Preparation method of fesoterodine intermediate

Abstract

The invention discloses a fesoterodine intermediate preparation method, and belongs to the technical field of chemical medicine raw material medicine synthesis, 6-(hydroxymethyl)-4-phenylchroman-2-ol and diisopropylamine are used as starting materials to prepare a fesoterodine intermediate, an inert conversion reagent is used, and the reaction temperature is controlled to be 30-60 DEG C, so that the fesoterodine intermediate is obtained. On the other hand, the excessive diisopropylamine reacts with an inert conversion reagent, the excessive diisopropylamine is converted into an excessive state which does not react with the product, and the excessive diisopropylamine is prevented from reacting with the product to generate a large amount of various impurities; a reducing agent and an inert conversion reagent are introduced to be combined, so that the problem of impurity generation caused by palladium catalytic hydrogenation reduction is avoided.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical raw material synthesis technology, and more specifically relates to a method for preparing a non-sorodine intermediate. Background Technology

[0002] Overactive bladder (OAB) is a common clinical condition. The International Continence Society defines it as a clinical syndrome characterized by urinary urgency, often accompanied by urinary frequency and nocturia, with or without acute urinary incontinence.

[0003] Fexolodine fumarate extended-release tablets are a drug for treating OAB (occlusive abscess). The key intermediate in the production of fexolodine fumarate is 3-[3-[diisopropylamino]-1-phenylpropyl]-4-hydroxy-benzyl alcohol, abbreviated as fexolodine intermediate. Its chemical structure and synthesis process are shown in the following figure:

[0004] The preparation of the nonsorodine intermediate from 6-(hydroxymethyl)-4-phenylbenzodihydropyran-2-ol and diisopropylamine via amination and reduction has several drawbacks: numerous byproducts and impurities, cumbersome purification processes, high costs, and significant safety risks associated with large-scale industrial production. For example, residual diisopropylamine can generate impurity A, and excessive reduction may lead to the loss of hydroxyl groups, forming impurity B. Furthermore, these impurities can generate other impurities. For example, patent CN101466695A mentions using palladium catalysts such as Pd / C or Pd(OH)2 / C for reductive amination to obtain the target product. This method generates impurity A and suffers from over-reduction, resulting in high impurity levels. Furthermore, the use of palladium catalysts introduces heavy metals, increasing the research and testing costs for drug quality control. Industrial production using the reported process is costly and risky due to quality and safety concerns. Some reports suggest that reducing the reduction pressure or the palladium catalyst content can solve the over-reduction problem, but this often leads to the generation of impurity D. The impurity generation process in some parts of the process is shown in the following figure:

[0005] Therefore, a simple, high-purity, and easily industrialized process for preparing non-sorodine intermediates has become the key to solving the problem. Summary of the Invention

[0006] To address the aforementioned problems and overcome the shortcomings of existing technologies, this invention provides a method for preparing non-sorodine intermediates, which can effectively solve the problems of high cost, numerous impurities, and high safety risks in the industrialization of key non-sorodine intermediates.

