Industrial production method of 9-iodo-9-borabicyclo[3.3.1]nonane solution

Abstract

The present invention provides an industrial production method for a 9-iodine-9-borane bicyclo[3.3.1] solution, comprising the steps of: 1) passing an appropriate amount of dry hydrogen iodide gas generated on site into a mixture of a 9-borane bicyclo[3.3.1]nonane dimer and an organic solvent under inert gas protection at 15 to 25° C. to carry out a heterogeneous system reaction; 2) after stopping the introduction of hydrogen iodide, stirring for 1 to 20 hours at 15 to 25° C., degassing the mixture by vacuum pumping negative pressure for 5 to 10 minutes and replenishing nitrogen to obtain a colorless transparent solution, which is then appropriately diluted to obtain a commercially available 9-iodine-9-borane bicyclo[3.3.1]nonane solution. The present invention is suitable for the industrial production of a 9-iodine-9-borane bicyclo[3.3.1]nonane solution and has the advantages of mild reaction conditions, safe and simple operation, low environmental production cost, and a stable production process.

Description

Technical Field

[0001] The present invention relates to an industrial preparation process of an iodinated boron compound, in particular to an industrial production method of a 9-iodine-9-borabicyclo[3.3.1]nonane solution. Background Art

[0002] 9-Iodo-9-borabicyclo[3.3.1]nonane (BI-9-BBN) (structure shown in Compound 1) is an important organoboronation reagent in organic synthesis and can be used to prepare high-value-added boron-containing pharmaceutical intermediates or boron-containing materials for specific applications.

[0003]

[0004] 9-Iodo-9-borabicyclo[3.3.1]nonane can undergo cis-addition reaction with 1-alkyne (Pure & Appl. Chem., Vol. 58, No. 4, pp. 629-638, 1986), as shown in Reaction Formula 1, to obtain an important intermediate iodinated boron compound having the structure of Chemical Formula 2. In research conducted by Yoshitaka Satoh et al., it was found that 9-iodo-9-borabicyclo[3.3.1]nonane reacts with ethoxyacetylene (as shown in Reaction Formula II) to produce iodinated boron compound 3, which can then react with certain aldehydes under mild conditions to give the corresponding trans-α,β-unsaturated ester 5 (as shown in Reaction Formula III) with high stereoselectivity and high yield (Tetrahedron Lett. Vo1.30, No.38, pp.5153-5156, 1989). Compound 3 can also react with certain ketones to produce δ-ketoester 6 (as shown in Reaction Formula IV) (Chem. Lett., pp.1723-1726, 1989). 9-Iodo-9-borabicyclo[3.3.1]nonane can also react with ketones to form boron enolates, which then provide highly selective cis-unsaturated ketones (as shown in Reaction Scheme V) (Chem. Eur. J., Vol. 22, No. 52, pp. 18686-18689, 2016). Furthermore, 9-iodo-9-borabicyclo[3.3.1]nonane can react with 3-enoates to form cis-addition products (as shown in Reaction Scheme VI) (Org. Lett., Vol. 15, No. 21, pp. 5436-5439, 2013). Thus, 9-iodo-9-borabicyclo[3.3.1]nonane is widely used in organic synthesis.

[0005]

[0006]

[0007] It is worth noting that according to patent application CN201280066974.9, compound 7 can be converted into compound 8 using 9-iodo-9-borabicyclo[3.3.1]nonane for subsequent reaction to synthesize (3R)-2,4-di-leaving group-3-methylbut-1-ene (compound 9).

[0008]

[0009] Among them, PG is a protecting group and LG is a leaving group.

[0010] Compound 9 is an important intermediate in the process of preparing natural products of halichondrin and its analogues with anti-tumor effects. Among them, the anti-tumor drug Eribulin (structure shown in compound 10) was developed by Japan Eisai Co., Ltd. It contains 19 chiral carbon atoms and the final commercial synthesis route is as long as 62 steps. It is one of the most structurally complex drugs developed by pure chemical synthesis and is also a popular drug for the treatment of tumor diseases. Eribulin is an analogue of halichondrin B that can bind to tubulin and microtubules. Similar to other types of microtubule inhibitors, it induces cell apoptosis by inhibiting cell mitosis (Biochem.Biophys.Res.Commun., Vol.570, pp.89-95, 2021). Eribulin mesylate has been approved for marketing in China and has clinical benefits for the overall survival (OS) of patients with advanced soft tissue sarcoma. Because it is very effective in treating metastatic breast cancer and its indications for later development are also very broad, the market prospects are broad.

[0011]

[0012] According to patent application WO2019 / 211877A1, Eribulin is synthesized from three key intermediates (Compound 11, Compound 12, Compound 13), and the synthesis is very difficult. Among them, the preparation of Compound 14 (as shown in Reaction Formula VII) with 9-iodo-9-borahertabicyclo[3.3.1]nonane is a key step in the preparation of Eribulin intermediate 11, and the key to achieving this step of reaction conversion is the use of high-purity, high-reactivity 9-iodo-9-borahertabicyclo[3.3.1]nonane. The quality control requirements of the required 9-iodo-9-borahertabicyclo[3.3.1]nonane solution are usually its molar concentration of about 1.0 to 1.2 mol / L and its purity greater than 95%. Therefore, the preparation of high-purity, high-reactivity 9-iodo-9-borahertabicyclo[3.3.1]nonane has important commercial value.

[0013]

[0014] In addition, 9-iodo-9-borabicyclo[3.3.1]nonane also plays an important role in the synthesis of other drugs. Its applications are constantly expanding and its demand is gradually increasing. For example, it is used in related research on electrochemical fuel cells using formic acid as a direct fuel or carrier (Chem. Sci. Vol. 7, pp. 5680-5685, 2016).

[0015] However, there are few literature reports on its synthesis process. Herbert C. Brown and his research team reported the following laboratory synthesis methods of 9-iodo-9-borahertabicyclo[3.3.1]nonane.

