A method for preparing cis-diiododiammine platinum (II)

Abstract

The present application relates to the technical field of inorganic synthesis, and provides a preparation method of cis-diiododiammine platinum (II). The present application dissolves potassium chloroplatinite in a polar solvent to obtain a potassium chloroplatinite solution; iodine source and nitrogen source are sequentially added into the potassium chloroplatinite solution to react, so as to obtain the cis-diiododiammine platinum (II). The present application uses potassium chloroplatinite, iodine source and nitrogen source as raw materials, can promote the efficient reaction under mild conditions, and improves the reaction efficiency and product yield. The results of examples show that the reaction time is only 0.5 h when the cis-diiododiammine platinum (II) is prepared by the method of the present application, and the product yield can reach more than 95%. In addition, the process of the present application is simple, the synthesis route is short, the safety is good, the raw materials are cheap and easy to obtain, and the present application is suitable for industrial batch production.

Description

Technical Field

[0001] This invention relates to the field of inorganic synthesis technology, and in particular to a method for preparing cis-diiododiammine platinum(II). Background Technology

[0002] Cisplatin, carboplatin, and oxaliplatin are classic platinum-based anticancer drugs widely used in clinical practice. Among them, cisplatin, as a first-generation platinum-based anticancer drug, occupies an important position in the field of tumor chemotherapy due to its unique anticancer mechanism and excellent therapeutic effect. Cisplatin can form cross-links with tumor cell DNA, inhibiting DNA replication and suppressing tumor cell division and proliferation, thus exhibiting extremely strong broad-spectrum anticancer activity. Simultaneously, it can also produce synergistic antitumor effects with various chemotherapeutic drugs without cross-resistance, making it one of the core drugs for the clinical treatment of various malignant tumors, with extremely high clinical application value and development prospects.

[0003] In the synthesis of cisplatin, cis-diiododiammineplatinum(II) is an indispensable key intermediate. This intermediate directly affects the synthesis efficiency, quality and production cost of cisplatin, and is one of the core links in the cisplatin synthesis process.

[0004] Currently, there are few published reports on the synthesis of cis-diamminediiodoplatinum(II), and all of them are laboratory preparations. Existing techniques for synthesizing cis-diamminediiodoplatinum(II) typically use potassium chloroplatinate as a starting material, transforming it through a series of chemical reactions to obtain the target product. However, the reported preparation methods all suffer from low product yields and insufficiently mild preparation conditions, making it difficult to meet the requirements for large-scale synthesis. Summary of the Invention

[0005] In view of this, the present invention provides a method for preparing cis-diiododiammineplatinum(II). The preparation method provided by the present invention has mild reaction conditions, high product yield, and is suitable for industrial-scale mass production.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: A method for preparing cis-diiododiammineplatinum(II) includes the following steps: Potassium chloride platinum is dissolved in a polar solvent to obtain a potassium chloride platinum solution; Iodine source and nitrogen source are added sequentially to the potassium chloride platinum solution to react and obtain cis-diiododiammine platinum(II); the molar ratio of iodine source to potassium chloride platinum is 4.0~15:1; the reaction temperature is 30~80℃.

[0007] Preferably, the polar solvent includes one or more of water, alcohol, dimethyl sulfoxide, and acetone; the alcohol solvent preferably includes one or both of methanol and ethanol.

[0008] Preferably, the volume ratio of the polar solvent to the mass ratio of potassium chloroplatinate is 1~10 mL:1 g, more preferably 4~8 mL:1 g.

[0009] Preferably, the dissolution temperature is 60~100℃, more preferably 80℃; the dissolution is preferably carried out under stirring conditions. In this invention, potassium chloroplatinate is heated and stirred in a polar solvent until completely dissolved, then filtered while hot; the resulting clear filtrate is the potassium chloroplatinate solution. By optimizing the type and amount of polar solvent, this invention precisely controls the raw material concentration of the reaction system, effectively reducing side reactions and improving the conversion rate.

