WO2018233273A1 - 一种高纯度双环铂针状晶体的工业化制备方法 - Google Patents

一种高纯度双环铂针状晶体的工业化制备方法 Download PDF

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WO2018233273A1
WO2018233273A1 PCT/CN2018/000229 CN2018000229W WO2018233273A1 WO 2018233273 A1 WO2018233273 A1 WO 2018233273A1 CN 2018000229 W CN2018000229 W CN 2018000229W WO 2018233273 A1 WO2018233273 A1 WO 2018233273A1
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carboplatin
reaction
purity
water
product
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PCT/CN2018/000229
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French (fr)
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宋勤华
范如霖
冯建科
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宋勤华
范如霖
冯建科
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Priority to US16/473,254 priority Critical patent/US10995109B2/en
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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 System
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a method for preparing a pharmaceutical compound, and in particular to an industrial preparation method for high-purity bicyclic platinum needle crystals.
  • Dicycloplatin is said to be a platinum-based anticancer drug independently invented in China. China's Food and Drug Administration has classified it as a new class I drug. The inventors believe that it is a supramolecule composed of the main molecule carboplatin and the guest molecule 1,1-cyclobutanedicarboxylic acid through four hydrogen bonds, and its structure is as follows:
  • bicyclo platinum required the product to be needle-like crystals, which we think makes sense. Because the purity of the product can be ensured by crystallization. Considering that bicyclo platinum is decomposed into carboplatin and dicarboxylic acid during the course of HPLC, the purity of the determination needs to simultaneously calculate the amount of carboplatin and dicarboxylic acid which are decomposed, cross-referenced, which may bring judgment on the purity of the product. Ambiguity. The strict requirements for product traits in this case are another guarantee for purity.
  • the original patent CN1311183A (and CN1314357A) illustrates the preparation of bicycloplatinum by four examples, namely Examples 1, 3, 4, and 7. Among them, only Example 1 is based on carboplatin:
  • the number of moles of the raw material carboplatin and the cyclobutanedicarboxylic acid is 10.0 mmol, and accordingly, the molar ratio of the cyclobutanedicarboxylic acid to the carboplatin is equal to 1 to 1 by the MR DA/KB.
  • the number of moles indicated by the inventors (3.54 g of carboplatin and 16.2 g of cyclobutanedicarboxylic acid) are respectively: carboplatin (molecular weight 371.3) 9.534 mmol and cyclobutanedicarboxylic acid (molecular weight 144.1).
  • CN104693245A also discloses a process for preparing bicycloplatinum.
  • Example 1 discloses a specific preparation method in which carboplatin is mixed with 1,1-cyclobutanedicarboxylic acid in a molar ratio of 1:1.
  • the product prepared in this patent does not involve crystals of bicyclic platinum, which does not even report the melting point of the product.
  • 1,1-cyclobutanedicarboxylic acid and carboplatin were mixed in a ratio of 1:1, and it was impossible to precipitate bicycloplatinum in the solution.
  • the preparation procedure of this patent does not exactly match the analytical results given. According to the procedure of this patent, the product obtained is a powdery mixture.
  • CN106132408A also discloses a process for the preparation of bicycloplatinum.
  • Ten examples were disclosed, except that in Example 5, 118.6 g of carboplatin was used, and the scale of carboplatin involved in the reaction was between 15 mg and 5 g.
  • the molar ratio of dicarboxylic acid to carboplatin used in Example 5 was 1.31 (417 mmol / 319 mmol), and the weight ratio of water to carboplatin was 5. Based on literature reports and our experiments, the solubility of carboplatin itself in water is only 1.8%, even considering the dissolution of dicarboxylic acid, it does not exceed 3%, so in order to dissolve carboplatin, the amount of water can not be used at room temperature.
  • CN106132408A also uses different solvents for preparation, such as ethanol, acetonitrile, isopropanol, etc., to obtain a mixture, the effect is not satisfactory, the reaction is incomplete, and it is difficult to completely separate the residual carboplatin from the expected product bicycloplatinum.
  • Patent CN 106995467 A is to accelerate the formation of bicycloplatinum by microwave under the condition that the molar ratio of dicarboxylic acid to carboplatin is from 1 to 1.5, thereby improving production efficiency.
  • the yield of the reaction product is 65.3% to 90.0%, and the purity is 81% to 97%, which has not yet met the requirements of the pharmacopoeia.
  • the analytical method was not known, and the DSC melting point of the product was not reported, nor was the melting point visually observed.
  • Another object of the present invention is to provide an industrially prepared process for producing high purity acicular bicyclic platinum crystals.
  • An industrial preparation method of high-purity bicyclic platinum needle crystals comprising the following steps:
  • the reaction conditions of the method are: the molar ratio of 1,1-cyclobutanedicarboxylic acid to carboplatin is 4-16; the reaction time is 0.5-6 h; the water is deionized water; the reaction temperature is room temperature to 50 °C, preferably, the room temperature is 10 to 35 ° C; preferably, the weight ratio of solvent water to carboplatin is 30 to 55; preferably, the crystallization condition is: after the reaction liquid is decolorized by activated carbon, at 2 It was naturally cooled to room temperature within 8 hours, then allowed to stand at 10-14 ° C in the dark, crystallized for 4-10 days, and finally allowed to stand at 0-6 ° C for 15-30 days.
  • the reaction conditions are: a molar ratio of 1,1-cyclobutanedicarboxylic acid to carboplatin of 4 to 10; a reaction time of 0.5 to 2 h; the water is deionized water; and the reaction temperature is room temperature. ⁇ 45° C., preferably, the room temperature is 10 to 35° C.; preferably, the weight ratio of solvent water to carboplatin is 40-50; preferably, the crystallization condition is: after the reaction solution is decolorized by activated carbon, It is naturally cooled to room temperature for 2-8 hours, then allowed to stand still in the dark at 10-14 ° C for 4-10 days, and finally allowed to stand at 0-4 ° C for 15-30 days.
  • the method further comprises the step (3) of recovering the mother liquor of the step (2) by using 2 to 6 times to increase the total yield of the product bicycloplatin to 85% or more; preferably, according to the calculation result or Based on the results of HPLC analysis of the amount of the substance in the crystallization mother liquor, the mother liquor was replenished with the corresponding amounts of 1,1-cyclobutanedicarboxylic acid and carboplatin, and steps (1) and (2) were repeated.
  • the method further comprises the step (4), that is, the bicycloplatin obtained for the steps (2) and (3) is naturally dried at room temperature, or pre-cooled to 5 ° C while being filtered under reduced pressure. Isopropanol and ethyl acetate are sprayed quickly and sequentially
  • the method further comprises the step (5) of separately concentrating the final mother liquor of the step (3) at a temperature below 55 ° C to recover bicycloplatinum.
  • the method further comprises the step (6), that is, the second mother liquid produced in the step (5) is completely concentrated to dryness at a temperature below 55 ° C, and washed by ethanol or isopropanol to recover an excess of 1,1. - cyclobutane dicarboxylic acid, the filter cake is recrystallized from water to recover carboplatin; after the mother liquor obtained by refining carboplatin is evaporated to dryness, it can be incinerated together with the previously decolorized activated carbon to recover precious metal platinum, so that the utilization rate of precious metal platinum More than 97%.
  • the method can also be purified by using a special mixed solution of bicyclo platinum having a low purity, which is an aqueous solution of 1,1-cyclobutanedicarboxylic acid, or a cyclobutane dicarboxylic acid and a card.
  • a mixed solution of platinum in water is an aqueous solution of 1,1-cyclobutanedicarboxylic acid, or a cyclobutane dicarboxylic acid and a card.
  • the invention also provides the use of bicycloplatin or a mother liquor for preparing bicycloplatinum in antibacterial or antiviral; preferably, the bacterium is Staphylococcus aureus, Staphylococcus epidermidis, Bacillus cereus, Bacillus subtilis, type B Hemolytic streptococcus, Propionibacterium acnes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Helicobacter pylori, Salmonella typhi, Yersinia, Vibrio parahaemolyticus, Stenotrophomonas maltophilia , Acinetobacter acetate or hepatitis B virus.
  • the bacterium is Staphylococcus aureus, Staphylococcus epidermidis, Bacillus cereus, Bacillus subtilis, type B Hemolytic streptococcus, Propionibacterium acnes, Kle
  • the bicycloplatin prepared by the invention is needle-like crystal, and the melting point of DSC is between 198 and 202 ° C, which is not only higher than the 182-184 ° C reported by the original patent, but also higher than the inventor's later announced 198 ° C (Analyst, 2015.140.2074-2712.).
  • the XRPD analysis did not show a diffraction peak of carboplatin at 11.4°.
  • HPLC analysis showed that the content of carboplatin and dicarboxylic acid was 97-103%, showing no other absorption peak.
  • the molar ratio between the calculated value of carboplatin and the analytical value of dicarboxylic acid was 0.95-1.05.
  • Example 1 of the patent CN1314357A it is stated that when preparing bicycloplatinum, the amount of carboplatin and 1,1-cyclobutanedicarboxylic acid is 10.0 mmol, that is, the molar ratio of dicarboxylic acid to carboplatin MR DA/ KB is 1 to 1.
  • our experiments show that in such a ratio, bicyclo platinum crystals cannot be obtained, only the raw material carboplatin is given, and Table 1 lists the more representative experiments under this ratio (unless otherwise noted, the product units are As shown in the header data).
  • 1,1-cyclobutanedicarboxylic acid has a certain solubility in carboplatin in water, and the solubility of carboplatin in water increases with the increase of cyclobutanedicarboxylic acid content in water.
  • MR DA/KB is equal to 1
  • MR DA/KB is equal to 2
  • neither bicyclo platinum is precipitated from the reaction liquid, and it is difficult to precipitate the raw material carboplatin.
  • Raising the MR DA/KB to 3, the reaction solution is subjected to a proper cooling procedure, and a mixed crystal of granules and needles is precipitated.
  • the NMR spectra of the two crystals show that they are the raw material carboplatin and the desired product bicycloplatinum. .
  • the ratio of MR DA/KB was 4 to 1, and the crystals precipitated were all needle-shaped bicyclic platinum. Further improving the MR DA/KB , it can be found that the formation and crystallization conditions of the bicyclic platinum are quite broad, and the parameters such as the reaction temperature, the amount of the solvent (H 2 O/KB), the temperature of the crystallization, and the time can be appropriately combined to give the bicyclic platinum. Crystals.
  • the reaction uses water as the solvent. Our research shows that the amount of water is too large for the weight of the raw material carboplatin. The needle-like crystal of bicyclo platinum precipitates slowly and the yield decreases. The ratio is too low, although the yield is improved, but the crystal shape is not good. . Moreover, in order to dissolve the raw materials, the reaction temperature has to be increased, and the product may be yellowish yellow due to the formation of by-products, and the product precipitates too quickly at a high concentration, which also affects the crystal form of the product.
  • Example 1 of the patent CN1311183A does not specify parameters such as temperature and time for the reaction.
  • parameters such as temperature and time for the reaction.
  • bicycloplatin is a supramolecular compound formed by hydrogen bonding between carboplatin and cyclobutanedicarboxylic acid, no destruction of any molecular structure occurs during the formation, and the bond energy of hydrogen bonding generally does not exceed 30 Kcal/ Mol is much lower than the bond energy of the normal covalent bond, so the energy barrier of the transition state of the reactant is not high, and the reaction conditions should be mild.
  • the reaction temperature range between 35 and 45 °C.
  • reaction solution was decolorized by activated carbon and filtered.
  • the obtained reaction solution was naturally cooled to room temperature, and transferred to a refrigerator at 12 ° C to cool the crystals. Transfer to a 4 ° C refrigerator to allow the crystals to grow and allow more crystals to precipitate. In order to obtain as much crystalline product as possible, it is required to be placed for 15 to 30 days in an environment of 4 °C.
  • the yield of this round is close to the quantification; however, as the number of mother liquors is increased, the inevitable operation loss and the presence of side reactions are improved to pass the HPLC check.
  • the raw materials are added in accordance with the amount of carboplatin and dicarboxylic acid remaining in the mother liquor. Using the mother liquor for 4 to 5 rounds, the overall yield is 90%.
  • mother liquor can significantly improve the utilization efficiency of raw materials, as shown in Table 3.
  • the mother liquor is used, the smaller the gain of the raw material utilization rate (total yield). The greater the likelihood of affecting product quality. We have used the mother liquid for no more than 5 times.
  • the bicyclic platinum needle crystals produced according to the process are subjected to nuclear magnetic NMR, mass spectrometry MS, differential scanning calorimetry DSC, X-ray powder diffraction XRPD, X-ray single crystal diffraction and other analytical items, and even inhibited against various tumor strains.
  • the verification of the activity was in accordance with the results reported by the inventors of the bicycloplatinum and proved acceptable, see Figures 3 to 7.
  • the crystallization mother liquor of bicycloplatinum is applied several times, and the last applied mother liquor will eventually face the problem of how to use or treat it.
  • the invention also provides a method for treating a crystallization mother liquor in the production of high-purity bicyclic platinum needle crystals.
  • This second crystallization mother liquid was evaporated to dryness at 55 ° C in the dark under reduced pressure, and the obtained residue was a pale yellow amorphous powder or a crystalline powder.
  • the solid was treated with isopropanol and stirred at room temperature for 8-12 hours.
  • the residue was converted to carboplatin and dicarboxylic acid (and contains by-product impurities produced in the reaction) and filtered.
  • the cyclobutane dicarboxylic acid enters the filtrate because of its high solubility in alcohol.
