Preparation method of xanthomeline tartrate

Abstract

The invention relates to the field of medicinal chemistry, in particular to a preparation method of xanthomeline tartrate. A preparation method of the xanthomeline tartrate comprises the following steps: taking a compound 1 to react with sodium tert-butoxide, and performing post-treatment to obtain a mixture containing a compound 2; adding methyl iodide, heating to 55-60 DEG C, reacting for 8-12 hours, cooling to 15-25 DEG C, separating out a solid, and filtering to obtain a compound 3; adding a modified palladium-based catalyst and isopropanol, adding ammonium formate in batches for reaction, and treating a crude product to obtain an ethyl acetate solution containing a compound 4; dropwise adding into isopropanol containing L-tartaric acid at the temperature of 45-50 DEG C, reacting, and recrystallizing a crude product to obtain the xanthomeline tartrate. According to the present invention, the problems of complex synthesis process steps and difficult separation and purification of the existing Nomeline tartrate are effectively improved, and the operation of the part of the separation and purification unit is simplified through the high-selectivity reaction system, the waste is less, and the method is more suitable for the amplified production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a preparation method of xanomeline tartrate. BACKGROUND

[0002] In the field of neurotransmitter research, acetylcholine as a very key neurotransmitter in the brain, its muscarinic receptors (M receptors) play an indispensable physiological role in human cognitive, behavior, sensation, movement and autonomic nervous processes. Once the M receptor signal is damaged, it will trigger a variety of serious problems, such as memory impairment, cognitive impairment often seen in patients with diseases such as schizophrenia, Alzheimer's disease (AD), and can further aggravate the symptoms of mental illness. Xanomeline as a partial agonist of muscarinic receptors can produce agonistic effects on all five subtypes of muscarinic receptors, which makes it show significant potential in the treatment of central nervous system disorders.

[0003] The selection of salt type of xanomeline is crucial in drug development, and xanomeline tartrate has become an ideal salt type for xanomeline drug development due to its good bioavailability, excellent handling properties and reproducible crystal form; however, the current xanomeline tartrate has a complex synthesis process, and when preparing xanomeline tartrate from the starting material, it needs to go through multiple reactions, and after each reaction, the intermediate needs to be separated and purified. This not only greatly increases the complexity and time cost of the operation, but also in the separation process, the product is easy to lose, ultimately leading to a decrease in yield, and in terms of product purity control, there are also great challenges. Due to the limitations of reaction conditions, various impurities will inevitably be produced during the preparation process, such as unreacted raw materials, substances generated by side reactions, etc. These impurities not only reduce the purity of xanomeline tartrate, but also some impurities may interfere with the normal metabolic process of the drug in the body, cause adverse reactions, and thus reduce the therapeutic effect of the drug, and thus pose a potential threat to the safety and effectiveness of the drug. Therefore, it is urgent to develop a more efficient, non-toxic side effect, and less waste, to ensure product quality, and meet the requirements of green chemistry preparation method, which is of great significance for promoting the wide application of xanomeline in clinical treatment. SUMMARY

[0004] In order to effectively improve the problems of complex synthesis process steps and inevitable generation of various impurities in the existing xanomeline tartrate, and difficult separation and purification, the present application provides a preparation method of xanomeline tartrate.

[0005] In a first aspect, the present application provides a preparation method of xanomeline tartrate, the reaction formula is as formula I, which comprises the following steps: (1) take compound 1 into tetrahydrofuran solution containing n-hexanol, then add sodium tert-butoxide, react at 20-25℃ for 2-5h, take sample HPLC to monitor compound 1≤1.0%, then get the mixture containing compound 2 after post-treatment; (2) add iodomethane to the mixture containing compound 2 obtained in step (1), heat to 55-60℃ for 8-12h, take sample HPLC to monitor compound 2≤1.0%, then cool the reaction solution to 15-25℃, precipitate solid, filter to obtain compound 3; (3) take compound 3 obtained in step (2), modified palladium-based catalyst into isopropanol, add ammonium formate in batches at 25-30℃, then warm to 60-65℃ and stir for 3-5h, HPLC monitor compound 3≤0.5%, then cool to room temperature, get ethyl acetate solution containing compound 4 after crude product treatment; (4) add the ethyl acetate solution containing compound 4 obtained in step (3) dropwise to isopropanol containing L-tartaric acid at a temperature of 45-50℃, stir for 0.5-1h; add 1% crystal seed at 45-50℃, crystallize, then incubate for 0.5-1h, cool to 5-10℃ and stir for 1-2h, then filter, recrystallize the crude product to obtain compound 5, i.e. zanamivir L-tartrate.

[0006] By adopting the above technical solutions, the continuous feeding mode is adopted, the high-selectivity reaction system is adopted, the partial separation and purification unit operation is simplified, the waste is less, and it is more suitable for scale-up production. The zanamivir L-tartrate crystal form prepared by the method has good stability, uniform crystal quality, low mixed crystal rate, small batch difference, can maintain effective concentration for a long time in vivo, and realizes further improvement of yield and purity, which meets the requirements of green chemistry.

[0007] Specifically, in step (1), sodium tert-butoxide as a strong base, first reacts with n-hexanol to generate a negative ion, as a nucleophile to attack the electropositive carbon connected with the chlorine atom in compound 1, a nucleophilic substitution reaction occurs, and the chlorine atom is removed as a leaving group. After treatment, a small amount of reactant and impurities generated in this step are removed. In step (2), the nitrogen atom of the pyridine ring of compound 2 is used as a nucleophile to attack the methyl carbon in iodomethane, and a quaternary ammonium salt, i.e. compound 3, is generated. Heating promotes the reaction, and solid is precipitated after cooling. Since step (1) is treated, the quaternary ammonium salt generated in step (2) is filtered to obtain compound 3. In step (3), the dispersion of the catalyst in the reaction system is improved by modifying the palladium-based catalyst, which increases the active sites exposed by palladium, and then ammonium formate is decomposed on the surface of palladium to generate active hydrogen, which can selectively reduce the imine bond and reduce the by-product of local over-reduction. The palladium-based catalyst and ammonium formate system in the present application have higher selectivity for the reduction of the pyridine ring to tetrahydropyridine, so the by-product is single, and the reduction degree can be accurately controlled to avoid over-reduction of the double bond, thereby reducing the yield. Through the treatment of the crude product, the impurities and residual metal can be effectively removed, and the purity of the product is improved, and then in step (4), the ethyl acetate solution containing compound 4 is directly reacted with L-tartaric acid to generate zanomeline tartrate by reacting zanomeline free base with L-tartaric acid, and crystal seeds are added to provide nucleation sites, reduce the nucleation energy barrier, promote the ordered arrangement of molecules into crystals, guide the growth of molecules according to specific crystal faces, and realize uniform particle size distribution. The recrystallization of the crude product further improves the purity of the product.