[0016] ① Hydroboration reaction of 1,5-cyclooctadiene with a methyl sulfide complex of iodinated borane (as shown in Reaction Formula VIII): Herbert C. Brown and his research team described a method for synthesizing 9-iodine-9-borahertabicyclo[3.3.1]nonane in a paper (J.Org.Chem., Vol.44, No.14, pp.2422-2425, 1979). 1,5-cyclooctadiene was hydroborated with a methyl sulfide complex of iodinated borane (H2BI·SMe2) to generate 9-iodine-9-borahertabicyclo[3.3.1]nonane. 3.1]nonane dimethyl sulfide complex (BI-9-BBN·SMe2) and its isomer (1,4-adduct); taking advantage of the isomer's poor thermal stability, the isomer is converted to 9-iodo-9-borabicyclo[3.3.1]nonane dimethyl sulfide complex by heating (as shown in Reaction Formula VIII); then, boron triiodide is added and distilled to obtain 9-iodo-9-borabicyclo[3.3.1]nonane (as shown in Reaction Formula IX). The disadvantages of this method are that the complex of 9-iodo-9-borabicyclo[3.3.1]nonane and dimethyl sulfide is easily released upon heating, which pollutes the environment and is harmful to the human body. The product needs to be distilled and purified with boron triiodide, otherwise the impurities produced will affect its purity and reaction performance. Boron triiodide is also relatively expensive, resulting in high production costs.

[0017]

[0018] ② Reaction of 9-borabicyclo[3.3.1]nonane with hydrogen iodide: In another document (J. Organomet. Chem, Vol. 168, pp. 281-293, 1979), when 9-borabicyclo[3.3.1]nonane is reacted with hydrogen iodide to prepare 9-iodo-9-borabicyclo[3.3.1]nonane (as shown in Reaction Formula X), Herbert C. Brown discovered that dichloromethane is required as the solvent, and dry ice is required to be added to acetone to form a -50°C cold bath to condense the hydrogen iodide gas into a liquid and control the total amount of hydrogen iodide involved in the reaction; during the reaction, dry ice and acetone are also required to be used in the condenser to prevent the loss of hydrogen iodide by volatilization; after the reaction, due to the large amount of impurities generated, the product needs to be purified by distillation, and 9-iodo-9-borabicyclo[3.3.1]nonane is finally obtained with a yield of 83%. The disadvantages of this method are: the reaction is a homogeneous system reaction, the equivalent ratio is uncontrollable during the reaction process, impurities are easily generated, and the reaction liquid needs to be distilled to obtain the product, with a low yield; the product is unstable under high temperature conditions and distillation is relatively difficult; and the gas cooling cost is high, making it difficult to achieve industrial scale-up production.

[0019]

[0020] ③ Reaction of 9-borabicyclo[3.3.1]nonane with elemental iodine: Herbert C. Brown described the laboratory implementation of this method (shown in Reaction Scheme XI). This method also uses dichloromethane as the solvent. After dissolving 9-borabicyclo[3.3.1]nonane, a solution of elemental iodine in dichloromethane is added dropwise to the solution for a homogeneous reaction. Dry ice and acetone are used in the condenser to cool the temperature below the boiling point of hydrogen iodide to prevent volatilization and loss of hydrogen iodide. This reaction takes a long time, requiring 36 hours to complete. The product requires distillation and purification, and the yield is only 78%.

[0021]

[0022] The disadvantages of this method are high production costs and unsatisfactory yields, making it unsuitable for industrial scale-up. The reaction is also a homogeneous system reaction, generating a large number of impurities. Furthermore, the 9-iodo-9-borabicyclo[3.3.1]nonane solution obtained by reaction with elemental iodine is purple, making it unsuitable for direct use in the reaction.

[0023] ④ Boron halide and 9-borabicyclo[3.3.1]nonane undergo an exchange reaction in pentane solution to produce halogenated 9-borabicyclo[3.3.1]nonane (as shown in Reaction Scheme XII). At 37°C, 9-borabicyclo[3.3.1]nonane reacts with boron iodide to produce 9-iodo-9-borabicyclo[3.3.1]nonane in a 90% yield. Disadvantages of this method include: the pentane must be stirred with concentrated sulfuric acid for one day, treated with anhydrous potassium carbonate, and distilled over lithium aluminum hydride; diborane gas is continuously produced during the reaction, posing significant safety and environmental risks; and boron triiodide is expensive, making it unsuitable for industrial scale-up.

[0024]

[0025] In summary, existing methods for synthesizing 9-iodo-9-borabicyclo[3.3.1]nonane have the following disadvantages: Method 1 requires the addition of boron triiodide during product preparation and distillation, resulting in high production costs and the unavoidable generation of odorous sulfides, which are unfriendly to the environment and the human body. Method 2, during product preparation, the reaction is a homogeneous system reaction, during which the equivalent ratio is uncontrollable and impurities are easily generated. During the reaction, dry ice is added to acetone to form a -50°C cold bath to condense hydrogen iodide gas into a liquid to determine the total amount of hydrogen iodide used, which is then distilled and added to the reaction system. This step is complex and has high cooling costs. Furthermore, due to the high impurity content of the product, distillation and purification are required, resulting in low product yields. In particular, 9-iodo-9-borabicyclo[3.3.1]nonane is known to be thermally unstable, which increases the difficulty of distillation. Furthermore, this method is limited to laboratory scale and has not been verified for large-scale industrial production, lacking practicality. Method 3, during the product preparation process, dichloromethane is also used as a solvent, and the reaction is a homogeneous system reaction, with a high impurity content, and iodine is used as a raw material, resulting in a purple reaction solution, requiring the product to be purified by distillation, with a low yield, and is not suitable for industrial production. Method 4, during the product preparation process, the reaction conditions are harsh, the solvent used requires a complex anhydrous and oxygen-free process, and the operation is dangerous, which increases production costs, and the use of a large amount of boron triiodide greatly increases the cost of raw materials; During the reaction process, diborane gas is continuously generated, which has a great safety risk and is unfriendly to the environment. It can be seen from this that currently known reaction systems are all homogeneous reaction systems, and the equivalent ratio is uncontrollable during the reaction process. More impurities are produced in the reaction system, requiring distillation purification, and a low yield.

[0026] Therefore, there is an urgent need to develop a practical process method that can prepare 9-iodo-9-borabicyclo[3.3.1]nonane solution with high purity, high yield, ease of use, low cost and high product quality and is suitable for industrial production. Summary of the Invention

[0027] In view of the shortcomings of the prior art, the present invention aims to provide an industrial production method for 9-iodo-9-borabicyclo[3.3.1]nonane solution, which has mild reaction conditions, stable process, low production cost, and is suitable for industrial scale-up and safe production.

