将实施例19-20总结于以下表6中。
表6：
Figure PCTCN2018106169-appb-000020
Figure PCTCN2018106169-appb-000021
实施例21
取1,1-环丁烷二羧酸50.60g，活性炭2.53g，加入纯化水440ml，40℃下搅拌10min，过滤除活性炭备用。
将上述1,1-环丁烷二羧酸溶液加热至70℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)40.0g，75℃下搅拌2min溶解，热过滤。滤液通入氮气并移至35℃下冷却30min后，移至20℃下冷却30min，最后移至5℃并停止氮气通入，冷却60min后过滤，常温水80ml搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例22
取1,1-环丁烷二羧酸6.33g，活性炭0.32g，加入纯化水55ml，40℃下搅拌10min，过滤除活性炭备用。
将上述1,1-环丁烷二羧酸溶液加热至71℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)5.0g，75℃下搅拌2min溶解，热过滤。滤液通入氮气并移至50℃下冷却30min后，移至35℃下冷却30min，再移至20℃下冷却30min，最后移至5℃并停止氮气通入，冷却60min后过滤，常温水15ml搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例23
取1,1-环丁烷二羧酸69.55g，活性炭3.48g，加入纯化水605ml，40℃下搅拌10min，过滤除活性炭备用。
将上述1,1-环丁烷二羧酸溶液加热至73℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)55.5g，75℃下搅拌2min溶解，热过滤。滤液通入氮气并移至35℃下冷却30min后，移至20℃下冷却30min，最后移至5℃并停止氮气通入，冷却60min后过滤，常温水100ml搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例24
取1,1-环丁烷二羧酸126.41g，活性炭6.33g，加入纯化水1100ml，40℃下搅拌10min，过滤除活性炭备用。
将上述1,1-环丁烷二羧酸溶液加热至71℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)99.98g，75℃下搅拌2min溶解，热过滤。滤液通入氮气并移至35℃下冷却30min后，移至20℃下冷却30min，最后移至5℃并停止氮气通入，冷却60min后过滤，常温水200ml搅洗一次，抽干，滤饼40℃干燥至恒重。
实施例25
取1,1-环丁烷二羧酸164.5g，活性炭8.22g，加入纯化水1430ml，40℃下搅拌10min，过滤除活性炭备用。
将上述1,1-环丁烷二羧酸溶液加热至73℃，加入待纯化的双(1,1-环丁烷二羧酸)二氨合铂(II)130.00g，75℃下搅拌3min溶解，热过滤。滤液通入氮气并移至35℃下冷却30min后，移至20℃下冷却30min，最后移至5℃并停止氮气通入，冷却60min后过滤，常温水200ml搅洗一次，抽干，滤饼40℃干燥至恒重。
将实施例21-25总结于以下表7中。
表7：
Figure PCTCN2018106169-appb-000022
Figure PCTCN2018106169-appb-000023
实施例12-25的试验结果表明，根据本发明的纯化方法可在各条件下实施，能够以较高的收率获得白色晶体状的双(1,1-环丁烷二羧酸)二氨合铂(II)产品，并且还能够用于纯化较大批量的质量不合格的双(1,1-环丁烷二羧酸)二氨合铂(II)。
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 (23)

  1. 一种式(I)的双二羧酸二氨络铂(II)衍生物的纯化方法，所述方法包括：
    a.将式(III)的二羧酸溶解于适量的水中，配制成浓度为0.05g/ml～0.20g/ml的第一溶液；
    b.将所述第一溶液加热至60℃～85℃，加入待纯化的式(I)的双二羧酸二氨络铂(II)衍生物，然后进行热过滤以获得第二溶液；
    c.冷却所述第二溶液以析出固体；
    Figure PCTCN2018106169-appb-100001
    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。
  2. 根据权利要求1所述的方法，所述方法还包括：
    d.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，其中步骤a包括：将式(III)的二羧酸溶解于适量的水中，配制成浓度为0.05g/ml～0.20g/ml的溶液，然后加入活性炭，搅拌后过滤以获得第一溶液。