[0008] The preparation method of the modified palladium-based catalyst is to stir 5-10% palladium-based catalyst and polyethylene glycol in isopropyl alcohol for 30-45 min to obtain the modified palladium-based catalyst.

[0009] Preferably, the 5-10% palladium-based catalyst is Pd / C.

[0010] The mass ratio of the palladium-based catalyst to polyethylene glycol is (4-6): 1.

[0011] By adopting the above technical scheme, the ether oxygen atom of the polyethylene glycol can form a coordination bond with Pd, thereby preventing the nanoparticles from agglomerating, and the hydrophilic segment of the polyethylene glycol can also stretch in isopropyl alcohol to form a steric hindrance layer, so that the active sites of Pd are increased, the local over-reduction by-products are reduced, the uniform nucleation condition is achieved, and then in the reaction system, the ammonium formate is decomposed into H2 and CO2 under the catalysis of the modified Pd / C, active hydrogen is generated in situ, the active hydrogen selectively reduces the imine bond, and then over-reduction of the double bond is avoided, thereby improving the yield and purity of the compound, and then helping the efficient implementation of the whole preparation process of zanomeline tartrate. If the content of the polyethylene glycol is too low, the polyethylene glycol coverage is insufficient, the dispersion degree of the catalyst is reduced, the reduction efficiency is reduced, mixed crystals may be produced, and then the uniformity and stability of the crystal product are affected; if the content of the polyethylene glycol is too high, the active sites are blocked, the reaction rate is reduced, the by-products are correspondingly increased, and the yield and purity of the target product are reduced.

[0012] The mass ratio of the compound 3 to the ammonium formate is 1:(0.75-0.85).

[0013] By adopting the above technical scheme, the mass ratio of the compound 3 to the ammonium formate in the present application can achieve the best balance point of in-situ generation of active hydrogen, selective reduction of the imine bond by the active hydrogen and side reactions, and improve the yield and purity. If the amount of the ammonium formate is insufficient, the hydrogen source is insufficient, compound 3 remains, the reduction is incomplete, and then the yield is reduced; if the amount of the ammonium formate is too much, excessive active hydrogen will produce side reactions, impurities will increase, and the purity and yield of the product will be affected.

[0014] In the step (1), the mass ratio of the compound 1 to the sodium tert-butoxide is 1:(0.5-0.7).

[0015] By adopting the above technical scheme, the sodium tert-butoxide can completely deprotonate n-hexanol, and the n-hexanol attacks the chlorine atom of the compound 1 under the action of the sodium tert-butoxide, so that the reaction can be smoothly carried out, and the yield and purity of the reaction product are improved. If the sodium tert-butoxide is insufficient, the reaction will be incomplete, and the yield will be reduced; if the sodium tert-butoxide is excessive, the generation of the alkylation by-product will be increased, and then the purity of the product will be reduced.

[0016] In the step (1), the post-treatment step is that a tetrahydrofuran solution containing concentrated hydrochloric acid is added dropwise, stirring is carried out at 10-20℃ for 0.5-1h, filtration is carried out, the filter cake is washed with tetrahydrofuran, and a mixture containing the compound 2 is obtained.

[0017] In the step (3), the crude product treatment step is that filtration is carried out first, isopropyl alcohol and an EDTA-2Na aqueous solution are used for washing, a NaOH solution is used for adjusting pH to 10-11, ethyl acetate is used for extraction, after the organic phases are combined, a mixed drying agent is added and stirred for 20-30min, and then filtration is carried out to obtain.

[0018] By adopting the above technical scheme, the catalyst in the reaction system can be separated by filtration to avoid residual pollution of the product, isopropanol washing can remove organic solvents adsorbed on the surface of the catalyst to reduce impurity interference, and EDTA-2Na aqueous solution can convert the residual colloidal Pd / Pd 2+ into a water-soluble complex to remove metal impurities, avoid side reactions, and meet environmental protection compliance requirements. NaOH solution can make the target product in the form of free base to facilitate extraction separation. Ethyl acetate extraction can separate the target product in the organic phase and remove the acidic impurities in the aqueous phase. Mixing and stirring of the drying agent can chemically adsorb water instead of reducing pressure concentration to avoid thermal degradation. The whole process can effectively improve the yield, purity and crystal form of montelukast sodium tartrate, reduce the post-processing steps and solvent consumption, and meet the requirements of green chemistry.

[0019] In the step (4), the recrystallization step is to mix the crude product with isopropanol, dissolve at 65-75℃, add activated carbon, filter hot, and crystallize the filtrate by cooling, and then filter and dry to obtain.

[0020] By adopting the above technical scheme, the recrystallization dissolution at high temperature can destroy the metastable crystal nucleus; the addition of activated carbon can remove impurities such as pigments; hot filtration can prevent the crystal from precipitating too early; and the crystallization of the filtrate by cooling can make the surface energy lowest to preferentially nucleate and further inhibit lattice defects, so as to finally realize the montelukast sodium tartrate with high purity, uniform particle size distribution, high yield, high purity and crystal form, and meet the requirements of high-performance application scenarios.

