Preparation method of ipratropium bromide

Abstract

The invention belongs to the technical field of medicine synthesis processes, and particularly provides a preparation method of ipratropium bromide, one-pot synthesis is adopted, separation operation is not needed in the process, lithium tert-butoxide is adopted as a reaction raw material, the total yield of a reaction route and the purity of a product are remarkably improved, the purity of the prepared ipratropium bromide product can reach 99.95% or above, and the yield of the ipratropium bromide product can reach 99.95% or above. The method has the advantages of short production period, less output of three wastes, environmental protection, high process safety, low production cost, simple operation, mild reaction conditions, high purity and high yield, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing high-purity and high-yield ipratropium bromide. Background Technology

[0002] Ipratropium bromide, chemical name is ( 1R,3r,5S,8r )-3-[[( 2RS Ipratropium bromide monohydrate (3.2.1) was developed by Boehringer Ingelheim and approved for marketing in the United States in 1986. It is a potent anticholinergic drug with high selectivity for bronchial smooth muscle M receptors, exhibiting strong bronchodilator effects but weaker effects on respiratory glands and the cardiovascular system. As a quaternary ammonium salt, it is not readily absorbed orally. It takes effect approximately 5 minutes after aerosol inhalation, reaches peak effect in about 30–60 minutes, and lasts for 4–6 hours. The structure of ipratropium bromide is as follows: .

[0003] Patents CN106831753B and CN111269226B, as well as the literature (Synthesis of Ipratropium Bromide–Related Compounds. Synthetic Communications, 2007, 37(3):439-446), all report a method for synthesizing ipratropium bromide. This route uses tropic acid as a raw material, which undergoes acetylation to obtain acetyltropic acid; then, acetyltropic acid is treated with an acyl chloride reagent to obtain acetyltropinyl chloride; finally, isopropyltropinol is reacted with acetyltropinyl chloride via transesterification to obtain (…). 1R, 3r, 5S 8-Isopropyl-8-azabicyclo[3.2.1]oct-3-yl-3-acetoxy-2-phenylpropionate (CAS 746540-97-6), which is then obtained by acid hydrolysis. N -Isopropylnoratropine (CAS 793603-45-9) was finally converted to anhydrous ipratropium bromide by bromomethylation with bromomethane. The reaction process is as follows:

[0004] This route uses acyl chloride reagents such as thionyl chloride, which are corrosive to the reaction apparatus and environmentally unfriendly. Furthermore, the synthesis involves five steps, each requiring separation, making the operation cumbersome, the production cycle long, and the generation of large amounts of waste. The hydrolysis step suffers from poor selectivity because both ester groups can be hydrolyzed, resulting in low yields and poor purity, making it unsuitable for industrial production.

[0005] Patent CN108640913A reports a method for synthesizing ipratropium bromide, in order to α- The product is obtained by reducing sodium borohydride with 8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester (CAS 22235-74-1) as a starting material. N- Isopropylnoratropine is methylated with iodomethane to give a quaternary ammonium salt, which then undergoes a metathesis reaction with a bromide salt to give ipratropium bromide. The reaction route is as follows:

[0006] This route requires a quaternization reaction with iodomethane first, followed by a displacement reaction with a bromide salt (such as copper bromide) or hydrobromic acid. Iodomethane is expensive, and the displacement reaction may result in incomplete displacement and poor product purity. Each step requires separation, making the operation cumbersome, the production cycle long, the output of waste large, and the cost high, making it unsuitable for industrial production.

[0007] Patent CN106349238A reports a method for synthesizing ipratropium bromide, which uses ethyl phenylacetate as a raw material and catalyzes the transesterification reaction of ethyl phenylacetate with isopropyltropinol to obtain the bromide. 1R, 3r, 5S Oct-3-yl-2-phenylacetic acid ester (CAS 88607-15-2), subsequently reacted with ethyl formate in the presence of sodium metal to obtain... α- Formylated phenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester, which is then reduced with sodium borohydride to obtain N- Isopropyl noratropine eventually reacts with bromomethane. N- Alkylation reaction yields anhydrous ipratropium bromide; the reaction route is as follows:

[0008] This route uses sodium metal, a high-risk reagent, posing safety risks during scale-up production. The first step introduces the expensive starting material isopropyltropine alcohol, and the overall process yield is low, resulting in a lack of cost advantage. Each reaction step requires separation, making the operation cumbersome, the production cycle long, and the output of waste large, making it unsuitable for industrial scale-up production.