[0028] After extensive research and experiments, the inventors discovered that when preparing 9-iodo-9-borabicyclo[3.3.1]nonane using 9-borabicyclo[3.3.1]nonane and hydrogen iodide gas in dichloromethane, both 9-borabicyclo[3.3.1]nonane and hydrogen iodide gas are readily soluble in dichloromethane, leading to a transient localized excess of hydrogen iodide and excessive concentration. This makes it impossible to control the equivalent ratio during the reaction, resulting in excessively rapid side reactions in the reaction system and an excessively high impurity content in the prepared 9-iodo-9-borabicyclo[3.3.1]nonane solution. Furthermore, the reaction temperature, concentration, and time all have significant effects on the reaction. Therefore, the product produced by this method requires distillation and purification.

[0029] The present invention creatively uses 9-borahertabicyclo[3.3.1]nonane dimer as a raw material and reacts it with hydrogen iodide gas in a specific poor solvent in a heterogeneous system (as shown in Reaction Formula XIII). This effectively controls the equivalent ratio during the reaction, reduces the generation of impurities, and improves the product yield. The synthesis of 9-borahertabicyclo[3.3.1]nonane dimer can be found in the method described in Org. Synth., 1992, vol. 70, pp. 169–169. Hydrogen iodide gas is generated on-site using inexpensive commercially available aqueous hydrogen iodide solution and phosphorus pentoxide, and can be used in the reaction after drying and scrubbing. The heterogeneous reaction system does not require strict control of the total amount of hydrogen iodide gas introduced, so there is no need to condense the hydrogen iodide into liquid hydrogen iodide, which can significantly reduce production costs. In addition, the aeration time, aeration rate, and aeration volume of the hydrogen iodide gas are easy to control, making the operation safe. The present invention finds through reaction solvent screening that 9-borabicyclo[3.3.1]nonane dimer has low solubility in some alkane solvents and can form a low-concentration 9-borabicyclo[3.3.1]nonane reaction solution. Slowly introduced hydrogen iodide gas can react with the dimer in a relatively stable heterogeneous system. In particular, when the aeration time, aeration speed and aeration volume of the hydrogen iodide gas, the reaction concentration, the temperature and the time are optimized and controlled, side reactions can be unexpectedly suppressed, thereby preparing a high-quality 9-iodine-9-borabicyclo[3.3.1]nonane solution suitable for industrial safe production.

[0030]

[0031] The optimum reaction temperature of the present invention is 15-25° C., and the best reaction effect can be achieved only at room temperature. If the reaction temperature is lower than 15° C., the solubility of hydrogen iodide is too high; if the reaction temperature is higher than 25° C., the solubility of 9-borahertabicyclo[3.3.1]nonane dimer is too high, both of which will result in a high impurity content in the prepared 9-iodine-9-borahertabicyclo[3.3.1]nonane solution.

[0032] The amount of hexane placed in the reaction apparatus for the reaction is preferably 2.5 to 4.5 kg of hexane per 1 kg of 9-borabicyclo[3.3.1]nonane dimer. If the amount of hexane is too much, the product concentration will be low and the market acceptance will be poor. If the amount of hexane is too little, the concentration of 9-iodo-9-borabicyclo[3.3.1]nonane in the reaction system will be too high, which will promote side reactions and produce undesirable impurities, affecting product quality.

[0033] The inventors discovered that, during the preparation of 9-iodo-9-borabicyclo[3.3.1]nonane, if hydrogen iodide is aerated too quickly, the reaction solution can become locally excessive and overly concentrated, easily leading to side reactions. Furthermore, the large amount of water carried by the gas produced in a short period of time cannot be fully dried, causing the water to react rapidly with both 9-borabicyclo[3.3.1]nonane and 9-iodo-9-borabicyclo[3.3.1]nonane, producing impurities. If hydrogen iodide is aerated too slowly, the total aeration time is prolonged, and the product and hydrogen iodide coexist for a long time, triggering side reactions. Therefore, controlling the reaction concentrations of 9-borabicyclo[3.3.1]nonane and hydrogen iodide in a heterogeneous reaction system is key to preparing high-purity 9-iodo-9-borabicyclo[3.3.1]nonane. The hydrogen iodide aeration rate and volume can be adjusted by controlling the air pressure of the reaction system. As a specific embodiment, the pressure difference between the gas generating kettle and the reaction kettle is maintained at 0.011-0.012 MPa.

[0034] The existing technologies all use 9-borahertabicyclo[3.3.1]nonane as a reactant, and the reaction system is homogeneous. It is difficult to control the reaction equivalent ratio of 9-borahertabicyclo[3.3.1]nonane to hydrogen iodide during the reaction process. During the reaction process, it is necessary to use infrared spectroscopy to determine the reaction endpoint, and the reaction needs to be monitored in real time. The detection method is not convenient, which easily causes instantaneous local excess or excessive concentration of hydrogen iodide, and the purity and yield of the product obtained are not ideal. The present invention creatively uses 9-borahertabicyclo[3.3.1]nonane dimer and hydrogen iodide to react in a poorly soluble solvent in a heterogeneous system, and produces the required dry hydrogen iodide gas in a cheap and easily controllable manner. By regulating the ventilation time, ventilation speed and ventilation volume of hydrogen iodide gas, side reactions are easily suppressed; the hydrogen iodide gas introduction speed can be controlled by the gas pressure of the system, and it is not easy to produce excessive hydrogen iodide concentration or excessive use; because the solubility of 9-borahertabicyclo[3.3.1]nonane dimer in the organic solvent used is low, the reaction product The produced 9-iodo-9-borabicyclo[3.3.1]nonane is easily soluble in the organic solvent used. Therefore, the presence of solids in the system can be used to determine whether the reaction is nearing its endpoint. The reaction can be confirmed by measuring the contents of 9-iodo-9-borabicyclo[3.3.1]nonane and 9-borabicyclo[3.3.1]nonane in the system. According to techniques known in the art, the concentration of 9-borabicyclo[3.3.1]nonane is measured by hydrogen displacement method, and the concentration of 9-iodo-9-borabicyclo[3.3.1]nonane is measured by iodide ion titration method.

[0035] The above is the essential difference between the present invention and the prior art.