[0021] In summary, the present application has at least one of the following beneficial technical effects: 1. The present application adopts a continuous feeding method, uses a highly selective reaction system to simplify part of the separation and purification unit operation, and has less waste, which is more suitable for large-scale production. The crystal form of montelukast sodium tartrate prepared by the present application has good stability, uniform crystal quality, and low mixed crystal rate. The batch difference is small, and the effective concentration can be maintained for a long time in vivo. This method realizes further improvement of yield and purity, meets the requirements of green chemistry, and makes the reaction of montelukast free base and tartaric acid to generate montelukast sodium tartrate, and the addition of crystal seeds provides nucleation sites, reduces the nucleation energy barrier, promotes the ordered arrangement of molecules into crystals, guides the growth of molecules according to specific crystal faces, realizes uniform particle size distribution, and further improves the purity of the product by recrystallization of the crude product.

[0022] 2. The modified palladium-based catalyst in the present application, the ether oxygen atoms of polyethylene glycol can form weak coordination bonds with Pd, thereby preventing nanoparticle agglomeration, and the hydrophilic segments thereof can also stretch in isopropyl alcohol to form a steric hindrance layer, thereby increasing the exposure of Pd active sites, reducing local over-reduction byproducts, and achieving uniform nucleation conditions. In this reaction system, ammonium formate generates active hydrogen in situ, which selectively reduces the imine bond, thereby avoiding over-reduction of the double bond, improving the yield and purity of the compound, and facilitating the efficient preparation of the entire zanomeline tartrate process. If the content of polyethylene glycol is too low, it will result in insufficient coverage of polyethylene glycol, reducing the dispersion of the catalyst and reducing the reduction efficiency, which may produce mixed crystals, thereby affecting the uniformity and stability of the crystal product; if the content of polyethylene glycol is too high, it will block the active sites, reduce the reaction rate, increase the byproducts, and reduce the yield and purity of the target product.

[0023] 3. The compound 3 and ammonium formate in the present application can achieve the best in-situ generation of active hydrogen, which selectively reduces the imine bond to improve the yield and purity. If the amount of ammonium formate is insufficient, the hydrogen source is insufficient, which will result in the residue of compound 3 and incomplete reduction, thereby reducing the yield; if the amount of ammonium formate is too much, excess active hydrogen will produce side reactions, increase impurities, and affect the purity and yield of the product. DETAILED DESCRIPTION

[0024] In the present application, 10% palladium-based catalyst is palladium-carbon catalyst, purchased from Biyun Tian Biotechnology, item number: Y000116; polyethylene glycol is polyethylene glycol-400, purchased from Shandong Longhui Chemical Co., Ltd.; ammonium formate is purchased from Aladdin; EDTA-2Na is purchased from Zhengzhou Kangyuan Chemical Industry. Other raw materials can be obtained through market purchase.

[0025] Preparation Example 1 Preparation of modified palladium-based catalyst: 2g of 10% Pd / C and 0.4g of polyethylene glycol-400 were stirred at 500rmp for 30min in 20ml of isopropyl alcohol to obtain the modified palladium-based catalyst.

[0026] Preparation Example 2 Preparation of modified palladium-based catalyst: 2.2g of 10% Pd / C and 0.2g of polyethylene glycol-400 were stirred at 500rmp for 30min in 20ml of isopropyl alcohol to obtain the modified palladium-based catalyst.

[0027] Preparation Example 2 Preparation of modified palladium-based catalyst: 1.8g of 10% Pd / C and 0.6g of polyethylene glycol-400 were stirred at 500rmp for 30min in 20ml of isopropyl alcohol to obtain the modified palladium-based catalyst.