  • the filtrate is evaporated to dryness to obtain a recovered 1,1-cyclobutanedicarboxylic acid, which is a white solid powder, and the recovery rate is over 90%.
  • the filter cake thus obtained was treated once with a small amount of alcohol.
  • the main component of the filter cake is carboplatin, and the impurities generated in the previous series of reactions and the previous series of mother liquor concentration are also included.
  • bicycloplatin is stable in the coexistence with a large excess of cyclobutane dicarboxylic acid, while pure bicycloplatin is decomposed in the alcohol.
  • the crude carboplatin thus obtained was dissolved in water at 40 ° C, and the water completely decomposed the residual bicyclo platinum, and the solution was slightly creamy. Can not be dissolved.
  • the activated carbon was added thereto and decolorized by stirring at 40 ° C, and after filtration, it was sequentially crystallized at 12 ° C and 4 ° C. Note: The crystals thus obtained are granular, which is pure carboplatin.
  • Bicyclic platinum decomposes in water, so it cannot be recrystallized with water.
  • Bicycloplatinum is insoluble in organic solvents and cannot be recrystallized from organic solvents. This problem plagued the relevant researchers and led to instability in the quality of the bicyclic platinum product. But as a set of production processes, a refined method is needed. Unqualified products due to accidental objective reasons or subjective errors cannot be absolutely avoided in production. For this reason, we have invented a method of recrystallization as follows:
  • a recrystallization solution is prepared.
  • Recrystallization Solution No. 1 For every 1 gram of weight of bicycloplatin to be purified: water (65 times by weight): cyclobutanedicarboxylic acid (11 gram weight): carboplatin (1 gram weight) The resulting solution.
  • Recrystallization Solution No. 2 For each 1 gram weight of the solution of the bicycloplatinum to be purified: water (32 times by weight): cyclobutanedicarboxylic acid (5 gram weight).
  • the yield of the recrystallization procedure is from 100% to 120%.
  • the reason for more than 100% is that a part of the carboplatin in the refining solution is also converted into bicycloplatinum.
  • the mother liquor produced by the crystallization is treated according to the recovery procedure of the aforementioned mother liquor.
  • bicycloplatinum to be purified 1 part by weight is dissolved in the above-mentioned No. 2 recrystallization solution at 30-50 ° C, and decolorized by stirring at the same temperature for 1 hour, filtered, and the filtrate is crystallized according to a preparation procedure of bicycloplatinum.
  • the purification yield of the recrystallization procedure is about 60%, and the residual bicycloplatinum is present in the crystallization mother liquor, and can be treated in accordance with the recovery procedure of the mother liquor described above.
  • Table 4 compares our manufacturing process to the existing process for preparing bicycloplatinum.
  • Fig. 1 is an NMR of bicyclo platinum precipitated from a reaction liquid in Example 2, wherein the ratio of the integrated value of the four-membered ring corresponding to the dicarboxylic acid moiety to the carboplatin moiety was 2.05 to 2.00, indicating that the product was adsorbed with dicarboxylic acid.
  • Acidic bicyclic platinum
  • Figure 2 is the NMR of the product after washing with ethanol in Example 2, in which ethanol decomposes part of the bicyclic platinum into dicarboxylic acid and carboplatin, the former being eluted, so the integral value of the four-membered ring corresponding to the dicarboxylic acid moiety is relatively
  • the proportion of the carboplatin portion is 1.71 to 2.00, indicating that the product is miscible with carboplatin;
  • Figure 3 is the MS of the product of Example 6 bicycloplatinum
  • Figure 4 is an NMR of the bicycloplatinum of the product of Example 6;
  • Figure 5 is a DSC of the product of the product of the bicyclo platinum of Example 6, wherein the melting point is 199.6 ° C;
  • Figure 6a is the XRPD of the bicycloplatinate of the product of Example 6, which corresponds to the diffraction peak of carboplatin 11.4° at all, indicating no carboplatin.
  • Figure 6b is an XRPD of carboplatin with a characteristic diffraction peak at 11.4°;
  • Figure 6c is an XRPD of a dicarboxylic acid
  • Figure 7a is a needle crystal of the product of Example 6;
  • Figure 7b is a crystal of the product bicycloplatin, the bicycloplatin obtained above 25 g of the preparation scale, the product crystal is still needle-like;
  • Figure 8a is an HPLC curve of bicycloplatinum
  • Figure 8b is an HPLC curve of carboplatin
  • Figure 8c is an HPLC of 1,1-cyclobutanedicarboxylic acid
  • Figure 9 is the NMR of the product crystal of Example 2, which is carboplatin
  • Figure 10 is an NMR of 1,1-cyclobutanedicarboxylic acid recovered in Example 2 by ethanol washing;
  • Figure 11 is a photograph of the crystal of the product of Example 2, which is granular carboplatin;
  • Figure 12 is a DSC curve of the product crystal of Example 2, the melting point is 232.6 ° C;
  • Figure 13 is the NMR of the product precipitated in Example 2 after washing with ethanol, and then treated with isopropanol, the main body is carboplatin, which contains 12% of bicycloplatinum;
  • Figure 14 is the NMR of the product precipitated in Example 2 after ethanol washing, and then treated with ethanol, the main body is carboplatin, wherein the bicyclo platinum is less than 2%, indicating that the decomposition of ethanol is stronger than that of isopropanol;
  • Figure 15 is a DSC of the product of Example 3.
  • Figure 16 is a DSC of the product of Example 5.
  • Figure 17 is a DSC curve of the product bicyclo platinum in the case of MR DA/KB of 7.0, the melting point of which is 199.5 ° C;
  • Figure 18 is a flow chart of the treatment process of the bicyclic platinum mother liquor.
  • Measurement conditions CuKa radiation; tube voltage 40 KV; tube cureent 40 mA; scanning mode 0/2 ⁇ scanning; scanning speed, 0.6 s / step; step length, 0.019 ° / step;
  • High Performance Liquid Chromatograph Agilent 1260 Infinity II High Performance Liquid Chromatograph, Agilent 1260 Infinity II Ultraviolet Detector, ICC Integrated Column Compartment, Agilent 1260 Infinity II Autosampler, Agilent OpenLAB CDS Workstation
  • Figures 8a-8c show HPLC plots of carboplatin, 1,1-cyclobutanedicarboxylic acid, bicycloplatinum.
  • Examples 1 and 2 are checks for the original patent CN1311183A (and CN1314357A).
  • Example 3 is an inspection of the prior patent application CN104693245A.
  • Examples 4 and 5 are for the examination of the prior patent application CN106132408A.
  • Example 1 Analog Example 1 in the original bicyclic platinum original patent CN1311183A, taking a molar ratio of 1,1-cyclobutanedicarboxylic acid to carboplatin of MRDA/KB of 1 to 1 (see Table 1 in "Summary of the Invention") And Table 2.)
  • Example 2 Strictly simulating Example 1 of the bicyclic platinum original patent CN1311183A, taking the molar ratio of 1,1-cyclobutanedicarboxylic acid to carboplatin MR DA/KB to 11.79
  • the mixture was further stirred for 25 minutes in accordance with the procedure of the original patent, and evaporated to dryness under reduced pressure at 60 ° C (water bath temperature) to obtain 27.7 g of a powdery solid.
  • 70.6 ml of absolute ethanol was added to the solid, and the mixture was stirred at room temperature for 2 hours; filtered, and the filter cake was washed with ethanol 14 ml ⁇ 3.
  • the filter cake was dried under vacuum and weighed 6.6 g.
  • Embodiment 3 this embodiment strictly simulates Embodiment 1 of the patent CN104693245A
  • the product obtained was 7.05 g, the yield was 99.3%; the sample was observed as a crystalline powder by the naked eye; the fine needle-like and very small granular crystals were observed under the microscope (the two crystals suggested that they were a mixture); the melting point was 165.3 ° C and turned to gray 185.2. Black spots appear at °C, and all black at 200.2 °C. DSC (see Figure 15), the dicarboxylic acid absorption peak is observed, and then gradually increases, shifting to the absorption peak of bicycloplatinum, which is the characteristic of carboplatin, apparently a mixture.
  • Embodiment 4 this embodiment strictly simulates Embodiment 5 of Patent CN106132408A, and only reduces the scale of the reaction.
  • Embodiment 5 this embodiment strictly simulates Embodiment 7 of the patent CN106132408A, and only enlarges the reaction scale to 10 times.
  • Example 6 The reaction mother liquid was applied three times in a ratio of MR DA/KB equal to 5.2, and each time the raw material carboplatin and the dicarboxylic acid were added according to the amount of the bicyclic platinum obtained in the previous round:
  • the obtained solution was transferred to a crystallization flask, naturally cooled to room temperature, placed in a refrigerator at 12 ° C to be cooled in the dark, and then placed in a refrigerator at 4 ° C for 5 days.
  • the needle-like crystals gradually grow and grow, forming flower-like transparent clusters within a few days.
  • the crystallization process lasts for more than half a month and is vacuum filtered. Drying under vacuum at room temperature gave 8.15 g of the first reaction product, bicycloplatinum, in a yield of 58.7%.
  • the second round of reaction the weight of the mother liquor obtained by filtration in the first round reaction was 423.0g, ignoring the loss in the process, calculated according to the yield of the first round (8.15g).
  • the reactants in the system were reduced. : Carboplatin 5.87 g and dicarboxylic acid 2.28 g.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 35 ° C for 30-60 minutes, 2.0 g of medical activated carbon powder was added, and the mixture was stirred at the same temperature for 30 minutes.
  • the filter residue was washed with 2 x 4 ml of purified water, and the washing liquid was taken to filtrate.
  • the obtained solution was transferred to a crystallization flask, cooled to room temperature, placed in a refrigerator at 12 ° C for 5 days, and transferred to a refrigerator at 4 ° C for crystallization.
  • the yield of carboplatin (5.87 g) was 98.2%; for the total amount of carboplatin (15.87 g) charged in this experiment, the total amount of the product was 16.15 g, and the total yield was 68.9%.
  • the third round of reaction the second round of mother liquor weighs 432.9g, ignoring the loss in the process, calculated according to the second round of yield (8.00g), after the second round of reaction, the reduced reactant in the system is: carboplatin 5.76g And 2.24 g of dicarboxylic acid.
  • carboplatin and the dicarboxylic acid corresponding to the reduction amount were added, and the third round reaction was started, and the third round of the product bicycloplatinum 7.00 g was obtained according to the same procedure, in terms of the added carboplatin (5.76 g).
  • the yield was 87.5%; for the total amount of carboplatin (21.63 g) charged in this experiment, the total amount of the product was 23.15 g, and the total yield was 77.10%.
  • the fourth round of reaction the third round of mother liquor weighs 413.4g, ignoring the loss in the process, according to the third round of yield (7.00g), after the third round of reaction, the reactants in the system are reduced: carboplatin 5.04g And 1.86 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduction amount were added, and the fourth round reaction was started, and the fourth round of product bicycloplatinum 6.9 g was obtained according to the same procedure, in terms of additional carboplatin (5.04 g).
  • the yield was 98.6%; for the total amount of carboplatin (26.67 g) charged in this experiment, the total amount of the product was 30.05 g, and the total yield was 81.2%.
  • the design and implementation of the second, third and fourth rounds of reaction is based on the use of the precursor liquid in the front wheel.
  • the result of using the mother liquor increases the overall yield of the reaction.
  • the products of the second, third and fourth rounds of the reaction all showed good quality, and the melting points characterized by DSC were consistent with the standard.
  • the mother liquor is used no more than five times. After the mother liquor is recycled, the mother liquor is treated for the recovery of bicycloplatinum, dicarboxylic acid and recycled carboplatin.
  • bicycloplatin Since the preparation of bicycloplatin requires that the molar ratio of the raw dicarboxylic acid to carboplatin exceeds 4, the concentration of dicarboxylic acid in the solution precipitated by the product is estimated to be more than 3.1% according to the ratio of 5; The needle-like crystals obtained by filtration are inevitably adsorbed to the mother liquor and should be removed. However, the bicycloplatinum will decompose rapidly with water or alcohol, and it is a problem to remove the adsorbent mother liquor. The method we used at first was to pour it onto the filter paper and blot it dry. On the basis of comparing several solvents, we rinsed with cold isopropanol and eluted isopropanol with cold ethyl acetate.
  • Example 7 the reaction mother liquid was applied three times at a ratio of MR DA/KB equal to 5.15, and each time the raw material carboplatin and the dicarboxylic acid were added according to the amount of the obtained bicyclo platinum obtained in the previous round:
  • the resulting solution was transferred to a crystallization flask, cooled at 8 ° C, and further cooled at the same temperature for 2 days, during which the crystal clusters grew and increased. Transfer to a 4 ° C refrigerator for 15 days. A flower-like transparent cluster is obtained.
  • the second round of reaction the first round of reaction mother liquor weighs 1170.9g, ignoring the loss in the process, calculated according to the first round of yield (18.09g), after the first round of reaction, the reactants reduced in the system are: carboplatin 13.03 g and 5.06 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 35 ° C for 30-60 minutes, 5.0 g of medical activated carbon powder was added, and the mixture was stirred at the same temperature for 30 minutes. Filtered, the filter residue was washed with 2 x 11.25 ml of purified water, and the washings were combined.
  • the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, transferred to a refrigerator at 12 ° C and allowed to stand at the same temperature for another 3 days, and transferred to a refrigerator at 4 ° C for 25 days in the dark. If the second round of product bicycloplatinum 17.00g is obtained by the operation, the yield is 94.0% with respect to the added carboplatin (13.03g); the total amount of the product is the total amount of carboplatin (38.03g) invested in the experiment. 35.09g, the total yield was 66.5%.