[0009] CN118388477A discloses a method for preparing ipratropium bromide, which uses ethyl phenylacetate as a raw material and reacts it with ethyl formate via a Claisen condensation reaction. The condensation produces... α- Ethyl formylphenylacetate reacts with isopropyltropine alcohol via transesterification to give α- Formylated phenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester, which is then reduced with sodium borohydride to obtain N-Isopropylnoratropine. Finally, it undergoes a quaternization reaction with methyl bromide to yield ipratropium bromide. The reaction route is as follows:

[0010] This scheme will prepare α- The base of octyl formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester was replaced with sodium methoxide as a high-risk reagent, NaH. NaH is flammable and explosive when wet, which poses a safety hazard in the production process. Moreover, the total yield is only 18.8%. In addition, each reaction step requires separation, which is cumbersome, has a long production cycle, and generates a large amount of waste, making it unsuitable for industrial scale-up production.

[0011] In summary, in the existing technology α- The preparation steps of octylformylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1] ester all involve the use of specific strong bases at high temperatures, resulting in low yields and poor purity in this step, which severely affects the overall yield and purity of ipratropium bromide. The published synthetic routes all suffer from drawbacks such as the need for separation at each reaction step, cumbersome operation, long production cycles, and large amounts of waste. Furthermore, some synthetic routes use high-risk reagents and high reaction temperatures, leading to low yields and poor product purity. These problems have consistently been key technical constraints on the scale-up production of ipratropium bromide. Summary of the Invention

[0012] To address the problems of low yield, poor purity, multiple separations required during the reaction, large amounts of waste, and low process safety in existing technologies for ipratropium bromide, this invention provides a one-pot synthesis method that eliminates the need for separation operations. Using lithium tert-butoxide as the reactant significantly improves the overall yield and product purity, achieving a purity of over 99.95% for the ipratropium bromide product. This method features a short production cycle, low waste generation, environmental friendliness, high process safety, low production cost, simple operation, mild reaction conditions, and high purity and yield, making it suitable for industrial production.

[0013] The preparation method of ipratropium bromide provided by this invention includes the following specific steps: (1) Prepared by reacting methyl phenylacetate and methyl formate in the presence of lithium tert-butoxide α methyl formylphenylacetate reaction solution; (2) Lithium tert-butoxide and isopropyltropine alcohol are added to the reaction solution of step (1) and reacted. During the reaction, methanol generated in the reaction is removed under reduced pressure to obtain a product containing... α- The reaction solution of octyl formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1] ester; (3) Add an organic solvent to the reaction solution from step (2), add sodium borohydride while controlling the temperature, and after the reaction is complete, quench with acid, separate the aqueous phase, adjust the pH of the aqueous phase to 10-11, extract with n-butanol, separate the organic phase, and obtain... N -Isopropylnoratropine reaction solution; (4) Add purified water and n-butanol solution of bromomethane to the reaction solution of step (3), react at controlled temperature and crystallize at controlled temperature, separate solid and liquid and dry under vacuum to obtain ipratropium bromide.

[0014] The specific synthesis route is as follows: .

[0015] Preferably, in step (1), the molar ratio of methyl phenylacetate to methyl formate is 1:2-8, the molar ratio of methyl phenylacetate to lithium tert-butoxide is 1:1-3, the reaction temperature is 0-40℃, and the reaction time is 2-5h; more preferably, in step (1), the molar ratio of methyl phenylacetate to methyl formate is 1:5, the molar ratio of methyl phenylacetate to lithium tert-butoxide is 1:2, and the reaction temperature is 20-30℃.

[0016] When the molar ratio of methyl phenylacetate to lithium tert-butoxide is 1:1-3, the yield can reach 51.5-77.1% and the purity can reach over 99.95%. If the reaction equivalent exceeds this range, the overall yield and product purity will decrease.

[0017] As a further preferred embodiment, in step (1), methyl phenylacetate and methyl formate are dissolved in a first solvent and lithium tert-butoxide is added. The mass-to-volume ratio of methyl phenylacetate to the first solvent is 1g:3-8mL. The temperature is controlled at 0-10℃ when adding lithium tert-butoxide to the solution containing methyl phenylacetate and methyl formate. After the reaction is completed, purified water with a volume of 1-4 times that of the first solvent is added and the aqueous phase is separated. The same type and volume of the first solvent used in the reaction are added to the aqueous phase, and acid is added to adjust the pH of the aqueous phase to 3-4. The aqueous phase is then separated and discarded to obtain the final product. α- Methyl formylphenylacetate reaction solution; the first solvent may be selected from toluene or dichloromethane; in the embodiments of the present invention, in step (1), the pH of the aqueous phase is adjusted with 2 mol / L hydrochloric acid.