[0007] The specific technical solution of this invention to solve the above-mentioned technical problems is as follows: a method for preparing non-sorodine intermediates, using raw material SM1, namely 6-(hydroxymethyl)-4-phenylbenzodihydropyran-2-ol and diisopropylamine, as starting materials to prepare non-sorodine intermediates, comprising: (1) Under nitrogen protection, turn on the stirring of the reaction device, add the reaction solvent and raw material SM1 into the reaction vessel, add the raw material diisopropylamine under controlled temperature after the material is dissolved, and after all the materials are added, keep the system at the temperature for 1~3 hours. (2) Weigh out an inert conversion reagent in a certain proportion to the raw material SM1, and add the inert conversion reagent dropwise into the reaction vessel at a controlled temperature of 20~50℃ to carry out the inert conversion reaction. After the addition is completed, keep the temperature and stir for 2~5 hours. (3) After the inert conversion is completed, the reducing agent is slowly added to the reaction system under controlled temperature. After the reducing agent is added, the reaction system is kept warm and stirred for 10-20 hours. (4) After the reaction system is kept at a constant temperature, the temperature is controlled below 40°C. Purified water is added to the reaction system to quench the reaction. Then the extraction solvent is added and stirred for 30 minutes. The system is adjusted to neutral with alkali solution. Stirring is stopped and the system is allowed to stand and separate into layers. This process is repeated three times with water. After the water washing is completed, the reaction system is concentrated under reduced pressure at a constant temperature of 90°C to obtain the concentrate. (5) The concentrate was heated to dissolve the product using a crystallization solvent, and then the system was cooled to 10~20℃, filtered, and dried to obtain the non-sorodine intermediate; Furthermore, the reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; Furthermore, the molar ratio of raw material SM1 to raw material diisopropylamine is 1:2~4; Furthermore, the amount of inert conversion reagent weighed is such that the molar ratio of raw material SM1 to inert conversion reagent is 1:1~1.5, and the inert conversion reagent is one of acetic acid, butyric acid, or propionic acid; Furthermore, the amount of reducing agent weighed is such that the molar ratio of raw material SM1 to reducing agent is 1:2~4, and the reducing agent is one or a mixture of sodium triacetoxyborohydride, sodium borohydride, sodium trimethoxyborohydride, and tetramethyltriammonium. Furthermore, the extraction solvent is one of ethyl acetate, isopropyl acetate, or toluene; the alkaline solution is one of 10% potassium carbonate solution, 10% sodium carbonate solution, or 10% sodium bicarbonate solution. Furthermore, the crystallization solvent is one or a mixture of ethyl acetate, tetrahydrofuran, toluene, and acetonitrile; The beneficial effects of this invention are: (1) The present invention uses an inert conversion reagent, which to a certain extent ensures that the amount of diisopropylamine added is sufficient, thereby improving the conversion rate of the product. On the other hand, the excess diisopropylamine reacts with the inert conversion reagent to convert the excess diisopropylamine into a transition state that does not react with the product, thus avoiding the generation of a large number of impurities by the reaction of excess diisopropylamine with the product. (2) This invention creatively combines a reducing agent and an inert conversion reagent to avoid the problem of impurities generated by using palladium-based catalytic hydrogenation reduction. Attached Figure Description

[0008] Appendix Figure 1 This is the high-performance liquid chromatography (HPLC) chromatogram of the non-sodrodin intermediate in Example 1 of the present invention: Appendix Figure 2 This is the high-performance liquid chromatography (HPLC) chromatogram of the non-sodrodin intermediate in Example 2 of the present invention: Appendix Figure 3 This is the high-performance liquid chromatography (HPLC) chromatogram of the non-sorodine intermediate in Example 3 of the present invention. Detailed Implementation

