A process for the preparation of norpinozol
By using lithium tritert-butoxy aluminum hydride to replace Raney nickel, a safe and low-temperature preparation of desmepine alcohol was achieved, which solved the safety hazards and production capacity limitations of Raney nickel catalytic hydrogenation reduction, and improved production efficiency and safety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- BEIJING MEDIKING BIOPHARM
- Filing Date
- 2025-10-31
- Publication Date
- 2026-07-07
AI Technical Summary
Existing methods for preparing nortropinol using Raney nickel-catalyzed hydrogenation reduction pose safety risks and production capacity limitations, and require high-pressure autoclave operation.
Using lithium tritert-butoxy aluminum hydride as a novel reducing agent, production under safe and low-temperature conditions is achieved through the demethylation reaction of tropidine with chloroformate and the low-temperature reduction reaction of demethylated tropidine, avoiding the use of Raney nickel.
It improves production safety and capacity, reduces energy consumption and costs, simplifies post-processing, and is suitable for large-scale industrial production.
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical and chemical technology, specifically to a method for preparing nortropinol. Background Technology
[0002] Nortropinol, chemically named 8-oxabicyclo[3,2,1]octane-3-ol, is an important pharmaceutical intermediate for the preparation of various tropinol drugs.
[0003] Its synthesis uses tropidine as a raw material, and there are two main methods: one method is to first react the raw material with chloroformate to remove the methyl group, and then use Raney nickel as a catalyst to hydrogenate and reduce the ketone group to a hydroxyl group to obtain the target product (Literature Letters in drug design and discovery, 2018, vol. 15, # 8, p. 895 - 904); the other method is to first use Raney nickel as a catalyst to hydrogenate and reduce the raw material to a hydroxyl group, and then treat it with chloroformate to remove the methyl group to obtain the target product (Patent US2007 / 179158, CN111393432A).
[0004] Both of the above methods use Raney nickel-catalyzed hydrogenation reduction to convert ketone groups to hydroxyl groups, which has obvious limitations in large-scale industrial production: Raney nickel is prone to spontaneous combustion during filtration if not handled properly, which may cause a fire; the hydrogenation reaction catalyzed by Raney nickel needs to be carried out in an autoclave, which is a special type of equipment, and the autoclave has a limited capacity, which limits production capacity. Summary of the Invention
[0005] Therefore, embodiments of the present invention provide a method for preparing nortropinol.
[0006] To achieve the above objectives, the embodiments of the present invention provide the following technical solutions:
[0007] A method for preparing nortropinol, the method comprising the following steps:
[0008] (1) Tropine ketone reacts with chloroethyl chloroformate in the presence of a solvent to undergo a demethylation reaction, and the mixture is concentrated under reduced pressure and evaporated to dryness to obtain demethylated tropine ketone;
[0009] (2) Demethyltropine and lithium tritert-butoxyhydroxide are reduced in the presence of a solvent to obtain the demethyltropine alcohol.
[0010] Furthermore, in step (1),
[0011] The molar ratio of tropinone to chloroethyl chloroformate is 1:1.1~1.5;
[0012] The solvent is dichloromethane or ethyl acetate;
[0013] The conditions for the demethylation reaction are: 20~40℃, 2.5~3.5 hours;
[0014] The conditions for vacuum concentration and evaporation are: temperature 50℃ and vacuum degree 50mmHg.
[0015] Further, in step (1), tropinone is dissolved in dichloromethane, cooled to -10~10℃, and chloroethyl chloroformate is slowly added dropwise, with the temperature controlled not exceeding 10℃. After the addition is complete, the temperature is raised to 20~40℃ and stirred for 2.5~3.5 hours.
[0016] Furthermore, in step (2),
[0017] The molar ratio of demethyltropine to lithium tritert-butoxyaluminum hydride is 1:1.01~1.5;
[0018] The solvent is tetrahydrofuran;
[0019] The conditions for the reduction reaction are: -10~0℃, 12~16 hours.
[0020] Furthermore, in step (2),
[0021] Dissolve demethyltropine in tetrahydrofuran, cool to -10~0℃, and slowly add lithium tritert-butoxy aluminum hydride dropwise under nitrogen protection, controlling the temperature not to exceed 0℃. After the addition is complete, maintain the temperature at -10~0℃ and stir for 12~16 hours.
[0022] Furthermore, the method further includes: after the reduction reaction is completed, keeping the solution temperature below 0°C, slowly adding water to quench the reaction, adding an extraction solvent, separating the layers, extracting the aqueous layer with ethyl acetate 2-3 times, combining the oil phases, washing with saturated brine 2-3 times, adding anhydrous sodium sulfate to dry, concentrating under reduced pressure to obtain the product demethyltropinol.
[0023] Furthermore, the extraction solvent is dichloromethane, chloroform, or ethyl acetate.