[0028] Example 1 The preparation method of zanomeline tartrate salt comprises the following steps: (1) 50 g of compound 1 is added into a 300 ml tetrahydrofuran solution containing 77.4 g of n-hexanol, 26.7 g of sodium tert-butoxide is added, and the reaction is carried out at 25 °C for 5 h. After the sample HPLC monitoring shows that the content of compound 1 is less than or equal to 1.0%, 0.25 g of 10 ml tetrahydrofuran solution containing 3 mol / l concentrated hydrochloric acid is added dropwise, and the reaction is carried out at 20 °C for 1 h. After filtration, the filter cake is washed with 50 ml of tetrahydrofuran for three times to obtain a mixture containing compound 2; (2) 53.9 g of iodomethane is added into the mixture containing compound 2 obtained in step (1), and the reaction is carried out at 60 °C for 8 h. After the sample HPLC monitoring shows that the content of compound 2 is less than or equal to 1.0%, the reaction solution is cooled to 25 °C, and the solid is precipitated. After filtration, the filter cake is washed with 50 ml of THF for two times. The obtained solid is dried at 55 °C until the weight is constant to obtain compound 3 (yield: 98.7%, purity: 98.5%). 20 g of compound 3 obtained in step (2) and 2 g of the modified palladium-based catalyst prepared in preparation example 1 are added into 20 ml of isopropyl alcohol. After 15.1 g of ammonium formate is added in three portions at 30 °C, the temperature is increased to 65 °C, and the reaction is carried out for 5 h. After the HPLC monitoring shows that the content of compound 3 is less than or equal to 0.5%, the solution is cooled to room temperature, and then filtered. After the filter cake is washed with 20 ml of isopropyl alcohol for two times and 50 ml of 0.1 mol / l EDTA-2Na aqueous solution, the combined filtrate is adjusted to pH = 11 by adding 10% NaOH solution, and stirred for 10 min. After the organic phase is extracted with 150 ml of ethyl acetate for two times, the combined organic phase is washed with 100 ml of 5% NaHCO3 solution, and then 10 g of Na2SO4 / MgSO4 mixed drying agent with a mass ratio of 1:1 is added. After stirring for 30 min, the drying agent is removed by filtration to obtain an ethyl acetate solution containing compound 4; (4) the ethyl acetate solution containing compound 4 obtained in step (3) is added dropwise into 22 ml of isopropyl alcohol containing 7.7 g of L-tartaric acid at a temperature of 50 °C, and stirred for 1 h. After 1% of zanomeline tartrate salt is added at 45 °C, the crystal is precipitated, and then the temperature is maintained for 0.5 h. After the temperature is decreased to 25 °C and stirred for 16 h, the temperature is continuously decreased to 10 °C and stirred for 1 h. After filtration, the crude product is mixed with 30 ml of isopropyl alcohol, and then the temperature is increased to 65 °C to dissolve the crude product. After 5 g of activated carbon is added, the mixture is filtered while hot. After the filtrate is stirred at 30 °C for 1 h, the temperature is continuously decreased to 10 °C and stirred for 1 h to crystallize. After filtration, the product is dried at 45 °C until the weight is constant to obtain compound 5, i.e., zanomeline tartrate salt (yield: 87.2%, purity: 98.5%). Example 2 The preparation method of tartrate of zenomelin includes the following steps: (1) Take 50g of compound 1 and add it to 300ml of tetrahydrofuran solution containing 77.4g of n-hexanol, then add 26.7g of sodium tert-butoxide, react at 25℃ for 5h, take a sample and monitor by HPLC that compound 1 is ≤1.0%, then add 0.25g of 10mL of tetrahydrofuran solution containing 3mol / L concentrated hydrochloric acid, stir at 20℃ for 1h, filter, and wash the filter cake with 50mL of tetrahydrofuran 3 times to obtain a mixture containing compound 2; (2) Add 53.9g of iodomethane to the mixture containing compound 2 obtained in step (1), heat to 60℃ for 8h, take a sample and monitor by HPLC that compound 2 is ≤1.0%, cool the reaction solution to 25℃, precipitate solid, filter, and wash the filter cake with 50mL of THF 2 times; dry the obtained solid at 55℃ to constant weight to obtain compound 3; Take 24g of compound 3 obtained in step (2) and 2g of the modified palladium-based catalyst prepared in Example 1, add them to 20ml of isopropanol, add 11.1g of ammonium formate in three portions at 30℃, raise the temperature to 65℃ and stir for 5h. After monitoring by HPLC that compound 3 is ≤0.5%, cool to room temperature, filter, wash twice with 20mL of isopropanol and wash with 50mL of 0.1mol / L EDTA-2Na aqueous solution, combine the filtrates, add 10% NaOH solution to adjust pH=11, stir for 10min, add 150mL of ethyl acetate to extract twice, combine the organic phases, and use 100mL of 5% NaOH solution to extract the organic phases. After washing with NaHCO3 solution, 10g of a Na2SO4 / MgSO4 mixed drying agent with a mass ratio of 1:1 was added, and the mixture was stirred for 30min to remove water. The drying agent was removed by filtration to obtain an ethyl acetate solution containing compound 4. (4) The ethyl acetate solution containing compound 4 obtained in step (3) was added dropwise to 22mL of isopropanol containing 7.7g of L-tartaric acid at a temperature of 50℃ and stirred for 1h. 1% of zenomelin tartrate was added at 45℃, and after crystallization, the mixture was kept warm for 0.5h, cooled to 25℃ and stirred for 16h, and then cooled to 10℃ and stirred for 1h. After filtration, the crude product was mixed with 30ml of isopropanol, heated to 65℃ to dissolve, 5g of activated carbon was added, and the mixture was filtered while hot. The filtrate was stirred at 30℃ for 1h, and then cooled to 10℃ and stirred to crystallize. After filtration, the mixture was dried at 45℃ to constant weight to obtain compound 5, namely zenomelin tartrate. (Yield 86.5%, purity 97.9%) Example 3 The preparation method of zanomeline tartrate salt comprises the following steps: (1) 50 g of compound 1 is added into a 300 ml tetrahydrofuran solution containing 77.4 g of n-hexanol, 26.7 g of sodium tert-butoxide is added, and the reaction is carried out at 25 °C for 5 h. After the sample HPLC monitoring shows that the content of compound 1 is less than or equal to 1.0%, 0.25 g of 10 ml tetrahydrofuran solution containing 3 mol / l concentrated hydrochloric acid is added dropwise, and the reaction is carried out at 20 °C for 1 h. After filtration, the filter cake is washed with 50 ml of tetrahydrofuran for three times to obtain a mixture containing compound 2; (2) 53.9 g of iodomethane is added into the mixture containing compound 2 obtained in step (1), and the reaction is carried out at 60 °C for 8 h. After the sample HPLC monitoring shows that the content of compound 2 is less than or equal to 1.0%, the reaction solution is cooled to 25 °C, and solid is precipitated. After filtration, the filter cake is washed with 50 ml of THF for two times. The obtained solid is dried at 55 °C until the weight is constant to obtain compound 3; 18 g of compound 3 obtained in step (2) and 2 g of modified palladium-based catalyst prepared in preparation example 1 are added into 20 ml of isopropyl alcohol. After 17.1 g of ammonium formate is added in three portions at 30 °C, the temperature is increased to 65 °C, and the reaction is carried out for 5 h. After HPLC monitoring shows that the content of compound 3 is less than or equal to 0.5%, the solution is cooled to room temperature, and then filtered. After the filter cake is washed with 20 ml of isopropyl alcohol for two times and 50 ml of 0.1 mol / l EDTA-2Na aqueous solution, the combined filtrate is adjusted to pH = 11 by adding 10% NaOH solution, stirred for 10 min, and extracted with 150 ml of ethyl acetate for two times. After the combined organic phase is washed with 100 ml of 5% NaHCO3 solution, 10 g of Na2SO4 / MgSO4 mixed drying agent with a mass ratio of 1:1 is added, stirred for 30 min, and then filtered to remove the drying agent to obtain an ethyl acetate solution containing compound 4; (4) the ethyl acetate solution containing compound 4 obtained in step (3) is added dropwise into 22 ml of isopropyl alcohol containing 7.7 g of L-tartaric acid at a temperature of 50 °C, and stirred for 1 h. After 1% of zanomeline tartrate salt is added at 45 °C, the crystal is precipitated, and then the temperature is maintained for 0.5 h. After the temperature is decreased to 25 °C and stirred for 16 h, the temperature is continuously decreased to 10 °C and stirred for 1 h. After filtration, the crude product is mixed with 30 ml of isopropyl alcohol, heated to 65 °C to dissolve, and then 5 g of activated carbon is added. After hot filtration, the filtrate is stirred at 30 °C for 1 h, and then the temperature is continuously decreased to 10 °C and stirred for 1 h to crystallize. After filtration, the product is dried at 45 °C until the weight is constant to obtain compound 5, i.e., zanomeline tartrate salt. (The yield is 86.4%, and the purity is 97.5%) Example 4 The preparation method of zanomeline tartrate salt comprises the following steps: (1) 55 g of compound 1 is added into a 300 ml tetrahydrofuran solution containing 77.4 g of n-hexanol, 21.7 g of sodium tert-butoxide is added, and the reaction is carried out at 25 °C for 5 h. After the sample HPLC monitoring shows that the content of compound 1 is less than or equal to 1.0%, 0.25 g of 10 ml tetrahydrofuran solution containing 3 mol / l concentrated hydrochloric acid is added dropwise, and the reaction is carried out at 20 °C for 1 h. After filtration, the filter cake is washed with 50 ml of tetrahydrofuran for three times to obtain a mixture containing compound 2; (2) 53.9 g of iodomethane is added into the mixture containing compound 2 obtained in step (1), and the reaction is carried out at 60 °C for 8 h. After the sample HPLC monitoring shows that the content of compound 2 is less than or equal to 1.0%, the reaction solution is cooled to 25 °C, and the solid is precipitated. After filtration, the filter cake is washed with 50 ml of THF for two times. The obtained solid is dried at 55 °C until the weight is constant to obtain compound 3 (yield 97.1%, purity 97.4%). 