[0018] Preferably, in step (2), the molar ratio of methyl phenylacetate in step (1) to lithium tert-butoxide added in step (2) is 1:0.1-1, the molar ratio of methyl phenylacetate in step (1) to isopropyltropine alcohol added in step (2) is 1:0.8-2, the reaction temperature is 20-50℃, and thin-layer chromatography (TLC) is used to detect isopropyltropine alcohol to ensure the reaction is completed; As a further preferred embodiment, in step (2), the molar ratio of methyl phenylacetate in step (1) to lithium tert-butoxide added in step (2) is 1:0.4, the molar ratio of methyl phenylacetate in step (1) to isopropyltropine alcohol added in step (2) is 1:1, the reaction temperature is 30-35℃, methanol generated in the reaction is removed under reduced pressure during the reaction, and isopropyltropine alcohol is detected by thin-layer chromatography (TLC) to ensure the reaction is completed.

[0019] The use of lithium tert-butoxide as a base in the above steps not only significantly reduced the reaction temperature but also significantly improved the reaction yield and product purity. The total product yield can reach up to 77.1%, and the purity of ipratropium bromide can reach up to 100%.

[0020] Preferably, in step (3), the temperature is controlled at -15-15℃ when sodium borohydride is added, the reaction temperature is -15-15℃, and thin-layer chromatography (TLC) is used for detection. α- The reaction of octyl formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1] was completed. The molar ratio of methyl phenylacetate in step (1) to sodium borohydride added in step (3) was 1:0.8-1.4. The organic solvent was selected from methanol and / or ethanol. The volume ratio of the organic solvent added to the mass ratio of methyl phenylacetate in step (1) was 2ml-5ml:1g. The acid used for acid quenching was selected from one or more of hydrochloric acid, hydrobromic acid, and sulfuric acid. The pH of the aqueous phase was adjusted to 3-4. The volume ratio of n-butanol used for extraction to the organic solvent in step (3) was 1-3:1. As a further preferred embodiment, when sodium borohydride is added in step (3), the temperature is controlled at -5 to 5°C, the reaction temperature is -5 to 5°C, the molar ratio of methyl phenylacetate in step (1) to sodium borohydride added in step (3) is 1:1; acid quenching is performed using 2 mol / L hydrochloric acid, and the pH of the aqueous phase is adjusted using 2 mol / L NaOH solution.

[0021] Preferably, the volume-to-mass ratio of purified water added in step (4) to methyl phenylacetate in step (1) is 0.1-0.4 mL:1 g, the molar ratio of methyl phenylacetate in step (1) to methyl bromide in step (4) is 1:2-5, the mass concentration of the n-butanol solution of methyl bromide is 25%, the reaction temperature is 20-30℃, and thin-layer chromatography (TLC) is used for detection. N - The reaction of isopropylnoratropine is complete; the crystallization temperature is -15 to 15°C, and the crystallization time is 2-5 hours. The solid-liquid separation is performed by centrifugation or filtration. As a further preferred embodiment, in step (4), the molar ratio of methyl phenylacetate in step (1) to bromomethane in step (4) is 1:3, and the crystallization temperature is -5 to 5°C.

[0022] Compared with the prior art, the present invention has the following beneficial effects: 1) This invention uses a "one-pot" process to directly produce ipratropium bromide. The reaction process does not require multiple separation operations or changing of reaction vessels, resulting in a short production cycle and low production cost. 2) In this invention, lithium tert-butoxide is used as the base for the reaction, which not only greatly reduces the reaction temperature, but also significantly improves the overall yield and purity of the product, thereby improving process safety, synthesis efficiency and product quality. 3) In the prior art, different reaction solvents are used in different steps. After each step, it is necessary to separate and purify the product and add it to the new reaction solvent in the next step, which generates a large amount of waste liquid. However, the present invention adopts a one-pot method, which eliminates the need for the aforementioned separation, purification and addition to the new reaction solvent between steps, thus reducing the amount of waste and making it green and environmentally friendly. 4) The overall process reaction conditions are mild, the operation is simple, and it is suitable for industrial production; 5) Ethyl phenylacetate was replaced with cheaper methyl phenylacetate, and ethyl formate was replaced with cheaper methyl formate, with better reaction results. Attached Figure Description

[0023] Figure 1 The image shows the 1H NMR spectrum of ipratropium bromide obtained by the method described in Example 1 of this invention. Figure 2 The above is a high-resolution mass spectrum (HRMS) of ipratropium bromide obtained by the method described in Example 1 of this invention. Figure 3 The image shows the liquid phase (HPLC) of ipratropium bromide prepared by the method described in Example 1 of this invention. Figure 4 Thermogravimetric analysis (TG) curve of ipratropium bromide prepared by the method described in Example 1 of this invention; Figure 5 The differential scanning calorimetry (DSC) curve of ipratropium bromide prepared by the method described in Example 1 of this invention; Figure 6 The 1H NMR spectrum of the intermediate α-formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester prepared by the method described in Example 1 of this invention. Figure 7 The intermediate obtained by the method described in Example 1 of this invention N - Isopropylnoratropine 1H NMR spectrum (H-NMR). Detailed Implementation

[0024] The technical solution of the present invention will be further described below with reference to specific embodiments. These embodiments are only used to illustrate the technical solution of the present invention in more detail and should not be construed as limiting the scope of protection of the present invention.

