Synthesis method of trospium chloride key intermediate
By combining the light radiation of photosensitizers and perchlorates with oxygen introduction, the problems of harsh reaction conditions and low yield in the synthesis of key intermediates of tres chloride have been solved, realizing a high-purity, high-yield, safe and environmentally friendly synthesis process suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG NEW TIME PHARMA CO LTD
- Filing Date
- 2026-02-02
- Publication Date
- 2026-05-15
AI Technical Summary
Existing methods for synthesizing key intermediates of trozine chloride suffer from problems such as harsh reaction conditions, long reaction times, low yields, and the use of highly toxic reagents and heavy metal catalysts, making it difficult to meet industrial requirements.
A method using photosensitizers and perchlorate in an organic solvent, followed by oxygen inhalation and light radiation, combined with subsequent extraction and pH adjustment steps, avoids the use of highly toxic reagents and heavy metal catalysts, simplifying the post-processing.
It achieves fewer side reactions, higher purity and yield, safety and environmental protection, and simple operation, reducing energy consumption and waste emissions, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing a key intermediate of tromethamine chloride. Background Technology
[0002] Trospium Chloride, chemically named 3-diphenylethanolylnorhyoscyamine-8-spiro-1-pyrrolidine, was launched in Germany in 1990. Clinically, it is mainly used to treat urinary frequency, urgency, and incontinence caused by various detrusor muscle instabilities or hyperfunctions. This drug is a novel and potent antimuscarinic antispasmodic that exerts its antiacetylcholine effect by blocking muscarinic receptors on organs innervated by cholinergic nerves, thereby reducing the tension of bladder smooth muscle. Due to its low lipid solubility, it does not easily cross the blood-brain barrier, and serious neurological complications are rare.
[0003] Currently, there are two main methods for the synthesis of troxammonium chloride: one is to esterify α-tropinol with diphenylhydroxyacetic acid to obtain intermediate 3, then remove the N-methyl group to obtain the key intermediate diphenylhydroxyacetic acid nortropin ester 4, and finally cyclize intermediate 4 with 1,4-dichlorobutane to obtain the target product. .
[0004] Secondly, the intermediate of (3a-nortropinol)-8-spiro-1'-pyrrole ammonium salt was synthesized from previous work, and then esterified with diphenylhydroxyacetic acid derivatives to obtain the target product.
[0005] Therefore, the key intermediate, diphenylhydroxyacetic acid nortropin ester 4, is a crucial intermediate in the synthesis of troxammonium chloride. Currently, the main methods for synthesizing this intermediate are as follows:
[0006] Method 1: Song Weiguo et al. reported on the synthesis process of tromethamine chloride [J]. Chinese Journal of Medicinal Chemistry, 2016, 26(05):394-396. N-ethoxycarbonyltromethamine was prepared by acylation of α-nortropinol with ethyl chloroformate. N-ethoxycarbonyl diphenylhydroxyacetic acid tropate was prepared by acylation of diphenylhydroxyacetic acid, and the ethoxycarbonyl group was removed by reduction in an ammonium formate / palladium-carbon catalytic hydrogen transfer reduction system to obtain diphenylhydroxyacetic acid nortropinol. .
[0007] The method is hampered by the fact that nortropinol is expensive, difficult to obtain, and hard to buy domestically, which is not conducive to industrialization; ethyl chloroformate has an irritating odor and is highly toxic, and can undergo serious side reactions with hydroxyl groups during this step; the Pd / C catalytic deesterification method is costly, carries the risk of excessive heavy metal impurities, and has a low yield of only 85%.
[0008] Method 2: Liu Suyun et al. (Synthesis of tropine chloride [J]. China Pharmaceutical Industry Journal, 2010, 41(03): 173-174.) obtained diphenylhydroxyacetic acid tropine ester by acylation of α-tropine alcohol and diphenylhydroxyacetic acid. This tropine ester was then mixed with triphenylphosphine and subjected to oxygen purging under light to remove the N-methyl group from the alcohol ring of tropine alcohol via a demethylation reaction. .