20 g of compound 3 obtained in step (2) and 2 g of modified palladium-based catalyst prepared in preparation example 1 are added into 20 ml of isopropyl alcohol. After 15.1 g of ammonium formate is added in three portions at 30 °C, the temperature is increased to 65 °C, and the reaction is carried out for 5 h. After the HPLC monitoring shows that the content of compound 3 is less than or equal to 0.5%, the solution is cooled to room temperature, and then filtered. After the filter cake is washed with 20 ml of isopropyl alcohol for two times and 50 ml of 0.1 mol / l EDTA-2Na aqueous solution, the combined filtrate is adjusted to pH = 11 by adding 10% NaOH solution, stirred for 10 min, and extracted with 150 ml of ethyl acetate for two times. After the combined organic phase is washed with 100 ml of 5% NaHCO3 solution, 10 g of Na2SO4 / MgSO4 mixed drying agent with a mass ratio of 1:1 is added, stirred for 30 min, and then filtered to remove the drying agent to obtain an ethyl acetate solution containing compound 4; (4) the ethyl acetate solution containing compound 4 obtained in step (3) is added dropwise into 22 ml of isopropyl alcohol containing 7.7 g of L-tartaric acid at a temperature of 50 °C, and stirred for 1 h. After 1% of zanomeline tartrate salt is added at 45 °C, the crystal is precipitated, and then the temperature is maintained for 0.5 h. After the temperature is decreased to 25 °C and stirred for 16 h, the temperature is continuously decreased to 10 °C and stirred for 1 h. After filtration, the crude product is mixed with 30 ml of isopropyl alcohol, heated to 65 °C to dissolve, and then 5 g of activated carbon is added. After hot filtration, the filtrate is stirred at 30 °C for 1 h, and then the temperature is continuously decreased to 10 °C and stirred for 1 h to crystallize. After filtration, the product is dried at 45 °C until the weight is constant to obtain compound 5, i.e. zanomeline tartrate salt (yield 85.9%, purity 97.1%). Example 5 The preparation method of zanomeline tartrate salt comprises the following steps: (1) 50 g of compound 1 is added into a 300 ml tetrahydrofuran solution containing 77.4 g of n-hexanol, 26.7 g of sodium tert-butoxide is added, and the reaction is carried out at 25 °C for 5 h. After the sample HPLC monitoring shows that the content of compound 1 is less than or equal to 1.0%, 0.25 g of 10 ml tetrahydrofuran solution containing 3 mol / l concentrated hydrochloric acid is added dropwise, and the reaction is carried out at 20 °C for 1 h. After filtration, the filter cake is washed with 50 ml of tetrahydrofuran for three times to obtain a mixture containing compound 2; (2) 53.9 g of iodomethane is added into the mixture containing compound 2 obtained in step (1), and the reaction is carried out at 60 °C for 8 h. After the sample HPLC monitoring shows that the content of compound 2 is less than or equal to 1.0%, the reaction solution is cooled to 25 °C, and solid is precipitated. After filtration, the filter cake is washed with 50 ml of THF for two times. The obtained solid is dried at 55 °C until the weight is constant to obtain compound 3; 20 g of compound 3 obtained in step (2) and 2 g of modified palladium-based catalyst prepared in preparation example 2 are added into 20 ml of isopropyl alcohol. After 15.1 g of ammonium formate is added in three portions at 30 °C, the temperature is increased to 65 °C, and the reaction is carried out for 5 h. After HPLC monitoring shows that the content of compound 3 is less than or equal to 0.5%, the solution is cooled to room temperature, and then filtered. After the filter cake is washed with 20 ml of isopropyl alcohol for two times and 50 ml of 0.1 mol / l EDTA-2Na aqueous solution, the combined filtrate is adjusted to pH = 11 by adding 10% NaOH solution, stirred for 10 min, and extracted with 150 ml of ethyl acetate for two times. After the combined organic phase is washed with 100 ml of 5% NaHCO3 solution, 10 g of Na2SO4 / MgSO4 mixed drying agent with a mass ratio of 1:1 is added, stirred for 30 min, and then filtered to remove the drying agent to obtain an ethyl acetate solution containing compound 4; (4) the ethyl acetate solution containing compound 4 obtained in step (3) is added dropwise into 22 ml of isopropyl alcohol containing 7.7 g of L-tartaric acid at a temperature of 50 °C, and stirred for 1 h. After 1% of zanomeline tartrate salt is added at 45 °C, the crystal is precipitated, and then the temperature is maintained for 0.5 h. After the temperature is decreased to 25 °C and stirred for 16 h, the temperature is continuously decreased to 10 °C and stirred for 1 h. After filtration, the crude product is mixed with 30 ml of isopropyl alcohol, heated to 65 °C to dissolve, and then 5 g of activated carbon is added. After hot filtration, the filtrate is stirred at 30 °C for 1 h, and then the temperature is continuously decreased to 10 °C and stirred for 1 h to crystallize. After filtration, the product is dried at 45 °C until the weight is constant to obtain compound 5, i.e., zanomeline tartrate salt. (The yield is 86.8%, and the purity is 96.8%) Example 6 The preparation method of zanomeline tartrate salt comprises the following steps: (1) 50 g of compound 1 is added into a 300 ml tetrahydrofuran solution containing 77.4 g of n-hexanol, 26.7 g of sodium tert-butoxide is added, and the reaction is carried out at 25 °C for 5 h. After the sample HPLC monitoring shows that the content of compound 1 is less than or equal to 1.0%, 0.25 g of 10 ml tetrahydrofuran solution containing 3 mol / l concentrated hydrochloric acid is added dropwise, and the reaction is carried out at 20 °C for 1 h. After filtration, the filter cake is washed with 50 ml of tetrahydrofuran for three times to obtain a mixture containing compound 2; (2) 53.9 g of iodomethane is added into the mixture containing compound 2 obtained in step (1), and the reaction is carried out at 60 °C for 8 h. After the sample HPLC monitoring shows that the content of compound 2 is less than or equal to 1.0%, the reaction solution is cooled to 25 °C, and solid is precipitated. After filtration, the filter cake is washed with 50 ml of THF for two times. The obtained solid is dried at 55 °C until the weight is constant to obtain compound 3; 20 g of compound 3 obtained in step (2) and 2 g of modified palladium-based catalyst prepared in preparation example 3 are added into 20 ml of isopropyl alcohol. After 15.1 g of ammonium formate is added in three portions at 30 °C, the temperature is increased to 65 °C, and the reaction is carried out for 5 h. After the HPLC monitoring shows that the content of compound 3 is less than or equal to 0.5%, the solution is cooled to room temperature, and then filtered. After the filter cake is washed with 20 ml of isopropyl alcohol for two times and 50 ml of 0.1 mol / l EDTA-2Na aqueous solution, the combined filtrate is adjusted to pH = 11 by adding 10% NaOH solution, and stirred for 10 min. After the organic phase is extracted twice with 150 ml of ethyl acetate, the combined organic phase is washed with 100 ml of 5% NaHCO3 solution, and then 10 g of Na2SO4 / MgSO4 mixed drying agent with a mass ratio of 1:1 is added. After stirring for 30 min, the drying agent is removed by filtration to obtain an ethyl acetate solution containing compound 4; (4) the ethyl acetate solution containing compound 4 obtained in step (3) is added dropwise into 22 ml of isopropyl alcohol containing 7.7 g of L-tartaric acid at a temperature of 50 °C, and stirred for 1 h. After 1% of zanomeline tartrate salt is added at 45 °C, the crystal is precipitated, and then the temperature is maintained for 0.5 h. After the temperature is decreased to 25 °C and stirred for 16 h, the temperature is continuously decreased to 10 °C and stirred for 1 h. After filtration, the crude product is mixed with 30 ml of isopropyl alcohol, and then the temperature is increased to 65 °C to dissolve the mixture. After 5 g of activated carbon is added, the mixture is filtered while hot. After the filtrate is stirred at 30 °C for 1 h, the temperature is continuously decreased to 10 °C and stirred for 1 h to crystallize. After filtration, the product is dried at 45 °C until the weight is constant to obtain compound 5, i.e. zanomeline tartrate salt. (The yield is 86.3%, and the purity is 95.9%) Comparative example 1 The preparation method of zanomeline tartrate salt comprises the following steps: (1) 50 g of compound 1 is added into a 300 ml tetrahydrofuran solution containing 77.4 g of n-hexanol, 26.7 g of sodium tert-butoxide is added, and the reaction is carried out at 25 °C for 5 h. After the sample HPLC monitoring shows that the content of compound 1 is less than or equal to 1.0%, 0.25 g of 10 ml tetrahydrofuran solution containing 3 mol / l concentrated hydrochloric acid is added dropwise, and the reaction is carried out at 20 °C for 1 h. After filtration, the filter cake is washed with 50 ml of tetrahydrofuran for three times to obtain a mixture containing compound 2; (2) 53.9 g of iodomethane is added into the mixture containing compound 