[0010] Preferably, the iodine source includes one or more of potassium iodide, sodium iodide, and trimethyliodosilane, more preferably potassium iodide. This invention strictly controls the molar ratio of iodine source to potassium chloroplatinate to be 4.0~15:1. The core reason is that the theoretical molar ratio of the target reaction is potassium iodide:potassium chloroplatinate = 4:1, and the four chloride ligands at the tetravalent platinum center must be completely replaced by iodide ions to avoid the formation of iodine-chlorine mixed intermediates (such as [PtI3Cl)). 2- This eliminates the presence of cis-[Pt(NH3)2ICl] impurities in the target product cis-diiododiammineplatinum(II); excess iodide ions further ensure the complete ligand substitution reaction, significantly improving product yield and purity.

[0011] Preferably, the nitrogen source includes one or more of ammonia, concentrated ammonia, sulfonamide, and triphenylsilane, more preferably 25 wt% concentrated ammonia; the molar ratio of the nitrogen source to potassium chloroplatinate is 2.0~15:1.

[0012] Preferably, the reaction is carried out at atmospheric pressure.

[0013] Preferably, the reaction time is 0.5-1 hour. In a specific embodiment of the present invention, an iodine source and a nitrogen source are preferably added sequentially to a potassium chloroplatinate solution. After the addition is completed, the reaction system is heated to 30-80°C and kept at that temperature for further reaction. The iodine source and nitrogen source are preferably added slowly in batches. By controlling the method of adding raw materials and the reaction temperature, the present invention can precisely regulate the reaction process, avoid the formation of by-products, and promote the efficient forward reaction.

[0014] Preferably, the preparation and reaction steps of the potassium chloroplatinate solution can be carried out in a batch reaction or a continuous reaction mode to meet the needs of industrial production.

[0015] Preferably, after the reaction is completed, the reaction solution is further subjected to post-treatment; the post-treatment includes: after stopping heating, the reaction solution is stirred until the system is cooled to room temperature and the solution is completely decolorized, and then subjected to vacuum filtration, washing and vacuum drying in sequence to obtain cis-diiododiammine platinum(II); the washing is preferably performed by washing the filter cake with ice water and ice anhydrous ethanol in sequence; after the solvent is recovered by distillation of the filtrate obtained by filtration, the remaining waste liquid is uniformly and compliantly treated, which greatly reduces the cost of waste treatment and environmental risks.

[0016] This invention provides a method for preparing cis-diiododiammineplatinum(II), using potassium chloroplatinate as the starting material. By strictly controlling the molar ratio of iodine source to potassium chloroplatinate at 4.0~15:1 and combining it with mild reaction conditions, the reaction can be efficiently promoted to complete, reducing the formation of mixed impurities at the source and significantly improving the product yield and purity. Example results show that the method of this invention for preparing cis-diiododiammineplatinum(II) requires only 0.5 h of reaction time and achieves a product yield of over 95%.

[0017] Meanwhile, the preparation method provided by this invention is simple and has a short synthesis route, requiring only one reaction step to obtain the target product; the reaction is carried out under mild conditions of normal pressure and 30~80℃, ensuring high operational safety; the raw materials used are all basic chemicals available on a large scale in the market, inexpensive and readily available, suitable for industrial mass production needs; in addition, the reaction solvent of this invention can be recovered and reused through distillation, which greatly reduces the generation and discharge of high-salt wastewater and lowers the safety and environmental risks of industrial production. Attached Figure Description

[0018] Figure 1 This is a process flow diagram for synthesizing cis-diiododiammine platinum(II) according to the present invention. Detailed Implementation

[0019] This invention provides a method for preparing cis-diiododiammine platinum(II), comprising the following steps: Potassium chloride platinum is dissolved in a polar solvent to obtain a potassium chloride platinum solution; Iodine source and nitrogen source are added sequentially to the potassium chloride platinum solution to react and obtain cis-diiododiammine platinum(II); the molar ratio of iodine source to potassium chloride platinum is 4.0~15:1; the reaction temperature is 30~80℃.

[0020] Figure 1 The following is a process flow diagram for synthesizing cis-diiododiammineplatinum(II) according to the present invention, in conjunction with... Figure 1 Please provide a detailed explanation.