[0024] The embodiments of the present invention have the following advantages:
[0025] This invention uses a novel reducing agent, lithium tritert-butoxyaluminum hydride, which is safe, insensitive to air and water, and has simple post-processing, thus avoiding safety hazards from the source. It avoids the use of dangerous Raney nickel and eliminates the need for autoclaves, greatly improving production capacity. The reaction is carried out at low temperature, resulting in low energy consumption and effectively reducing production costs. Furthermore, the reaction conditions are mild, the operation is safe and simple, and it is conducive to large-scale industrial production. Detailed Implementation
[0026] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0027] Example 1
[0028] This embodiment provides a method for preparing nortropinol, comprising the following steps:
[0029] (1) Add 139.2 g (1 mol) of tropinone to a 1000 ml reactor, add 556 g of dichloromethane, cool to -10 °C, and slowly add 157.3 g (1.1 mol) of chloroethyl chloroformate over 2 hours. The system temperature should not exceed 0 °C. After the addition is complete, heat to reflux and stir for 3 hours. After the reaction is complete, concentrate under reduced pressure at 50 °C and 50 mmHg to dryness to obtain 119 g of intermediate demethyltropinone, with a yield of 95% and a purity of 99.5%.
[0030] (2) Add 119g (0.95mol) of desmethyltropinone to a 1000ml vessel, add 476g of tetrahydrofuran, cool to -10℃, and slowly add 265.7g (1.045mol) of lithium aluminum hydride tritertoxy under nitrogen protection, controlling the system temperature to not exceed 0℃. After the addition is complete, keep the reaction at -10℃ and stir for 15 hours. After the reaction is complete, keep the internal temperature <0℃ and add 476g of water dropwise to quench the reaction. Add 300g of ethyl acetate and stir to extract. The layers are separated. The aqueous layer is washed twice with 100g of ethyl acetate. The oil phases are combined and washed with 100g of saturated brine twice. The oil layer is dried with 30g of anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain 108.7g of desmethyltropinol, with a yield of 90% and a purity of 99.6%.
[0031] Example 2
[0032] This embodiment provides a method for preparing nortropinol, comprising the following steps:
[0033] (1) Add 139.2 g (1 mol) of tropinone to a 1000 ml reactor, add 400 g of dichloromethane, cool to -5 °C, and slowly add 214.5 g (1.5 mol) of chloroethyl chloroformate over 2 hours. The system temperature should not exceed 0 °C. After the addition is complete, heat to reflux and stir for 3 hours. After the reaction is complete, concentrate and evaporate to dryness under reduced pressure at 50 °C and a vacuum of 50 mmHg to obtain 117.7 g of intermediate demethyltropinone, with a yield of 94% and a purity of 99.4%.
[0034] (2) Add 117.7g (0.94mol) of desmethyltropinone to a 1000ml vessel, add 350g of tetrahydrofuran, cool to -10℃, and slowly add 358.5g (1.41mol) of lithium aluminum hydride tritertoxy under nitrogen protection, controlling the system temperature to not exceed 0℃. After the addition is complete, keep the reaction at -10℃ and stir for 13 hours. After the reaction is complete, keep the internal temperature <0℃ and add 356g of water dropwise to quench the reaction. Add 300g of ethyl acetate and stir to extract. The layers are separated. The aqueous layer is washed twice with 100g of ethyl acetate. Combine the oil phases and wash with 100g of saturated brine twice. Add 30g of anhydrous sodium sulfate to the oil layer and dry. Filter and concentrate the filtrate under reduced pressure to obtain 106.4g of desmethyltropinol, with a yield of 89% and a purity of 99.3%.
[0035] Example 3
[0036] This embodiment provides a method for preparing nortropinol, comprising the following steps:
[0037] (1) Add 139.2 g (1 mol) of tropinone to a 1000 ml reactor, add 400 g of dichloromethane, cool to 0 °C, and slowly add 214.5 g (1.5 mol) of chloroethyl chloroformate over 2 hours. The system temperature should not exceed 5 °C. After the addition is complete, heat to reflux and stir for 3 hours. After the reaction is complete, concentrate and evaporate to dryness under reduced pressure at 50 °C and a vacuum of 50 mmHg to obtain 115 g of intermediate demethyltropinone, with a yield of 92% and a purity of 99.3%.
[0038] (2) Add 115g (0.92mol) of desmethyltropinone to a 1000ml vessel, add 350g of tetrahydrofuran, cool to -5℃, and slowly add 350.8g (1.38mol) of lithium aluminum hydride tritertoxy under nitrogen protection, keeping the temperature below 0℃. After the addition is complete, keep the mixture at -5℃ and stir for 13 hours. After the reaction is complete, keep the internal temperature <0℃ and add 356g of water dropwise to quench the reaction. Add 300g of ethyl acetate and stir to extract. The mixture is separated into layers. The aqueous layer is washed twice with 100g of ethyl acetate. The oil phases are combined and washed twice with 100g of saturated brine. The oil layer is dried with 30g of anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain 100.6g of desmethyltropinol, with a yield of 86% and a purity of 99.2%.