  • the third round of reaction the second round of reaction mother liquor weighs 1169.9g, ignoring the loss in the process, calculated according to the second round of yield (17.00g), after the second round of reaction, the reactants reduced in the system are: carboplatin 12.25 g and 4.75 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 35 ° C for 30-60 minutes, 5.0 g of medical activated carbon powder was added, and the mixture was stirred at the same temperature for 30 minutes. Filtered, the filter residue was washed with 2 x 11.25 ml of purified water, and the washings were combined.
  • the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, placed in a refrigerator at 12 ° C for 3 days in the dark, and placed in a refrigerator at 4 ° C for 25 days in the dark.
  • the yield of the carboplatin (12.25g) added by this round of reaction the yield of 93.5%; for the total amount of carboplatin (50.28g) invested in this experiment
  • the total amount of the product was 50.99 g, and the total yield was 73.1%.
  • the fourth round of reaction the third round reaction mother liquor weighs 1167.8g, ignoring the loss in the process, calculated according to the third round of yield (15.90g), after the third round of reaction, the reactants reduced in the system are: carboplatin 11.46 g and 4.44 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 35 ° C for 30-60 minutes, 5.0 g of medical activated carbon powder was added, and the mixture was stirred at the same temperature for 30 minutes. Filtered, the filter residue was washed with 2 x 11.25 ml of purified water, and the washings were combined.
  • Example 8 The reaction mother liquid was applied 3 times in a ratio of MR DA/KB of 4.5, and each time the raw material carboplatin and dicarboxylic acid were added according to the amount of the obtained bicyclic platinum obtained in the previous round.
  • the resulting solution was transferred to a crystallization flask, cooled at 8 ° C, and further cooled at the same temperature for 2 days, during which the crystal clusters grew and increased. Transfer to a 4 ° C refrigerator for 15 days. A flower-like transparent cluster is obtained. Vacuum filtration, vacuum-cooled with isopropanol precooled to 5 ° C and ethyl acetate precooled to 5 ° C, and vacuum dried at room temperature to obtain 36.8 g of the first reaction product bicycloplatin. 52.9%.
  • the second round of reaction the first round of reaction mother liquor weighs 2307.1g, ignoring the loss in the process, calculated according to the first round of yield (36.8g), after the first round of reaction, the reactants reduced in the system are: carboplatin 26.5 g and 10.3 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 35 ° C for 30-60 minutes, and 10.0 g of medical activated carbon powder was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Filtration, the filter residue was washed with 2 x 22.5 ml of purified water, and the washings were combined with filtrate.
  • the third round of reaction the second round reaction mother liquor weighs 2270.7g, ignoring the loss in the process, calculated according to the second round of yield (32.3g), after the second round of reaction, the reactants reduced in the system are: carboplatin 23.3 g and 9.0 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 35 ° C for 30-60 minutes, and 10.0 g of medical activated carbon powder was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Filtration, the filter residue was washed with 2 x 22.5 ml of purified water, and the washings were combined with filtrate.
  • the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, placed in a refrigerator at 12 ° C for 3 days in the dark, and placed in a refrigerator at 4 ° C for 25 days in the dark.
  • the yield of the carboplatin (23.3g) added in this round of reaction was 116.3%; for the total amount of carboplatin (99.9g) invested in this experiment
  • the total amount of the product was 106.7 g, and the total yield was 76.9%.
  • the fourth round of reaction the third round of reaction mother liquor weighs 2300g, ignoring the loss in the process, calculated according to the third round of yield (37.6g), after the third round of reaction, the reactants reduced in the system are: carboplatin 27.1 g and dicarboxylic acid 10.5 g.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 35 ° C for 30-60 minutes, and 10.0 g of medical activated carbon powder was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Filtration, the filter residue was washed with 2 x 22.5 ml of purified water, and the washings were combined with filtrate.
  • the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, placed in a refrigerator at 12 ° C for 3 days in the dark, and placed in a refrigerator at 4 ° C for 25 days.
  • the yield of carboplatin (27.1g) added by this round of reaction was 95.2%; for the total amount of carboplatin (127.0g) invested in this experiment
  • the total amount of the product was 142.5 g, and the total yield was 80.8%.
  • the resulting solution was transferred to a crystallization flask and allowed to stand at 12 ° C for 3 days, during which the crystal clusters grew and increased. Transfer to a 4 ° C refrigerator for 15 days. A flower-like transparent cluster is obtained. Vacuum filtration, vacuum-cooled with isopropanol precooled to 5 ° C and ethyl acetate precooled to 5 ° C, and dried under vacuum at room temperature to obtain the first reaction product of dicyclo platinum 131.4 g, yield 63.1%.
  • the second round of reaction the first round reaction mother liquor weighed 7225.3g, ignoring the loss in the process, calculated according to the first round of yield (131.4g), after the first round of reaction, the reduced reactant in the system is: carboplatin 94.7 g and 36.7 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 42 ° C for 30-60 minutes, and 30.0 g of medical activated carbon powder was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Filtered, the filter residue was washed with 2 x 65 ml of purified water, and the washings were combined with filtrate.
  • the third round of reaction the second round reaction mother liquor weighed 7243.8g, ignoring the loss in the process, calculated according to the second round of yield (129.7), after the second round of reaction, the reactants reduced in the system are: carboplatin 93.4 g and dicarboxylic acid 36.3 g.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 42 ° C for 30-60 minutes, and 30.0 g of medical activated carbon powder was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Filtered, the filter residue was washed with 2 x 65 ml of purified water, and the washings were combined with filtrate.
  • the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, placed in a refrigerator at 12 ° C for 3 days in the dark, and placed in a refrigerator at 4 ° C for 25 days in the dark.
  • the yield of carboplatin (93.4g) added in this round of reaction is 99.1%; for the total amount of carboplatin (338.1g) invested in this experiment
  • the total amount of the product was 389.6 g, and the total yield was 83.0%.
  • the fourth round of reaction the third round of reaction mother liquor weighs 7256.1g, ignoring the loss in the process, calculated according to the third round of yield (128.5g), after the third round of reaction, the reactants reduced in the system are: carboplatin 92.6 g and 35.9 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 42 ° C for 30-60 minutes, and 30.0 g of medical activated carbon powder was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Filtered, the filter residue was washed with 2 x 65 ml of purified water, and the washings were combined with filtrate.
  • the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, placed in a refrigerator at 12 ° C for 3 days in the dark, and placed in a refrigerator at 4 ° C for 25 days.
  • the yield of carboplatin (92.6g) added by this round reaction was 99.4%; for the total amount of carboplatin (430.7g) invested in this experiment
  • the total amount of the product was 517.3 g, and the total yield was 86.5%.
  • the fifth round of reaction the fourth round reaction mother liquor weighed 7263.2g, ignoring the loss in the process, calculated according to the fourth round of yield (127.7g), after the fourth round of reaction, the reduced reactant in the system is: carboplatin 92.0 g and 35.7 g of dicarboxylic acid.
  • carboplatin and dicarboxylic acid corresponding to the reduced amount were added, and the reaction was stirred at 42 ° C for 30-60 minutes, and 30.0 g of medical activated carbon powder was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Filtered, the filter residue was washed with 2 x 65 ml of purified water, and the washings were combined with filtrate.
  • the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, placed in a refrigerator at 12 ° C for 3 days in the dark, and placed in a refrigerator at 4 ° C for 25 days.
  • 123.5 g of bicycloplatin the yield of 96.7% of the carboplatin (92.0 g) added in this round of reaction; for the total amount of carboplatin (522.7 g) invested in the experiment
  • the total amount of the product was 640.8 g, and the total yield was 88.3%.
  • This round gave 7277.1 g of mother liquor.
  • the resulting solution was transferred to a crystallization flask and allowed to stand at 12 ° C for 11 days, during which the crystal clusters grew and increased. Transfer to a 4 ° C refrigerator for 7 days. A flower-like transparent cluster is obtained. Vacuum filtration, vacuum-cooled with isopropanol precooled to 5 ° C and ethyl acetate precooled to 5 ° C, and vacuum dried at room temperature to obtain the first reaction product of bicyclo platinum 8.963 g, yield 64.6%.
  • the mother liquor was collected to obtain 474 ml, and the mother liquor was analyzed by HPLC.
  • the carboplatin content was 4.9382 mg/ml, and the dicarboxylic acid content was 48.0559 mg/ml.
  • the second round of reaction According to the above-mentioned first round reaction mother liquor HPLC analysis data, the mother liquor contained 2.3407 g of carboplatin and 22.7785 g of dicarboxylic acid. To this mother liquor, carboplatin and dicarboxylic acid corresponding to the amount of reduction were added, that is, 7.6593 g of carboplatin and 4.4215 g of dicarboxylic acid were added. The reaction was stirred at 42 ° C for 30 minutes, 2.0 g of medical activated carbon powder was added, and the mixture was stirred at the same temperature for 30 minutes. It was filtered, and the residue was washed with 10 ml of purified water, and the filtrate was taken to filtrate.
  • the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, transferred to a refrigerator at 12 ° C for 8 days, and transferred to a refrigerator at 4 ° C for 12 days in the dark.
  • the yield of additional carboplatin (7.6593g) is 94.0%; for the total amount of carboplatin (17.6593g) invested in this experiment, the total amount of the product 18.9537g, the total yield was 77.3%.
  • the mother liquor was collected to obtain 470 ml, and 5 ml of water was added, and the mother liquor was analyzed by HPLC.
  • the carboplatin content was 4.8322 mg/ml, and the dicarboxylic acid content was 49.1537 mg/ml.
  • the third round of reaction According to the above-mentioned second round reaction mother liquor HPLC analysis data, the mother liquor contained 2.2953 g of carboplatin and 23.348 g of dicarboxylic acid. To the mother liquor, 7.7047 g of carboplatin and 3.852 g of dicarboxylic acid were added. The reaction was stirred at 42 ° C for 30 minutes, 2.0 g of medical activated carbon powder was added, and the mixture was stirred at the same temperature for 30 minutes. After filtration, the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, transferred to a refrigerator at 12 ° C for 8 days, and transferred to a refrigerator at 4 ° C for 14 days in the dark.
  • the fourth round of reaction According to the above-mentioned third round reaction mother liquor HPLC analysis data, the calculated mother liquor contained 2.3588 g of carboplatin and 21.4209 g of dicarboxylic acid. 25 ml of water, 7.6412 g of carboplatin and 5.7791 g of dicarboxylic acid were added to the mother liquor. The reaction was stirred at 42 ° C for 30 minutes, 2.0 g of medical activated carbon powder was added, and the mixture was stirred at the same temperature for 30 minutes.
  • the mother liquor was collected to obtain 485 ml, and the mother liquor was analyzed by HPLC.
  • the carboplatin content was 4.7729 mg/ml, and the dicarboxylic acid content was 48.9198 mg/ml.
  • the fifth round reaction According to the above-mentioned fourth round reaction mother liquor HPLC analysis data, the mother liquor contained 2.3149 g of carboplatin and 23.7261 g of dicarboxylic acid. To the mother liquor, 768851 g of carboplatin and 3.4739 g of dicarboxylic acid were added. The reaction was stirred at 42 ° C for 30 minutes, 2.0 g of medical activated carbon powder was added, and stirred at the same temperature for 30 minutes. After filtration, the obtained solution was transferred to a crystallization bottle, naturally cooled to room temperature, transferred to a refrigerator at 12 ° C for 8 days, and transferred to a refrigerator at 4 ° C for 14 days in the dark.
  • the mother liquor was collected to obtain 470 ml, and the mother liquor was analyzed by HPLC to determine a carboplatin content of 5.0647 mg/ml and a dicarboxylic acid content of 48.0071 mg/ml.
  • the sixth round reaction According to the above-mentioned fifth round reaction mother liquor HPLC analysis data, the calculated mother liquor contained 2.3804 g of carboplatin and 22.5633 g of dicarboxylic acid. To this mother liquid, 5 ml of water, 7.6196 g of carboplatin and 4.6367 g of dicarboxylic acid were added. The reaction was stirred at 42 ° C for 30 minutes, 2.0 g of medical activated carbon powder was added, and the mixture was stirred at the same temperature for 30 minutes. After filtration, the obtained solution was transferred to a crystallization flask, naturally cooled to room temperature, transferred to a refrigerator at 12 ° C for 8 days, and transferred to a refrigerator at 4 ° C for 12 days in the dark.
  • the vessel was washed with a small amount of purified water, and a total of 1063.1 g of a filtrate was obtained. One half of it was taken out, 532 g, and the fraction was subjected to rotary evaporation to dryness at 40 ° C under vacuum to give a residue of 28.2 g. The residue was poured into the remaining half of the filtrate, and the mixture was heated and stirred at a water bath temperature of 40 ° C, and dissolved for 10 minutes. 1.0 g of activated carbon was charged, and the mixture was decolorized and stirred for 30 minutes at the same temperature, and filtered. After standing at room temperature for 4 hours, it was transferred to a refrigerator at 12 °C.
  • the filter cake obtained by filtration was dried and weighed 3.4 g, which was the recovered crude carboplatin.
  • the mixture was poured into 84 ml of purified water, dissolved by heating at 75 ° C, decolorized with 1.24 g of activated carbon for 30 min, filtered, and cooled to obtain coarse and shiny granular crystals. After the filter was dried, it weighed 1.81 g, accounting for 9.1% of the initial input. After subtracting the product of bicycloplatin (yield 80.25%), the recovery was 45.8%. So far, the utilization rate of raw material carboplatin is 89.35%. The mother liquor of this refined carboplatin was evaporated to dryness under reduced pressure to give 1.62 g. If this residue is incinerated together with the activated carbon for decolorization during the reaction to recover platinum, the utilization rate of the precious metal platinum is 98%.