[0009] In the description of this invention, the specific details are merely for the purpose of fully understanding the embodiments of the invention. However, those skilled in the art should know that the implementation of the invention is not limited to these details. In addition, well-known structures and functions have not been described or shown in detail to avoid obscuring the key points of the embodiments of the invention. For those skilled in the art, the specific meaning of the above terms in this invention can be understood according to the specific circumstances. Example 1 Under nitrogen protection, 300g of N,N-dimethylformamide was added to a glass container equipped with a stirrer, and 30g of raw material SM1 was weighed and added. The mixture was stirred and dissolved for 20 minutes until the system was smooth. The temperature was controlled at 20℃, and 23.7g of diisopropylamine was added dropwise to the reaction system. The temperature of the system was strictly controlled during the dropwise addition process. After the dropwise addition was completed, the system was kept at this temperature for 1 hour. Weigh 7.1g of the inert conversion reagent acetic acid into a dropping funnel, and weigh 49.6g of the reducing agent sodium triacetoxyborohydride solid into a dry beaker. Add the inert conversion reagent dropwise while maintaining the system temperature at 20℃. The addition process is exothermic. After the addition is complete, maintain the temperature at 20℃ and stir for 2 hours. After the temperature is maintained, slowly add 49.6g of the reducing agent using a feeding device. During the addition process, the system gradually turns dark brown. After the addition is complete, maintain the temperature and stir for 10-20 hours to complete the reaction. Within a controlled temperature of 40℃, add 300g of purified water and 400g of ethyl acetate (the extraction solvent) to the system, stir for 30min, and adjust the pH of the system to neutral using a 10% potassium carbonate solution; let the system stand for 30min, separate the aqueous phase, add 100g of purified water to the organic phase, stir for 30min, let stand for 30min, and separate the aqueous phase; repeat this process of water washing and layering three times; after water washing, concentrate the system until no fraction remains under a vacuum of ≤-0.1Mpa at a temperature below 90℃ to obtain a solid concentrate, and the concentration process is complete; The concentrate was heated to a clear solution using 60g ethyl acetate and 30g acetonitrile, then cooled to 30°C, and further cooled to 15±5°C. The mixture was stirred and crystallized for 1-2 hours, filtered, and dried to obtain 33.8g of off-white nonsorodine intermediate. The total impurities in the non-sorodine intermediate were 0.2%, with a molar yield of 84.6%. Example 2 Under nitrogen protection, 300g of N,N-dimethylacetamide was added to a glass container equipped with a stirrer, and 30g of raw material SM1 was weighed and added. The mixture was stirred and dissolved for 20 minutes until the system was smooth. The temperature was controlled at 20℃, and 47.4g of diisopropylamine was added dropwise to the reaction system. The temperature of the system was strictly controlled during the dropwise addition process. After the dropwise addition was completed, the system was kept at this temperature for 2 hours. Weigh 21g of the inert conversion reagent butyric acid into a dropping funnel, and weigh 99.2g of the reducing agent sodium triacetoxyborohydride solid into a dry beaker. Add the inert conversion reagent dropwise while maintaining the system temperature at 20℃. Exothermic reaction is evident during the dropwise addition. After the addition of the inert conversion reagent is complete, maintain the temperature at 20℃ and stir for 2 hours. After the temperature is maintained, slowly add 99.2g of the reducing agent using a feeding device. During the addition process, the color of the system gradually turns dark brown. After the dropwise addition is complete, maintain the temperature and stir for 10-20 hours to complete the reaction. After the reaction was completed, the temperature was controlled at 40℃. 300g of purified water and 400g of isopropyl acetate (extraction solvent) were added to the system, and the mixture was stirred for 30min. The pH of the system was adjusted to neutral using 10% sodium bicarbonate. The system was allowed to stand for 30min, and the aqueous phase was separated. 100g of purified water was added to the organic phase, and the mixture was stirred for 30min and allowed to stand for 30min. The aqueous phase was then separated. This process of washing with water was repeated three times. After washing, the system was concentrated to the point of no fractionation at 90℃ and a vacuum degree ≤-0.1Mpa to obtain a solid concentrate. The concentration process was then complete. The concentrate was heated to a clear solution using 60g ethyl acetate and 30g tetrahydrofuran, then cooled to 30°C, and further cooled to 15±5°C with stirring to crystallize for 1-2 hours. After filtration and drying, 33.3g of off-white nonsorodine intermediate was obtained. The total impurities in the non-sorodine intermediate were 0.17%, with a molar yield of 83.4%. Example 3 Under nitrogen protection, add 300g of dimethyl sulfoxide to a glass container equipped with a stirrer, weigh in 30g of raw material SM1, and stir to dissolve for 20min until the system is smooth; control the temperature at 20℃, add 35.53g of raw material diisopropylamine to the reaction system, strictly control the temperature of the system during the dropwise addition process, and keep the system at the temperature for 1.5h after the dropwise addition is completed; Weigh 9.0 g of inert conversion reagent acetic acid into a dropping funnel, and weigh 38.0 g of reducing agent sodium borohydride solid into a dry beaker. Add the inert conversion reagent dropwise while maintaining the system temperature at 20°C. The addition process is markedly exothermic. After the addition is complete, maintain the temperature at 20°C and stir for 2 hours. After the temperature is maintained, slowly add 38.0 g of reducing agent using a feeding device. During the addition process, the system gradually turns dark brown. After the addition is complete, maintain the temperature and stir for 10–20 hours. After the reaction was completed, the temperature was controlled at 40℃. 300g of purified water and 400g of toluene (extraction solvent) were added to the system, and the mixture was stirred for 30min. The pH of the system was adjusted to neutral using 10% sodium bicarbonate. The system was allowed to stand for 30min, and the aqueous phase was separated. 100g of purified water was added to the organic phase, and the mixture was stirred for 30min and allowed to stand for 30min. The aqueous phase was then separated. This process of washing with water was repeated three times. After washing, the system was concentrated to the point of no fractionation at 90℃ and a vacuum degree ≤-0.1Mpa to obtain a solid concentrate. The concentration process was then complete. The concentrate was heated to a clear state using 60g toluene and 30g acetonitrile, then cooled to 30°C, and further cooled to 15±5°C with stirring to induce crystallization for 1-2 hours. After filtration and drying, 34.8g of the off-white target product, nonsorodine intermediate, was obtained. The non-sorodine intermediate was analyzed for related substances, with a total impurity content of 0.32% and a molar yield of 87%.