[0009] The disadvantages of this process are: the reaction time required in the second step of the N-methyl removal reaction is very long and the substrate conversion is incomplete; in the second step of the reaction, the photocatalytic deprotection takes a long time (10 hours) and the yield is low (79%).
[0010] Therefore, given the shortcomings in the synthesis of the key intermediate 4 of trexammonium chloride in the existing technology, there is an urgent need for a synthesis method with mild reaction conditions, short reaction time, safety and environmental protection, few by-products, and high yield to meet practical needs. Summary of the Invention
[0011] To address the above shortcomings, this invention aims to provide a novel method for synthesizing key intermediates of troxammonium chloride. This route avoids the use of highly toxic reagents and heavy metal catalysts, features mild reaction conditions, high safety, and simple operation, and possesses significant technical advantages.
[0012] This invention is specifically achieved through the following technical solution:
[0013] This invention provides a method for preparing a key intermediate of trox chloride, specifically comprising the following steps:
[0014] Compound SM, photosensitizer, and perchlorate were added to an organic solvent, oxygen was continuously introduced, and light radiation was applied using a high-pressure mercury lamp. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate and 1.0 N hydrochloric acid aqueous solution were added. The mixture was stirred and allowed to stand for separation. The aqueous phase solution was washed once with ethyl acetate. The pH of the aqueous phase solution was adjusted to alkaline with 10% sodium hydroxide aqueous solution. The resulting suspension was filtered, washed with water, and dried under vacuum to obtain compound 4.
[0015] The synthesis route is as follows:
[0016] Preferably, the photosensitizer is selected from 9,10-dicyanoanthracene (DCA) and tetraphenylporphyrin (TPP), with DCA being particularly preferred;
[0017] Preferably, the perchlorate is selected from lithium perchlorate, sodium perchlorate, and magnesium perchlorate, with lithium perchlorate being particularly preferred;
[0018] Preferably, the organic solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, and acetonitrile, with acetonitrile being particularly preferred;
[0019] Preferably, the power of the high-pressure mercury lamp is selected from 100W to 800W, with 500W being particularly preferred;
[0020] Preferably, the wavelength of the light radiation is 420~600 nm.
[0021] Preferably, the molar ratio of compound SM, photosensitizer, and perchlorate is 1.0:0.05~0.20:0.2~1.0, and particularly preferably 1.0:0.1:0.5;
[0022] Preferably, the pH is 7.5 to 11.0, and particularly preferably 8.5 to 9.5.
[0023] Compared with the prior art, the technical effects achieved by the present invention are as follows:
[0024] 1. Fewer side reactions, higher purity and yield;
[0025] 2. It avoids the use of expensive catalysts, ensuring safety and environmental protection while avoiding the risk of excessive heavy metal content;
[0026] 3. The reaction conditions are mild, the post-processing purification is simple and easy to operate, the energy consumption is low, the working time is short, and the waste discharge is minimal. Detailed Implementation
[0027] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.
[0028] Preparation of Compound 1
[0029] Example 1
[0030] Compound SM (70.3 g, 200 mmol), 9,10-dicyanoanthracene (4.5 g, 20 mmol), and lithium perchlorate (10.6 g, 100 mmol) were added to acetonitrile (2 L). The mixture was stirred under oxygen permeation for 1 hour under irradiation with a 500 W high-pressure mercury lamp (equipped with a cutoff filter, 420–600 nm). The reaction solution was concentrated under reduced pressure, and ethyl acetate (1 L) and 1 M HCl (500 mL) were added to the concentrate. After stirring for 30 minutes, the mixture was allowed to stand and separated. The aqueous phase was washed with ethyl acetate (500 mL), and the pH was adjusted to 8.5–9.5 with 10% sodium hydroxide aqueous solution. The mixture was filtered, and the filter cake was washed with water (200 mL × 2). The filter cake was dried under reduced pressure at 65–75 °C for 12 hours to give a white to off-white solid product 4, with a yield of 96.6% and a purity of 99.22%.