  • the mother liquid of Example 9 was taken as a raw material for recovery treatment.
  • the obtained cake was poured into 1500 g of purified water, and stirred at room temperature for 2 hours to obtain a slightly turbid solution. 8 g of activated carbon was added, and the mixture was decolorized by stirring at 45 ° C for 1 hour, and filtered, and the filtrate was naturally cooled to room temperature and then transferred to 12 ° C. Crystallize in the refrigerator. After the crystal appeared, it was transferred to a refrigerator at 4 ° C for 20 days to obtain granular carboplatin crystals. Filtered to 17.1 g. For the total amount of carboplatin invested in this example, it accounts for 3.27%. Therefore, the total utilization rate of carboplatin reached 97.3%.
  • the product obtained from the past two years has a slightly lower melting point or a poor crystalline form of bicycloplatinum, which has a total of 9.8 g. They are divided into different reaction batches, all of which are elongated needle-like crystals with melting points of 192.3 ° C to 194.5 ° C. Between, below the standard melting point of bicycloplatinum (above 198 ° C), to test the process of recrystallization.
  • the washing solution was incorporated into the filtrate, naturally cooled to room temperature, transferred to a refrigerator at 12 ° C for 3 days, and transferred to a refrigerator at 4 ° C for 30 days in the dark.
  • the crystals were sequentially rinsed with 5 ml of isopropanol precooled to 5 ° C and 5 ml of ethyl acetate precooled to 5 ° C, and transferred to a vacuum drier to remove residual solvent to obtain 6.13 g of colorless needle crystals.
  • the yield was 125.1%.
  • the molar ratio of 1,1-cyclobutanedicarboxylic acid to bicycloplatinum to be purified is 11.0
  • the molar ratio of carboplatin to bicycloplatinum to be purified is 1 to 1 for MR KB/DCP
  • water is for the bicyclic platinum to be purified.
  • the weight ratio is 65.3.
  • the refined yield exceeded 100% because part of the carboplatin formed bicyclo platinum during this process.
  • the crystallization mother liquid thus obtained is treated in the same manner as described above for the mother liquid treatment.
  • Recrystallization procedure 2 Recrystallization solution No. 2: 6.85 g (47.54 mmol) of 1,1-cyclobutanedicarboxylic acid was dissolved in 160 ml of purified water to prepare a recrystallization solution, and 4.00 g of bicycloplatinum to be purified ( 9.51 mmol) was put into the solution under stirring at 40 ° C, stirred and dissolved, and 0.3 g of activated carbon was added for decolorization for half an hour, followed by filtration. The filter residue was washed with 5 ml of purified water. The washing solution was incorporated into the filtrate, naturally cooled to room temperature, and placed in a refrigerator at 12 ° C for 3 days.

Abstract

提供一种高纯度双环铂针状晶体的工业化制备方法，包括：将卡铂和1，1-环丁烷二羧酸，以及水混合反应，结晶，制备得到的双环铂为针状晶体，收率超过85％，贵金属铂利用率超过97％。所述方法绿色环保，易于工业化生产。

Description

一种高纯度双环铂针状晶体的工业化制备方法 技术领域
本发明涉及一种医药化合物的制备方法，具体而言，本发明涉及高纯度双环铂针状晶体的工业化制备方法。
背景技术
双环铂(Dicycloplatin)据称是我国独立发明的铂类抗癌药。我国食品药品总局将其归入I类新药。其发明人认为，它是由主体分子卡铂与客体分子1，1-环丁烷二羧酸通过四条氢键所构成的超分子，其结构如下图：
Figure PCTCN2018000229-appb-000001
我们迄今已发现双环铂的研究报告和论文近50篇其中4件专利涉及其制备方法。双环铂发明人要求产品呈针状的结晶体，我们认为很有道理。因为通过结晶可以保证产品的纯度。考虑到双环铂在HPLC的过程中分解为卡铂和二羧酸，其纯度的测定需要同时计算这分解出的卡铂和二羧酸的数量，相互参照，这可能给产品纯度的判断带来歧义。在此情况下对产品性状的严格要求乃成为对于纯度的又一重保障。但是发明人的原创专利所披露的制备程序无法重复，其余三件专利所给出的产物均非双环铂发明人所要求的针状晶体。纯度也不够。我们迄今尚未见有任何一种程序适合工业生产。
原创专利CN1311183A(和CN1314357A)通过四个实施例说明双环铂的制备，即实施例1、3、4、7。其中唯有实施例1是以卡铂为原料：
Figure PCTCN2018000229-appb-000002
但该实施例没有提及产物的纯度和熔点。在其制备程序中，注明原料卡铂和环丁烷二羧酸的克分子数均为10.0mmol，据此，环丁烷二羧酸对于卡铂的摩尔比MR DA/KB等于1比1。但是该发明人所陈述的数值(卡铂3.54g，环丁烷二羧酸16.2g)所对应的摩尔数则分别为：卡铂(分子量371.3)9.534mmol和环丁烷二羧酸(分子量 144.1)112.42mmol，二者的摩尔比MR DA/KB为11.79。我们研究发现，遵循上述程序，无论MR DA/KB等于1比1还是11.79比1，都不能获得高纯度的双环铂针状晶体，得到的产物仅仅为原料卡铂。该专利中实施例3、4、7是以顺铂为原料合成双环铂，并报道产物的熔点为182-184℃。在这三个实施例中，实际投料的数量与发明人所注明的克分子数也有矛盾，没有说明全部必要的反应参数，尤其是全部4个实施例无一例外地以乙醇处理粗产品，并以水重结晶。作为一名化学家，理所当然地将“乙醇洗涤”理解为洗脱杂质，将“水重结晶”理解为精制，似乎十分合理。然而基于我们的研究，乙醇处理将令双环铂分解为卡铂和二羧酸，水的分解作用更快而且彻底。双环铂的针状晶体是从水溶液内析出的，却不能接触水，这一情况出乎人们的意料之外。这也许正是一些化学家不能成功获得合格产品的原因之一。总之上述专利中的四个实施例均不能给出该发明人所描述的双环铂针状晶体。因为分解所产生的二羧酸被乙醇洗脱而进入滤液，水重结晶导致残余的双环铂彻底分解，重结晶溶液在冷却下所给出的只能是反应的原料卡铂。发明人在2012年获得双环铂的新药证书之后2年，通过又一件专利CN104122280A发明人也婉转地承认了双环铂遇水分解的性质。
CN104693245A也公开了一种双环铂的制备方法。其实施例1公开了具体的制备方法，其中的卡铂与1，1-环丁烷二羧酸按照摩尔比1∶1混合。但该专利制备的产品并未涉及双环铂的晶体，其甚至没有报道产物的熔点。基于我们的研究，1，1-环丁烷二羧酸与卡铂按照1比1的比例混合，在溶液内不可能析出双环铂。该专利的制备程序与其所给出的分析结果不完全匹配。我们按照该专利的程序，所得到的产物是粉末状混合物。
CN106132408A也公开了一种双环铂的制备方法。其中公开了10个实施例，除实施例5使用卡铂118.6g而外，参与反应的卡铂规模为15mg至5g之间。实施例5所用的二羧酸对于卡铂的摩尔比为1.31(417mmol/319mmol)，水对于卡铂的重量比为5。基于文献报道和我们的实验，卡铂本身在水中的溶解度仅为1.8％，即使考虑到二羧酸的助溶作用，也不超过3％，所以欲令卡铂溶解，在室温下水的用量不能低于卡铂重量的30倍。该实施例5所用的水的量仅为卡铂重量的5倍，所以反应必定是非均相的。在室温甚至5℃的低温下的非均相反应，难以均匀彻底，难以给出完整的晶体。而且该专利没有指明每一实施例的收率，特别是没有说明实施例产品的纯度。另外，该专利发明人对其产品无一例外地均以水洗涤。基于我们的研究， 水能很快并且彻底地令双环铂分解成卡铂和二羧酸。这一事实也已经被双环铂的发明人在其后期专利CN104122280A中所认可，其中说明书第2页，第4和7行公开了“双环铂在溶液中完全解离成卡铂和环丁二酸”；“双环铂在溶液状态下(例如水溶液)中完全解离成卡铂和环丁二酸。”，所以经过水洗的双环铂必定含有其所分解而成的卡铂，影响产品的纯度。
为了制得高纯度的双环铂针状晶体，基于我们的研究，必须提供足量的溶剂水以备双环铂温和地结晶。在此前提下，二羧酸对于卡铂的克分子配比MR DA/KB必须大于3。否则，即便溶剂水的量足够，双环铂也不可能以针状晶体析出。而且也有文献(Determination methods for the anticancer drug dicyclopatin，a supramolecule assembled through hydrogen bongding.，Xuqing Yang，Jianwei Zheng，Qinghua Song，et al；Analyst，2015.140.2074-2712.)指出，将卡铂和二羧酸的混合溶液旋转蒸发至干或者冷冻干燥，均可产生双环铂，但转化不可能彻底，更不可能形成好的晶体，所以这不能成为一种制备方法，更不可能成为一种工业化制备方法。
另外，CN106132408A还将不同的溶剂试用于制备，如乙醇、乙腈、异丙醇等，得到混合物，效果也不理想，反应不完全，难以将残余的卡铂与所期待的产物双环铂彻底分离。
对于现有的前述三件专利所提出的双环铂的制备方法，我们不止于上述理论和逻辑的分析，更对其实施例加以严格的模拟(参见本申请的实施例部分)，结果显示，现有的技术或者不能给出正确的产品，或者产物的纯度不明，或者不能给出高纯度的产物结晶，不能满足食药总局对于药物纯度的基本要求。他们的反应规模也很小，距离工业化很远。因此我们提出一种制备高纯度针状双环铂晶体的制备方法和工业化程序。
专利CN 106995467 A是在二羧酸对卡铂的克分子比例为1至1.5的条件下，利用微波加速双环铂的形成，提高生产效率。其反应产物的收率为65.3％至90.0％，纯度为81％至97％，尚未符合药典要求。分析方法不明，没有报道产物的DSC熔点，也没有目测熔点。
上述专利文献和非专利文献，其内容在此全部引入并做参考。
发明内容
本发明的目的在于提供一种高纯度针状双环铂晶体的制备方法。
本发明的另一目的在于提供一种高纯度针状双环铂晶体的可工业化的制备工 艺。
为达到上述发明目的，本发明采取下述技术方案：
一种高纯度双环铂针状晶体的工业化制备方法，其包括下述步骤：
(1)将卡铂和1，1-环丁烷二羧酸，以及水混合形成澄清溶液，反应；