[0010] To more intuitively demonstrate the technological advantages of this invention, a comparison is made using the same process but with equivalent substitution. Comparative Example 1 The preparation of non-sorodine intermediates is based on patent number CN101466695A, which is cited by way of reference. A mixture consisting of methanol, a Pd / C catalyst, 30 g of feedstock SM1(R)-6-hydroxymethyl·4-phenylchroman-2-(R)-ol, and excess diisopropylamine was hydrogenated at room temperature and 4 bar. After at least 18 hours, the reaction mixture was filtered and evaporated to dryness. Subsequently, the mixture was treated with 1 eq of a tetrahydrofuran solution of lithium aluminum hydride to cleave all cyclic hemiacetal amines. The reaction was quenched with water, and the product was extracted with ethyl acetate. The solvent was removed and the product was dried under vacuum to give 21.6 g of a white solid, a nonsorodine intermediate. The total impurities in the non-sorodine intermediate were 1.4%, with a molar yield of 54%. Comparative Example 2 30 g of starting material SM1 6-(2-hydroxy-ethyl)-4-phenyl-carbazole-2-ol, 33.7 g of diisopropylamine, and 6 g (0.2 eq) of palladium hydroxide supported on carbon catalyst (50% wet catalyst (50% water by weight), 0.2 eq)) were mixed with toluene (120 mL) and hydrogenated at 110°C under a hydrogen pressure of 621 × 10³ Pa (90 psi). The reaction mixture was cooled to room temperature, filtered, and evaporated under reduced pressure. The resulting oil was dissolved in acetonitrile (200 mL), and then 11.6 mL (1.05 eq) of concentrated hydrochloric acid was added. The mixture was distilled at atmospheric pressure to remove approximately 100 mL of acetonitrile, and then the distillation solvent was replaced with fresh acetonitrile. The mixture was allowed to stand overnight under cooling conditions to crystallize. The product was filtered and washed with a small amount of acetonitrile, and then dried overnight under vacuum at 50°C to give 26 g of a white solid nonsorodine intermediate. The total impurities in the non-sorodine intermediate were 1.1%, with a molar yield of 61%. Comparative Example 3 Same as Example 3, except that the inert conversion reagent is replaced with hydrochloric acid; The detection of related substances in non-sorodine intermediates showed that the total impurities in the final non-sorodine intermediates exceeded 5%, and the molar yield of the non-sorodine intermediates was less than 50%. Excessive acidification can disrupt the reduction process of the product, resulting in poor yield and quality. Comparative Example 4 Same as Example 3, except that the inert conversion reagent is replaced with oxalic acid; The non-sorodine intermediate was tested for related substances. The final non-sorodine intermediate impurity B was 2.5%, the total impurities were about 4%, and the non-sorodine intermediate yield was 64%. Oxalic acid has reducing ability under certain conditions, so there was an over-reduction in the reduction stage, which ultimately led to the high impurity B. Comparative Example 5 Same as Example 1, except that the reduction reaction is replaced by the Pd / C catalyst reduction method from the cited patent, wherein impurity B is approximately 1%, the total impurities are 3%, and the yield of the non-sorodin intermediate is 70%; The Pd / C catalytic reduction reaction has the potential for over-reduction, resulting in impurity B (see figure below). The use of nitrogen-containing diisopropylamine can cause catalyst deactivation, leading to raw material residue and low product conversion rate. Furthermore, the hydrogen-based Pd / C catalytic reduction method has high requirements for production equipment and poses excessive safety risks, hindering its industrialization. Comparative Example 6 In the form of reference, the difference is that sodium borohydride, as the reducing agent of the present invention, is used; 30 g of raw material SM1 6-(2-hydroxy-ethyl)-4-phenyl-carbazole-2-ol, 33.7 g of diisopropylamine, and toluene (120 mL) were mixed, and sodium borohydride was slowly added while maintaining a temperature of 40-50 °C. The reaction mixture was stirred and cooled to room temperature, filtered through a filter, and evaporated under reduced pressure. The resulting oil was dissolved in acetonitrile (200 mL), and then 11.6 mL (1.05 eq) of concentrated hydrochloric acid was added. The mixture was distilled under normal pressure to remove about 100 mL of acetonitrile, and then the distillation solvent was replaced with fresh acetonitrile. The mixture was allowed to stand overnight under cooling conditions to crystallize. The product was filtered and washed with a small amount of acetonitrile, and then dried overnight under vacuum at 50 °C to obtain 22 g of a white solid nonsorodine intermediate. The detection of non-sorodine intermediates and related substances showed a total impurity content of approximately 5% and a molar yield of 55%. The detection method for non-sorodin intermediates and related substances is as follows: The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0011] Diluent: Acetonitrile-water (15:85) Test solution: Weigh approximately 10 mg of this product accurately, place it in a 10 ml volumetric flask, add approximately 1.5 ml of acetonitrile to dissolve it, then add water dropwise to dilute to the mark and shake well.

