Platinum product filtering and washing device and platinum bulk drug continuous manufacturing method
By designing a platinum product filtering and washing device with integrated feeding, discharging, filtering and stirring functions, the problem of continuous manufacturing of platinum APIs in the existing technology was solved, and an efficient and quality-controlled production process was achieved.
Patent Information
- Application Number
- CN202410496288.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-04-24
- Publication Date
- 2025-09-12
AI Technical Summary
Existing technologies make it difficult to achieve continuous manufacturing of platinum APIs, and existing equipment cannot meet the integrated requirements of functions such as filtration, washing, and stirring, resulting in low production efficiency and uneven product quality.
A platinum product filtering and washing device was designed. The device consists of a shell consisting of an upper and lower part, and has functions such as feeding, discharging, filtering, and stirring. The amount of silver salt added is controlled by conductivity monitoring to achieve precise control of the silver content in the product.
It has achieved efficient and continuous manufacturing of platinum APIs, improved production efficiency and product quality, reduced production costs, and effectively controlled the silver content within the pharmacopoeia range.
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Figure CN120618378A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of manufacturing platinum raw materials, and in particular to a platinum product filtering and washing device and a continuous manufacturing method of platinum raw materials. Background Art
[0002] Continuous manufacturing is a method for manufacturing products uninterruptedly, manifested in the uninterrupted supply of materials and the output or removal of products (including by-products) during the production process. The advantages of continuous pharmaceutical manufacturing include significantly improved production efficiency, stable product quality, and increased manufacturing flexibility and agility. Furthermore, it can effectively reduce costs, minimize the chance of defects and errors, and be environmentally friendly. Therefore, continuous pharmaceutical manufacturing is an advanced concept and an inevitable trend in achieving modern production in today's pharmaceutical industry.
[0003] Nearly half a century has passed since the first generation of platinum drugs were approved for the treatment of human tumor cells. However, the preparation of platinum APIs has still been plagued by problems such as small laboratory production batches, uneven product quality, and low production efficiency. The main reasons are: ① There has been no significant innovation in production technology; ② The product has unique performance, making large-scale production difficult; ③ The raw materials are expensive, and the cost of technological improvement is high; ④ The early market size was small.
[0004] With the recognition of platinum APIs in the market, the increasing number of cancer patients and the surge in demand for drugs among patients, and in order to improve the competitiveness of enterprises in the industry, it is very necessary to provide a device and method for producing platinum APIs with controllable quality, visualization, and continuous batch manufacturing.
[0005] Another key aspect of continuous manufacturing of platinum APIs lies in product filtration, washing, and collection. Existing equipment lacks the integrated feeding, discharging, filtration, and stirring functions required in the production of platinum compounds, making continuous manufacturing of platinum APIs difficult. Summary of the Invention
[0006] In view of the various problems existing in the continuous manufacturing of platinum APIs mentioned above, the first object of the present invention is to provide a platinum product filtering and washing device for realizing the continuous manufacturing of platinum APIs; the second object of the present invention is to provide a continuous manufacturing method of platinum APIs.
[0007] In order to achieve the second object of the present invention, the present invention also provides a method for effectively and accurately controlling the silver content in cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, and miplatin raw materials to within the pharmacopoeia standard range, and a method for accurately controlling the silver content in platinum raw materials and controlling the amount of silver salt added, specifically relating to a more accurate method for controlling the silver content in platinum compound products, that is, monitoring the reaction system with conductivity, which can effectively reflect the cation concentration in the system. After the silver salt is added, the cation Ag + Rapid Binding I - AgI precipitation occurs, the conductivity decreases, and the conductivity value in the system is within the specified qualified range, which indicates that the addition of silver salt is qualified. This process does not require additional treatment and the production of platinum compounds can be carried out according to normal steps.
[0008] According to the first aspect, the technical solution adopted by the present invention is as follows:
[0009] A filtering and washing device for platinum products, the device consists of two parts, the upper part of which is composed of a shell as a whole, the top of the shell is a box cover 1, the box cover 1 is provided with a stirring paddle 5 extending downward to near the bottom of the shell, and a visual window 4 is provided in the shell at the level of the stirring paddle 5, and the visual window 4 is connected to the shell with a transparent material to form a closed whole; an openable and closable feed port 2 is provided on one side of the upper half of the shell, and an openable and closable air pressure inlet 3 is provided on the other side; a filter element layer 6 is provided at the bottom of the shell, and a metal partition 8 is provided below the filter element layer 6; the metal partition 8 separates the upper and lower parts of the device, and the lower part is also composed of a nearly closed box, an air extraction port 9 is provided on one side of the top of the box, and a liquid discharge port 10 is provided on one side of the bottom of the box, the air extraction port 9 is connected to the negative pressure device when the product is filtered, and the liquid discharge port 10 is openable and closable.