(2)直接将步骤(1)的反应液结晶，不经精制直接得到高纯度针状晶体；
术语“精制”是本领域技术人员熟知的，指的是化学领域中，对制备得到的产物进行纯化处理，优选重结晶或色谱纯化。
所述方法的反应条件为：1，1-环丁烷二羧酸对于卡铂的摩尔比为4～16；反应时间为0.5～6h；所述水为去离子水；反应温度为室温～50℃，优选地，所述室温为10～35℃；优选地，溶剂水对于卡铂的重量比例为30～55；优选地，所述的结晶条件为：反应液经活性炭脱色后，在2-8小时内自然冷却至室温，然后在10-14℃避光静置，结晶4-10天，最后于0～6℃静置结晶15-30天。
优选地，所述的反应条件为：1，1-环丁烷二羧酸对于卡铂的摩尔比为4～10；反应时间为0.5～2h；所述水为去离子水；反应温度为室温～45℃，优选地，所述室温为10～35℃；优选地，溶剂水对于卡铂的重量比例为40-50；优选地，所述的结晶条件为：反应液经活性炭脱色后，在2-8小时自然冷却至室温，然后在10-14℃避光静置结晶4-10天，最后于0～4℃静置结晶15-30天。
优选地，所述方法还包括步骤(3)，即对于步骤(2)的母液加以回收套用2至6次，使产品双环铂的总收率提高至85％以上；优选地，根据计算结果或者根据结晶母液中物质数量的HPLC分析结果，向所述母液中补充相应量的1，1-环丁烷二羧酸和卡铂，重复步骤(1)和(2)。
优选地，所述方法还包括步骤(4)，即对于步骤(2)和(3)所获得的产品双环铂在室温下自然晾干，或者在减压过滤的同时用预先冷却至5℃的异丙醇和乙酸乙酯顺次迅速喷雾淋洗
优选地，所述方法还包括步骤(5)，即对于步骤(3)的最终母液在55℃以下避光加以适当浓缩，回收双环铂。
优选地，所述方法还包括步骤(6)，即对于步骤(5)所产生的二次母液在55℃以下避光彻底浓缩至干，通过乙醇或者异丙醇洗涤以回收过量的1，1-环丁烷二羧酸，滤饼再以水重结晶以回收卡铂；精制卡铂所得到的母液蒸干之后，可与历次脱色的活性炭一同焚烧以回收贵金属铂，使得贵金属铂的利用率达到97％以上。
优选地，所述方法还可以对纯度低的双环铂使用特制混和溶液进行精制，所述特制混和溶液为：1，1-环丁烷二羧酸的水溶液，或环丁烷二羧酸与卡铂在水中的混合溶液。
本发明还提供了双环铂或制备双环铂的母液在抗菌或抗病毒方面的用途；优选地，所述的菌为金黄色葡萄球菌、表皮葡萄球菌、蜡样芽孢杆菌、枯草芽孢杆菌、乙型溶血性链球菌、痤疮丙酸杆菌、克雷伯氏肺炎菌、铜绿假单胞菌、大肠杆菌、幽门螺旋杆菌、伤寒沙门菌、鼠疫菌、副溶血性弧菌、嗜麦芽窄食单胞菌、醋酸钙不动杆菌或乙肝病毒。
本发明制备得到的双环铂为针状晶体，DSC熔点处于198至202℃之间，不仅远高于原创专利所报道的182-184℃，也高于发明人其后宣布的198℃(Analyst，2015.140.2074-2712.)。XRPD分析不显示卡铂11.4°的衍射峰。HPLC分析显示卡铂和二羧酸的含量均处于97-103％，不显示任何其它的吸收峰，卡铂的分析计算值与二羧酸的分析计算值之间的克分子比例在0.95-1.05之间，符合双环铂发明人所提出的要求。此三项HPLC指标，结合晶形、DSC熔点以及XRPD的要求，足以保证产物的纯度超过99.9％。未套用母液时所得双环铂收率达到70％，套用母液数次后所得双环铂收率大于85％。
专利CN1314357A的实施例1中记载了：制备双环铂时，卡铂和1，1-环丁烷二羧酸的投料量均为10.0mmol，也就是二羧酸对于卡铂的摩尔比例MR DA/KB为1比1。但我们的实验显示，在如此配比下，不能获得双环铂晶体，只给出原料卡铂，表1列出了在该配比下较有代表性的实验(除非另有标注，产物单位均以表头数据所示)。
表1 MR DA/KB等于1比1的实验
Figure PCTCN2018000229-appb-000003
Figure PCTCN2018000229-appb-000004
总之，当MR DA/KB等于1时不能得到所期待的产物双环铂，参见本申请实施例1。
按照专利CN1314357A实施例1所投入的环丁烷二羧酸(16.2g)和卡铂(3.54g)的实际数量，计算MR DA/KB并非等于1比1而是等于11.79比1。我们发现，按照如此配比，“搅拌溶解”的确可以产生双环铂。产物在反应后期即有部分析出，再“旋转蒸发至干”，便得到双环铂与大大过量的1，1-环丁烷二羧酸的混合物，它以结晶性的粉末状态出现。按照专利中所述步骤，向混合物中“加入乙醇50ml，搅拌2小时， 过滤，10ml×3乙醇洗”。因为环丁烷二羧酸在乙醇中的溶解度很大(而双环铂或者卡铂在乙醇中的溶解度很小)，经过洗涤和过滤，过量的环丁烷二羧酸进入溶液，便得到双环铂固体。那是一种白色的结晶性粉末，收率达到95％。DSC显示卡铂的存在，熔点也相应地偏高，熔距很长，197.3-204.9℃。更加严重的问题在于，按照其公开的内容，下一步骤为“蒸馏水重结晶”。我们发现双环铂在水中即彻底分解为组成它的主体和客体分子卡铂和环丁烷二羧酸。所以投入“蒸馏水重结晶”之后所得到的结晶体，呈粒状，核磁共振谱证明其为卡铂，并非“标题化合物”，参见本申请实施例2。
还需指出的是，专利CN1314357A所述程序中的乙醇洗涤并不是一项安全的措施，因为乙醇对于双环铂有破坏作用。试对比核磁共振图谱：在乙醇洗涤之前表征双环铂分子内卡铂部分的峰值为2.00，环丁烷二羧酸部分的峰值为2.05，二者的比例为0.976比1(参见图1)。经过乙醇洗涤之后，相应的比例变成了2.00比1.71，等于1.17(参见图2)，这显示对应于卡铂部分的峰值增加，增加的数值对应于真正的卡铂，它是因为双环铂被乙醇分解而产生的。分解所产生的环丁烷二羧酸随着洗涤液进入了吸滤瓶。
我们发现，1，1-环丁烷二羧酸对于卡铂在水中有一定的助溶作用，卡铂在水中的溶解度，随着水中环丁烷二羧酸含量的增加而提高。当MR DA/KB等于1时，从中不难析出卡铂。而当MR DA/KB等于2时，从反应液中既不析出双环铂，甚至也难以析出原料卡铂。将MR DA/KB提高到3，反应液经过适当的冷却程序，就会析出粒状与针状的混合晶体，这两种晶体的核磁共振谱显示它们分别是原料卡铂和所期待的产品双环铂。配比MR DA/KB达到4比1，析出的晶体全部是针状的双环铂。进一步提高MR DA/KB，则可发现双环铂的生成和结晶条件相当宽泛，将反应温度、溶剂量(H 2O/KB)、结晶的温度和时间这些参数适当组合，都能给出双环铂的晶体。
虽然在广泛范围内的参数组合都能给出双环铂的结晶体，这些参数不仅影响产物晶体析出的速度，晶体的完美程度，还影响晶体的DSC吸热峰值(熔点)和晶体的颜色。双环铂晶体的特征是细而长，我们得到的正是针状的晶体。
反应以水为溶剂，我们的研究显示，水量对于原料卡铂的重量比例太大，双环铂的针状晶体析出很慢，收率降低；比例太低，虽然收率提高，但晶体形状欠佳。而且为使原料溶解，不得不提高反应温度，产物可能因副产物的形成而显微黄色，高浓度下产物析出太快，也影响产物的晶形。
我们选择水对于原料卡铂的重量比为50和45倍。在这两种溶剂量的配比下，我们进一步研究了不同MR DA/KB比值的影响，见表2
表2，在H 2O/KB＝45和反应温度40℃下，不同MR DA/KB配比所给出的反应结果
Figure PCTCN2018000229-appb-000005
Figure PCTCN2018000229-appb-000006
从上表可见MR DA/KB高于4(不包括4)不超过10的情况下，产物双环铂的DSC熔点数据均高于198℃。HPLC分析结果显示全部样品均符合双环铂发明人的质量标准。
专利CN1311183A的实施例1没有明确反应的温度和时间等参数。我们认为，既然双环铂是卡铂与环丁烷二羧酸通过氢键形成的超分子化合物，在形成的过程中不发生任一分子结构的破坏，而氢键的键能一般不超过30Kcal/Mol，远低于正常共价键的键能，所以反应物过渡态的能垒不高，反应的条件应该温和。我们乃将制备反应温度的范围设置于35至45℃之间。
反应液经过活性炭脱色，过滤。得到的反应液自然冷却至室温，移入12℃冰箱内冷却结晶。再转入4℃的冰箱内，让晶体成长，且令更多的晶体析出。为获得尽可能多的结晶产物，在4℃的环境下需要放置15至30天。
过滤得到闪亮的无色针状晶体。在室温下晾干，或者在真空下用预先冷却至5℃的异丙醇快速喷淋洗涤，随即用预冷的醋酸乙酯洗除残余的醇。立即真空干燥，得到所期待的双环铂针状晶体。
为提高双环铂制备的总收率，我们在从制备反应液中分离出产物双环铂的针状晶体之后，向此结晶母液中补加相应数量的卡铂、二羧酸和水，执行第2轮制备反应。起初我们基于产物双环铂的数量计算出所消耗的卡铂和二羧酸，据此向第二轮制备补充原料。这第2轮反应通常依然给出与第1轮反应相同的结果。就所补加的反应原料卡铂而言，此轮的收率接近定量；但是随着母液套用次数的增加，考虑到不可避免的操作损耗以及副反应的存在，乃改进为通过HPLC检核，依据母液内剩余卡铂和二羧酸的量添加原料。利用母液4至5轮，总收率率达到90％。
母液套用可以显著地提高原料的利用效率，如表3所示
表3，母液套用的优势，按单次卡铂投料1Kg，MR DA/KB＝6，每轮收率60％计算
Figure PCTCN2018000229-appb-000007
Figure PCTCN2018000229-appb-000008
对比可见，母液回收套用5次，总收率可达到90％。通过此法制备大约5Kg(4998g)双环铂晶体，可以比不套用母液节约2Kg卡铂以及10.5Kg 1，1-环丁烷二羧酸，也就是每公斤产品可节约卡铂400g，1，1-环丁烷二羧酸2100g。卡铂当前的市场价格是每公斤20万元，经济效益明显。
另一方面，母液的利用次数愈多，原料的利用率(总收率)的增益越小。影响产品质量的可能性越大。我们将母液套用的次数掌握在不超过5次。
按照本工艺生产的双环铂针状晶体，经过核磁NMR、质谱MS、差示扫描量热分析DSC、X射线粉末衍射XRPD、X射线单晶衍射等分析项目的检测，乃至针对多种肿瘤株抑制活性的验证，均符合双环铂发明人所报道的结果，证明合格，参见图3至图7。所得产物的晶胞数据为：
Figure PCTCN2018000229-appb-000009
α＝90.00°，β＝95.06(0)°，γ＝90.00°，
Figure PCTCN2018000229-appb-000010
Z＝4。
双环铂的结晶母液经过数次套用，最后一次套用的母液终将面对如何利用或处理的问题。本发明还提供了一种高纯度双环铂针状晶体生产中结晶母液的处理方法。
我们首先取出20％至50％的母液(取决于母液经过套用的次数，未经套用的母液取50％，参见实施例11)，在45℃以下减压避光浓缩至干。再将残余物在45℃下溶解于其余的母液主体中。加入残余母液重量3％的活性炭，在45℃下避光搅拌脱色1小时。过滤，顺次在12℃和4℃的环境中结晶。可获得又一份双环铂针晶，收率达到5-10％。同时给出第二次结晶母液。
将这第二次结晶母液在55℃下避光减压蒸发至干，所得残余物为淡黄色的无定形粉末或者结晶性粉末。用异丙醇处理该固体，在室温下搅拌8-12小时，该残余物转化为卡铂和二羧酸(并包含反应中所产生的副产物杂质)，过滤。环丁烷二羧酸因为在醇中的溶解度很大而进入滤液。滤液蒸干得到回收的1，1-环丁烷二羧酸，为洁白的固体粉末，回收率超过90％，稍加精制甚至不精制即可用于双环铂的制备反应。如此得到的滤饼再用少量醇处理一次。滤饼的主要成分即为卡铂，前期的数轮反应以及历次母液浓缩这一系列过程中所产生的杂质亦在其中。
在乙醇或者异丙醇中，双环铂在与大大过量的环丁烷二羧酸共存时尚属稳定，而单纯的双环铂在醇中分解。如此得到的粗品卡铂在40℃以水溶解，水令残余的双环铂彻底分解，溶液略显乳色。不能尽溶。向其中加入活性炭于40℃搅拌脱色，过滤后，顺次在12℃和4℃下结晶。注意：如此所得到的晶体呈粒状，此即为纯粹的卡铂。
这精制卡铂所得到的母液蒸干之后，可与历次脱色的活性炭一同焚烧以回收贵金属铂。
遵循本工艺，贵金属铂的利用率达97％。
可见本工艺简洁严谨，原料利用率高，完全不造成环境污染。
双环铂的精制
双环铂遇水分解，所以不能用水重结晶。双环铂不溶于有机溶剂，不能用有机溶剂重结晶。这问题困扰相关的研究者，并导致双环铂产品质量的不稳定。但作为一套生产工艺，需要一种精制的方法。因为意外的客观原因或者主观的错误而产生不合格的产品在生产中不能绝对避免，为此我们发明出一种重结晶的方法如下：
第一步，配制重结晶溶液。
重结晶溶液1号：对于每1克分子重量的待精制双环铂：水(65倍重量)：环丁烷二羧酸(11克分子重量)：卡铂(1克分子重量)三者所配成的溶液。
重结晶溶液2号：对于每1克分子重量的待精制双环铂：水(32倍重量)：环丁烷二羧酸(5克分子重量)二者所配成的溶液。
第二步，将1克分子重量的待精制双环铂在30-50℃下溶解于上述1号重结晶溶液，在同温度下搅拌脱色1小时，过滤，滤液按照双环铂的制备程序结晶。
该重结晶程序的收率为100％至120％。超过100％的原因是，精制溶液内的部分卡铂也转化为双环铂析出。结晶所产生的母液按照前述母液的回收程序处理。
或者：将1克分子重量的待精制双环铂在30-50℃下溶解于上述2号重结晶溶液，在同温度下搅拌脱色1小时，过滤，滤液按照双环铂的制备程序结晶。该重结晶程序的精制收率为60％左右，残余的双环铂存在于结晶母液内，可以按照前述母液的回收程序处理。
最后，表4将我们的生产工艺与已有制备双环铂的方法加以对比。
表4，本申请工艺与现有技术所得产品技术指标之比较
Figure PCTCN2018000229-appb-000011
Figure PCTCN2018000229-appb-000012
附图说明
图1是实施例2从反应液内析出的双环铂的NMR，其中对应于二羧酸部分的四元环的积分值相对于卡铂部分的比例为2.05比2.00，显示产物为吸附有二羧酸的双环铂)；
图2是实施例2经过乙醇洗涤之后的产物的NMR，其中乙醇令部分双环铂分解成二羧酸和卡铂，前者被洗脱，故对应于二羧酸部分的四元环的积分值相对于卡铂部分的比例为1.71比2.00，显示产物中杂有卡铂；
