Preparation method of ipratropium bromide

Abstract

This invention discloses a method for preparing ipratropium bromide, belonging to the field of organic synthesis technology. It includes the following steps: (1) In a mixed solvent of toluene and n-hexane, using sodium ethoxide as a catalyst, ethyl phenylacetate and ethyl formate undergo a condensation reaction at 25-35°C. After the reaction is completed, the mixture is quenched with an acid solution, then extracted with dichloromethane, dried, and concentrated to obtain intermediate 4; (2) In toluene, using sodium hydride as a catalyst, intermediate 4 undergoes an ester exchange reaction with isopropyltropinol at 100-110°C. After the reaction is completed, acetonitrile is added, and the mixture is crystallized and separated into solid and liquid components to obtain intermediate 3; (3) In methanol, intermediate 3 is added, the temperature is lowered to 5-15°C, and sodium borohydride is added in batches. A reduction reaction is carried out at 0-10°C. After the reaction is completed, water is added to the system, crystallized, and filtered to obtain intermediate 2; (4) Intermediate 2 reacts with bromomethane to form a salt to obtain ipratropium bromide.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing ipratropium bromide. Background Technology

[0002] Ipratropium bromide, chemically named (1R,3r,5s,8r)-3-[[(2RS)-3-hydroxy-2-phenylpropoxy]oxo]-8-methyl-8-(1-methylethyl)-8-azabicyclo(3.2.1)octane bromide, is a white or off-white crystalline powder, soluble in water, readily soluble in methanol, and slightly soluble in ethanol. Its common English name is Ipratropium Bromide. International trade names include ATROWENT Nasal Spray, while domestic trade names include AITUNLE and KEBIT. Its structural formula is as follows: .

[0003] Ipratropium bromide is a potent anticholinergic drug with high selectivity for bronchial smooth muscle M receptors. It has a strong bronchodilatory effect on bronchial smooth muscle, but a weaker effect on respiratory glands and the cardiovascular system. Its bronchodilatory dose is only 1 / 20 to 1 / 10 of the dose that inhibits glandular secretion and increases heart rate. Inhalation of 40 μg or 80 μg of this product via aerosol is equivalent to the efficacy of inhaling 2 mg of atropine, 70-200 μg of isoproterenol, or 200 μg of salbutamol in asthmatic patients. There is no significant change in sputum volume or viscosity after administration; however, foreign reports indicate that this product can promote ciliary movement of the bronchial mucosa, facilitating sputum expectoration. This product is a quaternary ammonium salt and is not well 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.

[0004] The method for preparing ipratropium bromide is summarized below.

[0005] (1) The synthetic route of ipratropium bromide was first reported in patent US3505337 (1970), which uses isopropyl atropine as the starting material and reacts with bromomethane in toluene to obtain target compound 1. This method has the following drawbacks: a. Isopropyl atropine has low solubility in toluene, requiring the reaction solution to be heated to 60°C to dissolve. However, bromomethane has a boiling point of 3.6°C, leading to a large amount of bromomethane volatilizing during the reaction. Bromomethane is a highly toxic chemical reagent, posing a significant hazard to laboratory personnel and easily causing environmental pollution. b. The reaction time is long, and the reaction endpoint is difficult to control, which is not conducive to industrial production.

[0006] (2) In the literature Aust, J. Chem. (2006) 59, 53-58, the structure of the target compound was analyzed. Using 2,5-dimethoxytetrahydrofuran as the starting material, isopropyltropine was synthesized with 3-ketoglutaric acid under the action of hydrochloric acid. After hydrogenation, isopropyltropine alcohol was obtained. Then, it underwent transesterification with ethyl α-formaldehyde phenylacetate under the action of sodium methoxide. After hydrogenation, isopropyl atropine was obtained. Finally, it was reacted with bromomethane to generate the target product 1. This method has the following drawbacks: a. The reaction process uses metallic sodium, which causes significant equipment corrosion and requires high levels of worker protection, making it unsuitable for safe operation in the workshop; b. The preparation process has poor reproducibility. Because isopropyltropineone has multiple reactive sites, the reaction selectivity is low, resulting in low product yield, poor purity, and difficulty in separation, which is not conducive to large-scale preparation.