  4. 根据权利要求1-3中任一项所述的方法，其中步骤b包括：将所述第一溶液加热至60℃～85℃，加入待纯化的式(I)的双二羧酸二氨络铂(II)衍生物，在60℃～85℃下混合，然后进行热过滤以获得第二溶液。
  5. 权据权利要求1-4中任一项所述的方法，所述方法还包括按照以下方法制备式(I)的双二羧酸二氨络铂(II)衍生物：
    Figure PCTCN2018106169-appb-100002
    使式(II)的卡铂或卡铂类似物和式(III)的二羧酸反应以生成式(I)的双二羧酸二氨络铂(II)衍生物。
  6. 根据权利要求5所述的方法，所述方法还包括采用以下方法制备式(II)的卡铂或卡铂类似物：
    方法1)
    Figure PCTCN2018106169-appb-100003
    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 PCTCN2018106169-appb-100004
    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中所述；
    X表示卤素，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。
  7. 根据权利要求1-6中任一项所述的方法，其特征在于，步骤a中式(III)的二羧酸的浓度为0.05g/ml～0.20g/ml，优选0.08g/ml～0.16g/ml，更优选0.11g/ml～0.12g/ml。
  8. 根据权利要求1-6中任一项所述的方法，其特征在于，步骤a中配制第一溶液的温度为20℃～50℃，优选25℃～45℃，更优选30℃～45℃；或者，步骤a中配制第一溶液的温度为室温。
  9. 根据权利要求3-8中任一项所述的方法，其特征在于，步骤a中式(III)的二羧酸与活性炭的质量比为1:0.01～1:0.1，优选1:0.02～1:0.08，更优选1:0.03～1:0.06。
  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b中待纯化的式(I)的双二羧酸二氨络铂(II)衍生物与第一溶液的质量体积比为1:5g/ml～1:20g/ml，优选1:8g/ml～1:16g/ml，更优选1:10g/ml～1:12g/ml。
  11. 根据权利要求1-10中任一项所述的方法，其特征在于，步骤b中将第一溶液加热至65℃～80℃，优选70℃～75℃。
  12. 根据权利要求4-11中任一项所述的方法，其特征在于，步骤b中在65℃～80℃，优选70℃～75℃下进行所述混合。
  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c中的冷却包括使第二溶液冷却至结晶终点温度。
  14. 根据权利要求13所述的方法，其特征在于，所述结晶终点温度为1℃～10℃，优选2℃～8℃，更优选4℃～6℃。
  15. 根据权利要求13或14所述的方法，其特征在于，步骤c中的冷却包括将第二溶液连续冷却至结晶终点温度，或者将第二溶液 逐级冷却至结晶终点温度。
  16. 根据权利要求15所述的方法，其特征在于，所述连续冷却包括对第二溶液施加连续降温的环境，或者将第二溶液移至具有结晶终点温度的环境。
  17. 根据权利要求15所述的方法，其特征在于，所述逐级冷却包括在连续冷却的过程中，使第二溶液在结晶终点温度前的一个或更多个温度下各维持适当的时间。
  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c中的冷却还包括在使第二溶液冷却至结晶终点温度后继续维持适当的时间。
  19. 根据权利要求18所述的方法，其特征在于，在结晶终点温度下维持的时间为1min～180min，优选30min～120min，更优选60min～90min。
  20. 根据权利要求2-19中任一项所述的方法，其特征在于，步骤d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。
  21. 根据权利要求2-20中任一项所述的方法，其特征在于，步骤d中所述的洗涤包括用水洗涤分离的固体一次或更多次。
  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d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。
  23. 一种根据权利要求1-22中任一项所述的方法纯化的式(I)的双二羧酸二氨络铂(II)衍生物。
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