图3是实施例6产物双环铂的MS；
图4是实施例6产物双环铂的NMR；
图5是实施例6产物双环铂的DSC，其中熔点为199.6℃；
图6a是实施例6产物双环铂的XRPD，对应于卡铂的衍射峰11.4°完全不显现，说明不含卡铂。
图6b是卡铂的XRPD，卡铂在11.4°处有特征衍射峰；
图6c是二羧酸的XRPD；
图7a是实施例6产物的针状晶体；
图7b是产物双环铂的晶体，超过25g制备规模所得到的双环铂，产物晶体依然呈针状；
图8a是双环铂的HPLC曲线；
图8b是卡铂的HPLC曲线；
图8c是1，1-环丁烷二羧酸的HPLC；
图9是实施例2产物晶体的NMR，为卡铂；
图10是实施例2通过乙醇洗涤所回收的1，1-环丁烷二羧酸的NMR；
图11是实施例2产物的晶体照片，为粒状的卡铂；
图12是实施例2产物晶体的DSC曲线，熔点为232.6℃；
图13是实施例2析出的产物经过乙醇洗涤后，再经异丙醇处理的NMR，主体为卡铂，其中含双环铂12％；
图14是实施例2析出的产物经过乙醇洗涤后，再经乙醇处理的NMR，主体为卡铂，其中含双环铂不足2％，说明乙醇的分解作用强于异丙醇；
图15是实施例3产物的DSC；
图16是实施例5产物的DSC；
图17是实施例11，MR DA/KB为7.0的条件下产品双环铂的DSC曲线，熔点为199.5℃；
图18是双环铂母液处理工艺流程图。
实施例
下面通过实施例对本发明作进一步说明。应该理解的是，本发明实施例所述方法仅仅是用于说明本发明，而不是对本发明的限制，在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。如无特别说明，本发明所有原料和试剂，均为市售产品。
分析仪器
1、熔点测定，予华显微熔点测定仪仪器有限责任公司，型号X-5；
2、X射线粉末衍射分析，XRPD测试仪器：D8 ADVANCE X-ray diffraction instrument，德国Bruker公司；
测定条件：CuKa radiation；tube voltage 40 KV；tube cureent 40 mA；Scanning mode 0/2 θscanning；scanning speed，0.6s/step；step length，0.019°/step；
3、核磁共振仪(NMR)瑞士BRUKER AVENCE II，400MHz；
4、示差扫描量热分析仪(DSC)，德国耐施，NETZSCH，型号DSC204F1，2005；
5、X射线单晶衍射，CCD Single crystal X-ray diffractometer，日本理学，SATURN724+。
6、高效液相层析仪：Agilent 1260 Infinity II高效液相色谱仪，Agilent 1260 Infinity II紫外检测器，ICC集成式柱温箱，Agilent 1260 Infinity II自动进样器，Agilent OpenLAB CDS工作站
HPLC的条件是：色谱柱：Poroshell 120 EC-C18 4.6x150mm，4um；流动相：Ph3.0磷酸盐缓冲液∶甲醇＝95∶5；流速：1ml/min；进样量：5ul；柱温：40℃；检测波长：220nm。
附图8a-8c显示卡铂、1，1-环丁烷二羧酸、双环铂的HPLC图线。
实施例1和2是对于原创专利CN1311183A(和CN1314357A)的检核。实施例3是对于已有专利申请CN104693245A的检核。实施例4和5是对于已有专利申请CN106132408A的检核。
实施例1：模拟双环铂原创专利CN1311183A中的实施例1，取1，1-环丁烷二羧酸对卡铂的摩尔比MRDA/KB为1比1(参见“发明内容”中的表1和表2。)
将卡铂3.5464g(9.5513mmol)投入于200g纯净水(水/KB＝56.4)，在42℃(水浴温度)下避光搅拌约25分钟至全溶。搅拌下加入1，1-环丁烷二羧酸1.3789g(9.5690mmol，MR DA/KB＝1.0)，搅拌溶解。继续搅拌30分钟。在55℃(水浴温度)下减压蒸干。向此固体中加入无水乙醇50ml，室温下搅拌2小时；过滤，滤饼用乙醇10ml×3洗涤。滤饼真空干燥后重3.7g。将其投入纯净水130ml中，42℃下搅拌溶解，得到澄清的溶液，将其放入12℃的冰箱内冷却。5天后析出粒状的晶体。移入4℃冰箱并保持6天。过滤分离出晶体，重1.21g，回收率34.1％。NMR与本申请实施例2的产物相同(参见图9)显示其为卡铂。熔点227.5℃(分解炭化)，与市售的商品卡铂(熔点227.4℃，分解炭化)相同
实施例2：严格模拟双环铂原创专利CN1311183A中的实施例1，取1，1-环丁烷二羧酸对卡铂的摩尔比MR DA/KB为11.79
本实施例严格遵从双环铂原创者专利CN1311183A中的实施例1的程序，仅按比例略微增加投料量(卡铂3.54g增加为5.0g；环丁烷二羧酸16.2g相应增加为22.9g，溶剂水的量以及此后洗涤所用的乙醇量均按比例增加。)
将5.0g(13.47mmol)卡铂投入488.6g纯净水，室温下搅拌35分钟溶解。加入22.9g(158.9mmol)1，1-环丁烷二羧酸(对于卡铂的摩尔比例MR DA/KB等于11.79)，5分钟后溶清；10分钟后溶液转呈乳白色，析出细小的晶体。用不锈钢括刀挑出数粒结晶，NMR(参见图1)：(D 2O)δ，1.79，pent，2H(积分值2.00，卡铂部分)；1.89，pent，2H，(积分值2.05二羧酸部分)；2.43，t，4H(二羧酸部分)；2.75，t，4H(卡铂部分)。依据卡铂部分对应峰值(2.00)和二羧酸部分对应峰值(2.05)推测，这是内含残余二羧酸大约3％的双环铂。
按照原创专利的程序再搅拌25分钟，在60℃(水浴温度)下减压蒸干，得到粉末状固体27.7g。按照原创专利，向此固体中加入无水乙醇70.6ml，室温下搅拌2小时；过滤，滤饼用乙醇14ml×3洗涤。滤饼真空干燥后重6.6g。NMR(参见图2)：(D 2O)δ，1.77，pent，2H(积分值2.00，卡铂部分)；1.88，pent，2H，(积分值1.71，二羧酸部分)；2.43，t，4H(二羧酸部分)；2.75，t，4H(卡铂部分)。基于卡铂对应吸收峰值(2.00)和二羧酸对应峰值(1.71)可以推断，这是内含卡铂约15％的双环铂。该粗品的熔点为197.3-204.9℃。
滤液旋转蒸发至干，得20.5g，核磁共振谱：NMR(参见图10)：(D 2O)δ，；1.87，pent，2H；2.42，t，4H。显示其为纯度很好的1，1-环丁烷二羧酸，内含少量乙醇。
取上述粗品双环铂3.4g(总量6.6g)继续执行原创专利CN1311183A实施例1的操作程序“蒸馏水重结晶”：在42℃下将其溶解于100g纯水，置于12℃冰箱内结晶1天后即出现漂亮的粒状晶体(参见图11)，转入4℃继续结晶16天，过滤分离，晶体干燥后重1.1g，NMR(参见图9)：(D 2O)δ，1.80，pent，2H；2.77.t，4H显示其为卡铂，DSC谱图参见图12，熔点232.6℃，对反应所投入的原料而言，回收率44.7％。
该实验给出如下3项结论：
1、遵照双环铂发明人的操作程序只能给出卡铂，不能获得期待的产物双环铂。
2、对比乙醇洗涤前后的晶体，核磁共振谱显示：前者是含有大约3％残余二羧 酸的双环铂。乙醇洗涤后，成为含有大约15％卡铂的双环铂，这说明对应于卡铂部分的峰值权重增加，这部分卡铂是因为部分双环铂被乙醇以及双环铂粗品中所含的微量水分解而产生的。由此可见乙醇对于双环铂有破坏作用，乙醇洗涤不是一项安全的措施。专利原创者以乙醇洗涤粗产物不妥。
为了进一步了解醇类对于双环铂的破坏作用，我们作了如下次级实验：
从乙醇洗涤并干燥的滤饼中取出115.6mg，加入异丙醇5.0ml，室温下搅拌过夜，过滤得到异丙醇处理的产物85mg。NMR(参见图13)：(D 2O)δ，1.78，pent，2H(积分值2.00，卡铂部分)；1.88，pent，2H，(积分值0.22，二羧酸部分)；2.41，t，4H(二羧酸部分)；2.76，t，4H(卡铂部分)。由此推断该样品是含有约12％双环铂的卡铂。
同时从乙醇洗涤并干燥的滤饼中取出119.3mg，再加入乙醇5.0ml，室温下搅拌过夜，过滤得到再经过乙醇处理的产物78mg。NMR(参见图14)：(D 2O)δ，1.78，pent，2H(积分值2.00，卡铂部分)；1.88，pent，2H，(积分值＜0.05，二羧酸部分)；2.41，t，4H(二羧酸部分)；2.76，t，4H(卡铂部分)。由此推断该样品是卡铂，所含双环铂的量低于2％。
对比上述两个产物，二者的主要成分均为卡铂，而前者所含双环铂的数量(12％)明显高于后者(2％)，这说明在同样的条件下，异丙醇对于双环铂的破坏作用比乙醇轻微。
如果将上述两个产物和二次处理前的滤饼加以对比，则可得出又一结论：双环铂与过量的二羧酸共存时，对于醇的抵抗力较强。
3、水对于双环铂的破坏作用超过醇类，双环铂在水中彻底分解。乃至用“蒸馏水”对双环铂“重结晶”的结果只能给出卡铂。原创专利中的实施例1继用乙醇处理后再用水重结晶，所给出的产品必定是原料卡铂。
实施例3，本实施例严格模拟专利CN104693245A中的实施例1
将卡铂5.1g(137.4mmol)和二羧酸2.0g(138.8mmol，MR DA/KB等于1.0)投入225ml注射用水，室温(25℃)下搅拌，经2.5小时溶解。再搅拌1小时，在室温下避光静置7天，在40℃下减压浓缩至干。得产物7.05g，收率99.3％；肉眼观察该样品呈结晶性粉末；在显微镜下呈现细碎的针状和很小的粒状晶体(两种晶体暗示其为混合物)；熔点165.3℃转为灰色185.2℃出现黑点，200.2℃全部变黑。DSC(参见图15)，可见二羧酸吸收峰，此后逐渐升高，转向双环铂的吸收峰，这是卡铂存在的特点， 显然是一个混合物。
实施例4，本实施例严格模拟专利CN106132408A中的实施例5，只缩小了反应的规模
将二羧酸2.53g(175.5mmol)投入25ml水中，室温避光搅拌，立即溶解。再加入卡铂5.0g(134.7mmol，MR DA/KB等于1.30)在搅拌下形成乳白色的混悬液，室温搅拌6小时。分批向水浴内加入冰块，控制降温速度为每小时20℃，降温到5℃后转入5℃冰箱内避光静置19小时。在此整个过程中，反应物始终为非均相的混合物。过滤，滤饼用少量水洗，真空干燥，得到固体产物6.2g，收率89.3％。熔点202.4℃变灰色，205.2℃全黑。
实施例5，本实施例严格模拟专利CN106132408A中的实施例7，只将反应规模放大至10倍
在室温下将卡铂500mg(1.347mmol)投入水28ml中，40分钟后，向其中加入二羧酸194mg(1.346mmol，MR DA/KB等于1比1)，很快溶解。继续搅拌70分钟，50-55℃下减压旋转蒸发至干，得到白色固体粉末689mg，收率99.3％。该样品即使在显微镜下依然呈粉末状。熔点180.3℃转为灰色，193.4℃变黑，202.7℃显微镜视野下全黑一片。熔距如此之长，DSC谱图见图16，显示为混合物。
实施例6 在MR DA/KB等于5.2的配比下对反应母液套用3次，每次套用按照前一轮所得双环铂的量补加原料卡铂和二羧酸：
第一轮反应：将卡铂10g(26.9mmol)和1，1-环丁烷二羧酸20.1g(139.5mmol，MR DA/KB等于5.2)在35℃下溶解于400ml医用纯净水(H 2O/KB等于40)，在同温度下搅拌至完全溶解，大约需要半小时。继续搅拌30分钟，加入2.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×4ml(反应用水量的2％)纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后放入12℃冰箱内避光冷却，5天后再放入4℃冰箱内结晶。针状的晶体逐渐长大、增多，在数天内形成花朵样透明的晶簇。结晶过程持续半月以上，真空吸滤。室温下真空干燥，得到第一轮反应产物双环铂8.15g，收率58.7％。
第二轮反应：上述第一轮反应中过滤所得母液重423.0g，忽略过程中的损失，按第一轮的收率(8.15g)计算，经过第一轮反应，系统内减少的反应物是：卡铂5.87g和二羧酸2.28g。向此母液中补加与减少量相对应的卡铂和二羧酸，在35℃下搅拌反应30-60分钟，加入2.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤 渣用2×4ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，冷却至室温后放入12℃冰箱内结晶5天，再转入4℃冰箱内结晶。真空吸滤，在真空下用预冷至5℃的异丙醇和预冷至5℃的乙酸乙酯迅速顺次淋洗，室温下真空干燥，得到第二轮产物双环铂8.00g，就补加的卡铂(5.87g)而言收率98.2％；就本实验所投入的卡铂总量(15.87g)而言，产物总量16.15g，总收率68.9％。
第三轮反应：此第二轮母液重432.9g，忽略过程中的损失，按第二轮收率(8.00g)计算，经过第二轮反应，系统内减少的反应物是：卡铂5.76g和二羧酸2.24g。向此母液中补加与减少量相对应的卡铂和二羧酸，启动第三轮反应，按照同样程序获得第三轮产物双环铂7.00g，就补加的卡铂(5.76g)而言收率87.5％；就本实验所投入的卡铂总量(21.63g)而言，产物总量23.15g，总收率77.10％。
第四轮反应：此第三轮母液重413.4g，忽略过程中的损失，按照第三轮收率(7.00g)计算，经过第三轮反应，系统内减少的反应物是：卡铂5.04g和二羧酸1.96g。向此母液中补加与减少量相对应的卡铂和二羧酸，启动第四轮反应，按照同样程序获得第四轮产物双环铂6.9g，就补加的卡铂(5.04g)而言收率98.6％；就本实验所投入的卡铂总量(26.67g)而言，产物总量30.05g，总收率81.2％。