[0007] (3) Patent application number CN201610717295.3 discloses a method for preparing ipratropium bromide, including the following steps: (1) Ethyl phenylacetate and isopropyltropinol react in an aprotic solvent with an organic base as a catalyst to obtain intermediate 4; (2) Intermediate 4 is dissolved in a nonpolar organic solvent, and an alkali metal is added to react to obtain intermediate 3; (3) Intermediate 3 is dissolved in a nonpolar organic solvent, and a metal hydride is added as a reducing agent to react to obtain intermediate 2; (4) Intermediate 2 is dissolved in a nonpolar organic solvent, and bromomethane is added to react to obtain ipratropium bromide.

[0008] This method has the following drawbacks: a. The reaction process uses metallic sodium, metallic lithium, or metallic potassium, which causes significant equipment corrosion, requires high levels of worker protection, and is not conducive to safe operation in the workshop; b. The large amount of alkali metals used is not only dangerous but also costly; in addition, water needs to be added after the reaction is completed, and the alkali metals react violently with water, which is highly dangerous; c. Alkali washing and water washing are required after the steps, making the process complex. Summary of the Invention

[0009] Compared to existing technologies, the order of the condensation reaction and transesterification reaction has been adjusted, avoiding the use of alkali metals, simplifying the production process, and facilitating industrialization. The proposed solution is as follows: This invention provides a method for preparing ipratropium bromide, the reaction flow of which is as follows: ; ; ; .

[0010] The preparation process of intermediate 4 is as follows: In a nonpolar organic solvent, using organic base A as a catalyst, ethyl phenylacetate and ethyl formate undergo a condensation reaction at 25-35°C to obtain intermediate 4. The molar ratio of ethyl phenylacetate, ethyl formate, and organic base A is 1:4-7:1.5-2.5. In this step, a very large excess of ethyl formate is required to increase the yield.

[0011] The preparation process of intermediate 5 is as follows: In an aprotic solvent, using organic base B as a catalyst, intermediate 4 and isopropyltropine alcohol undergo transesterification reaction at 100-110℃. After the reaction is completed, acetonitrile is added, and the mixture is crystallized and separated into solid and liquid components to obtain intermediate 3. The amount of organic base B used is 0.1-0.5% of the weight of intermediate 4, and the molar ratio of intermediate 4 to isopropyltropine alcohol is 1:1.1-1.5.

[0012] Organic base A is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, or n-butyllithium, etc. Preferably, organic base A is selected from sodium ethoxide.

[0013] The nonpolar organic solvent is selected from one or more of tetrahydrofuran, benzene, toluene, dichloromethane, and n-hexane. Preferably, the nonpolar organic solvent is a mixture of toluene and n-hexane.

[0014] Organic base B is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, or n-butyllithium, etc. Preferably, organic base B is sodium hydride.

[0015] The aprotic solvent is selected from dichloromethane, chloroform, tetrahydrofuran, benzene, toluene, or acetonitrile, etc. Preferably, the aprotic solvent is selected from toluene.

[0016] After the condensation reaction is completed, the mixture is quenched with an acid solution, then extracted with dichloromethane, dried, and concentrated to obtain intermediate 4. The acid solution is selected from hydrochloric acid, acetic acid, or sulfuric acid solution, etc., with a concentration of 1-2.5 mol / L. Preferably, the acid solution is selected from hydrochloric acid, and the amount of hydrochloric acid used is 1.1-1.5 times the weight of organic base A.

[0017] The preparation process of intermediate 2 is as follows: intermediate 3 is added to a polar organic solvent, the temperature is lowered to 5-15℃, sodium borohydride is added in batches, and a reduction reaction is carried out at 0-10℃. After the reaction is completed, water is added to the system, crystallization is performed, and filtration is carried out to obtain intermediate 2. The molar ratio of intermediate 3 to sodium borohydride is 1:1-2. The polar organic solvent is selected from methanol, ethanol, ethyl acetate, or acetone, etc.; preferably, methanol is selected as the polar organic solvent.