[0010] The platinum product filtration and washing device can effectively and quickly filter and wash the product, preventing the product from redissolving in the solvent due to low filtration efficiency, thus reducing the product yield. It can also effectively remove byproducts (related substances) and solvent residues in the product, improving product uniformity and ensuring product quality. In the continuous manufacturing process of platinum APIs, it plays a connecting role, allowing each process to be connected in an orderly manner.
[0011] According to the second aspect, the technical solution adopted by the present invention is as follows:
[0012] A method for continuous production of platinum APIs, comprising the following steps:
[0013] Step 1: dissolving chloroplatinite in pure water, adding iodine salt, and then adding amine ligand to react to form an intermediate - cis-diiodine-platinum-amine complex;
[0014] Step 2: discharging the solid-liquid mixed system containing the intermediate into a filtering and washing device for filtering and washing;
[0015] Step 3: The washed and filtered intermediate is discharged into a reactor, and pure water and silver salt are added. The reaction is complete when the conductivity value in the reaction system is stable and within the qualified range. The intermediate is discharged into a filter washing device and filtered twice;
[0016] Step 4: The clarified filtrate can be directly concentrated to obtain a crude product, or the clarified filtrate can be introduced into a solution containing a leaving group (or a salt formed by a leaving group) and concentrated to obtain a crude product after the reaction is complete;
[0017] Step 5: The crude product is discharged into a filtering and washing device for filtration and washing, and the washed and filtered crude product is discharged into a boiling solvent for dissolution;
[0018] Step 6: After the crude product is dissolved, it is filtered through a filter-washing device, and the filtrate is added to refrigerated pure water or directly crystallized under stirring in a low-temperature environment. After the crystallization is completed, it is filtered and washed through a filter and washing device, and the product is completely dried to obtain a platinum raw material.
[0019] Preferably, the synthesis process of the cis-diiodine-platinum-amine complex in step 1 comprises:
[0020] An appropriate amount of sodium chloroplatinite or potassium chloroplatinite is dissolved at 20-100°C in a mass ratio of chloroplatinite to pure water of 1:1-20. Sodium iodide or potassium iodide is added at a molar ratio of chloroplatinite to iodized salt of 1:4-5, and the reaction is continued for 10-120 minutes. An amine ligand, such as ammonia water, (1R,2R)-(-)-1,2-cyclohexanediamine, or trans-1,2-di(aminomethyl)cyclobutane, or a salt formed by the amine ligand with hydrochloric acid, nitric acid, or sulfuric acid, is then added and the reaction is continued for 30-300 minutes to produce cis-diiodo-diammineplatinum(II), cis-diiodo-(1R,2R)-(-)-1,2-cyclohexanediamineplatinum(II), or cis-diiodo-trans-1,2-di(aminomethyl)cyclobutaneplatinum(II). When the amine ligand is ammonia water or a salt formed with hydrochloric acid, nitric acid or sulfuric acid, the molar ratio of the amount thereof added to chloroplatinite is 2 to 3:1; when the amine ligand is (1R,2R)-(-)-1,2-cyclohexanediamine or trans-1,2-di(aminomethyl)cyclobutane, or a salt formed with hydrochloric acid, nitric acid or sulfuric acid, the molar ratio of the amount thereof added to chloroplatinite is 1 to 1.5:1.
[0021] Preferably, the filtering and washing process includes:
[0022] When the system to be filtered needs to pass through the filter washing device, close the stirring paddle 5, close the air pressure port 3, close the discharge port 7, open the metal partition 8, and close the liquid discharge port 10. The filtration system enters the device through the feed port 2, close the metal partition 8, open the air suction port 9 to vacuum, and the filtrate enters the lower part of the device; close the air suction port 9, open the metal partition 8, add the cleaning solvent into the device through the feed port 2, open the stirring paddle 5, and the filtration system is in the washing state; close the metal partition 8, open the air suction port 9 to vacuum, and the washing filtrate enters the lower part of the device. Close the stirring paddle 5, close the air suction port 9, open the metal partition 8, close the feed port 2, open the air pressure port 3 to connect the compressed air, open the discharge port 7 to collect the washed solid product; when the metal partition 8 is in the open state, the air suction port 9 is not connected to the vacuum equipment, and the liquid discharge port 10 can be opened to collect the filtrate.