[0031] Example 2
[0032] Compound SM (70.3 g, 200 mmol), 9,10-dicyanoanthracene (2.3 g, 10 mmol), and magnesium perchlorate (22.4 g, 100 mmol) were added to tetrahydrofuran (2 L). The mixture was stirred under oxygen for 6 hours under irradiation with a 100 W high-pressure mercury lamp (equipped with a cutoff filter, 420–600 nm). The reaction solution was concentrated under reduced pressure, and ethyl acetate (1 L) and 1 M HCl (500 mL) were added to the concentrate. After stirring for 30 minutes, the mixture was allowed to stand and separated. The aqueous phase was washed with ethyl acetate (500 mL), and the pH was adjusted to 7.5–8.5 with 10% sodium hydroxide aqueous solution. The mixture was filtered, and the filter cake was washed with water (200 mL × 2). The filter cake was dried under reduced pressure at 65–75 °C for 12 hours to give a white to off-white solid product 4, with a yield of 94.3% and a purity of 95.11%.
[0033] Example 3
[0034] Compound SM (70.3 g, 200 mmol), 9,10-dicyanoanthracene (9.1 g, 40 mmol), and sodium perchlorate (12.2 g, 100 mmol) were added to dichloromethane (1 L). The mixture was stirred under oxygen for 1 hour under irradiation with an 800 W high-pressure mercury lamp (equipped with a cutoff filter, 420–600 nm). The reaction solution was concentrated under reduced pressure, and ethyl acetate (1 L) and 1 M HCl (500 mL) were added to the concentrate. After stirring for 30 minutes, the mixture was allowed to stand and separated. The aqueous phase was washed with ethyl acetate (500 mL), and the pH was adjusted to 7.5–8.5 with 10% sodium hydroxide aqueous solution. The mixture was filtered, and the filter cake was washed with water (200 mL × 2). The filter cake was dried under reduced pressure at 65–75 °C for 12 hours to give a white to off-white solid product 4, with a yield of 95.6% and a purity of 99.50%.
[0035] Example 4
[0036] Compound SM (70.3 g, 200 mmol), tetraphenylporphyrin (12.3 g, 20 mmol), and lithium perchlorate (4.3 g, 40 mmol) were added to ethyl acetate (2 L). The mixture was stirred continuously with oxygen for 1 hour under irradiation by a 500 W high-pressure mercury lamp (equipped with a cutoff filter, 420–600 nm). 1 M HCl (500 mL) was added, and the mixture was stirred for 30 minutes before being allowed to stand and separated. The aqueous phase was washed with ethyl acetate (500 mL), and the pH was adjusted to 8.5–9.5 with 10% sodium hydroxide aqueous solution. The mixture was filtered, and the filter cake was washed with water (200 mL × 2). The filter cake was dried under reduced pressure at 65–75 °C for 12 hours to obtain a white to off-white solid product 4, with a yield of 94.8% and a purity of 99.66%. (Ethyl acetate and hydrochloric acid can be directly separated without the need for concentration under reduced pressure.)
[0037] Example 5
[0038] Compound SM (70.3 g, 200 mmol), 9,10-dicyanoanthracene (4.5 g, 20 mmol), and lithium perchlorate (21.5 g, 200 mmol) were added to ethyl acetate (2 L). The mixture was stirred continuously with oxygen for 1 hour under irradiation by an 800 W high-pressure mercury lamp (equipped with a cutoff filter, 420–600 nm). 1 M HCl (50 mL) was added, and the mixture was stirred for 30 minutes before being allowed to stand and separated. The aqueous phase was washed with ethyl acetate (500 mL), and the pH was adjusted to 8.5–9.5 with 10% sodium hydroxide aqueous solution. The mixture was filtered, and the filter cake was washed with water (200 mL × 2). The filter cake was dried under reduced pressure at 65–75 °C for 12 hours to obtain a white to off-white solid product 4, with a yield of 95.5% and a purity of 99.51%. (Ethyl acetate and hydrochloric acid can be directly separated without the need for concentration under reduced pressure.)