[0036] To achieve the purpose of the present invention, the following technical solutions are adopted:

[0037] The present invention provides an industrial production method of 9-iodo-9-borabicyclo[3.3.1]nonane solution, comprising the following steps:

[0038] S1. Introducing dry hydrogen iodide gas into a reaction apparatus containing 9-borabicyclo[3.3.1]nonane dimer and a suitable organic solvent and stirring under inert gas protection, controlling the amount of hydrogen iodide involved in the reaction by regulating the ventilation time and ventilation volume of the dry hydrogen iodide gas, and controlling the heterogeneous system reaction at a suitable reaction temperature;

[0039] S2. After stopping ventilation, stirring, degassing by using a vacuum pump to draw negative pressure and replenishing inert gas to obtain a colorless and transparent solution.

[0040] As one embodiment of the present invention, dry hydrogen iodide gas is prepared by the following method: under the protection of an inert gas, a commercially available aqueous solution of hydroiodic acid is dripped into a gas generating device filled with phosphorus pentoxide; at a suitable temperature, the generated hydrogen iodide gas is dried with a desiccant and subjected to a scrubbing treatment to obtain dry hydrogen iodide gas.

[0041] As an embodiment of the present invention, the inert gas is nitrogen or argon, preferably nitrogen.

[0042] As one embodiment of the present invention, the concentration of the hydroiodic acid aqueous solution is 45-100%, preferably 50-60%, and the amount used is 2.0-5.0 kg, preferably 2.0-3.0 kg, of the hydroiodic acid aqueous solution per 1 kg of 9-borahertabicyclo[3.3.1]nonane dimer.

[0043] As one embodiment of the present invention, the amount of phosphorus pentoxide used is 1.2 to 10.0 kilograms per kilogram of hydroiodic acid aqueous solution. If less than 1.2 kilograms of phosphorus pentoxide is used per kilogram of hydroiodic acid aqueous solution, the hydroiodic acid aqueous solution will not react completely and will not produce sufficient hydrogen iodide gas. If more than 10 kilograms of phosphorus pentoxide is used per kilogram of hydroiodic acid aqueous solution, the phosphorus pentoxide at the bottom will not participate in the reaction and will not be conducive to the subsequent cleaning of the reactor. Preferably, 1.2 to 5.0 kilograms of phosphorus pentoxide is used per kilogram of hydroiodic acid aqueous solution, more preferably 1.5 to 3.0 kilograms, and most preferably 1.5 to 2.0 kilograms.

[0044] As one embodiment of the present invention, the appropriate temperature in the gas generator is 0-40°C. A temperature below 0°C slows gas generation, while a temperature above 40°C rapidly increases gas generation, affecting the ventilation speed and time, and thus the entire reaction. Furthermore, moisture carried by the gas is difficult to dry, affecting the reaction effect. The preferred temperature is 10-30°C, and more preferably 15-25°C.

[0045] As one embodiment of the present invention, the pressure difference between the gas generating device and the reaction device is 0.011 to 0.012 MPa.

[0046] As an embodiment of the present invention, the hydrogen iodide gas is dried with a desiccant and scrubbed, which means that the generated hydrogen iodide gas passes through a graphite condenser in a room temperature water bath, a drying tower with a light-shielding material filled with anhydrous calcium chloride particles, and a solvent storage tank device filled with a suitable solvent.

[0047] As one embodiment of the present invention, in step S1, the suitable organic solvent is a C5-C9 alkane, petroleum ether, or toluene, or a mixture of at least two of the C5-C9 alkane, petroleum ether, and toluene in any proportion. The C5-C9 alkane is preferably at least one of pentane, hexane, heptane, and cyclohexane, more preferably hexane.

[0048] As one embodiment of the present invention, the amount of hexane placed in the solvent storage tank for scrubbing is preferably 0 to 10 kg of organic solvent per 1 kg of 9-borahertabicyclo[3.3.1]nonane dimer, preferably 0.5 to 1.0 kg of organic solvent.

[0049] As one embodiment of the present invention, the amount of organic solvent placed in the reaction apparatus for the reaction is 1 to 10 kg of organic solvent per 1 kg of 9-borahebicicyclo[3.3.1]nonane dimer, preferably 2 to 5 kg of organic solvent, and more preferably 2.5 to 4.5 kg of organic solvent. As a specific embodiment, the amount of hexane placed in the reaction apparatus for the reaction is preferably 3.3 kg of hexane per 1 kg of 9-borahebicicyclo[3.3.1]nonane dimer.

[0050] As an embodiment of the present invention, the ventilation time refers to the total ventilation time of hydrogen iodide is 1 to 48 hours, preferably 8 to 36 hours.

[0051] As one embodiment of the present invention, the amount of hydrogen iodide used is such that the molar ratio of 9-borabicyclo[3.3.1]nonane dimer to generated hydrogen iodide gas is 1:(2.0-10.0). If the molar ratio of 9-borabicyclo[3.3.1]nonane dimer to generated hydrogen iodide gas is higher than 1:2, the reaction is incomplete and excessive raw materials remain. If the molar ratio of 9-borabicyclo[3.3.1]nonane dimer to generated hydrogen iodide gas is lower than 1:10, excessive hydrogen iodide gas is present and side reactions are likely to occur. Preferably, the ratio is 1:(2.0-5.0), and more preferably 1:(2.0-3.0).

[0052] As an embodiment of the present invention, in step S1, the suitable reaction temperature is 0-50° C., preferably 10-30° C., more preferably 15-25° C. As a specific implementation example, the reaction temperature of the reaction mixture in the reaction device is preferably 15-25° C.

[0053] As one embodiment of the present invention, in step S1, whether the reaction is approaching the end point is determined by the presence of solids in the system. When the solids disappear, the reaction is approaching the end point. Further, whether to stop aeration of the reaction is determined by measuring the content of 9-borabicyclo[3.3.1]nonane in the system. When the content of 9-borabicyclo[3.3.1]nonane is less than 0.1 mol / L, aeration of the reaction is stopped.

[0054] As an embodiment of the present invention, in step S2, the stirring time is 1 to 20 hours. If the stirring time is too short, the reaction is incomplete; if the stirring time is too long, the product and hydrogen iodide coexist for too long, which is likely to cause side reactions.