[0023] Preferably, the preparation process of the hydrolyzate or crude mother liquor in step 3 includes:
[0024] The washed and filtered cis-diiodide-platinum-amine complex is discharged into a reactor, and pure water is added in an amount of 5 to 50:1 of the mass ratio of chloroplatinite. Then, one or more silver salts selected from silver nitrate, silver sulfate, silver 1,1-cyclobutanedicarboxylate, and silver glycolate are added. The reaction temperature is 20 to 80° C., the reaction time is 30 to 300 minutes, and the reaction is complete when the conductivity value in the reaction system is stable in the range of 600 to 800 μS / cm. Filtering is performed once, and activated carbon is added to the filtrate of the first filtration in an amount of 0.001 to 0.1:1 of the mass ratio of chloroplatinite. Filtering is performed again to obtain a hydrolyzate or a crude mother liquor. When the silver salt is silver sulfate or silver 1,1-cyclobutanedicarboxylate, the added amount is 0.8 to 1.0:1 of the molar ratio of chloroplatinite; when the silver salt is silver nitrate or silver glycolate, the added amount is 1.5 to 2.0:1 of the molar ratio of chloroplatinite.
[0025] Preferably, the preparation process of the crude platinum compound product in step 4 comprises:
[0026] The clarified crude mother liquor is concentrated at a vacuum degree of 200-20 hPa / mbar and 40-80° C. to obtain a crude product; or the clarified hydrolyzed liquid is introduced into a solution containing a leaving group (or a salt formed by the leaving group) for reaction at 20-80° C. for 30-600 minutes, and then concentrated at a vacuum degree of 200-20 hPa / mbar and 40-80° C. to obtain a crude product. Wherein, when the leaving group (or the salt formed by the leaving group) is hydrogen chloride, tetradecanoic acid, sodium chloride, potassium chloride, sodium myristate, or potassium myristate, the amount added is 2.0-3.0:1 of the molar ratio of the chloroplatinite; when the leaving group (or the salt formed by the leaving group) is glycolic acid, oxalic acid, lactic acid, sodium glycolate, potassium glycolate, sodium oxalate, potassium oxalate, sodium lactate, or potassium lactate, the amount added is 1.0-1.5:1 of the molar ratio of the chloroplatinite.
[0027] Preferably, the dissolution process of the crude platinum compound product in step 5 comprises:
[0028] The crude product is discharged into a filtering and washing apparatus for filtration, washed with one or more of water, ethanol, ether, ethyl acetate, and acetone, and then dissolved in one or more of boiling water, ethanol, methanol, ether, ethyl acetate, acetone, dichloromethane, N,N-dimethylformamide, and dimethyl sulfoxide. The mass ratio of the boiling solvent to chloroplatinite is 1 to 20:1.
[0029] Preferably, the preparation process of the platinum API in step 6 comprises:
[0030] After the crude product is dissolved, it is filtered and washed, and the filtrate is added to pure water at 0-10°C and stirred for crystallization. The product is filtered and washed, and washed with one or more of water, ethanol, ether, ethyl acetate, and acetone. The product is dried at 40-100°C for 2-10 hours to obtain a platinum API. Alternatively, after the crude product is dissolved, it is filtered and washed, and the filtrate is placed in a low-temperature environment of -10-10°C and stirred for crystallization. The product is filtered and washed, and washed with one or more of water, ethanol, ether, ethyl acetate, and acetone. The product is dried at 40-100°C for 2-10 hours to obtain a platinum API. The amount of pure water added at 0-10°C is 1-10:1 by mass of the chloroplatinous salt, and the crystallization time is 1-10 hours.
[0031] Preferably, the drying method is vacuum drying or forced air drying.
[0032] Preferably, the platinum APIs include cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, and miplatin.
[0033] The beneficial effects of the present invention are:
[0034] The continuous manufacturing method of platinum raw materials described in the present invention has the same high-efficiency production, low-cost investment, high-quality / yield products, and green manufacturing as the continuous manufacturing technology of pharmaceuticals. It can effectively control the feed amount of starting materials and the output of platinum raw materials, thereby improving the flexibility of on-demand production. It breaks the dilemma that platinum raw materials can only be produced in small batches and product uniformity cannot be guaranteed. A new method for controlling the feed amount of silver salt and the silver content in the product has been established, which can respond during the reaction process. The detected amount of silver element in the platinum raw materials obtained in actual production is within the range required by the pharmacopoeia. The filtering and washing device for the platinum product can filter and wash the product efficiently and quickly, and can avoid the phenomenon of reduced product yield caused by the redissolution of the platinum product in the solvent due to low filtration efficiency. It can effectively remove by-products (related substances) and solvent residues in the product to ensure product quality. In addition, the filtering and washing device is not only limited to the filtering and washing of platinum products, but can also be applied to "small, fine and advanced" products. BRIEF DESCRIPTION OF THE DRAWINGS
[0035] Figure 1 : A structural diagram of a filtering and washing device for platinum products of the present invention. DETAILED DESCRIPTION
[0036] The present invention is further described in detail below with reference to the embodiments, but the protection scope of the present invention is not limited to the contents described above.