[0012] Chromatographic conditions: Octadecylsilane-bonded silica gel (NanoChromChromCore120 C18, 4.6mm x 250mm, 3µm or equivalent column) was used as the stationary phase. 0.01 mol / L sodium perchlorate solution (pH adjusted to 5.5 with 1% high-acid solution) was used as mobile phase A, and acetonitrile was used as mobile phase B, with gradient elution. The flow rate was 1 mL / min; the column temperature was 40℃; the detection wavelength was 220 nm; the injection volume was 10 mL; the injector temperature was 5℃; acetonitrile was used as the needle wash solution, and impurities were calculated using area normalization.

[0013] Table 1: Comparison of non-sorodin intermediates produced in different embodiments and comparative examples

[0014] Analysis of the data in Table 1: (1) In order to achieve a relatively high conversion rate, an excess of diisopropylamine needs to be added. Comparative Examples 1 and 2 both use hydrogenation reduction, which is an existing technology. The temperature and pressure are high. Based on the principle of adding excess diisopropylamine, under these conditions, the product is prone to continue reacting and generating impurity A. At the same time, the high pressure makes it easy for impurities in the product to lose hydroxyl groups and generate impurity B. Therefore, the final product yields of Comparative Examples 1 and 2 are low, the impurity levels are high, and the safety and quality risks of industrial production are relatively large. Therefore, based on existing technology, simply adding excessive amounts of diisopropylamine not only fails to achieve the desired high conversion rate, but also unexpectedly generates impurity B, which in turn leads to the formation of other impurities. Thus, adding excessive amounts of diisopropylamine cannot achieve a high conversion rate for the non-sorodine intermediate. The process of impurity formation in some stages is shown in the following figure:

[0015] (2) Comparative Example 6 did not use an inert conversion reagent. Based on the results of Comparative Examples 1 and 2, adding excess diisopropylamine did not yield a high conversion rate of the non-sorodine intermediate; the applicant further investigated the effect of catalyst activity in the reduction reaction on the yield of the final product and related substances when "excess diisopropylamine was added". In Comparative Examples 1 and 2, the reduction of hydrogen Pd / C catalyst still showed signs of over-reduction, and the catalyst was prone to deactivation, resulting in poor final experimental results. Comparative Example 6 used sodium borohydride as a catalyst according to the present invention, with high levels of both impurities A and C. Therefore, adding excessive diisopropylamine and adjusting the reduction reaction catalyst sodium borohydride not only fails to obtain a high conversion rate of the solid non-sorodin intermediate, but the conversion rate of the non-sorodin intermediate is even lower than that of Comparative Example 1-2. (3) In Comparative Example 5, the applicant further investigated the effect of the inert conversion reagent of the present invention on the reduction of diisopropylamine with hydrogen Pd / C catalyst based on existing comparative examples 1 and 2. The results of the experiment were found to be less than expected and had no research value. The problem with Comparative Example 5 is similar to that of Comparative Examples 1-2. The reducing agents such as hydrogen and palladium on carbon are relatively strong, resulting in more reaction sites and higher levels of impurities A, B, and C. The addition of inert conversion reagent cannot solve the problem of more reaction sites and higher levels of impurities A, B, and C. (4) In both Comparative Examples 3 and 4, different types of inert reagents were used. The applicant also attempted to study the problem of the generation of related substance impurity B caused by the addition of excessive diisopropylamine by different inert reagents. Furthermore, different types of inert reagents were studied. Among them, Comparative Examples 3 and 4 were limited by strong acidity or their own certain reducing ability, resulting in the experimental results being less than expected. Therefore, it can be seen that: Examples 1 to 3 of the present invention introduce a relatively mild reducing agent, and use raw material SM1 and excess raw material diisopropylamine to react first. In particular, the ingenious addition of an inert conversion reagent to complex with the remaining raw material diisopropylamine ensures that the amount of diisopropylamine added is sufficient. The excess diisopropylamine reacts with the inert conversion reagent to convert the excess diisopropylamine into a transition state that does not react with the product, and unexpectedly, a high conversion rate and yield of non-sodrodin intermediate are obtained.

[0016] In summary: (1) The present invention uses an inert conversion reagent, which to a certain extent ensures that the amount of diisopropylamine added is sufficient, thereby improving the conversion rate of the product. On the other hand, the excess diisopropylamine reacts with the inert conversion reagent to convert the excess diisopropylamine into a transition state that does not react with the product, thus avoiding the generation of a large number of impurities by the reaction of excess diisopropylamine with the product. (2) The present invention creatively introduces a combination of reducing agent and inert conversion reagent, avoiding the problem of impurities that still occur when using palladium-based catalytic hydrogenation reduction.

Claims

1. A process for the preparation of a fesoxodol intermediate, characterized in that A nonsofodine intermediate is prepared from 6-(hydroxymethyl)-4-phenyl chroman-2-ol and diisopropylamine, comprising the following steps: (1) under nitrogen protection, a reaction solvent and 6-(hydroxymethyl)-4-phenyl chroman-2-ol are added into a reaction container, an excess of diisopropylamine is added, and the system is incubated and controlled at 20-50℃ for 1-3h; (2) an inert conversion reagent is added into the reaction container for inert conversion reaction, and incubation and stirring are performed for 2-5h; (3) a reducing agent is slowly added into the reaction system under temperature control of 20-50℃, and the reaction system is incubated and stirred for 10-20h; (4) under temperature control of below 40℃, purified water is added into the reaction system to quench the reaction; an extraction solvent is added, the system is stirred, adjusted to neutral, and allowed to stand to separate into layers, washed with water, and concentrated under reduced pressure to obtain a concentrate; (5) the concentrate is heated to product dissolution using a crystallization solvent, the system is cooled to 10-20℃ for filtration, and dried to obtain a nonsofodine intermediate.

2. The method of claim 1, wherein The reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

3. The method for preparing non-sodrodin intermediates according to claim 1, characterized in that... The molar ratio of 6-(hydroxymethyl)-4-phenyl chroman-2-ol to diisopropylamine is 1:2-4.

4. The method of claim 1, wherein The inert conversion reagent is one of acetic acid, butyric acid and propionic acid.

5. The method for preparing the non-sodrodin intermediate according to claim 4, characterized in that... The molar ratio of 6-(hydroxymethyl)-4-phenyl chroman-2-ol to inert conversion reagent is 1:1-1.

5.

6. The method of claim 1, wherein The reducing agent is one or a mixture of two of sodium triacetoxyborohydride, sodium borohydride, sodium trimethoxyborohydride and tetramethyl triammonium.

7. The method for preparing non-sodrodin intermediates according to claim 6, characterized in that... The molar ratio of 6-(hydroxymethyl)-4-phenyl chroman-2-ol to reducing agent is 1:2-4.

8. The method of claim 1, wherein The extraction solvent is one of ethyl acetate, isopropyl acetate and toluene.

9. The method of claim 1, wherein The crystallization solvent is one or a mixture of two or more of ethyl acetate, tetrahydrofuran, toluene and acetonitrile.

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