[0039] Example 6
[0040] Compound SM (70.3 g, 200 mmol), 9,10-dicyanoanthracene (1.8 g, 8 mmol), and lithium perchlorate (1.9 g, 18 mmol) were added to acetonitrile (2 L). The mixture was stirred under continuous oxygen permeation for 8 hours under irradiation with a 100 W high-pressure mercury lamp (equipped with a cutoff filter, 420–600 nm). The reaction solution was concentrated under reduced pressure, and ethyl acetate (1 L) and 1 M HCl (500 mL) were added to the concentrate. After stirring for 30 minutes, the mixture was allowed to stand and separated. The aqueous phase was washed with ethyl acetate (500 mL), and the pH was adjusted to 8.5–9.5 with 10% sodium hydroxide aqueous solution. The mixture was filtered, and the filter cake was washed with water (200 mL × 2). The filter cake was dried under reduced pressure at 65–75 °C for 12 hours to obtain a white to off-white solid product 4, with a yield of 86.2% and a purity of 98.98%. (Due to low light intensity, the reaction was incomplete, and the reaction time needed to be extended.)
[0041] Example 7
[0042] Compound SM (70.3 g, 200 mmol), 9,10-dicyanoanthracene (13.7 g, 60 mmol), and lithium perchlorate (23.4 g, 220 mmol) were added to acetonitrile (1.5 L). The mixture was stirred under continuous oxygen permeation for 1 hour under irradiation with an 800 W high-pressure mercury lamp (equipped with a cutoff filter, 420–600 nm). The reaction solution was concentrated under reduced pressure, and ethyl acetate (1 L) and 1 M HCl (500 mL) were added to the concentrate. After stirring for 30 minutes, the mixture was allowed to stand and separated. The aqueous phase was washed with ethyl acetate (500 mL), and the pH was adjusted to 8.5–9.5 with 10% sodium hydroxide aqueous solution. The mixture was filtered, and the filter cake was washed with water (200 mL × 2). The filter cake was dried under reduced pressure at 65–75 °C for 12 hours to give a white to off-white solid product 4, with a yield of 88.9% and a purity of 98.25%.
Claims
1. A method for synthesizing a key intermediate of trexammonium chloride, characterized in that, The synthesis method includes the following steps: Compound SM, photosensitizer, and perchlorate were added to an organic solvent, oxygen was continuously introduced, and light radiation was applied using a high-pressure mercury lamp. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate and 1.0 N hydrochloric acid aqueous solution were added. The mixture was stirred and allowed to stand for separation. The aqueous phase solution was washed once with ethyl acetate. The pH of the aqueous phase solution was adjusted to alkaline with 10% sodium hydroxide aqueous solution. The resulting suspension was filtered, washed with water, and dried under vacuum to obtain compound 4. The synthesis route is as follows: 。 2. The synthesis method according to claim 1, characterized in that, The photosensitizer is selected from 9,10-dicyanoanthracene and tetraphenylporphyrin.
3. The synthesis method according to claim 1, characterized in that, The perchlorate is selected from one of lithium perchlorate, sodium perchlorate, and magnesium perchlorate.
4. The synthesis method according to claim 1, characterized in that, The organic solvent is selected from one of dichloromethane, ethyl acetate, tetrahydrofuran, and acetonitrile.
5. The synthesis method according to claim 1, characterized in that, The power of the high-pressure mercury lamp is selected from 100W to 800W.
6. The synthesis method according to claim 1, characterized in that, The wavelength of the light radiation is 420~600 nm.
7. The synthesis method according to claim 1, characterized in that, The molar ratio of compound SM, photosensitizer, and perchlorate is 1.0:0.05~0.20:0.2~1.
0.
8. The synthesis method according to claim 1, characterized in that, The pH is 7.5~11.0, preferably 8.5~9.5.