[0037] like Figure 1 As shown, a filtering and washing device for platinum products consists of two parts, an upper part of which is composed of a shell as a whole, the top of the shell is a box cover 1, the box cover 1 is provided with a stirring paddle 5 extending downward close to the bottom of the shell, and a visual window 4 is provided on the shell at the level of the stirring paddle 5, and the visual window 4 is sealed and connected to the shell with a transparent material; an openable and closable feed port 2 is provided on one side of the upper half of the shell, and an openable and closable air pressure inlet 3 is provided on the other side; a filter element layer 6 is provided at the bottom of the shell, and a metal partition 8 is provided below the filter element layer 6; the metal partition 8 separates the upper and lower parts of the device, and the lower part is also composed of a nearly closed box body, an air extraction port 9 is provided on one side of the top of the box body, and a liquid discharge port 10 is provided on one side of the bottom of the box body. The air extraction port 9 is connected to the negative pressure device when the product is filtered, and the liquid discharge port 10 is openable and closable.
[0038] Example 1
[0039] A method for continuous manufacturing of platinum APIs, wherein the specific operations are as follows:
[0040] Weigh 10.0 kg of potassium chloroplatinite, add 100.0 kg of pure water, and dissolve at 60°C. Then, add potassium iodide at a molar ratio of 1:4.5. The mixture is allowed to react for 60 minutes. Ammonia water is then added (at a molar ratio of 2.5:1 to potassium chloroplatinite) and allowed to react for 120 minutes to produce cis-diiodo-diammineplatinum(II). The solid-liquid mixture enters the filtration and washing apparatus through feed port 2. Before feeding, close the stirring paddle 5, the air compressor port 3, the discharge port 7, and the metal partition 8. Close the metal partition 8, open the vacuum port 9, and apply vacuum. The filtrate enters the lower portion of the apparatus. Close the vacuum port 9, open the metal partition 8, and add pure water to the apparatus through feed port 2. Open the stirring paddle 5, and the filtration system enters the washing state. Close the metal partition 8, open the vacuum port 9, and apply vacuum. The washing filtrate enters the lower portion of the apparatus. Close the stirring paddle 5, close the exhaust port 9, open the metal partition 8, close the feed port 2, open the air compressor port 3 to connect the air compressor, and open the discharge port 7 to collect the washed cis-diiodide-diammineplatinum (II).
[0041] Cis-diiodide-diammineplatinum (II) was discharged into the reactor, and 100 kg of pure water was added, followed by silver nitrate (at a molar ratio of 1.8:1 to potassium chloroplatinate). The reaction temperature was adjusted to 50°C and the reaction time was 120 minutes. The conductivity value in the reaction system stabilized at 710 μS / cm, indicating complete reaction. The mixture entered the filtration and washing device through feed port 2. Before feeding, the stirring paddle 5, air compressor port 3, and discharge port 7 should be closed, and the metal partition 8 should be opened. The metal partition 8 was then closed, and the vacuum port 9 was opened to evacuate the air. The filtrate entered the lower part of the device and was collected. 0.1 kg of activated carbon was added to the filtrate, and the above filtration steps were repeated to collect the hydrolyzed solution.
[0042] The clarified hydrolyzed liquid is discharged into a reactor containing a solution of potassium chloride (added in an amount of 1.2:1 of a potassium chloroplatinate molar ratio), and the reaction temperature is adjusted to 50°C for 300 min. After the reaction is complete, the reaction system is concentrated to substantially no droplets at 60°C under a vacuum of 100 hPa, and crude cisplatin is collected. The crude cisplatin enters the filtration and washing device through the feed port 2. Before feeding, the stirring paddle 5, the air pressure port 3, the discharge port 7, and the metal partition 8 should be closed. Pure water is added from the feed port 2, the stirring paddle 5 is opened, the metal partition 8 is closed, the vacuum port 9 is opened, and the filtrate enters the lower part of the device. The stirring paddle 5 is closed again, the vacuum port 9 is closed, the metal partition 8 is opened, the feed port 2 is closed, the air pressure port 3 is opened to connect to the air pressure, and the cleaned crude cisplatin is collected by opening the discharge port 7.