[0055] As an embodiment of the present invention, in step S2, the degassing treatment refers to pumping the negative pressure to -0.09 MPa with a vacuum pump for 5 to 10 minutes, and then returning to normal pressure with an inert gas.

[0056] As an embodiment of the present invention, step S2 further includes the step of diluting the colorless transparent solution with a suitable organic solvent to obtain a 9-iodo-9-borabicyclo[3.3.1]nonane solution of desired concentration.

[0057] In one embodiment of the present invention, the suitable organic solvent is a C5-C9 alkane, petroleum ether, or toluene, or a mixture of at least two of the C5-C9 alkane, petroleum ether, and toluene in any proportion. The C5-C9 alkane is preferably at least one of pentane, hexane, heptane, and cyclohexane, more preferably hexane.

[0058] As one embodiment of the present invention, the required concentration refers to a commercially required molar concentration of 0.1 to 2.0 mol / L of 9-iodo-9-borabicyclo[3.3.1]nonane solution, that is, the molar concentration C is 0.1 to 2.0 mol / L; preferably, the molar concentration C is 0.5 to 1.5 mol / L, and more preferably, the molar concentration C is 1.0 to 1.2 mol / L.

[0059] The present invention provides an industrial production method for the 9-iodine-9-borabicyclo[3.3.1]nonane solution, which is a colorless, transparent 0.1-2.0 mol / L hexane solution of 9-iodine-9-borabicyclo[3.3.1]nonane with a purity greater than 95% and a yield greater than 95%. Preferably, the 9-iodine-9-borabicyclo[3.3.1]nonane n-hexane solution has a molar concentration of 1.0-1.2 mol / L.

[0060] Compared with the existing methods, the present invention also adopts milder and more energy-saving reaction conditions to prepare 9-iodo-9-borabicyclo[3.3.1]nonane solution. The beneficial effects of the present invention are as follows:

[0061] 1. The synthesis process of the present invention has mild reaction conditions, stirring at room temperature, and slightly positive pressure reaction; the raw materials used are cheap and easily available, the production cost is low, the operation difficulty is small, and safe production is easy;

[0062] 2. The synthesis process of the present invention is stable and can obtain a colorless and transparent solution of the required fixed concentration;

[0063] 3. The 9-iodo-9-borabicyclo[3.3.1]nonane solution prepared by the synthesis process of the present invention has high purity and the solvent is an inert solvent, and can be directly used in the reaction without purification;

[0064] 4. In the synthesis process of the present invention, the ventilation speed and ventilation volume of hydrogen iodide are easy to control, and the unreacted hydrogen iodide gas is easily soluble in water, avoiding tail gas pollution. It can be recycled and reused, reducing production costs, and realizing a green and environmentally friendly synthesis process and technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0066] Figure 1 This is the boron spectrum of 9-borahertabicyclo[3.3.1]nonane dimer;

[0067] Figure 2 is the boron spectrum of 9-iodo-9-borabicyclo[3.3.1]nonane prepared in Example 1;

[0068] Figure 3 is the boron spectrum of 9-iodo-9-borabicyclo[3.3.1]nonane prepared in Example 2;

[0069] Figure 4 is the boron spectrum of 9-iodo-9-borabicyclo[3.3.1]nonane prepared in Example 3;

[0070] Figure 5 is the boron spectrum of 9-iodo-9-borabicyclo[3.3.1]nonane prepared in Example 4;

[0071] Figure 6 This is the boron spectrum of the product prepared in Example 5. DETAILED DESCRIPTION

[0072] In response to the shortcomings of existing methods for synthesizing 9-iodo-9-borabicyclo[3.3.1]nonane, the present inventors, through in-depth research, discovered that a 9-iodo-9-borabicyclo[3.3.1]nonane solution can be obtained by reacting dry hydrogen iodide gas with a 9-borabicyclo[3.3.1]nonane dimer in an organic solvent at room temperature. This method offers mild reaction conditions, safe operation, high product quality, low cost, and ease of industrial production. This approach led to the completion of the present invention.

[0073] In one embodiment of the present invention, in an industrial production method of 9-iodo-9-borabicyclo[3.3.1]nonane or a solution thereof, step 1) under nitrogen protection, slowly passing dry hydrogen iodide gas into a mixed solution of 9-borabicyclo[3.3.1]nonane dimer and hexane at 20°C for reaction; wherein the molar ratio of 9-borabicyclo[3.3.1]nonane dimer to generated hydrogen iodide gas is approximately 1:2.4, and the pressure difference between the two kettles is controlled to be 0.011 to 0.012 MPa. The aeration time is 36 hours, and the reaction is stirred for 12 hours after the aeration is completed.

[0074] In a specific embodiment of the present invention, in the industrial production method of 9-iodine-9-borabicyclo[3.3.1]nonane solution, after step 2) stopping the introduction of hydrogen iodide, stirring at 20°C for 12 hours, the negative pressure was evacuated to -0.09 MPa by a vacuum pump, degassed for 8 minutes, and the inert gas was replenished to normal pressure to obtain a colorless transparent solution, namely the 9-iodine-9-borabicyclo[3.3.1]nonane solution.

[0075] In the process of the present invention, a commercially available 9-iodine-9-borabicyclo[3.3.1]nonane solution can be obtained directly, and the 9-iodine-9-borabicyclo[3.3.1]nonane solution can be directly used for the reaction.

[0076] The present invention is described in detail below with reference to the examples. The following examples will help those skilled in the art to further understand the present invention, but they do not limit the present invention in any form. It should be pointed out that for those skilled in the art, several adjustments and improvements can be made without departing from the concept of the present invention. These all fall within the scope of protection of the present invention. The experimental methods for which specific conditions are not specified in the following examples are generally carried out in accordance with the conditions described in the conventional conditions or in accordance with the conditions recommended by the manufacturer. In addition, the reagents involved in the following examples are commercial products unless otherwise specified. The 9-borahertabicyclo[3.3.1]nonane dimer used in the following examples is a white crystal with a purity greater than 97%; the hydrogen iodide solution (hydroiodic acid) used to prepare hydrogen iodide gas is an aqueous solution with a mass fraction of not less than 55%.