[0021] This invention dissolves potassium platinum chloride in a polar solvent to obtain a potassium platinum chloride solution. In this invention, the polar solvent preferably includes one or more of water, alcohol solvents, dimethyl sulfoxide, and acetone; the alcohol solvent preferably includes one or both of methanol and ethanol; the volume ratio of the polar solvent to the mass of potassium platinum chloride is preferably 1-10 mL:1 g, specifically 4 mL:1 g, 7.5 mL:1 g, or 8 mL:1 g; the dissolution temperature is preferably 60-100℃, specifically 80℃; the dissolution is preferably carried out under stirring conditions. Preferably, the potassium platinum chloride is heated and stirred in a polar solvent until the solid is completely dissolved, then filtered while hot, and the resulting clear filtrate is the potassium platinum chloride solution. This invention uses a polar solvent and controls its amount, enabling precise control of the raw material concentration in the reaction system, effectively reducing the occurrence of side reactions and improving the process conversion rate.

[0022] After obtaining a potassium chloroplatinate solution, the present invention sequentially adds an iodine source and a nitrogen source to the potassium chloroplatinate solution to react and obtain the cis-diiododiammineplatinum(II). In the present invention, the iodine source preferably includes one or more of potassium iodide, sodium iodide, and trimethyliodosilane, more preferably potassium iodide; the molar ratio of the iodine source to potassium chloroplatinate is 4.0~15:1, specifically 4.2:1, 5:1, 10:1, or 15:1; in a specific embodiment of the present invention, in order to ensure that the iodide ions completely replace the four chloride ions in the potassium chloroplatinate molecule and avoid the formation of iodine-chlorine mixed intermediates (such as [PtI3Cl)). 2- This invention aims to prevent the appearance of cis-[Pt(NH3)2ICl] impurities in the target product cis-diiododiammineplatinum(II) (cis-[Pt(NH3)2I2]). The invention strictly controls the excess of iodine source relative to potassium chloroplatinate to ensure that the ligand substitution reaction proceeds completely in the forward direction.

[0023] In this invention, the nitrogen source preferably includes one or more of ammonia, concentrated ammonia, sulfonamide and triphenylsilane, more preferably 25wt% concentrated ammonia; the molar ratio of the nitrogen source to potassium chloroplatinate is preferably 2.0~15:1, specifically 2.0:1, 5:1, 10:1 or 15:1.

[0024] In this invention, the reaction temperature is 30-80°C, specifically 40°C, and the reaction pressure is preferably atmospheric pressure; the reaction time is preferably 0.5-1 hour. In a specific embodiment of this invention, iodine and nitrogen sources are preferably added slowly in batches to a potassium chloroplatinate solution at room temperature. After the addition is complete, the reaction system is heated to 30-80°C and maintained at that temperature for further reaction. By controlling the addition method of the iodine and nitrogen sources and the reaction temperature, this invention can precisely regulate the reaction process, avoid the formation of by-products, promote efficient forward reaction, and improve product yield and purity.

[0025] In this invention, the reaction formula is shown in Formula 1: Formula 1.

[0026] In this invention, the steps of preparing the potassium chloroplatinate solution and the reaction steps are preferably carried out by batch reaction or continuous reaction to meet the needs of industrial scale-up production.

[0027] In this invention, after the reaction is completed, the resulting reaction solution is preferably post-treated; the post-treatment includes: after stopping heating, the reaction solution is stirred until the system is cooled to room temperature and the solution is completely decolorized, and then subjected to vacuum filtration, washing and vacuum drying in sequence to obtain cis-diiododiammine platinum(II); the washing is preferably done by washing the filter cake with ice water and ice anhydrous ethanol in sequence; the filtrate obtained by filtration is preferably distilled to recover the solvent, and the remaining waste liquid is uniformly and compliantly treated.