[0043] The crude cisplatin product is dissolved in boiling water (the mass ratio of pure water to potassium chloroplatinite is 15:1) and then enters the filtration and washing unit through feed port 2. Before adding, the stirring paddle 5, the air compressor port 3, the discharge port 7, and the metal partition 8 are closed. The metal partition 8 is then closed, and the vacuum port 9 is opened to induce vacuum. The filtrate enters the lower section of the unit and is collected. The filtrate is stirred and crystallized at 0°C for 4 hours and then enters the filtration and washing unit through feed port 2. Before adding, the stirring paddle 5, the air compressor port 3, the discharge port 7, and the metal partition 8 are closed. Pure water is added through feed port 2, the stirring paddle 5 is opened, the metal partition 8 is closed, the vacuum port 9 is opened, and the filtrate enters the lower section of the unit. The stirring paddle 5, the air compressor port 9, the metal partition 8 are opened, the feed port 2 is closed, the air compressor port 3 is opened to connect, and the discharge port 7 is opened to collect the clean cisplatin product. The product was taken out and dried at 80°C for 6h to obtain 6.1kg of cisplatin API with a yield of 84.7% (based on the starting material potassium chloroplatinite). The cisplatin content was 100.03% and the content of related substances was 0.42% by high performance liquid chromatography. The silver content in the product was 4.7ppm by atomic absorption spectrometry.
[0044] Example 2
[0045] A method for continuous manufacturing of platinum APIs, wherein the specific operations are as follows:
[0046] Weigh 10.0 kg of potassium chloroplatinite, add 200.0 kg of pure water, and dissolve at 100°C. Then add potassium iodide at a molar ratio of 1:5.0, and let it react for 120 minutes. Then add ammonia water (at a molar ratio of 3.0:1 to potassium chloroplatinite) and let it react for 300 minutes to produce cis-diiodo-diammineplatinum(II). The solid-liquid mixture enters the filtration and washing device through feed port 2. Before feeding, close the stirring paddle 5, the air compressor port 3, the discharge port 7, and the metal partition 8. Close the metal partition 8, open the exhaust port 9 to evacuate, and the filtrate enters the lower part of the device. Close the exhaust port 9, open the metal partition 8, add pure water to the device through feed port 2, open the stirring paddle 5, and the filtration system is in a washing state. Close the metal partition 8, open the exhaust port 9 to evacuate, and the washing filtrate enters the lower part of the device. Close the stirring paddle 5, close the exhaust port 9, open the metal partition 8, close the feed port 2, open the air compressor port 3 to connect the air compressor, and open the discharge port 7 to collect the washed cis-diiodide-diammineplatinum (II).
[0047] Cis-diiodo-diammineplatinum(II) was added to a reactor, followed by 500 kg of pure water and silver 1,1-cyclobutanedicarboxylate (at a molar ratio of 1.0:1 to chloroplatinite). The reaction temperature was adjusted to 80°C and the reaction time was 300 minutes. The conductivity within the reaction system stabilized at 780 μS / cm, indicating complete reaction. The reaction was then fed into the filtration and washing apparatus through feed port 2. Before feeding, the stirring paddle 5, air compressor port 3, and discharge port 7 should be closed, and metal partition 8 should be opened. Metal partition 8 should then be closed, and vacuum port 9 should be opened to apply vacuum. The filtrate was then fed into the lower portion of the apparatus and collected. 1.0 kg of activated carbon was added to the filtrate, and the filtration process was repeated to obtain the crude carboplatin mother liquor.
[0048] The clarified crude carboplatin mother liquor is concentrated at 80°C under a vacuum of 20 hPa until virtually no liquid drips, and the crude carboplatin is collected. The crude carboplatin enters the filtration and washing apparatus through feed port 2. Before feeding, the stirring paddle 5, air compressor port 3, discharge port 7, and metal partition 8 should be closed. Pure water is added through feed port 2, the stirring paddle 5 is turned on, the metal partition 8 is closed, and the vacuum port 9 is opened to induce vacuum. The filtrate enters the lower portion of the apparatus. The stirring paddle 5, air compressor port 9, metal partition 8, feed port 2, and air compressor port 3 are opened to connect. The cleaned crude carboplatin is then collected by opening discharge port 7.
[0049] The crude carboplatin product is dissolved in boiling water (pure water to potassium chloroplatinate ratio of 1:1 by mass) and then enters the filtration and washing unit through feed port 2. Before adding, the stirring paddle 5, air compressor port 3, and discharge port 7 should be closed, and the metal partition 8 should be opened. The metal partition 8 should be closed again, and the vacuum port 9 should be opened to induce vacuum. The filtrate enters the lower part of the unit and is collected. The filtrate is stirred and crystallized at a low temperature of 10°C for 10 hours, then enters the filtration and washing unit through feed port 2. Before adding, the stirring paddle 5, air compressor port 3, and discharge port 7 should be closed, and the metal partition 8 should be opened. Pure water is added through feed port 2, the stirring paddle 5 is opened, the metal partition 8 is closed, the vacuum port 9 is opened, and the filtrate enters the lower part of the unit. The stirring paddle 5, the vacuum port 9, and the metal partition 8 should be opened again, the feed port 2 should be closed, the air compressor port 3 should be opened to connect, and the discharge port 7 should be opened to collect the clean carboplatin product. The product was taken out and dried at 100° C. for 10 h to obtain 6.7 kg of carboplatin API with a yield of 75.3% (based on the starting material potassium chloroplatinate). The carboplatin content was 99.84% and the related substance content was 0.15% as measured by high performance liquid chromatography. The silver content in the product was 0.5 ppm as determined by inductively coupled plasma spectrometry.