[0025] The yield and purity were determined by high performance liquid chromatography (HPLC); the method was performed in accordance with the European Pharmacopoeia EP11.7 Related Substances Determination Method (6667-6668).

[0026] Unless otherwise specified, all substances and reagents used are commercially available products.

[0027] Example 1: A method for preparing ipratropium bromide, the specific steps of which are as follows: (1) Add 50 mL of toluene, 10.0 g of methyl phenylacetate (0.0666 mol, 1 equiv.), and 20.0 g of methyl formate (0.333 mol, 5 equiv.) to a 250 mL three-necked flask. Stir continuously during the reaction, maintaining the temperature between 0℃ and 10℃. Add lithium tert-butoxide (10.6 g, 0.133 mol, 2 equiv.). After the addition is complete, maintain the temperature at 20℃ to 30℃ and react for 3 hours. Add 100 mL of purified water and separate the layers. Add 50 mL of toluene to the aqueous phase, slowly add 2 mol / L hydrochloric acid solution, adjust the pH of the aqueous phase to 3-4, separate the layers, discard the aqueous phase, and obtain the final product. α methyl formylphenylacetate reaction solution; (2) To the above α Lithium tert-butoxide (2.1 g, 0.4 equiv.) and isopropyltropine alcohol (11.3 g, 0.0666 mol, 1 equiv.) were added to the methyl formyl phenylacetate reaction solution. The reaction was carried out at 30-35℃, and methanol generated during the reaction was removed under reduced pressure of -0.08 MPa to -0.1 MPa. After 6 hours of reaction, TLC monitoring was started (using a dichloromethane solution of the starting material isopropyltropine alcohol (0.1 g: 5 ml) as the control solution; the reaction solution was diluted 3 times with toluene to obtain the test solution, which was then spotted onto GF... 254 Develop the sample solution using a silica gel plate with a methanol:dichloromethane (volume ratio) = 1:7 mixture (with iodine fuming for color development). If the reaction is not complete, continue the reaction, monitoring by TLC every 0.5 h, until the test solution no longer contains spots of the reference solution. α- Formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester reaction solution; (3) To α- 20 ml of methanol was added to the reaction solution of 8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester of formylphenylacetic acid, and the temperature was controlled at -5℃ to 5℃. 2.5 g of sodium borohydride (0.0666 mol, 1 equiv.) was added, and the reaction was maintained at -5℃ to 5℃ for 3 hours. TLC monitoring was then started (specific monitoring was performed using...). α-A toluene solution (0.1 g: 5 ml) of octyl formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester was used as the reference solution, and the reaction solution was used as the test solution. The reference solution, the test solution, and the mixed sample were spotted onto a GF254 silica gel plate. The reaction was developed with a mixed solvent of formic acid:ethanol:dichloromethane (volume ratio) = 0.5:2:12 (with iodine fuming for color development). If the reaction was not complete, the reaction was continued, and TLC monitoring was performed every 0.5 h until the test solution did not contain any spots of the reference solution. After the reaction was completed, 2 mol / L hydrochloric acid solution was slowly added to adjust the pH of the aqueous phase to 3-4, and the phase was separated. 2 mol / L sodium hydroxide solution was added to the aqueous phase to adjust the pH to 10-11, and 20 ml of n-butanol was used to extract the aqueous phase once. The phase was separated and the aqueous phase was discarded to obtain the final product. N -Isopropylnoratropine reaction solution; (4) To N Add 2 ml of purified water and 75.9 g (0.198 mol, 3 equiv.) of a 25% bromomethane n-butanol solution to the isopropylnoratropine reaction solution. Maintain the temperature at 20℃~30℃ and react for 12 h. TLC monitoring begins afterward (specific monitoring is based on...). N Isopropylnoratropine methanol solution (0.1 g: 5 ml) was used as the reference solution. The solution obtained by dissolving the reaction solution in methanol was used as the test solution. The reference solution, test solution, and mixed spot were spotted onto a GF254 silica gel plate. The mixture was developed with a methanol:dichloromethane (volume ratio) of 1:10 (with iodine fuming for color development). If the reaction was not complete, the reaction was continued. The test solution was monitored by TLC every 0.5 h until the test solution did not contain any spots of the reference solution. The solution was cooled to -5℃ to 5℃ to crystallize for 3 h, filtered, and dried at 45±2℃ / -0.08MPa to -0.1MPa for about 6 h to obtain 22.1 g of ipratropium bromide, with a total yield of 77.1%.