[0018] Specifically, the method for preparing ipratropium bromide provided in this embodiment of the invention includes the following steps: (1) In a mixed solvent of toluene and n-hexane, using sodium ethoxide as a catalyst, ethyl phenylacetate and ethyl formate undergo a condensation reaction at 25-35°C. After the reaction is complete, the mixture is quenched with hydrochloric acid solution, then extracted with dichloromethane, dried, and concentrated to obtain intermediate 4. The molar ratio of ethyl phenylacetate, ethyl formate, and organic base A is 1:4-7:1.5-2.5. Compared with existing technologies, this step does not require the use of alkali metals.

[0019] (2) In toluene, using sodium hydride as a catalyst, intermediate 4 undergoes transesterification with isopropyltropine alcohol at 100-110℃. After the reaction is complete, acetonitrile is added, followed by crystallization and solid-liquid separation to obtain intermediate 3. The amount of sodium hydride used is 0.1-0.5% of the weight of intermediate 4, and the molar ratio of intermediate 4 to isopropyltropine alcohol is 1:1.1-1.5. Compared with the prior art, this step uses less sodium hydride, does not require purification, and the product can be directly crystallized, which simplifies the processing of step (3).

[0020] (3) Add intermediate 3 to methanol, cool to 5-15℃, then add sodium borohydride in batches, carry out reduction reaction at 0-10℃, add water to the system after the reaction is completed, crystallize, filter, and obtain intermediate 2; the molar ratio of intermediate 3 to sodium borohydride is 1:1-2.

[0021] (4) Intermediate 2 reacts with bromomethane to form a salt to give ipratropium bromide, which is consistent with the existing technology.

[0022] The beneficial effects of this patent are as follows: Compared with CN201610717295.3, this patent has the following advantages: (1) No active alkali metals are required, making production safer; (2) The amount of sodium hydride used is very small, only 0.1-0.5%, which can reduce costs; (3) After the reaction, sodium hydride does not need to be separated, which reduces the number of steps; (4) The preparation process of intermediate 3 is simple. Although the purity is not high, the subsequent reaction can obtain a high-purity product. That is, the impurities obtained in the preparation process of intermediate 3 do not affect the subsequent reaction and can be removed in the subsequent reaction. Intermediate 2 was purified under the premise of a simpler process. That is, steps (2) and (3) of this patent are complementary. (5) The purification process is simple, such as no need for water washing, alkali washing and recrystallization. (6) During the preparation of intermediate 2, due to the characteristics of the product itself and the use of special solvents, the extraction, concentration and recrystallization processes were avoided. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of the present invention clearer, the embodiments of the present invention will be described in further detail below.

[0024] All raw materials and reagents used in this invention are commercially available, including ethyl phenylacetate (content > 98.5%), isopropyl tropidine alcohol (purity > 99.0%), and ethyl formate (content > 98.5%). All reagents are chemically pure.

[0025] Example 1 (1) Synthesis of intermediate 4 Toluene (6.39 g), sodium ethoxide (2.44 g), n-hexane (14.64 g), ethyl phenylacetate (3 g), and ethyl formate (7.44 g) were added sequentially to the reaction flask. The reaction was carried out at T = 25-35 °C for 7 h. After the reaction was confirmed to be complete by TLC, 8.1 g of water and 3.0 g of hydrochloric acid were added to the system. The mixture was extracted with dichloromethane at T = 0-10 °C, dried, and concentrated to obtain 3.16 g of intermediate 4 (mw 315.41), yield: 54.86%, purity: 99.22% (HPLC normalization method). (2) Synthesis of intermediate 3 Isopropyltropine alcohol (2.33 g), intermediate 4 (3.16 g), and toluene (20.06 g) were added sequentially to a reaction flask and stirred until dissolved. Sodium hydride (0.00695 g) was then added, and the reaction was carried out at T = 100-110 °C. After the reaction was confirmed to be complete by TLC, acetonitrile was added to the system, and the mixture was stirred to crystallize. The mixture was then filtered to obtain 2.21 g of intermediate 3 (mw 315.41), with a yield of 69.93% and a purity of 94.90% (HPLC normalization method).