[0077] Example 1. Preparation of 9-iodo-9-borabicyclo[3.3.1]nonane solution

[0078] 9-borahertabicyclo[3.3.1]nonane dimer (boron spectrum as shown in Figure 1 ), using commercially available aqueous hydroiodic acid solution as a raw material, phosphorus pentoxide as a dehydrating agent, and n-hexane as a solvent, a 1 mol / L n-hexane solution of 9-iodo-9-borabicyclo[3.3.1]nonane was prepared in 20-L and 30-L reaction bottles as follows:

[0079] 1. Prepare a clean, anhydrous 20-liter reaction bottle as a hydrogen iodide gas generator, equipped with a dropping funnel, a condenser, and a solvent storage tank as a scrubber; the 20-liter reaction bottle, the condenser, the scrubber, and a clean, anhydrous 30-liter reaction bottle are connected in sequence through a ventilation pipe, and the 30-liter reaction bottle is connected to a gas receiving tail gas device.

[0080] 2. Replace the above-mentioned gas generation and reaction system with nitrogen twice and evacuate to below 0.08 MPa. Then, under nitrogen protection, pump 6.56 kg of n-hexane into the 30-liter reaction bottle and 1.3 kg of n-hexane into the solvent storage tank, and fill the entire gas generation and reaction device system with nitrogen.

[0081] 3. Open the 30-liter reaction flask and stir. Under nitrogen protection, add 1.72 kg of 9-borahertabicyclo[3.3.1]nonane dimer into the reaction flask, and maintain the pressure of the 30-liter reaction flask at normal pressure.

[0082] 4. Control the temperature in the 20-liter reaction flask to 10°C.

[0083] 5. Add 7.5 kg of phosphorus pentoxide to the aforementioned 20-liter reaction flask and add 4.6 kg of 55% hydroiodic acid aqueous solution to the dropping funnel.

[0084] 6. Maintain the internal temperature of the 20-L reaction flask at 10°C and begin dropwise addition of aqueous hydroiodic acid to prepare hydrogen iodide gas. Aeration should be continued for 5 hours. During this process, the aeration rate should be controlled by the addition rate to maintain a pressure differential between the two reaction flasks of 0.020-0.022 MPa. Maintain the internal temperature of the 30-L reaction flask at 30°C.

[0085] 7. After the addition was complete, the concentrations of the 9-iodo-9-borabicyclo[3.3.1]nonane solution and 9-borabicyclo[3.3.1]nonane in the 30-liter reaction flask were measured. The solution concentration was C = 1.15 mol / L, and no 9-borabicyclo[3.3.1]nonane remained. Aeration was stopped.

[0086] 8. Subsequently, the reaction system temperature in the 30-L reaction flask was maintained at 30°C and stirred for 20 hours. The concentrations of the 9-iodo-9-borabicyclo[3.3.1]nonane solution and 9-borabicyclo[3.3.1]nonane in the 30-L reaction flask were measured, and the solution concentration was C = 1.15 mol / L. No 9-borabicyclo[3.3.1]nonane remained. After degassing by vacuum pump to -0.09 MPa, degassing for 5 minutes, and then replenishing the inert gas to atmospheric pressure, 0.26 kg of n-hexane was added to obtain 9.85 kg of a light red, transparent 9-iodo-9-borabicyclo[3.3.1]nonane n-hexane solution (C = 1.11 mol / L).

[0087] Figure 2 This is the boron spectrum of 9-iodo-9-borabicyclo[3.3.1]nonane prepared in this example. The 9-borabicyclo[3.3.1]nonane of this product has no residue and the impurity content is 23.43%.

[0088] Example 2: Preparation of 9-iodo-9-borabicyclo[3.3.1]nonane solution

[0089] Using 9-borabicyclo[3.3.1]nonane dimer and commercially available aqueous hydroiodic acid solution as raw materials, phosphorus pentoxide as a dehydrating agent, and n-hexane as a solvent, a 1 mol / L n-hexane solution of 9-iodo-9-borabicyclo[3.3.1]nonane was industrially produced in 200-L and 300-L reactors. The steps are as follows:

[0090] 1. Prepare a clean, anhydrous 200-liter reactor as a hydrogen iodide gas generator, equipped with a dropping tank, a graphite condenser, a drying tower with a light-shielding material filled with anhydrous calcium chloride, and a solvent storage tank as a scrubber; the 200-liter reactor, the graphite condenser, the drying tower with a light-shielding material, the scrubber, and a clean, anhydrous 300-liter reactor are connected in sequence through ventilation pipes, and the 300-liter reactor is connected to a gas receiving tail gas device.

[0091] 2. Replace the above-mentioned gas generation and reaction system with nitrogen twice and evacuate to below 0.08 MPa. Then, under nitrogen protection, pump 65.6 kg of n-hexane into the 300-liter reactor and 10 kg of n-hexane into the solvent storage tank, and fill the entire gas generation and reaction device system with nitrogen.

[0092] 3. Open the 300-liter reactor and stir. Add 17.2 kg of 9-borahertabicyclo[3.3.1]nonane dimer into the reactor under nitrogen protection, and maintain the pressure of the 300-liter reactor at normal pressure.

[0093] 4. Control the temperature inside the 200-liter reactor to 30°C.

[0094] 5. Add 75 kg of phosphorus pentoxide to the aforementioned 200-liter reactor and add 44 kg of 55% hydroiodic acid aqueous solution to the dropping tank.

[0095] 6. Maintain the internal temperature of the 200-liter reactor at 30°C and begin dropwise addition of aqueous hydrogen iodide solution to prepare hydrogen iodide gas. Aeration is performed for 17 hours. During the aeration process, the aeration rate is controlled by the dropwise addition rate to maintain a pressure difference between the two reactors between 0.020 and 0.022 MPa. During the aeration process, maintain the internal temperature of the 300-liter reactor at 10°C.

[0096] 7. After the addition was completed, the concentrations of the 9-iodo-9-borabicyclo[3.3.1]nonane solution and 9-borabicyclo[3.3.1]nonane in the 300-liter reactor were measured. The solution concentration was C = 1.18 mol / L, and the 9-borabicyclo[3.3.1]nonane concentration was 0.10 mol / L. Aeration was stopped.

