Preparation method of nortropine

Abstract

The embodiment of the invention discloses a preparation method of nortropine. The method comprises the following steps: carrying out a demethylation reaction on tropinone and chloroethyl chloroformate in the presence of a solvent, and carrying out vacuum concentration and evaporation to dryness to obtain demethylated tropinone; the preparation method comprises the following steps: carrying out reduction reaction on demethylated tropinone and lithium tri-tert-butoxy aluminum hydride in the presence of a solvent to obtain the nortropine alcohol. According to the method, a novel reducing agent lithium tri-tert-butoxy aluminum hydride is adopted, the reducing agent is safe and insensitive to air and water, aftertreatment is simple, and potential safety hazards are avoided from the source; the use of dangerous Raney nickel is avoided, and an autoclave is not needed, so that the production capacity is greatly improved; the reaction is carried out under a low-temperature condition, the energy consumption is low, the production cost can be effectively reduced, the reaction condition is mild, the operation is safe, simple and convenient, and large-scale industrial production is facilitated.

Description

TECHNICAL FIELD

[0001] The embodiment of the present application relates to the technical field of medicine and chemical industry, and particularly relates to a preparation method of nor-tropinol. BACKGROUND

[0002] Nor-tropinol, chemical name 8-oxabicyclo[3,2,1]octan-3-ol, is an important pharmaceutical intermediate for preparing various tropinol drugs.

[0003] Its synthesis takes tropinone as raw material, and mainly has the following two methods: one method is to first react the raw material with chloroformate to remove the methyl group, and then to convert the ketone group into a hydroxyl group by hydrogenation reduction with Raney nickel as a catalyst to obtain the target product (literature Letters in drug design and discovery, 2018, vol. 15, # 8, p. 895 - 904); another method is to first hydrogenate the raw material with Raney nickel as a catalyst to convert the ketone group into a hydroxyl group, and then remove the methyl group by chloroformate treatment to obtain the target product (patent US2007 / 179158, CN111393432A).

[0004] Both of the above two methods use Raney nickel catalytic hydrogenation reduction to convert the ketone group into a hydroxyl group, which has obvious limitations in industrial mass production: if the operation is not proper, Raney nickel is easy to self-ignite in the filtration operation, which may cause fire; the hydrogenation reaction catalyzed by Raney nickel needs to be carried out in a high-pressure kettle, the equipment is special, and the capacity of the high-pressure kettle is limited, which limits the production capacity. SUMMARY

[0005] Therefore, the embodiment of the present application provides a preparation method of nor-tropinol.

[0006] In order to achieve the above purpose, the embodiment of the present application provides the following technical scheme:

[0007] A preparation method of nor-tropinol, the method comprising the following steps:

[0008] (1) Tropinone and chloroethyl chloroformate are subjected to a demethylation reaction in the presence of a solvent, and then vacuum concentration and evaporation are carried out to obtain demethylated tropinone;

[0009] (2) The demethylated tropinone and lithium tri-t-butoxyaluminum hydride are subjected to a reduction reaction in the presence of a solvent to obtain the nor-tropinol.

[0010] Further, in step (1),

[0011] The molar ratio of the tropinone to the chloroethyl chloroformate is 1:1.1-1.5;

[0012] The solvent is dichloromethane or ethyl acetate.

[0013] The conditions of the demethylation reaction are 20-40 DEG C and 2.5-3.5 hours.

[0014] The conditions of the vacuum concentration and dry distillation are 50 DEG C and a vacuum degree of 50 mmHg.

[0015] Further, in step (1), the tropinone is dissolved in dichloromethane, cooled to -10-10 DEG C, and chloroethyl chloroformate is slowly added dropwise, with the temperature controlled to be no more than 10 DEG C; after the addition is completed, the temperature is raised to 20-40 DEG C and the reaction is stirred for 2.5-3.5 hours.

[0016] Further, in step (2),

[0017] The molar ratio of the desmethyl tropinone to lithium tri-t-butoxyaluminum hydride is 1:1.01-1.5.

[0018] The solvent is tetrahydrofuran.

[0019] The conditions of the reduction reaction are -10-0 DEG C and 12-16 hours.

[0020] Further, in step (2),

[0021] The desmethyl tropinone is dissolved in tetrahydrofuran, cooled to -10-0 DEG C, and lithium tri-t-butoxyaluminum hydride is slowly added dropwise under nitrogen protection, with the temperature controlled to be no more than 0 DEG C; after the addition is completed, the temperature is maintained at -10-0 DEG C and the reaction is stirred for 12-16 hours.

[0022] Further, the method further comprises the following steps: after the reduction reaction is completed, the temperature of the solution is maintained to be no more than 0 DEG C, water is slowly added dropwise for quenching, an extraction solvent is added, the layers are separated, the water layer is extracted with ethyl acetate for 2-3 times, the oil phases are combined, washed with saturated brine for 2-3 times, dried by adding anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product desmethyl tropinol.

[0023] Further, the extraction solvent is dichloromethane, chloroform or ethyl acetate.