[0039] Comparative Example 1
[0040] This comparative example provides a method for preparing nortropinol, comprising the following steps:
[0041] (1) Add 139.2 g (1 mol) of tropinone to a 1000 ml reactor, add 400 g of dichloromethane, cool to 15 °C, and slowly add 214.5 g (1.5 mol) of chloroethyl chloroformate over 2 hours. The system temperature should not exceed 20 °C. After the addition is complete, heat to reflux and stir for 3 hours. After the reaction is complete, concentrate and evaporate to dryness under reduced pressure at 50 °C and a vacuum of 50 mmHg to obtain 100 g of intermediate demethyltropinone with a yield of 80% and a purity of 97%.
[0042] (2) Add 115g (0.92mol) of desmethyltropinone to a 1000ml vessel, add 350g of tetrahydrofuran, cool to 5℃, and slowly add 350.8g (1.38mol) of lithium aluminum hydride tritertoxy under nitrogen protection. After the addition is complete, the system temperature does not exceed 10℃. After the addition is complete, keep the temperature at 5℃ and stir for 13 hours. After the reaction is complete, keep the internal temperature <5℃ and add 356g of water dropwise to quench the reaction. Add 300g of ethyl acetate and stir to extract. The layers are separated. The aqueous layer is washed twice with 100g of ethyl acetate. The oil phases are combined and washed with 100g of saturated brine twice. The oil layer is dried with 30g of anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain 82g of desmethyltropinol, with a yield of 70% and a purity of 98.5%.
[0043] Comparative Example 2
[0044] This comparative example provides a method for preparing nortropinol, comprising the following steps:
[0045] (1) Add 139.2 g (1 mol) of tropinone to a 1000 ml reactor, add 400 g of dichloromethane, cool to 20 °C, and slowly add 214.5 g (1.5 mol) of chloroethyl chloroformate over 2 hours. After the addition is complete, heat to reflux and stir for 3 hours. After the reaction is complete, concentrate under reduced pressure and evaporate to dryness at 50 °C and 50 mmHg to obtain 87.5 g of intermediate demethyltropinone, with a yield of 70% and a purity of 97.2%.
[0046] (2) Add 115g (0.92mol) of desmethyltropinone to a 1000ml vessel, add 350g of tetrahydrofuran, cool to 10℃, and slowly add 350.8g (1.38mol) of lithium aluminum hydride tritertoxy under nitrogen protection. The system temperature should not exceed 15℃. After the addition is complete, stir the reaction at 10℃ for 13 hours. After the reaction is complete, add 356g of water dropwise to quench the reaction while keeping the internal temperature <5℃. Add 300g of ethyl acetate and stir to extract. The layers are separated. The aqueous layer is washed twice with 100g of ethyl acetate. Combine the oil phases and wash with 100g of saturated brine twice. Add 30g of anhydrous sodium sulfate to the oil layer and dry. Filter and concentrate the filtrate under reduced pressure to obtain 70g of desmethyltropinol, with a yield of 60% and a purity of 97%.
[0047] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.
Claims
1. A method for preparing nortropinol, characterized in that, The method includes the following steps: (1) Dissolve tropinone in the first solvent, cool to -10~10℃, slowly add chloroethyl chloroformate, control the temperature not to exceed 10℃, after the addition is complete, heat to 20~40℃ and stir for 2.5~3.5 hours, concentrate under reduced pressure and evaporate to dryness to obtain demethyltropinone; (2) Dissolve desmethyltropine in a second solvent, cool to -10~0℃, and slowly add lithium tritert-butoxy-aluminum hydride under nitrogen protection, controlling the temperature not to exceed 0℃. After the addition is complete, stir the reaction at -10~0℃ for 12~16 hours to obtain the desmethyltropine alcohol.
2. The method for preparing nortropinol according to claim 1, characterized in that, In step (1), The molar ratio of tropinone to chloroethyl chloroformate is 1:1.1~1.5; The first solvent is dichloromethane or ethyl acetate; The conditions for vacuum concentration and evaporation are: temperature 50℃ and vacuum degree 50mmHg.
3. The method for preparing nortropinol according to claim 1, characterized in that, In step (2), The molar ratio of demethyltropine to lithium tritert-butoxyaluminum hydride is 1:1.01~1.5; The second solvent is tetrahydrofuran.
4. The method for preparing nortropinol according to claim 1, characterized in that, The method further includes: after the reaction is completed, keeping the solution temperature below 0°C, slowly adding water to quench the reaction, adding an extraction solvent, separating the layers, extracting the aqueous layer with ethyl acetate 2-3 times, combining the oil phases, washing with saturated brine 2-3 times, adding anhydrous sodium sulfate to dry, concentrating under reduced pressure to obtain the product demethyltropinol.
5. The method for preparing nortropinol according to claim 4, characterized in that, The extraction solvent is dichloromethane, chloroform, or ethyl acetate.