[0097] 8. Subsequently, the reaction system temperature in the 300-L reactor was maintained at 10° C. and the reaction was stirred for 15 hours. The concentrations of the 9-iodine-9-borabicyclo[3.3.1]nonane solution and the 9-borabicyclo[3.3.1]nonane in the 300-L reactor were measured. The solution concentration was C = 1.17 mol / L, and the 9-borabicyclo[3.3.1]nonane concentration was 0.05 mol / L. 4.5 kg of n-hexane was added to obtain 98.6 kg of a colorless, transparent n-hexane solution of 9-iodine-9-borabicyclo[3.3.1]nonane (C = 1.11 mol / L).

[0098] Figure 3 This is the boron spectrum of 9-iodo-9-borabicyclo[3.3.1]nonane prepared in this example. The product has 1.62% residual 9-borabicyclo[3.3.1]nonane, 7.1% impurities, and a purity of 91.28%.

[0099] Example 3. Preparation of 9-iodo-9-borabicyclo[3.3.1]nonane solution

[0100] Using 9-borabicyclo[3.3.1]nonane dimer and commercially available aqueous hydroiodic acid solution as raw materials, phosphorus pentoxide as a dehydrating agent, and n-hexane as a solvent, a 1 mol / L n-hexane solution of 9-iodo-9-borabicyclo[3.3.1]nonane was industrially produced in 200-L and 300-L reactors. The steps are as follows:

[0101] 1. Prepare a clean, anhydrous 200-liter reactor as a hydrogen iodide gas generator, equipped with a dropping tank, a graphite condenser, a drying tower with a light-shielding material filled with anhydrous calcium chloride, and a solvent storage tank as a scrubber; the 200-liter reactor, the graphite condenser, the drying tower with a light-shielding material, the scrubber, and a clean, anhydrous 300-liter reactor are connected in sequence through ventilation pipes, and the 300-liter reactor is connected to a gas receiving tail gas device.

[0102] 2. Replace the above-mentioned gas generation and reaction system with nitrogen twice and evacuate to below 0.08 MPa. Then, under nitrogen protection, pump 58 kg of n-hexane into the 300-liter reactor and 8 kg of n-hexane into the solvent storage tank, and fill the entire gas generation and reaction device system with nitrogen.

[0103] 3. Open the 300-liter reactor and stir. Add 13.1 kg of 9-borahertabicyclo[3.3.1]nonane dimer into the reactor under nitrogen protection, and maintain the pressure of the 300-liter reactor at normal pressure.

[0104] 4. Control the temperature inside the 200-liter reactor to 20°C.

[0105] 5. Add 72.5 kg of phosphorus pentoxide to the aforementioned 200-liter reactor and add 36 kg of 55% hydroiodic acid aqueous solution to the dropping tank.

[0106] 6. Maintain the internal temperature of the 200-liter reactor at 20°C and begin dropwise addition of aqueous hydrogen iodide solution to prepare hydrogen iodide gas. Aeration should be continued for 30 hours. During the aeration process, the aeration rate should be controlled by the addition rate to maintain the pressure difference between the two reactors at 0.011-0.012 MPa. Maintain the internal temperature of the 300-liter reactor at 20°C.

[0107] 7. After the addition was completed, the concentrations of the 9-iodo-9-borabicyclo[3.3.1]nonane solution and 9-borabicyclo[3.3.1]nonane in the 300-liter reactor were measured. The solution concentration was C = 1.26 mol / L, and the 9-borabicyclo[3.3.1]nonane concentration was 0.10 mol / L. Aeration was stopped.

[0108] 8. Subsequently, the temperature of the reaction system in the 300-L reactor was maintained at 20° C. and the reaction was stirred for 12 hours. The concentrations of the 9-iodine-9-borabicyclo[3.3.1]nonane solution and the 9-borabicyclo[3.3.1]nonane in the 300-L reactor were measured. The solution concentration was C = 1.28 mol / L, and the 9-borabicyclo[3.3.1]nonane concentration was 0.08 mol / L. After degassing by a vacuum pump to a negative pressure of -0.09 MPa for 5 minutes and replenishing the inert gas to normal pressure, 2.5 kg of n-hexane was added to obtain 72 kg of a colorless, transparent n-hexane solution of 9-iodine-9-borabicyclo[3.3.1]nonane (C = 1.10 mol / L).

[0109] Figure 4 This is the boron spectrum of 9-iodo-9-borabicyclo[3.3.1]nonane prepared in this example. The product has a 9-borabicyclo[3.3.1]nonane residue of 3.37%, an impurity content of 1.55%, and a purity of 95.09%.

[0110] Example 4: Industrial Production of 9-iodo-9-borabicyclo[3.3.1]nonane Solution

[0111] Using 9-borabicyclo[3.3.1]nonane dimer and commercially available aqueous hydroiodic acid solution as raw materials, phosphorus pentoxide as a dehydrating agent, and n-hexane as a solvent, a 1 mol / L n-hexane solution of 9-iodo-9-borabicyclo[3.3.1]nonane was industrially produced in two 300-L reactors. The steps are as follows:

[0112] 1. Prepare a clean, anhydrous 300-liter reactor as a hydrogen iodide gas generator, equipped with a dropping tank, a graphite condenser, a light-shielding drying tower filled with anhydrous calcium chloride, and a solvent storage tank as a scrubber. The 300-liter reactor R1, the graphite condenser, the light-shielding drying tower, the scrubber, and another clean, anhydrous 300-liter reactor R2 are sequentially connected via ventilation pipes. The 300-liter reactor R2 is also connected to an exhaust device for receiving gas.

[0113] 2. Replace the above-mentioned gas generation and reaction system with nitrogen twice and evacuate to below 0.08 MPa. Then, under nitrogen protection, pump 160 kg of n-hexane into the 300-liter reactor R2 and 13 kg of n-hexane into the solvent storage tank, and fill the entire gas generation and reaction device system with nitrogen.

[0114] 3. Open the 300-liter reactor R2 and stir. Add 49.0 kg of 9-borahertabicyclo[3.3.1]nonane dimer into the reactor under nitrogen protection, and maintain the pressure of the 300-liter reactor R2 at normal pressure.

[0115] 4. Control the internal temperature of the 300-liter reactor R1 to 20°C.

[0116] 5. Add 200 kg of phosphorus pentoxide into the aforementioned 300-liter reactor R1, and add 110 kg of 55% hydroiodic acid aqueous solution into the dropping tank.