[0028] The 1H NMR spectrum (H-NMR) of ipratropium bromide prepared in Example 1 is as follows: Figure 1 As shown, the mass spectrum (HRMS) is as follows: Figure 2 As shown, the high-performance liquid chromatography (HPLC) diagram is as follows: Figure 3 As shown, the thermogravimetric analysis (TG) curve is as follows: Figure 4 As shown, the differential scanning calorimetry (DSC) curve is as follows: Figure 5 As shown; the intermediate α-formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester and N - The 1H NMR spectra of isopropylnoratropine are shown below. Figure 6 and 7 As shown.

[0029] The preparation methods of ipratropium bromide in Comparative Examples 1-9 are basically the same as those in Example 1, except that in steps (1) and (2), other types of bases are used in equimolar amounts to replace lithium tert-butoxide in Example 1 (the base in step (1) is called base one, and the base in step (2) is called base two), as shown in Table 1 below.

[0030] Experimental Example 1: The yield and purity of ipratropium bromide in Example 1 and Comparative Examples 1-9 were determined. The detection method employed was high-performance liquid chromatography (HPLC); the method was performed according to the European Pharmacopoeia EP11.7 Related Substances Detection Method (6667-6668); the detection results are shown in Table 1. Table 1. Effect of different bases used in Examples 1 and Comparative Examples 1-9 on the yield and purity of ipratropium bromide. Experimental results show that using lithium tert-butoxide as a base in Example 1 yields the best results in terms of both yield and purity.

[0031] The preparation methods of Examples 2-5 and Comparative Examples 10-14 are basically the same as those of Example 1, except that the lithium tert-butoxide equivalents in steps (1) and (2) are different, as shown in Table 2 below.

[0032] Experimental Example 2: The yield and purity of ipratropium bromide in Examples 2-5 and Comparative Examples 10-14 were tested using the same methods as in Experimental Example 1. The results are shown in Table 2. Table 2. Effects of different equivalents of tert-butanol on the yield and purity of ipratropium bromide in Examples 1-5 and Comparative Examples 10-14 in steps (1) and (2). Lithium tert-butoxide (1) is the lithium tert-butoxide equivalent used in step (1), and lithium tert-butoxide (2) is the lithium tert-butoxide equivalent used in step (2).

[0033] Experimental results show that when the lithium tert-butoxide equivalent in step (1) is between 1 and 3, the yield and purity of the prepared ipratropium bromide are better, and the optimal lithium tert-butoxide equivalent (1) is 2. When the lithium tert-butoxide equivalent in step (2) is between 0.1 and 1, the yield and purity of the prepared ipratropium bromide are better, and the optimal lithium tert-butoxide equivalent (2) is 0.4.

[0034] The preparation methods of Comparative Examples 15-17 are basically the same as those of Example 1, except that in Comparative Example 15, ethyl formate is used instead of methyl formate in Example 1; in Comparative Example 16, ethyl phenylacetate is used instead of methyl phenylacetate in Example 1; and in Comparative Example 17, ethyl phenylacetate is used instead of methyl phenylacetate in Example 1, and ethyl formate is used instead of methyl formate in Example 1.

[0035] Experimental Example 3 tested the yield and purity of ipratropium bromide in Comparative Examples 15-17 and compared them with those in Example 1. The detection method was the same as in Experimental Example 1, and the results are shown in Table 3. Table 3. Effects of different phenylacetic acid esters and formate esters on the yield and purity of ipratropium bromide in Examples 1 and Comparative Examples 15-17 Experimental results show that, compared with comparative examples 15-17, the use of methyl formate and methyl phenylacetate in Example 1 resulted in better purity and yield.

[0036] The preparation methods of Examples 6-11 and Comparative Examples 18-21 are basically the same as those of Example 1. The only difference is that different equivalents of methyl formate and different reaction temperatures were used in step (1) of Examples 6-11 and Comparative Examples 18-21, as shown in Table 4 below.

[0037] Experiment 4: The yield and purity of ipratropium bromide in Examples 6-11 and Comparative Examples 18-21 were determined and compared with those in Example 1. The detection method was the same as in Experiment 1, and the results are shown in Table 4. Table 4. Effects of different methyl formate equivalents and reaction temperatures on the yield and purity of ipratropium bromide in Examples 1, 6-11, and Comparative Examples 18-21. Note: Temperature (1) is the reaction temperature in step (1).

[0038] Experimental results show that the yield and purity of ipratropium bromide prepared when the methyl formate equivalent is 2 to 8 are better, and the optimal methyl formate equivalent is 5; the yield and purity of ipratropium bromide prepared when the reaction temperature in step (1) is 0℃ to 40℃ are better, and the optimal reaction temperature is 20℃ to 30℃.