二、三、四轮反应的设计和执行乃基于前轮反应母液的利用。利用母液的结果令反应的总收率提高。第二、三、四轮反应的产物均显示很好的品质，DSC所表征的熔点均与标准品相符。另一方面，母液利用的次数越多，总收率的增益越小。优选，母液利用的次数为不超过五次。母液结束循环套用后，即对母液作回收双环铂、二羧酸和回收卡铂的处理。
因为双环铂的制备要求原料二羧酸对于卡铂的克分子比例超过4，按照配比为5估算，产物所析出的溶液中二羧酸的浓度超过3.1％；按配比7估算则超过4.6％，过滤得到的针状晶体难免吸附母液，应予清除。但双环铂遇水或醇将迅速分解，清除吸附母液乃成为一项难题。我们起初采用的方法是将其倾倒在滤纸上吸干。在对比数种溶剂的基础上，我们乃采用冷的异丙醇喷雾淋洗，再用冷的醋酸乙酯洗脱异丙醇。两种方法所得到的产品均符合晶形、熔点、HPLC含量这三项质量指标。因为异丙醇也能分解双环铂，喷雾淋洗所用的溶剂不仅必须预先冷却，也应控制数量，通常淋洗至出现滤液为止。
实施例7，在MR DA/KB等于5.15的配比下对反应母液套用3次，每次套用按照前一轮所得双环铂的量补加原料卡铂和二羧酸：
第一轮反应：将卡铂25.0g(67.33mmol)和1，1-环丁烷二羧酸50.0g(346.98mmol，MR DA/KB等于5.15)在35℃下溶解于1125ml医用纯净水(H 2O/KB等于45)，在同温度下搅拌至完全溶解，大约需要半小时。继续搅拌15至30分钟，加入4.2g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×11.25ml(反应用水量的2％)纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，于8℃冷却，在同温度下继续冷却2天，期间晶簇长大、增多。移入4℃冰箱冷却15天。得到花朵样透明的晶簇。真空吸滤，在真空下用预冷至5℃的异丙醇和预冷至5℃的乙酸乙酯迅速顺次喷雾淋洗，室温下真空干燥，得到第一轮反应产物双环铂18.09g，收率52.1％。
第二轮反应：上述第一轮反应母液重1170.9g，忽略过程中的损失，按第一轮的收率(18.09g)计算，经过第一轮反应，系统内减少的反应物是：卡铂13.03g和二羧酸5.06g。向此母液中补加与减少量相对应的卡铂和二羧酸，在35℃下搅拌反应30-60分钟，加入5.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×11.25ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后转入12℃冰箱在同温度下再静置3天，移入4℃冰箱内避光静置25天。如法操作得到第二轮产物双环铂17.00g，就补加的卡铂(13.03g)而言收率94.0％；就本实验所投入的卡铂总量(38.03g)而言，产物总量35.09g，总收率66.5％。
第三轮反应：上述第二轮反应母液重1169.9g，忽略过程中的损失，按第二轮的收率(17.00g)计算，经过第二轮反应，系统内减少的反应物是：卡铂12.25g和二羧酸4.75g。向此母液中补加与减少量相对应的卡铂和二羧酸，在35℃下搅拌反应30-60分钟，加入5.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×11.25ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温，放入12℃冰箱内避光静置3天，再放入4℃冰箱避光静置结晶25天。如法操作得到第三轮产物双环铂15.90g，就此轮反应所补加的卡铂(12.25g)而言，收率93.5％；就本实验所投入的卡铂总量(50.28g)而言，产物总量50.99g，总收率73.1％。
第四轮反应：上述第三轮反应母液重1167.8g，忽略过程中的损失，按第三轮的收率(15.90g)计算，经过第三轮反应，系统内减少的反应物是：卡铂11.46g和二羧酸4.44g。向此母液中补加与减少量相对应的卡铂和二羧酸，在35℃下搅拌反应30-60分钟，加入5.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×11.25ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后放入12℃冰箱内避光静置3天，再放入4℃冰箱静置结晶25天。如法操作得到第 四轮产物双环铂16.95g，就此轮反应所补加的卡铂(11.46g)而言，收率106.6％；就本实验所投入的卡铂总量(61.71g)而言，产物总量67.95g，总收率79.3％。
实施例8：，在MR DA/KB等于4.5的配比下对反应母液套用3次，每次套用按照前一轮所得双环铂的量补加原料卡铂和二羧酸
第一轮反应：将卡铂50.1g(134.9mmol)和1，1-环丁烷二羧酸87.5g g(607.2mmol，MR DA/KB等于4.50)在35℃下溶解于2250ml医用纯净水(H 2O/KB等于45)，在同温度下搅拌至完全溶解，大约需要半小时。继续搅拌15至30分钟，加入10g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×22.5ml(反应用水量的2％)纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，于8℃冷却，在同温度下继续冷却2天，期间晶簇长大、增多。移入4℃冰箱冷却15天。得到花朵样透明的晶簇。真空吸滤，在真空下用预冷至5℃的异丙醇和预冷至5℃的乙酸乙酯迅速顺次淋洗，室温下真空干燥，得到第一轮反应产物双环铂36.8g，收率52.9％。
第二轮反应：上述第一轮反应母液重2307.1g，忽略过程中的损失，按第一轮的收率(36.8g)计算，经过第一轮反应，系统内减少的反应物是：卡铂26.5g和二羧酸10.3g。向此母液中补加与减少量相对应的卡铂和二羧酸，在35℃下搅拌反应30-60分钟，加入10.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×22.5ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后转入12℃冰箱，在同温度下再静置3天，移入4℃冰箱内避光静置25天。如法操作得到第二轮产物双环铂32.3g，就补加的卡铂(26.5g)而言收率87.8％；就本实验所投入的卡铂总量(76.6g)而言，产物总量69.1g，总收率65.0％。
第三轮反应：上述第二轮反应母液重2270.7g，忽略过程中的损失，按第二轮的收率(32.3g)计算，经过第二轮反应，系统内减少的反应物是：卡铂23.3g和二羧酸9.0g。向此母液中补加与减少量相对应的卡铂和二羧酸，在35℃下搅拌反应30-60分钟，加入10.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×22.5ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温，放入12℃冰箱内避光静置3天，再放入4℃冰箱避光静置结晶25天。如法操作得到第三轮产物双环铂37.6g，就此轮反应所补加的卡铂(23.3g)而言，收率116.3％；就本实验所投入的卡铂总量(99.9g)而言，产物总量106.7g，总收率76.9％。
第四轮反应：上述第三轮反应母液重2300g，忽略过程中的损失，按第三轮的收率(37.6g)计算，经过第三轮反应，系统内减少的反应物是：卡铂27.1g和二羧酸 10.5g。向此母液中补加与减少量相对应的卡铂和二羧酸，在35℃下搅拌反应30-60分钟，加入10.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×22.5ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后放入12℃冰箱内避光静置3天，再放入4℃冰箱静置结晶25天。如法操作得到第四轮产物双环铂35.8g，就此轮反应所补加的卡铂(27.1g)而言，收率95.2％；就本实验所投入的卡铂总量(127.0g)而言，产物总量142.5g，总收率80.8％。
实施例9：150g卡铂的反应
第一轮反应：在MR DA/KB＝6.0的配比下对反应母液套用4次，每次套用按照前一轮所得双环铂的量补加原料卡铂和二羧酸
将卡铂150.0g(0.404mol)和1，1-环丁烷二羧酸349.0g(2.424mol，MR DA/KB＝6)在42℃下投入于6.75L医用纯净水(H 2O/KB＝45)，在同温度下搅拌至完全溶解。继续搅拌15至30分钟，加入30.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×65ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，于12℃静置3天，期间晶簇长大、增多。移入4℃冰箱冷却15天。得到花朵样透明的晶簇。真空吸滤，在真空下用预冷至5℃的异丙醇和预冷至5℃的乙酸乙酯迅速顺次淋洗，室温下真空干燥，得到第一轮反应产物双环铂131.4g，收率63.1％。
第二轮反应：上述第一轮反应母液重7225.3g，忽略过程中的损失，按第一轮的收率(131.4g)计算，经过第一轮反应，系统内减少的反应物是：卡铂94.7g和二羧酸36.7g。向此母液中补加与减少量相对应的卡铂和二羧酸，在42℃下搅拌反应30-60分钟，加入30.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×65ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后转入12℃冰箱，在同温度下再静置3天，移入4℃冰箱内避光静置25天。如法操作得到第二轮产物双环铂129.7g，就补加的卡铂(94.7g)而言收率98.7％；就本实验所投入的卡铂总量(244.7g)而言，产物总量261.1g，总收率76.9％。
第三轮反应：上述第二轮反应母液重7243.8g，忽略过程中的损失，按第二轮的收率(129.7)计算，经过第二轮反应，系统内减少的反应物是：卡铂93.4g和二羧酸36.3g。向此母液中补加与减少量相对应的卡铂和二羧酸，在42℃下搅拌反应30-60分钟，加入30.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×65ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温，放入12℃冰箱内避光静置3天，再放入4℃冰箱避光静置结晶25天。如法操作得到 第三轮产物双环铂128.5g，就此轮反应所补加的卡铂(93.4g)而言，收率99.1％；就本实验所投入的卡铂总量(338.1g)而言，产物总量389.6g，总收率83.0％。
第四轮反应：上述第三轮反应母液重7256.1g，忽略过程中的损失，按第三轮的收率(128.5g)计算，经过第三轮反应，系统内减少的反应物是：卡铂92.6g和二羧酸35.9g。向此母液中补加与减少量相对应的卡铂和二羧酸，在42℃下下搅拌反应30-60分钟，加入30.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×65ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后放入12℃冰箱内避光静置3天，再放入4℃冰箱静置结晶25天。如法操作得到第四轮产物双环铂127.7g，就此轮反应所补加的卡铂(92.6g)而言，收率99.4％；就本实验所投入的卡铂总量(430.7g)而言，产物总量517.3g，总收率86.5％。
第五轮反应：上述第四轮反应母液重7263.2g，忽略过程中的损失，按第四轮的收率(127.7g)计算，经过第四轮反应，系统内减少的反应物是：卡铂92.0g和二羧酸35.7g。向此母液中补加与减少量相对应的卡铂和二羧酸，在42℃下搅拌反应30-60分钟，加入30.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用2×65ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后放入12℃冰箱内避光静置3天，再放入4℃冰箱静置结晶25天。如法操作得到第五轮产物双环铂123.5g，就此轮反应所补加的卡铂(92.0g)而言，收率96.7％；就本实验所投入的卡铂总量(522.7g)而言，产物总量640.8g，总收率88.3％。此轮得到母液7277.1g。
实施例10，在MR DA/KB＝7.0的配比下对反应母液套用5次，每次套用按照前一轮母液HPLC测定的残余卡铂和二羧酸数量补加原料卡铂和二羧酸
第一轮反应：将卡铂10.0g(0.027mol)和1，1-环丁烷二羧酸27.2g(0.189mol，MR DA/KB＝7)在42℃下溶解于450ml医用纯净水(H 2O/KB＝45)，在同温度下搅拌至完全溶解。继续搅拌15至30分钟，加入2.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用10ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，于12℃静置11天，期间晶簇长大、增多。移入4℃冰箱冷却7天。得到花朵样透明的晶簇。真空吸滤，在真空下用预冷至5℃的异丙醇和预冷至5℃的乙酸乙酯迅速顺次淋洗，室温下真空干燥，得到第一轮反应产物双环铂8.963g，收率64.6％。
收集母液得474ml，HPLC分析母液，测得卡铂含量4.9382mg/ml，二羧酸含量48.0559mg/ml。