[0050] Example 3
[0051] A method for continuous manufacturing of platinum APIs, wherein the specific operations are as follows:
[0052] Weigh 10.0 kg of potassium chloroplatinite, add 10.0 kg of pure water, and dissolve at 20°C. Then add potassium iodide at a molar ratio of 1:4.0. Let the mixture react for 10 minutes. Then add trans-1,2-di(aminomethyl)cyclobutane (at a molar ratio of 1.0:1 to potassium chloroplatinite) and let the reaction continue for 30 minutes to produce cis-diiodo-trans-1,2-di(aminomethyl)cyclobutane platinum(II). Pass the solid-liquid mixture through feed port 2 into the filtration and washing device. Before feeding, close the agitator 5, the air compressor port 3, the discharge port 7, and the metal partition 8. Close the metal partition 8, open the vacuum port 9 to induce vacuum, and the filtrate enters the lower part of the device. Close the vacuum port 9, open the metal partition 8, add pure water to the device through the feed port 2, turn on the stirring paddle 5, and the filtration system enters the washing state. Close the metal partition 8, open the vacuum port 9 to induce vacuum, and the washing filtrate enters the lower part of the device. Close the stirring paddle 5, close the vacuum port 9, open the metal partition 8, close the feed port 2, open the air compressor port 3 to connect to the air compressor, and open the discharge port 7 to collect the washed cis-diiodo-trans-1,2-bis(aminomethyl)cyclobutaneplatinum(II).
[0053] cis-diiodo-trans-1,2-bis(aminomethyl)cyclobutane platinum(II) was added to a reactor, followed by 50 kg of pure water and silver nitrate (at a molar ratio of 1.5:1 to potassium chloroplatinate). The reaction temperature was adjusted to 80°C for 30 minutes. The conductivity within the reaction system stabilized at 650 μS / cm, indicating complete reaction. The reaction was then fed into the filtration and washing apparatus through feed port 2. Before feeding, the stirring paddle 5, air compressor port 3, and discharge port 7 should be closed, and metal partition 8 should be opened. Metal partition 8 should then be closed, and vacuum port 9 should be opened to apply vacuum. The filtrate was then fed into the lower portion of the apparatus and collected. 10 g of activated carbon was added to the filtrate, and the filtration process was repeated to collect the hydrolyzed solution.
[0054] The clarified hydrolyzate was discharged into a reactor containing a lactic acid solution (added in an amount of 1.0:1 potassium chloroplatinate molar ratio), and the reaction temperature was adjusted to 80°C for 30 minutes. After the reaction was complete, the reaction system was concentrated at 40°C and a vacuum of 200 hPa until there was essentially no droplet dripping, and the crude lobaplatin product was collected. The crude lobaplatin product entered the filtration and washing device through the feed port 2. Before feeding, the stirring paddle 5, the air pressure port 3, the discharge port 7, and the metal partition 8 should be closed. Pure water and acetone were added from the feed port 2, the stirring paddle 5 was opened, the metal partition 8 was closed, the vacuum port 9 was opened, and the filtrate entered the lower part of the device. The stirring paddle 5 was then closed, the vacuum port 9 was closed, the metal partition 8 was opened, the feed port 2 was closed, the air pressure port 3 was opened to connect to the air compressor, and the discharge port 7 was opened to collect the cleaned crude lobaplatin product.
[0055] Discharge the crude lobaplatin into boiling water-ether (the water-ether ratio is 1:1 for potassium chloroplatinite by mass, and the volume ratio of water to ether is 1:1) to dissolve the crude product. The product then enters the filtration and washing unit through feed port 2. Before feeding, turn off the stirring paddle 5, the air compressor port 3, the discharge port 7, and open the metal partition 8. Close the metal partition 8, open the vacuum port 9, and induce vacuum. The filtrate enters the lower section of the unit and is collected. The filtrate is stirred and crystallized at -10°C for 1 hour. The product then enters the filtration and washing unit through feed port 2. Before feeding, turn off the stirring paddle 5, the air compressor port 3, the discharge port 7, and open the metal partition 8. Add water and ether through feed port 2, open the stirring paddle 5, close the metal partition 8, and open the vacuum port 9 to induce vacuum. The filtrate then enters the lower section of the unit. The stirred paddle 5 was then closed, the exhaust port 9 was closed, the metal partition 8 was opened, the feed port 2 was closed, the air compressor port 3 was opened to connect the air compressor, and the discharge port 7 was opened to collect the cleaned lobaplatin product. The product was removed and dried at 40°C for 10 hours to obtain 5.7 kg of lobaplatin (trihydrate) API, with a yield of 52.3% (based on the starting material potassium chloroplatinate). The lobaplatin content was 101.28% and the related substance content was 0.30% as measured by high performance liquid chromatography. The silver content in the product was 1.9 ppm as determined by atomic absorption spectrometry.