[0039] The preparation methods of Examples 12-16 and Comparative Examples 22-27 are basically the same as those of Example 1. The only difference is that different equivalents of isopropyltropine alcohol and reaction temperatures are used in step (2) of Examples 12-16 and Comparative Examples 22-27, as shown in Table 5 below.

[0040] Experimental Example 5: The yield and purity of ipratropium bromide in Examples 12-16 and Comparative Examples 22-27 were determined and compared with those in Example 1. The detection method was the same as in Experimental Example 1, and the results are shown in Table 5. Table 5. Effects of different isopropyltropinol equivalents and reaction temperatures in step (2) on the yield and purity of ipratropium bromide in Examples 1, 12-16, and Comparative Examples 22-27. Temperature (2) is the reaction temperature in step (2).

[0041] Experimental results show that the yield and purity of ipratropium bromide prepared when the equivalent of isopropyltropinol is 0.8 to 2 are better, and the optimal equivalent of isopropyltropinol is 1. The yield and purity of ipratropium bromide prepared when the reaction temperature in step (2) is 20℃ to 50℃ are better, and the optimal reaction temperature is 30℃ to 35℃.

[0042] The preparation methods of Examples 17-21 and Comparative Examples 28-31 are basically the same as those of Example 1. The only difference is that different equivalents of sodium borohydride and reaction temperatures are used in step (3) of Examples 17-21 and Comparative Examples 28-31, as shown in Table 6 below.

[0043] Experiment 6: The yield and purity of ipratropium bromide in Examples 17-21 and Comparative Examples 28-31 were determined and compared with those in Example 1. The detection method was the same as in Experiment 1, and the results are shown in Table 6. Table 6. Effects of different sodium borohydride equivalents and reaction temperatures in step (3) on the yield and purity of ipratropium bromide in Examples 1, 17-21, and Comparative Examples 28-31. Temperature (3) is the reaction temperature in step (3).

[0044] Experimental results show that the ipratropium bromide prepared with a sodium borohydride equivalent of 0.8 to 1.4 has a better yield and purity, and the optimal sodium borohydride equivalent is 1. The ipratropium bromide prepared in step (3) with a reaction temperature of -15℃ to 15℃ has a better yield and purity, and the optimal reaction temperature is -5℃ to 5℃.

[0045] The preparation methods of Examples 22-25 and Comparative Examples 32-35 are basically the same as those of Example 1. The only difference is that different equivalents of bromomethane and crystallization temperatures are used in step (4) of Examples 22-25 and Comparative Examples 32-35, as shown in Table 7 below.

[0046] Experiment 7: The yield and purity of ipratropium bromide in Examples 22-25 and Comparative Examples 32-35 were determined and compared with those in Example 1. The detection method was the same as in Experiment 1, and the results are shown in Table 7. Table 7. Effects of different bromomethane equivalents and crystallization temperatures in step (4) on the yield and purity of ipratropium bromide in Examples 1, 22-25, and Comparative Examples 32-35. Experimental results show that the yield and purity of ipratropium bromide prepared when the methyl bromide equivalent is above 2 equivalences are better, with the optimal methyl bromide equivalent being 3 equivalences. Excessive methyl bromide equivalents will cause material waste and environmental pollution, so the preferred equivalent is 2-5 equivalences. The yield and purity of ipratropium bromide prepared when the crystallization temperature is between -15℃ and 15℃ are better. The purity is poor when the crystallization temperature is too low (Comparative Example 34), and the yield is low when the crystallization temperature is too high (Comparative Example 35). The optimal crystallization temperature is between -5℃ and 5℃.

[0047] The preparation methods of Examples 26-28 and Comparative Examples 36-41 are basically the same as those of Example 1. The only difference is that different solvents are used in steps (1) and (3) of Examples 26-28 and Comparative Examples 36-41, as shown in Table 8 below.

[0048] Experimental Example 8: The yield and purity of ipratropium bromide in Examples 26-28 and Comparative Examples 36-41 were tested and compared with those in Example 1. The testing methods were the same as those in Experimental Example 1.

[0049] Table 8. Effect of different solvents on the yield and purity of ipratropium bromide in Examples 1, 26-28 and Comparative Examples 36-41 The first solvent is the solvent used in step (1), and the organic solvent is the solvent used in step (3).

[0050] Experimental results show that when toluene or dichloromethane is used in step (1) and methanol or ethanol is used in step (2), the yield and purity of ipratropium bromide prepared are better.