2 obtained in step (1), and the reaction is carried out at 60 °C for 8 h. After the sample HPLC monitoring shows that the content of compound 2 is less than or equal to 1.0%, the reaction solution is cooled to 25 °C, and solid is precipitated. After filtration, the filter cake is washed with 50 ml of THF for two times. The obtained solid is dried at 55 °C until the weight is constant to obtain compound 3; 20 g of compound 3 obtained in step (2) and 2 g of modified palladium-based catalyst prepared in preparation example 1 are added into 20 ml of isopropyl alcohol. After 15.1 g of ammonium formate is added in three portions at 30 °C, the temperature is increased to 65 °C, and the reaction is carried out for 5 h. After the HPLC monitoring shows that the content of compound 3 is less than or equal to 0.5%, the solution is cooled to room temperature, and then filtered. After the filter cake is washed with 20 ml of isopropyl alcohol for two times, the combined filtrate is added into 10% NaOH solution to adjust the pH to 11, and stirred for 10 min. After the organic phase is extracted with 150 ml of ethyl acetate for two times, the combined organic phase is washed with 100 ml of 5% NaHCO3 solution, and then 10 g of Na2SO4 / MgSO4 mixed drying agent with a mass ratio of 1:1 is added. After stirring for 30 min, the drying agent is removed by filtration to obtain an ethyl acetate solution containing compound 4; (4) the ethyl acetate solution containing compound 4 obtained in step (3) is added dropwise into 22 ml of isopropyl alcohol containing 7.7 g of L-tartaric acid at a temperature of 50 °C, and stirred for 1 h. After 1% of zanomeline tartrate salt is added at 45 °C, the crystal is precipitated, and then the temperature is maintained for 0.5 h. After the temperature is decreased to 25 °C and stirred for 16 h, the temperature is continuously decreased to 10 °C and stirred for 1 h. After filtration, the crude product is mixed with 30 ml of isopropyl alcohol, and then the temperature is increased to 65 °C to dissolve the mixture. After 5 g of activated carbon is added, the mixture is filtered while hot. After the filtrate is stirred at 30 °C for 1 h, the temperature is continuously decreased to 10 °C and stirred for 1 h to crystallize. After filtration, the product is dried at 45 °C until the weight is constant to obtain compound 5, i.e., zanomeline tartrate salt. (The yield is 86.8%, and the purity is 95.1%) Comparative example 2 The preparation method of zanomeline tartrate salt comprises the following steps: (1) 50 g of compound 1 is added into a 300 ml tetrahydrofuran solution containing 77.4 g of n-hexanol, 26.7 g of sodium tert-butoxide is added, and the reaction is carried out at 25 °C for 5 h. After the sample HPLC monitoring shows that the content of compound 1 is less than or equal to 1.0%, 0.25 g of 10 ml tetrahydrofuran solution containing 3 mol / l concentrated hydrochloric acid is added dropwise, and the reaction is carried out at 20 °C for 1 h. After filtration, the filter cake is washed with 50 ml of tetrahydrofuran for three times to obtain a mixture containing compound 2; (2) 53.9 g of iodomethane is added into the mixture containing compound 2 obtained in step (1), and the reaction is carried out at 60 °C for 8 h. After the sample HPLC monitoring shows that the content of compound 2 is less than or equal to 1.0%, the reaction solution is cooled to 25 °C, and solid is precipitated. After filtration, the filter cake is washed with 50 ml of THF for two times. The obtained solid is dried at 55 °C until the weight is constant to obtain compound 3; 20 g of compound 3 obtained in step (2) and 2 g of modified palladium-based catalyst prepared in preparation example 1 are added into 20 ml of isopropyl alcohol. After 15.1 g of ammonium formate is added in three portions at 30 °C, the temperature is increased to 65 °C, and the reaction is carried out for 5 h. After the HPLC monitoring shows that the content of compound 3 is less than or equal to 0.5%, the solution is cooled to room temperature, and then filtered. After the filter cake is washed with 20 ml of isopropyl alcohol for two times and 50 ml of 0.1 mol / l EDTA-2Na aqueous solution, the combined filtrate is adjusted to pH = 11 by adding 10% NaOH solution, and stirred for 10 min. After the organic phase is extracted twice with 150 ml of ethyl acetate, the combined organic phase is washed with 100 ml of 5% NaHCO3 solution to obtain an ethyl acetate solution containing compound 4; (4) the ethyl acetate solution containing compound 4 obtained in step (3) is added dropwise into 22 ml of isopropyl alcohol containing 7.7 g of L-tartaric acid at a temperature of 50 °C, and stirred for 1 h. After 1% of zanomeline tartrate salt is added at 45 °C, the crystal is precipitated, and then the temperature is maintained for 0.5 h. After the temperature is decreased to 25 °C and stirred for 16 h, the temperature is continuously decreased to 10 °C and stirred for 1 h. After filtration, the crude product is mixed with 30 ml of isopropyl alcohol, and then dissolved by increasing the temperature to 65 °C. After 5 g of activated carbon is added, the mixture is filtered while hot. After the filtrate is stirred at 30 °C for 1 h, the temperature is continuously decreased to 10 °C and stirred for 1 h to crystallize. After filtration, the product is dried at 45 °C until the weight is constant to obtain compound 5, i.e., zanomeline tartrate salt. (The yield is 86.7%, and the purity is 96.8%) Comparative example 3 The preparation method of zanomeline tartrate salt comprises the following steps: (1) 50 g of compound 1 is added into a 300 ml tetrahydrofuran solution containing 77.4 g of n-hexanol, 26.7 g of sodium tert-butoxide is added, and the reaction is carried out at 25 °C for 5 h. After the sample HPLC monitoring shows that the content of compound 1 is less than or equal to 1.0%, 0.25 g of 10 ml tetrahydrofuran solution containing 3 mol / l concentrated hydrochloric acid is added dropwise, and the reaction is carried out at 20 °C for 1 h. After filtration, the filter cake is washed with 50 ml of tetrahydrofuran for three times to obtain a mixture containing compound 2; (2) 53.9 g of iodomethane is added into the mixture containing compound 2 obtained in step (1), and the reaction is carried out at 60 °C for 8 h. After the sample HPLC monitoring shows that the content of compound 2 is less than or equal to 1.0%, the reaction solution is cooled to 25 °C, and solid is precipitated. After filtration, the filter cake is washed with 50 ml of THF for two times. The obtained solid is dried at 55 °C until the weight is constant to obtain compound 3; 20 g of compound 3 obtained in step (2) and 2 g of modified palladium-based catalyst prepared in preparation example 1 are added into 20 ml of isopropyl alcohol. After 15.1 g of ammonium formate is added in three portions at 30 °C, the temperature is increased to 65 °C, and the reaction is carried out for 5 h. After the HPLC monitoring shows that the content of compound 3 is less than or equal to 0.5%, the solution is cooled to room temperature, and then filtered. After the filter cake is washed with 20 ml of isopropyl alcohol for two times and 50 ml of 0.1 mol / l EDTA-2Na aqueous solution, the combined filtrate is adjusted to pH = 11 by adding 10% NaOH solution, stirred for 10 min, and extracted with 150 ml of ethyl acetate for two times. After the combined organic phase is washed with 100 ml of 5% NaHCO3 solution, 10 g of Na2SO4 / MgSO4 mixed drying agent with a mass ratio of 1:1 is added, stirred for 30 min, and then filtered to remove the drying agent to obtain an ethyl acetate solution containing compound 4; (4) the ethyl acetate solution containing compound 4 obtained in step (3) is added dropwise into 22 ml of isopropyl alcohol containing 7.7 g of L-tartaric acid at a temperature of 50 °C, and stirred for 1 h. After 1% of zanomeline tartrate salt is added at 45 °C, the crystal is precipitated, and then the temperature is maintained for 0.5 h. After the temperature is decreased to 25 °C and stirred for 16 h, the temperature is continuously decreased to 10 °C and stirred for 1 h. After filtration, the filter cake is dried at 45 °C until the weight is constant to obtain compound 5, i.e., zanomeline tartrate salt. (The yield is 87.3%, and the purity is 96.6%) Based on the above example comparative example, example 1 and examples 5-6, it can be seen that, by using the palladium-based catalyst with polyethylene glycol in a specific mass ratio range, the ether oxygen atom of the modified palladium-based catalyst polyethylene glycol can form a weak coordination bond with Pd, thereby preventing carbon nanoparticles from agglomerating, and the hydrophilic segment thereof can also stretch in isopropyl alcohol to form a steric hindrance layer, thereby increasing the exposure of active sites of Pd, reducing local over-reduction byproducts, and achieving uniform nucleation conditions, so that the stability of the zanamivir tartrate crystal form is good, the particle size is uniform, and the entire zanamivir tartrate preparation process is facilitated. If the content of polyethylene glycol is too low, the polyethylene glycol coverage will be insufficient, the catalyst dispersion will be reduced, the reduction efficiency will be reduced, a small amount of mixed crystals will be produced, and the uniformity and stability of the crystals will be affected; if the content of polyethylene glycol is too high, the reaction rate will be reduced, the byproducts will increase accordingly, and the yield and purity of the target product will be reduced.