[0028] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0029] Example 1 (1) At room temperature, add 200g potassium chlorite (0.48mol) and 1.5L purified water to a glass container, turn on the stirrer, heat to 80℃, filter while hot after the solid is completely dissolved, transfer the filtrate to a clean glass reaction vessel to obtain a clear potassium chlorite solution. (2) To the above potassium chloroplatinate solution, slowly add 336g of potassium iodide (2.02mol, with a molar ratio of 4.2:1 to potassium chloroplatinate) and 72.0mL of concentrated ammonia (0.96mol, with a molar ratio of 2.0:1 to potassium chloroplatinate) in batches. After the addition is complete, heat the reaction system to 40℃ and keep it at that temperature for 0.5h. A pale yellow solid product gradually precipitates in the reaction system. Stop heating and continue stirring until the reaction solution cools to room temperature and completely decolorizes. Then, filter under reduced pressure. Wash the filter cake 3-4 times each with ice water and ice-cold anhydrous ethanol. After vacuum drying, the target product cis-diiododiammineplatinum(II) is obtained. After the solvent is recovered by distillation, the remaining waste liquid is disposed of in accordance with regulations.

[0030] In this embodiment, 230 g of cis-diiododiammineplatinum(II) was prepared with a yield of 98.9%. The elemental analysis results were: H: 1.08%, N: 5.92%, I: 52.99%, Pt: 39.98%, which were consistent with the theoretical elemental composition of the target product.

[0031] Example 2 (1) At room temperature, add 100g potassium chlorite (0.24mol) and 0.8L purified water to a glass container, turn on the stirrer, heat to 80℃, filter while hot after the solid is completely dissolved, transfer the filtrate to a clean glass reaction vessel to obtain a clear potassium chlorite solution. (2) To the above potassium chloroplatinate solution, slowly add 168g of potassium iodide (1.01mol, with a molar ratio of 4.2:1 to potassium chloroplatinate) and 36.0mL of 25wt% concentrated ammonia (0.48mol, with a molar ratio of 2.0:1 to potassium chloroplatinate) in batches. After the addition is complete, heat the reaction system to 40℃ and keep it at that temperature for 0.5h. A pale yellow solid product gradually precipitates in the reaction system. Stop heating and continue stirring until the reaction solution cools to room temperature and completely decolorizes. Then, filter under reduced pressure. Wash the filter cake 3-4 times each with ice water and ice-cold anhydrous ethanol. After vacuum drying, the target product cis-diiododiammineplatinum(II) is obtained. After the solvent is recovered by distillation, the remaining waste liquid is treated in accordance with regulations.

[0032] In this embodiment, 114.86 g of cis-diiododiammineplatinum(II) was prepared, with a yield of 98.8%. The elemental analysis results were: H: 1.19%, N: 5.74%, I: 52.92%, Pt: 40.12%, which were consistent with the theoretical elemental composition of the target product.

[0033] Example 3 (1) At room temperature, add 500g potassium chloroplatinate (1.20mol) and 2L purified water to a glass container, turn on the stirrer, heat to 80℃, filter while hot after the solid is completely dissolved, transfer the filtrate to a clean glass reaction vessel to obtain a clear potassium chloroplatinate solution. (2) To the above potassium chloroplatinate solution, slowly add 840g of potassium iodide (5.06mol, with a molar ratio of 4.2:1 to potassium chloroplatinate) and 180.0mL of 25wt% concentrated ammonia (2.41mol, with a molar ratio of 2.0:1 to potassium chloroplatinate) in batches. After the addition is complete, heat the reaction system to 40℃ and keep it at that temperature for 0.5h. A pale yellow solid product gradually precipitates in the reaction system. Stop heating and continue stirring until the reaction solution cools to room temperature and completely decolorizes. Then, filter under reduced pressure. Wash the filter cake 3-4 times each with ice water and ice-cold anhydrous ethanol. After vacuum drying, the target product cis-diiododiammineplatinum(II) is obtained. After the solvent is recovered by distillation, the remaining waste liquid is disposed of in accordance with regulations.

[0034] In this embodiment, 573.95 g of cis-diiododiammineplatinum(II) was prepared, with a yield of 98.7%. The elemental analysis results were: H: 1.27%, N: 5.94%, I: 52.50%, Pt: 40.26%, which were consistent with the theoretical elemental composition of the target product.