第二轮反应：根据上述第一轮反应母液HPLC分析数据，计算得母液中含卡铂2.3407g，二羧酸22.7785g。向此母液中补加与减少量相对应的卡铂和二羧酸，即补加卡铂7.6593g，二羧酸4.4215g。在42℃下搅拌反应30分钟，加入2.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤渣用10ml纯净水洗涤，洗涤液并入滤液。所得溶液转入结晶瓶，自然冷却至室温后转入12℃冰箱静置8天，移入4℃冰箱内避光静置12天。如法操作得到第二轮产物双环铂9.9907g，就补加的卡铂(7.6593g)而言收率94.0％；就本实验所投入的卡铂总量(17.6593g)而言，产物总量18.9537g，总收率77.3％。
收集母液得470ml，补加水5ml后HPLC分析母液，测得卡铂含量4.8322mg/ml，二羧酸含量49.1537mg/ml。
第三轮反应：根据上述第二轮反应母液HPLC分析数据，计算得母液中含卡铂2.2953g，二羧酸23.348g。向此母液补加卡铂7.7047g，二羧酸3.852g。在42℃下搅拌反应30分钟，加入2.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，所得溶液转入结晶瓶，自然冷却至室温后转入12℃冰箱静置8天，移入4℃冰箱内避光静置14天。如法操作得到第三轮产物双环铂9.8238g，就补加的卡铂(7.7047g)而言收率91.9％；就本实验所投入的卡铂总量(25.364g)而言，产物总量28.7775g，总收率81.7％。
收集母液得450ml，HPLC分析母液，测得卡铂含量5.2417mg/ml，二羧酸含量47.6019mg/ml。
第四轮反应：根据上述第三轮反应母液HPLC分析数据，计算得母液中含卡铂2.3588g，二羧酸21.4209g。向此母液补加水25ml，卡铂7.6412g，二羧酸5.7791g。在42℃下搅拌反应30分钟，加入2.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，滤饼用15ml水洗涤，所得溶液转入结晶瓶，自然冷却至室温后转入12℃冰箱静置8天，移入4℃冰箱内避光静置14天。如法操作得到第四轮产物双环铂9.9577g，就补加的卡铂(7.6412g)而言收率93.9％；就本实验所投入的卡铂总量(33.0052g)而言，产物总量38.7352g，总收率84.5％。
收集母液得485ml，HPLC分析母液，测得卡铂含量4.7729mg/ml，二羧酸含量48.9198mg/ml。
第五轮反应：根据上述第四轮反应母液HPLC分析数据，计算得母液中含卡铂2.3149g，二羧酸23.7261g。向此母液补加卡铂7.6851g，二羧酸3.4739g。在42℃ 下搅拌反应30分钟，加入2.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，所得溶液转入结晶瓶，自然冷却至室温后转入12℃冰箱静置8天，移入4℃冰箱内避光静置14天。如法操作得到第五轮产物双环铂9.9967g，就补加的卡铂(7.6851g)而言收率93.7％；就本实验所投入的卡铂总量(40.6903g)而言，产物总量48.7319g，总收率86.3％。
收集母液得470ml，HPLC分析母液，测得卡铂含量5.0647mg/ml，二羧酸含量48.0071mg/ml。
第六轮反应：根据上述第五轮反应母液HPLC分析数据，计算得母液中含卡铂2.3804g，二羧酸22.5633g。向此母液补加水5ml，卡铂7.6196g，二羧酸4.6367g。在42℃下搅拌反应30分钟，加入2.0g医用活性炭粉，在同温度下搅拌30分钟。过滤，所得溶液转入结晶瓶，自然冷却至室温后转入12℃冰箱静置8天，移入4℃冰箱内避光静置12天。如法操作得到第六轮产物双环铂9.8984g，就补加的卡铂(7.6196g)而言收率93.6％；就本实验所投入的卡铂总量(48.3099g)而言，产物总量58.6303g，总收率87.4％。
实施例11，在MR DA/KB＝7.0的配比下制备双环铂，只进行一次，不套用母液，随即从母液中回收双环铂以及从二次母液回收卡铂
将1，1-环丁烷二羧酸54.34g(377.10mmol)投入1000ml纯净水，在42℃下下搅拌，经30min溶解。向溶液中加入卡铂20.0g(53.86mmol，MR DA/KB＝7.0)，在同温度下继续搅拌20min，得到澄明的溶液。再搅拌20min，加入活性炭3.06g；同温度下搅拌脱色30min后过滤。自然冷却4小时，移入12℃冰箱静置2天后可见析出的针状晶体，移入4℃冰箱中静置19天。滤集晶体，在室温下自然干燥，得针状的无色晶体17.95g，收率64.64％。DSC谱图参见图17。
容器以少量纯净水荡涤，共得滤液1063.1g。从中取出一半，532g，分数次在40℃和真空下旋转蒸发至干，得残余物28.2g。将此残余物投入保留的另一半滤液中，在40℃水浴温度下加热搅拌，经10min溶解。投入活性炭1.0g，同温度下搅拌脱色30min，过滤。室温下静置4小时后移入12℃冰箱。次日可见有晶体析出，移入4℃冰箱中静置14天后滤集形成的无色针状晶体，得4.334g，折合收率15.61％；至此双环铂的总收率为80.25％。
将得到的滤液554.4g在40℃下真空旋转蒸发至干，得残余物46.4g。向其中加入IPA 226ml(配比V/W4.7)，室温搅拌5小时，过滤。将滤液旋转蒸发至干， 得到洁白的晶状粉末42.3g，此为第一批回收的1，1-环丁烷二羧酸。占反应投入量的77.8％，占理论残余量(除去消耗于双环铂中的部分)的90.8％。
得到滤饼5.0g。向其中加入IPA 65ml(配比V/W 13)，室温下搅拌过夜，过滤。滤液旋转蒸发至干，得0.734g，此为第二批回收的1，1-环丁烷二羧酸，占理论残余量的1.58％，HPLC显示其含有包括卡铂在内的杂质。
过滤给出的滤饼经干燥后重3.4g，此为回收的粗品卡铂。将其投入84ml纯净水，75℃加热溶解，以活性炭1.24g脱色30min，过滤，冷却结晶，得到粗大闪亮的粒状晶体。滤集干燥后重1.81g，占初始投入量的9.1％，扣除所产物双环铂(收率80.25％)后，回收率45.8％。至此，原料卡铂的利用率是89.35％。将这精制卡铂的母液减压蒸干，得1.62g。如果将这残余物与反应过程中脱色用的活性炭一同焚烧以回收铂，贵金属铂的利用率达到98％。
实施例12：从最后一轮制备反应的母液中回收双环铂
取实施例9的母液作为原料进行回收处理。
该实施例总共投入卡铂522.7g(1.408mol)，1，1-环丁烷二羧酸493.6g(3.425mol)，共计得到产物双环铂640.8g，总收率88.3％。产生回收母液7277.1g。忽略过程中的损失，母液内应该含有双环铂84.8g和二羧酸290.8g。
从上述母液内称取1500g(总重量的20.6％)，在真空和55℃下浓缩至干，得到残余物70.4g。将此残余物投入未经浓缩的母液主体，加入活性炭20g，在45℃下搅拌脱色1小时。趁热过滤，滤渣用纯净水80ml洗涤。洗液与滤液合并。自然冷却至室温，移入12℃冰箱内避光结晶。3天后针状晶体析出，转入4℃冰箱中避光静置20天。过滤收集晶体，顺次用预先冷至5℃的异丙醇和乙酸乙酯淋洗，得到双环铂41.5g，回收率48.9％。实施例9前已给出产物双环铂640.8g，至此，该系列反应产出的双环铂达到682.3g，相当于总收率94.0％。以上程序并给出二次母液5817g。
实施例13：从二次母液中回收卡铂
实施例12所给出的二次母液5817g中，忽略过程中的损失，应含有双环铂43.3g和二羧酸290.8g。将其在55℃下减压浓缩至干，再于油泵真空下室温干燥过夜，得到残余物309.1g。对该固体在1立升砂心漏斗内用乙醇300ml×3充分洗涤，得到滤饼52.3g。滤液为回收1，1-环丁烷二羧酸，浓缩至干，得到质量很好的二羧酸241g，回收率82.9％。将得到的滤饼投入纯净水1500g中，室温下搅拌2小时， 得到略显浑浊的溶液，加入活性炭8g，在45℃下搅拌脱色1小时，过滤，所得滤液自然冷却至室温后转入12℃冰箱内结晶。待晶体出现后再转移至4℃冰箱内结晶20天，得到粒状的卡铂晶体。过滤得17.1g。就本实施例所投入的卡铂总量而言，占3.27％。故卡铂的总利用率达到97.3％。
实施例14：双环铂的重结晶
收集过去2年间所得到的熔点稍低或者结晶形态较差的产品双环铂，共得9.8g，它们分属于不同的反应批次，均为细长的针状晶体，熔点处于192.3℃至194.5℃之间，低于双环铂的标准熔点(198℃以上)，以其检验重结晶的工艺。
重结晶程序之一：使用1号重结晶溶液：将1，1-环丁烷二羧酸15.1g(104.8mmol)和卡铂3.53g(9.51mmol)溶于320ml纯净水中制成重结晶溶液，将待精制的双环铂4.90g(9.51mmol)在40℃下投入此溶液内，搅拌溶解，加入活性炭0.5g脱色半小时，过滤。滤渣用5ml纯净水洗涤。洗液并入滤液，自然冷却至室温，移入12℃冰箱中静置3天，转入4℃冰箱内避光静置30天。过滤，晶体顺次用5ml预冷至5℃的异丙醇和5ml预冷至5℃的醋酸乙酯迅速淋洗，转入真空干燥器内抽除残余溶剂，得到无色的针状晶体6.13g，收率125.1％。本程序中1，1-环丁烷二羧酸对于待精制双环铂的摩尔比为11.0，卡铂对于待精制双环铂的摩尔比MR KB/DCP为1比1，水对于待精制双环铂的重量比为65.3。精制的收率超过100％是因为在此过程中部分的卡铂形成了双环铂。如此得到的结晶母液按照前述的母液处理的方法处理。
重结晶程序之二：使用2号重结晶溶液：将1，1-环丁烷二羧酸6.85g(47.54mmol)溶于160ml纯净水中制成重结晶溶液，将待精制的双环铂4.90g(9.51mmol)在搅拌和40℃下投入此溶液内，搅拌溶解，加入活性炭0.3g脱色半小时，过滤。滤渣用5ml纯净水洗涤。洗液并入滤液，自然冷却至室温，移入12℃冰箱中静置3天。转入4℃冰箱内避光静置30天。过滤，滤饼顺次用5ml预冷至5℃的异丙醇和5ml预冷至5℃的醋酸乙酯迅速淋洗，转入真空干燥器内抽除残余溶剂，得到无色的针状晶体3.1g，收率63.3％。本程序中1，1-环丁烷二羧酸对于待精制双环铂的摩尔比MR DA/DCP为5.0，水对于待精制双环铂的重量比为32.7。如此得到的结晶母液按照前述的母液处理方法处理。

Claims (9)

  1. 一种高纯度双环铂针状晶体的工业化制备方法，其特征在于包括下述步骤：
    (1)将卡铂和1，1-环丁烷二羧酸，以及水混合形成澄清溶液，反应；
    (2)直接将步骤(1)的反应液结晶，不经精制直接得到高纯度针状晶体；其中，控制晶体析出率不超过75％，保证产品纯度不低于99.5％；优选地，控制析出率为50～75％，更优选地，析出率为50～60％，保证产品纯度超过99.9％。
  2. 根据权利要求1所述的高纯度双环铂针状晶体的工业化制备方法，其特征在于，所述的反应条件为：1，1-环丁烷二羧酸对于卡铂的摩尔比为4～16；反应时间为0.5～6h；所述水为去离子水；反应温度为室温～50℃，优选地，所述室温为10～35℃；优选地，溶剂水对于卡铂的重量比例为30～55；优选地，所述的结晶条件为：反应液经活性炭脱色后，在2-8小时内自然冷却至室温，然后在10-14℃避光静置，结晶4-10天，最后于0～6℃静置结晶15-30天。
  3. 根据权利要求1所述的高纯度双环铂针状晶体的工业化制备方法，其特征在于，所述的反应条件为：1，1-环丁烷二羧酸对于卡铂的摩尔比为4～10；反应时间为0.5～2h；所述水为去离子水；反应温度为室温～45℃，优选地，所述室温为10～35℃；优选地，溶剂水对于卡铂的重量比例为40-50；优选地，所述的结晶条件为：反应液经活性炭脱色后，在2-8小时自然冷却至室温，然后在10-14℃避光静置结晶4-10天，最后于0～4℃静置结晶15-30天。
  4. 根据权利要求1所述的高纯度双环铂针状晶体的工业化制备方法，其特征在于：还包括步骤(3)，即对于步骤(2)的母液加以回收套用2至6次，使产品双环铂的总收率提高至80％以上；优选地，在所述母液中加入相应量的1，1-环丁烷二羧酸和卡铂，重复步骤(1)和(2)。
  5. 根据权利要求1所述的高纯度双环铂针状晶体的工业化制备方法，其特征在于：还包括步骤(4)，即对于步骤(2)和(3)所获得的产品双环铂用预先冷却至5℃的异丙醇和乙酸乙酯顺次洗涤。
  6. 根据权利要求1所述的高纯度双环铂针状晶体的工业化制备方法，其特征在于：还包括步骤(5)，即对于步骤(3)的最终母液在55℃以下避光加以适当浓缩，回收双环铂，从而使双环铂的总收率达到90％以上。
  7. 根据权利要求1所述的高纯度双环铂针状晶体的工业化制备方法，其特征在于：还包括步骤(6)，即对于步骤(5)所产生的二次母液在55℃以下避光彻底浓缩 至干，通过乙醇或者异丙醇洗涤以回收过量的1，1-环丁烷二羧酸，滤饼再以水重结晶以回收卡铂，使得卡铂的利用率达到97％以上。
  8. 根据权利要求1所述的高纯度双环铂针状晶体的工业化制备方法，其特征在于：对纯度低的双环铂使用特定溶液进行精制，所述特定溶液为：1，1-环丁烷二羧酸的水溶液，或环丁烷二羧酸与卡铂在水中的混合溶液。
  9. 双环铂或制备双环铂的母液在抗菌或抗病毒方面的用途；优选地，所述的菌为金黄色葡萄球菌、表皮葡萄球菌、蜡样芽孢杆菌、枯草芽孢杆菌、乙型溶血性链球菌、痤疮丙酸杆菌、克雷伯氏肺炎菌、铜绿假单胞菌、大肠杆菌、幽门螺旋杆菌、伤寒沙门菌、鼠疫菌、副溶血性弧菌、嗜麦芽窄食单胞菌、醋酸钙不动杆菌；所述病毒为乙肝病毒。
PCT/CN2018/000229 2017-06-21 2018-06-20 一种高纯度双环铂针状晶体的工业化制备方法 WO2018233273A1 (zh)

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