[0051] Example 29 A method for preparing ipratropium bromide, the specific steps of which are as follows: (1) Same as step (1) in Example 1; (2) To α-Lithium tert-butoxide (2.1 g, 0.4 equiv.) and isopropyltropine alcohol (11.3 g, 0.0666 mol, 1 equiv.) were added to the methyl formyl phenylacetate reaction solution. The reaction was carried out at 30-35℃, and methanol generated during the reaction was removed under reduced pressure at -0.08 MPa to -0.1 MPa. After 6 hours of reaction, TLC monitoring was started until the reaction was complete (same as step (2) in Example 1). The organic phase was concentrated under reduced pressure at -0.08 MPa to -0.1 MPa and 50℃ to 60℃. After concentration, 20 ml of acetone was added, and the temperature was lowered to -5℃ to 5℃. Crystallization was carried out for 2 hours, filtered, and dried at 45±2℃ / -0.08 MPa to -0.1 MPa for about 4 hours to obtain the desired product. α- 16.0 g of octyl 8-(1-methylethyl)-8-azabicyclo[3.2.1]formylphenylacetic acid, with an overall yield of 76.2% in both steps; (3) Add 18 ml of methanol and 40 ml of toluene to the reaction flask. α- 16.0 g of octyl formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1] was added at a controlled temperature of -5℃ to 5℃. Sodium borohydride 1.9 g (0.0502 mol) was added, and the reaction was carried out at a controlled temperature of -5℃ to 5℃ for 3 h. TLC monitoring was then started until the reaction was complete (same as step (3) in Example 1). After the reaction was complete, 2 mol / L hydrochloric acid solution was slowly added to adjust the pH of the aqueous phase to 3 to 4, and the phase was separated. 2 mol / L sodium hydroxide solution was added to the aqueous phase to adjust the pH to 10 to 11. 20 ml of n-butanol was used to extract the aqueous phase once, and the phase was separated and discarded. The organic phase was concentrated under reduced pressure at -0.08 MPa to -0.1 MPa and 70℃ to 80℃. After concentration, 20 ml of acetone was added, and the temperature was lowered to -5℃ to 5℃. Crystallization was carried out for 3 h, filtered, and dried at 45±2℃ / -0.08 MPa to -0.1 MPa for about 4 h to obtain the desired product. N - Isopropylnoratropine 13.0g, yield of this step: 80.7%; (4) Add 18 ml of n-butanol and 2 ml of purified water to the reaction flask. N - 13.0 g of isopropylnoratropine and 46.7 g (0.123 mol, 3 equiv.) of a 25% bromomethane n-butanol solution were reacted at 20℃~30℃ for 12 h. TLC monitoring was started until the reaction was complete (same as step (4) in Example 1). The temperature was lowered to -5℃~5℃, crystallization was allowed for 3 h, and the mixture was filtered and dried at 45±2℃ / -0.08MPa~-0.1MPa for about 6 h to obtain 15.0 g of ipratropium bromide. The yield of this step was 88.8%; the total yield of all steps was calculated to be 54.6%.

[0052] Comparative Example 42: Ipratropium bromide was prepared according to the method of Example 1 in CN 118388477 A.

[0053] Experimental Example 9: The yield and purity of ipratropium bromide in Examples 29 and 42 were tested and compared with those in Example 1. The testing method was the same as that in Experimental Example 1.

[0054] The test results are shown in Table 9: Table 9. Effects of Examples 1, 29, and Comparative Example 42 on the yield and purity of ipratropium bromide. Experimental results show that the yield of Example 1 using the process without separating the intermediates is higher than that of Example 29 using the process with separating the intermediates, and both are significantly higher than the yield and purity of Example 1 in CN 118388477 A.

[0055] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any equivalent substitutions or modifications made by those skilled in the art within the spirit and principle of the present invention without any creative effort should be included within the protection scope of the present invention.

Claims

1. A method for preparing ipratropium bromide, characterized in that, The specific steps are as follows: (1) Prepared by reacting methyl phenylacetate and methyl formate in the presence of lithium tert-butoxide α- Methyl formylphenylacetate reaction solution; (2) Lithium tert-butoxide and isopropyltropine alcohol are added to the reaction solution of step (1) and reacted. During the reaction, methanol generated in the reaction is removed under reduced pressure to obtain a product containing... α- The reaction solution of octyl formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1] ester; (3) Add an organic solvent to the reaction solution from step (2), add sodium borohydride while controlling the temperature, and after the reaction is complete, quench with acid, separate the aqueous phase, adjust the pH of the aqueous phase to 10-11, extract with n-butanol, separate the organic phase, and obtain... N -Isopropylnoratropine reaction solution; (4) Add purified water and n-butanol solution of bromomethane to the reaction solution of step (3), react at controlled temperature and crystallize at controlled temperature, separate solid and liquid and dry under vacuum to obtain ipratropium bromide.