[0029] As can be seen from examples 1 and examples 2-3, the compound 3 and ammonium formate in the mass ratio of the present application can achieve the best in-situ generation of active hydrogen, and the active hydrogen selectively reduces the imine bond, thereby improving the yield and purity. If the amount of ammonium formate is insufficient, the hydrogen source will be insufficient, which will result in incomplete reduction of compound 3 and thus reduce the yield; if the amount of ammonium formate is excessive, the excess active hydrogen will produce side reactions, increase impurities, and affect the purity and yield of the product.

[0030] As can be seen from example 1 and example 4, compound 1 and sodium tert-butoxide in the range of the present application can completely deprotonate n-hexanol, and n-hexanol can attack the chlorine atom of compound 1 under the action of sodium tert-butoxide, thereby ensuring the smooth progress of the reaction and helping to improve the yield and purity of the reaction product. If the amount of sodium tert-butoxide is insufficient, the reaction will be incomplete and the yield will be reduced; if the amount of sodium tert-butoxide is excessive, the generation of alkylation byproducts will be increased, thereby reducing the purity of the product.

[0031] The above are preferred embodiments of the present application, and do not limit the protection scope of the present application, therefore: any equivalent changes made in accordance with the structure, shape, principle of the present application should be covered within the protection scope of the present application.