[0024] The embodiments of the present application have the following advantages:

[0025] The present application uses a novel reducing agent, lithium tri-t-butoxyaluminum hydride, which is safe, not sensitive to air and water, and simple to handle, thus avoiding safety hazards from the source; dangerous Raney nickel is not used, and an autoclave is not needed, thus greatly improving the production capacity; the reaction is carried out at low temperature, with low energy consumption, which can effectively reduce the production cost, and the reaction conditions are mild, safe and simple to operate, which is conducive to large-scale industrial production. DETAILED DESCRIPTION

[0026] The following embodiments of the present application are illustrated by way of specific examples, and other advantages and effects of the present application will be readily understood by those skilled in the art from the disclosure of the present specification. It is obvious that the described embodiments are part of the embodiments of the present application, but not all the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of the present application.

[0027] Embodiment 1

[0028] The present embodiment provides a preparation method of nor-tropinol, comprising the following steps:

[0029] (1) Tropinone 139.2 g (1 mol) was added into a 1000 ml kettle, dichloromethane 556 g was added, and the temperature was lowered to -10°C. Chloroethyl chloroformate 157.3 g (1.1 mol) was slowly added dropwise for 2 hours, the temperature of the system was not more than 0°C, after the addition was completed, the temperature was raised to reflux, and the reaction was stirred for 3 hours. After the reaction was completed, the vacuum concentration was carried out at a temperature of 50°C and a vacuum degree of 50 mmHg, and the product was evaporated to dryness. The intermediate nor-tropinone 119 g was obtained, with a yield of 95% and a purity of 99.5%.

[0030] (2) Nor-tropinone 119 g (0.95 mol) was added into a 1000 ml kettle, tetrahydrofuran 476 g was added, and the temperature was lowered to -10°C. Lithium tri-t-butoxyaluminum hydride solid 265.7 g (1.045 mol) was slowly added dropwise under nitrogen protection, the temperature of the system was controlled to be not more than 0°C, after the addition was completed, the reaction was stirred for 15 hours at -10°C, after the reaction was completed, water 476 g was added dropwise to quench the reaction at an internal temperature of less than 0°C, ethyl acetate 300 g was added for stirring and extraction, the water layer was washed with ethyl acetate 100 g*2 times, the oil phase was combined and washed with saturated brine 100 g*2 times, anhydrous sodium sulfate 30 g was added to the oil layer for drying, filtration was carried out, and the filtrate was vacuum concentrated. The product nor-tropinol 108.7 g was obtained, with a yield of 90% and a purity of 99.6%.

[0031] Embodiment 2

[0032] The present embodiment provides a preparation method of nor-tropinol, comprising the following steps:

[0033] (1) Tropinone 139.2 g (1 mol) was added into a 1000 ml kettle, dichloromethane 556 g was added, and the temperature was lowered to -10°C. Chloroethyl chloroformate 157.3 g (1.1 mol) was slowly added dropwise for 2 hours, the temperature of the system was not more than 0°C, after the addition was completed, the temperature was raised to reflux, and the reaction was stirred for 3 hours. After the reaction was completed, the vacuum concentration was carried out at a temperature of 50°C and a vacuum degree of 50 mmHg, and the product was evaporated to dryness. The intermediate nor-tropinone 119 g was obtained, with a yield of 95% and a purity of 99.5%.

[0034] (2) Into a 1000ml kettle, 117.7g (0.94mol) of nor-tropinone was added, 350g of tetrahydrofuran was added, and the temperature was lowered to -10°C. Under nitrogen protection, 358.5g (1.41mol) of lithium tri-t-butoxyaluminum hydride solid was slowly added, and the temperature of the system was controlled to be not higher than 0°C. After the addition was completed, the reaction was stirred at -10°C for 13 hours. After the reaction was completed, water 356g was added dropwise to quench the reaction at an internal temperature <0°C. Ethyl acetate 300g was added to stir and extract, the layers were separated, the water layer was washed with ethyl acetate 100g*2 times, the oil phases were combined, saturated brine 100g*2 was used for washing, anhydrous sodium sulfate 30g was added to the oil layer for drying, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 106.4g of nor-tropine alcohol, the yield was 89%, and the purity was 99.3%.

[0035] Example 3

[0036] The embodiment provides a preparation method of nor-tropine alcohol, which comprises the following steps:

[0037] (1) Into a 1000ml kettle, 139.2g (1mol) of tropinone was added, 400g of dichloromethane was added, and the temperature was lowered to 0°C. Chloroethyl chloroformate 214.5g (1.5mol) was slowly added dropwise within 2 hours, and the temperature of the system was controlled to be not higher than 5°C. After the addition was completed, the temperature was increased to reflux, and the reaction was stirred for 3 hours. After the reaction was completed, the intermediate nor-tropinone 115g was obtained by concentrating and evaporating under reduced pressure at a temperature of 50°C and a vacuum degree of 50mmHg, the yield was 92%, and the purity was 99.3%.