2. The method for preparing ipratropium bromide according to claim 1, characterized in that, In step (1), the molar ratio of methyl phenylacetate to methyl formate is 1:2-8, the molar ratio of methyl phenylacetate to lithium tert-butoxide is 1:1-3, the reaction temperature is 0-40℃, and the reaction time is 2-5h.

3. The method for preparing ipratropium bromide according to claim 1 or 2, characterized in that, In step (1), the molar ratio of methyl phenylacetate to methyl formate is 1:5, the molar ratio of methyl phenylacetate to lithium tert-butoxide is 1:2, and the reaction temperature is 20-30℃.

4. The method for preparing ipratropium bromide according to claim 1, 2, or 3, characterized in that, In step (1), methyl phenylacetate and methyl formate are dissolved in the first solvent and lithium tert-butoxide is added. The mass-to-volume ratio of methyl phenylacetate to the first solvent is 1g:3-8mL. The temperature is controlled at 0-10℃ when adding lithium tert-butoxide to the solution containing methyl phenylacetate and methyl formate. After the reaction is completed, purified water with a volume of 1-4 times that of the first solvent is added and the aqueous phase is separated. The same type and volume of the first solvent used in the reaction are added to the aqueous phase. The pH of the aqueous phase is adjusted to 3-4 by adding acid. The aqueous phase is then separated and discarded to obtain the final product. α - Methyl formylphenylacetate reaction solution; wherein the first solvent is selected from toluene or dichloromethane; the pH of the aqueous phase is adjusted with 2 mol / L hydrochloric acid.

5. The method for preparing ipratropium bromide according to claim 1, characterized in that, In step (2), the molar ratio of methyl phenylacetate in step (1) to lithium tert-butoxide added in step (2) is 1:0.1-1, the molar ratio of methyl phenylacetate in step (1) to isopropyltropine alcohol added in step (2) is 1:0.8-2, the reaction temperature is 20-50℃, methanol generated in the reaction is removed under reduced pressure during the reaction, and isopropyltropine alcohol is detected by thin-layer chromatography to ensure the reaction is completed.

6. The method for preparing ipratropium bromide according to claim 5, characterized in that, In step (2), the molar ratio of methyl phenylacetate in step (1) to lithium tert-butoxide added in step (2) is 1:0.4, the molar ratio of methyl phenylacetate in step (1) to isopropyltropine alcohol added in step (2) is 1:1, and the reaction temperature is 30-35℃.

7. The method for preparing ipratropium bromide according to claim 1, characterized in that, In step (3), the temperature is controlled at -15-15℃ when sodium borohydride is added, the reaction temperature is -15-15℃, and thin-layer chromatography is used for detection. α- The reaction of formylphenylacetic acid-8-(1-methylethyl)-8-azabicyclo[3.2.1]octyl ester was completed; the molar ratio of methyl phenylacetate in step (1) to sodium borohydride added in step (3) was 1:0.8-1.4, the organic solvent was selected from methanol and / or ethanol, the volume of organic solvent added was 2ml-5ml:1g of methyl phenylacetate in step (1), the acid quenching acid was selected from one or more of hydrochloric acid, hydrobromic acid, and sulfuric acid, and the pH of the aqueous phase was adjusted to 3-4; the volume ratio of n-butanol used for extraction to the organic solvent in step (3) was 1-3:

1.

8. The method for preparing ipratropium bromide according to claim 7, characterized in that, In step (3), the temperature is controlled at -5 to 5℃ when sodium borohydride is added, and the reaction temperature is -5 to 5℃. The molar ratio of methyl phenylacetate in step (1) to sodium borohydride added in step (3) is 1:

1. Acid quenching is performed using 2 mol / L hydrochloric acid, and the pH of the aqueous phase is adjusted using 2 mol / L NaOH solution.

9. The method for preparing ipratropium bromide according to claim 1, characterized in that, The volume-to-mass ratio of purified water added in step (4) to methyl phenylacetate in step (1) is 0.1-0.4 mL:1 g; the molar ratio of methyl phenylacetate in step (1) to methyl bromide in step (4) is 1:2-5; the mass concentration of the n-butanol solution of methyl bromide is 25%; the reaction temperature is 20-30℃; and thin-layer chromatography is used for detection. N - The isopropyl demethylatropine reaction is completed; the crystallization temperature is -15 to 15°C, and the crystallization time is 2-5 hours. The solid-liquid separation is performed by centrifugation or filtration.

10. The method for preparing ipratropium bromide according to claim 9, characterized in that, In step (4), the molar ratio of methyl phenylacetate in step (1) to bromomethane in step (4) is 1:3, and the crystallization temperature is -5 to 5℃.

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