Claims
1. A platinum product filtering and washing device, characterized in that: The filtering and washing device is composed of an upper and lower part, wherein the upper part is composed of a shell as a whole, the top of the shell is a box cover (1), and the box cover (1) is provided with a stirring paddle (5) extending downward to the bottom of the shell; a feed port (2) that can be opened and closed is provided on one side of the upper half of the shell, and an air pressure inlet (3) that can be opened and closed is provided on the other side; a filter core layer (6) is provided at the bottom of the shell, and a metal partition (8) that can be opened and closed is provided below the filter core layer (6); the metal partition (8) separates the upper and lower parts of the device when closed; the lower part is composed of a closed box body, a suction port (9) is provided on one side of the top of the box body, and a liquid discharge port (10) that can be opened and closed is provided on one side of the bottom of the box body, and the suction port (9) is connected to the negative pressure device when the product is filtered.
2. The platinum product filtering and washing device according to claim 1, characterized in that: A visual window (4) is provided on the housing at a level with the stirring paddle (5). The visual window (4) is connected to the housing with a transparent material to form a sealed whole.
3. A continuous manufacturing method for platinum raw materials, characterized in that: The method uses a platinum product filtering and washing device as claimed in claim 1, comprising the following steps: Step 1: dissolving chloroplatinite in pure water, adding iodine salt, and then adding amine ligand to react to form an intermediate - cis-diiodine-platinum-amine complex; Step 2: discharging the solid-liquid mixed system containing the intermediate into a filtering and washing device for filtering and washing; Step 3: The washed and filtered intermediate is discharged into a reactor, and pure water and silver salt are added. The reaction is complete when the conductivity value in the reaction system is stable and within the qualified range. The intermediate is discharged into a filter washing device and filtered twice; Step 4: The clarified filtrate is directly concentrated to obtain a crude product, or the clarified filtrate is introduced into a solution containing a leaving group or a salt formed by the leaving group and concentrated to obtain a crude product after the reaction is complete; Step 5: The crude product is discharged into a filtering and washing device for filtration and washing, and the washed and filtered crude product is discharged into a boiling solvent for dissolution; Step 6: After the crude product is dissolved, it is filtered through a filter-washing device, and the filtrate is added to refrigerated pure water or directly crystallized under stirring in a low-temperature environment. After the crystallization is completed, it is filtered and washed through a filter and washing device, and the product is completely dried to obtain a platinum raw material.
4. The method for continuous production of platinum-based pharmaceutical raw materials according to claim 3, wherein: The filtering and washing process comprises: When the filtration system needs to pass through the filtration washing device, close the stirring blade (5), close the air pressure port (3), close the discharge port (7), open the metal partition (8), and close the liquid discharge port (10); the filtration system enters the device from the feed port (2), close the metal partition (8), open the air extraction port (9) to evacuate, and the filtrate enters the lower part of the device; close the air extraction port (9), open the metal partition (8), add the cleaning solvent into the device from the feed port (2), open the stirring blade (5), and the filtration system The device is in a washing state; the metal partition (8) is closed, the air extraction port (9) is opened to perform vacuuming, and the washing filtrate enters the lower part of the device; the stirring paddle (5) is closed, the air extraction port (9) is closed, the metal partition (8) is opened, the feed port (2) is closed, the air pressure port (3) is opened to receive compressed air, and the discharge port (7) is opened to collect the washed solid product; when the metal partition (8) is in an open state, the air extraction port (9) is not connected to the vacuuming device, and the liquid discharge port (10) is opened to collect the filtrate.
5. The method for continuous production of platinum API according to claim 3, wherein: In step 3: After the silver salt is added, Ag + Combined I - The generation of AgI precipitation reduces the conductivity. The conductivity value in the system is in the range of 600 to 800 μS / cm, indicating that the addition of silver salt is qualified.