[0038] (2) Into a 1000ml kettle, 115g (0.92mol) of nor-tropinone was added, 350g of tetrahydrofuran was added, and the temperature was lowered to -5°C. Under nitrogen protection, 350.8g (1.38mol) of lithium tri-t-butoxyaluminum hydride solid was slowly added, and the temperature was controlled to be not higher than 0°C. After the addition was completed, the reaction was stirred at -5°C for 13 hours. After the reaction was completed, water 356g was added dropwise to quench the reaction at an internal temperature <0°C. Ethyl acetate 300g was added to stir and extract, the layers were separated, the water layer was washed with ethyl acetate 100g*2 times, the oil phases were combined, saturated brine 100g*2 was used for washing, anhydrous sodium sulfate 30g was added to the oil layer for drying, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 100.6g of nor-tropine alcohol, the yield was 86%, and the purity was 99.2%.

[0039] Comparative Example 1

[0040] The comparative example provides a preparation method of nor-tropine alcohol, which comprises the following steps:

[0041] (1) Add tropinone 139.2 g (1 mol) into a 1000 ml kettle, add dichloromethane 400 g, cool to 15 °C, slowly drop chloroethyl chloroformate 214.5 g (1.5 mol) for 2 hours, the temperature of the system is not more than 20 °C, after the addition, warm to reflux, stir for 3 hours, after the reaction is completed, concentrate and evaporate under reduced pressure at 50 °C and 50 mmHg vacuum, to obtain intermediate desmethyl tropinone 100 g, the yield is 80%, the purity is 97%.

[0042] (2) Add desmethyl tropinone 115 g (0.92 mol) into a 1000 ml kettle, add tetrahydrofuran 350 g, cool to 5 °C, slowly add tri-tert-butoxy aluminum hydride lithium solid 350.8 g (1.38 mol) under nitrogen protection, after the addition, the temperature of the system is not more than 10 °C, after the addition, keep 5 °C and stir for 13 hours, after the reaction is completed, keep the internal temperature <5 °C, drop water 356 g to quench the reaction, add ethyl acetate 300 g to stir and extract, separate the layers, use ethyl acetate 100 g*2 times to wash the water layer, combine the oil phases, wash with saturated brine 100 g*2, add anhydrous sodium sulfate 30 g to the oil layer to dry, filter, concentrate the filtrate under reduced pressure, to obtain product desmethyl tropinol 82 g, the yield is 70%, the purity is 98.5%.

[0043] Comparative Example 2

[0044] The present comparative example provides a preparation method of desmethyl tropinol, comprising the following steps:

[0045] (1) Add tropinone 139.2 g (1 mol) into a 1000 ml kettle, add dichloromethane 400 g, cool to 20 °C, slowly drop chloroethyl chloroformate 214.5 g (1.5 mol) for 2 hours, after the addition, warm to reflux, stir for 3 hours, after the reaction is completed, concentrate and evaporate under reduced pressure at 50 °C and 50 mmHg vacuum, to obtain intermediate desmethyl tropinone 87.5 g, the yield is 70%, the purity is 97.2%.

[0046] (2) Add desmethyl tropinone 115 g (0.92 mol) into a 1000 ml kettle, add tetrahydrofuran 350 g, cool to 10 °C, slowly add tri-tert-butoxy aluminum hydride lithium solid 350.8 g (1.38 mol) under nitrogen protection, the temperature of the system is not more than 15 °C, after the addition, keep 10 °C and stir for 13 hours, after the reaction is completed, keep the internal temperature <5 °C, drop water 356 g to quench the reaction, add ethyl acetate 300 g to stir and extract, separate the layers, use ethyl acetate 100 g*2 times to wash the water layer, combine the oil phases, wash with saturated brine 100 g*2, add anhydrous sodium sulfate 30 g to the oil layer to dry, filter, concentrate the filtrate under reduced pressure, to obtain product desmethyl tropinol 70 g, the yield is 60%, the purity is 97%.

[0047] While the application has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various modifications and improvements can be made to the application. Accordingly, no limitation is implied by the description went to the particulars of the application as set forth in the description above. The application is intended to cover any and all modifications and changes as may come within the spirit and scope of the application.

Claims

1. A method for preparing nortropinol, characterized in that, The method includes the following steps: (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; (2) Demethyltropine and lithium tritert-butoxyhydroxide are reduced in the presence of a solvent to obtain the demethyltropine 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 solvent is dichloromethane or ethyl acetate; The conditions for the demethylation reaction are: 20~40℃, 2.5~3.5 hours; The conditions for vacuum concentration and evaporation are: temperature 50℃ and vacuum degree 50mmHg.

3. The method for preparing nortropinol according to claim 2, characterized in that, 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 the mixture is stirred for 2.5~3.5 hours.

4. 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 solvent is tetrahydrofuran; The conditions for the reduction reaction are: -10~0℃, 12~16 hours.

5. The method for preparing nortropinol according to claim 1, characterized in that, In step (2), 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.

6. The method for preparing nortropinol according to claim 1, characterized in that, 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.

7. The method for preparing nortropinol according to claim 6, characterized in that, The extraction solvent is dichloromethane, chloroform, or ethyl acetate.