[0035] Comparative Example 1 (1) At room temperature, add 5g of potassium chloroplatinate (about 10.3mmol) to a 100mL glass container, add 20mL of purified water, turn on the stirrer, heat to 80℃ until the solid is completely dissolved, filter while hot, and transfer the filtrate into a clean reaction vessel; (2) Add 3.42 g potassium iodide (20.6 mmol, with a molar ratio of 2.0:1 to potassium chloroplatinate) and 1.80 mL of 25 wt% concentrated ammonia to the filtrate in portions, and heat to 40 °C and keep the temperature for 1 h. (3) After the reaction is complete, stop heating and continue stirring until the solution color becomes lighter. Filter under reduced pressure and wash the filter cake three times each with ice water and ice anhydrous ethanol. Dry under vacuum to obtain the solid product.

[0036] In this comparative example, 2.1 g of product was obtained, with a yield of 42.3%. The elemental analysis results were: H: 1.35%, N: 5.52%, I: 51.88%, Pt: 40.12%.

[0037] Comparative Example 2 (1) Same as step (1) in Example 1, to obtain potassium chloroplatinate solution; (2) Slowly add potassium iodide and ammonia (molar ratio as in Example 1) to the solution and stir the reaction at room temperature of 25°C for 1 hour; (3) After the reaction is complete, stop heating and continue stirring until the solution color becomes lighter. Filter under reduced pressure, wash three times with ice water and ice ethanol, and dry to obtain solid product.

[0038] In this embodiment, 120g of product was obtained, with a yield of 51.6%. The elemental analysis results were: H: 1.34%, N: 5.52%, I: 51.88%, Pt: 40.13%.

[0039] Comparative Example 3 (1) Same as step (1) in Example 1, to obtain potassium chloroplatinate solution; (2) First, slowly add ammonia water to the solution and stir at 40°C for 0.5 hours; (3) Slowly add potassium iodide and continue the reaction for 0.5 hours; (4) After the reaction is complete, stop heating and continue stirring until the solution color becomes lighter. Filter under reduced pressure, wash three times with ice water and ice ethanol, and dry to obtain solid product.

[0040] In this embodiment, 195g of product was obtained, with a yield of 83.8%. The elemental analysis results were: H: 1.34%, N: 5.52%, I: 51.88%, Pt: 40.13%.

[0041] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing cis-diiododiammineplatinum(II), characterized in that, Includes the following steps: Potassium chloride platinum is dissolved in a polar solvent to obtain a potassium chloride platinum solution; Iodine source and nitrogen source are added sequentially to the potassium chloride platinum solution to react and obtain cis-diiododiammine platinum(II); the molar ratio of iodine source to potassium chloride platinum is 4.0~15:1; the reaction temperature is 30~80℃.

2. The preparation method according to claim 1, characterized in that, The polar solvent includes one or more of water, alcohol, dimethyl sulfoxide, and acetone.

3. The preparation method according to claim 1, characterized in that, The volume ratio of the polar solvent to the mass of potassium chloroplatinate is 1~10 mL: 1 g.

4. The preparation method according to claim 1, characterized in that, The melting temperature is 60~100℃.

5. The preparation method according to claim 1, characterized in that, The iodine source includes one or more of potassium iodide, sodium iodide, and trimethyliodosilanol.

6. The preparation method according to claim 1, characterized in that, The nitrogen source includes one or more of ammonia, ammonia sulfonylimide, and triphenylsilane.

7. The preparation method according to claim 1 or 6, characterized in that, The molar ratio of the nitrogen source to potassium chloroplatinate is 2.0~15:

1.

8. The preparation method according to claim 1, characterized in that, The reaction was carried out at atmospheric pressure.

9. The preparation method according to claim 1, characterized in that, The reaction time is 0.5 to 1 hour.

10. The preparation method according to claim 1, characterized in that, After the reaction is completed, the reaction solution is further subjected to post-treatment; the post-treatment includes: after stopping heating, the reaction solution is stirred until it reaches room temperature and the solution is completely decolorized, and then filtered, washed and dried in sequence to obtain cis-diiododiammineplatinum(II).

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