6. The method for continuous production of platinum API according to claim 3, wherein: In step 1: The chloroplatinite is sodium chloroplatinite or potassium chloroplatinite; The mass ratio of the chloroplatinite to pure water is 1:1-20, and the dissolution temperature is 20-100°C; The iodized salt is sodium iodide or potassium iodide, and the molar ratio of chloroplatinite to the iodized salt is 1:4-5; The reaction time after adding the iodized salt is 10 to 120 minutes; The amine ligand is one of ammonia water, (1R,2R)-(-)-1,2-cyclohexanediamine, and trans-1,2-di(aminomethyl)cyclobutane, or a salt formed by ammonia water, (1R,2R)-(-)-1,2-cyclohexanediamine, and trans-1,2-di(aminomethyl)cyclobutane with hydrochloric acid, nitric acid, or sulfuric acid, respectively; When the amine ligand is ammonia water or a salt formed with hydrochloric acid, nitric acid, or sulfuric acid, the molar ratio of the amount of the amine ligand added to the chloroplatinite is 2 to 3:1; When the amine ligand is (1R,2R)-(-)-1,2-cyclohexanediamine or trans-1,2-di(aminomethyl)cyclobutane, or a salt formed by (1R,2R)-(-)-1,2-cyclohexanediamine or trans-1,2-di(aminomethyl)cyclobutane with hydrochloric acid, nitric acid, or sulfuric acid, the molar ratio of the added amount to the chloroplatinite is 1 to 1.5:1; The reaction time after adding the amine ligand is 30 to 300 minutes; The cis-diiodine-platinum-amine complex is one of cis-diiodine-diammine platinum (II), cis-diiodine-(1R, 2R)-(-)-1,2-cyclohexanediamine platinum (II), and cis-diiodine-trans-1,2-di(aminomethyl)cyclobutane platinum (II).
7. The method for continuous production of platinum API according to claim 3, wherein: In step 3: The silver salt is one or more of silver nitrate, silver sulfate, 1,1-cyclobutanedicarboxylic acid silver, and silver glycolate; The amount of pure water added is 5 to 50:1 of the mass ratio of chloroplatinite; When the silver salt is silver sulfate or silver 1,1-cyclobutanedicarboxylate, the amount thereof added is 0.8 to 1.0:1 of the molar ratio of chloroplatinite; When the silver salt is silver nitrate or silver glycolate, the amount thereof added is 1.5 to 2.0:1 in molar ratio to chloroplatinite; The reaction time after adding pure water and silver salt is 30 to 300 minutes; The temperature of the reaction system is 20 to 80°C; The two filtrations include coarse filtration and fine filtration. The coarse filtration is normal filtration, and the fine filtration is to add activated carbon to the filtrate of the coarse filtration, and the added amount is 0.001 to 0.1:1 of the mass ratio of chloroplatinite.
8. The method for continuous production of platinum API according to claim 3, wherein: In step 4: The concentration temperature is 40-80°C and the vacuum degree is 200-20hPa / mbar; The leaving group is hydrogen chloride, glycolic acid, oxalic acid, lactic acid, tetradecanoic acid; The salt formed by the leaving group is sodium chloride, potassium chloride, sodium glycolate, potassium glycolate, sodium oxalate, potassium oxalate, sodium lactate, potassium lactate, sodium myristate, potassium myristate; When the leaving group or the salt formed by the leaving group is hydrogen chloride, tetradecanoic acid, sodium chloride, potassium chloride, sodium myristate, or potassium myristate, the amount added is 2.0 to 3.0:1 of the molar ratio of chloroplatinite; When the leaving group or the salt formed by the leaving group is glycolic acid, oxalic acid, lactic acid, sodium glycolate, potassium glycolate, sodium oxalate, potassium oxalate, sodium lactate, or potassium lactate, the amount added is 1.0 to 1.5:1 of the molar ratio of chloroplatinite; The reaction temperature is 20-80°C; The reaction time is 30 to 600 minutes.
9. The method for continuous production of platinum API according to claim 3, wherein: In step 5: The solvent used for washing is one or more of water, ethanol, ether, ethyl acetate, and acetone; The boiling solvent is one or more of water, ethanol, methanol, ether, ethyl acetate, acetone, dichloromethane, N,N-dimethylformamide, and dimethyl sulfoxide; The mass ratio of the boiling solvent to chloroplatinite is 1 to 20:
1.
10. A method for continuous production of a platinum-based pharmaceutical raw material according to any one of claims 3 to 9, characterized in that: In step 6: The temperature of the pure water for refrigeration is 0-10°C; The low temperature environment is -10 to 10°C; The crystallization time is 1 to 10 hours; The solvent used for washing is one or more of water, ethanol, ether, ethyl acetate, and acetone; The amount of pure water added at 0-10°C is 1-10:1 of the mass ratio of chloroplatinite; The drying temperature is 40-100° C., and the drying time is 2-10 hours.