Claims

1. A process for the preparation of xanomeline tartrate, characterized by: The method comprises the following steps: (1) adding compound 1 into a tetrahydrofuran solution containing n-hexanol, and then adding sodium tert-butoxide, and reacting at 20-25 ℃ for 2-5 h, and then taking a sample for HPLC monitoring to ensure that the content of compound 1 is less than or equal to 1.0%, and then performing post-treatment to obtain a mixture containing compound 2; (2) adding methyl iodide into the mixture containing compound 2 obtained in step (1), and heating at 55-60 ℃ until the reaction is completed, and then taking a sample for HPLC monitoring to ensure that the content of compound 2 is less than or equal to 1.0%, and then cooling the reaction solution to 15-25 ℃, and then precipitating a solid, and then filtering to obtain compound 3; (3) adding compound 3 obtained in step (2) and a modified palladium-based catalyst into isopropanol, and then adding ammonium formate in batches at 25-30 ℃, and then increasing the temperature to 60-65 ℃ and stirring for 3-5 h, and then taking a sample for HPLC monitoring to ensure that the content of compound 3 is less than or equal to 0.5%, and then cooling to room temperature, and then performing crude product treatment to obtain an ethyl acetate solution containing compound 4; (4) adding the ethyl acetate solution containing compound 4 obtained in step (3) into isopropanol containing L-tartaric acid at a temperature of 45-50 ℃, and stirring for 0.5-1 h, and then adding 1% crystal seeds at 45-50 ℃, and then crystallizing and then keeping warm for 0.5-1 h, and then cooling to 5-10 ℃ and stirring for 1-2 h, and then filtering, and then recrystallizing the crude product to obtain compound 5, i.e., zanamivir L-tartrate.

2. The process for preparing the xanomeline tartrate salt according to claim 1, characterized by: The modified palladium-based catalyst is prepared by stirring 5-10% palladium-based catalyst and polyethylene glycol in isopropanol for 30-45 min.

3. The process for preparing the xanomeline tartrate salt according to claim 2, characterized by: The mass ratio of the palladium-based catalyst to the polyethylene glycol is (4-6) :

1.

4. The process for preparing the xanomeline tartrate salt according to claim 1, characterized by: The mass ratio of compound 3 to ammonium formate is 1 : (0.75-0.85).

5. The process for preparing the xanomeline tartrate salt according to claim 1, characterized by: In step (1), the mass ratio of compound 1 to sodium tert-butoxide is 1 : (0.5-0.7).

6. The process for preparing the xanomeline tartrate salt according to claim 1, characterized by: In step (1), the post-treatment step is adding a tetrahydrofuran solution containing concentrated hydrochloric acid dropwise, stirring at 10-20 ℃ for 0.5-1 h, filtering, and then washing the filter cake with tetrahydrofuran to obtain the mixture containing compound 2.

7. The process for preparing the xanomeline tartrate salt according to claim 1, characterized by: In step (3), the crude product treatment step is filtering first, washing with isopropanol and an aqueous EDTA-2Na solution, adjusting the pH to 10-11 with a NaOH solution, extracting with ethyl acetate, adding a mixed drying agent to the combined organic phase and stirring for 20-30 min, and then filtering to obtain the product.

8. The process for preparing the xanomeline tartrate salt according to claim 1, characterized by: In step (4), the recrystallization step is mixing the crude product with isopropanol, dissolving at 65-75 ℃, adding activated carbon, filtering while hot, crystallizing the filtrate by cooling, and then filtering and drying to obtain the product.

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