[0026] (3) Synthesis of intermediate 2 Intermediate 3 (2.21 g) and methanol (8.769 g) were added sequentially to the reaction flask. The mixture was cooled to 10 °C, and sodium borohydride (0.26 g) was added in portions. The reaction was carried out at T = 0-10 °C for 4 h. After the reaction was confirmed to be complete by TLC, water (30 g) was added to the system, crystallization was performed, and the mixture was filtered to obtain 1.47 g of intermediate 2 (mw317.42), with a yield of 66.2% and a purity of 98.60% (HPLC normalization method). (4) Synthesis of ipratropium bromide Intermediate 2 (1.47 g) and acetone (16.28 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and methyl bromide (0.9 g) was added. The mixture was reacted at T = 50-70 °C for 3 h. After cooling, the mixture was filtered and dried to obtain 1.47 g of ipratropium bromide 1 (mw 430.4), with a yield of 73.9% and a purity of 99.12% (HPLC normalization method).

[0027] Example 2 (1) Synthesis of intermediate 4 Toluene (6.39 g), sodium ethoxide (2.44 g), n-hexane (14.64 g), ethyl phenylacetate (3 g), and ethyl formate (7.44 g) were added sequentially to the reaction flask. The reaction was carried out at T = 25-35 °C for 7 h. After the reaction was confirmed to be complete by TLC, 8.1 g of water and 3.0 g of hydrochloric acid were added to the system. The mixture was extracted with dichloromethane at T = 0-10 °C, dried, and concentrated to obtain 3.05 g of intermediate 4 (mw 315.41), yield: 52.95%, purity: 99.22% (HPLC normalization method). (2) Synthesis of intermediate 3 Isopropyltropine alcohol (2.26 g), intermediate 4 (3.05 g), and toluene (19.36 g) were added sequentially to a reaction flask and stirred until dissolved. Sodium hydride (0.00671 g) was then added, and the reaction was carried out at T = 100-110 °C. After the reaction was confirmed to be complete by TLC, acetonitrile was added to the system, and the mixture was stirred to crystallize. The mixture was then filtered to obtain 2.09 g of intermediate 3 (mw 315.41), with a yield of 68.84% and a purity of 94.90% (HPLC normalization method).

[0028] (3) Synthesis of intermediate 2 Intermediate 3 (2.09 g) and methanol (8.25 g) were added sequentially to the reaction flask. The mixture was cooled to 10 °C, and sodium borohydride (0.25 g) was added in portions. The reaction was carried out at T = 0-10 °C for 4 h. After the reaction was confirmed to be complete by TLC, water (30 g) was added to the system, crystallization was performed, and the mixture was filtered to obtain 1.39 g of intermediate 2 (mw 317.42), with a yield of 66.19% and a purity of 98.60% (HPLC normalization method). (4) Synthesis of ipratropium bromide Intermediate 2 (1.39 g) and acetone (15.29 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and methyl bromide (0.84 g) was added. The mixture was reacted at T = 50-70 °C for 3 h. After cooling, the mixture was filtered and dried to obtain 1.36 g of ipratropium bromide 1 (mw 430.4), with a yield of 72.6% and a purity of 99.12% (HPLC normalization method).

[0029] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing ipratropium bromide, characterized in that, The reaction flow is as follows: ； ； ； ； Includes the following steps: (1) In a mixed solvent of toluene and n-hexane, ethyl phenylacetate and ethyl formate were condensed at 25-35°C using sodium ethoxide as a catalyst. After the reaction was completed, the mixture was quenched with hydrochloric acid solution, then extracted with dichloromethane, dried, and concentrated to obtain intermediate 4. The molar ratio of ethyl phenylacetate, ethyl formate and sodium ethoxide was 1:4-7:1.5-2.

5. (2) In toluene, using sodium hydride as a catalyst, intermediate 4 undergoes transesterification with isopropyltropine alcohol at 100-110℃. After the reaction is complete, acetonitrile is added, and intermediate 3 is obtained by crystallization and solid-liquid separation. The amount of sodium hydride is 0.1-0.5% of the weight of intermediate 4, and the molar ratio of intermediate 4 to isopropyltropine alcohol is 1:1.1-1.

5. (3) Add intermediate 3 to methanol, cool to 5-15℃, then add sodium borohydride in batches, carry out reduction reaction at 0-10℃, add water to the system after the reaction is completed, crystallize, filter, and obtain intermediate 2; the molar ratio of intermediate 3 to sodium borohydride is 1:1-2. (4) In acetone, intermediate 2 reacts with bromomethane at a reaction temperature of 50-70℃, and is filtered and dried to obtain ipratropium bromide.

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