[0117] 6. Control the internal temperature of the 300-liter reactor R1 to 20°C and begin dropwise addition of aqueous hydrogen iodide solution to prepare hydrogen iodide gas. Aeration is performed for 36 hours. During the aeration process, the aeration rate is controlled by the dropwise addition rate, and the pressure difference between the two reactors is maintained at 0.011-0.012 MPa. During the aeration process, the internal temperature of the 300-liter reactor R2 is maintained at 20°C.

[0118] 7. After the addition was completed, the concentrations of the 9-iodo-9-borabicyclo[3.3.1]nonane solution and 9-borabicyclo[3.3.1]nonane in the 300-liter reactor were measured. The solution concentration was C = 1.308 mol / L, and the 9-borabicyclo[3.3.1]nonane concentration was 0.09 mol / L. Aeration was stopped.

[0119] 8. Subsequently, the reaction system temperature in the 300-L reactor R2 was maintained at 20° C. and stirred for 12 hours. The concentrations of the 9-iodine-9-borabicyclo[3.3.1]nonane solution and the 9-borabicyclo[3.3.1]nonane in the 300-L reactor were measured. The solution concentration was C = 1.320 mol / L, and the 9-borabicyclo[3.3.1]nonane concentration was 0.04 mol / L. After degassing by vacuum pump to a negative pressure of -0.09 MPa for 8 minutes and replenishing the inert gas to normal pressure, 38 kg of n-hexane was added to obtain 288.4 kg of a colorless, transparent n-hexane solution of 9-iodine-9-borabicyclo[3.3.1]nonane (C = 1.10 mol / L).

[0120] Figure 5 This is the boron spectrum of 9-iodo-9-borabicyclo[3.3.1]nonane prepared in this example. The product has a 9-borabicyclo[3.3.1]nonane residue of 1.22%, an impurity content of 1.46%, and a purity of 97.32%.

[0121] Example 5: Reaction of 9-iodo-9-borabicyclo[3.3.1]nonane solution with water

[0122] Using 9-iodo-9-borabicyclo[3.3.1]nonane produced in Example 3 and distilled water as raw materials, a reaction was carried out in a 100 ml three-necked flask. The experimental steps were as follows: the 100 ml three-necked flask was replaced with nitrogen three times, 9-iodo-9-borabicyclo[3.3.1]nonane and distilled water were respectively added to the three-necked flask using a syringe, and the reaction was stirred for 30 minutes. After the reaction, the reaction solution was taken and the boron spectrum was measured.

[0123] Figure 6It is the boron spectrum of the product prepared in this example.

[0124] Through repeated exploration by technical personnel, the optimal reaction scheme was developed. Through a heterogeneous system, the instantaneous reaction concentration of the two raw materials in the system was precisely controlled, thereby obtaining a 9-iodine-9-borabicyclo[3.3.1]nonane solution with a purity and yield exceeding 95%, realizing the commercial production of 9-iodine-9-borabicyclo[3.3.1]nonane solution.

[0125] All documents mentioned in the present invention are cited as reference in this application. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A method for preparing a 9-iodo-9-borabicyclo[3.3.1]nonane solution, characterized in that: The method comprises the following steps: S1. Introducing dry hydrogen iodide gas into a reaction apparatus containing 9-borabicyclo[3.3.1]nonane dimer and a suitable organic solvent and stirring under nitrogen or argon protection, controlling the amount of hydrogen iodide involved in the reaction by regulating the ventilation time and ventilation volume of the dry hydrogen iodide gas, and controlling the heterogeneous system reaction at 15-25° C.; the suitable organic solvent is a C5-C9 alkane or petroleum ether, or a mixture of at least two of C5-C9 alkanes and petroleum ether in any proportion; Dry hydrogen iodide gas is prepared by the following method: under the protection of inert gas, an aqueous solution of hydroiodic acid is dripped into a gas generating device filled with phosphorus pentoxide; the generated hydrogen iodide gas is dried with a desiccant and scrubbed at 0-40°C to obtain dry hydrogen iodide gas; the pressure difference between the gas generating device and the reaction device is 0.011-0.012 MPa; S2. After stopping ventilation, stirring, degassing by using a vacuum pump to draw negative pressure and replenishing inert gas to obtain a colorless and transparent solution.

2. The method for preparing 9-iodo-9-borabicyclo[3.3.1]nonane solution according to claim 1, wherein The concentration of the hydroiodic acid aqueous solution is 50-60%, and the amount used is 2.0-5.0 kg per 1 kg of 9-borahabicyclo[3.3.1]nonane dimer; the amount used of the phosphorus pentoxide is 1.2-10.0 kg per 1 kg of the hydroiodic acid aqueous solution.

3. The method for preparing 9-iodo-9-borabicyclo[3.3.1]nonane solution according to claim 1, wherein The amount of organic solvent placed in the reaction device for the reaction is 1 to 10 kilograms of organic solvent per 1 kilogram of 9-borabicyclo[3.3.1]nonane dimer; the ventilation time refers to the total ventilation time of hydrogen iodide is 1 to 48 hours; the amount of hydrogen iodide refers to the molar ratio of 9-borabicyclo[3.3.1]nonane dimer to generated hydrogen iodide gas is 1:(2.0 to 10.0).

4. The method for preparing the 9-iodo-9-borabicyclo[3.3.1]nonane solution according to claim 1, wherein In step S2, the stirring time is 1 to 20 hours; the degassing treatment refers to pumping the negative pressure to -0.09 MPa with a vacuum pump for 5 to 10 minutes, and then filling it back to normal pressure with an inert gas.

5. The method for preparing 9-iodo-9-borabicyclo[3.3.1]nonane solution according to claim 1, wherein After step S2, the method further comprises the step of diluting the colorless transparent solution with a suitable organic solvent to obtain a 9-iodo-9-borabicyclo[3.3.1]nonane solution of desired concentration.

6. The method for preparing the 9-iodo-9-borabicyclo[3.3.1]nonane solution according to claim 5, wherein The suitable organic solvent refers to a C5-C9 alkane or petroleum ether, or a mixture of at least two of the C5-C9 alkanes and petroleum ether in any proportion; the required concentration refers to the molar concentration of the commercially required 9-iodo-9-borabicyclo[3.3.1]nonane solution, that is, the molar concentration C is 0.1 to 2.0 mol / L.

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