Preparation process of high-purity deuterated dihydrodibenzothiazepine compound

Abstract

The invention belongs to the field of drug synthesis, and particularly relates to a preparation process of a high-purity deuterated dihydrodibenzothiazepine compound. Adding the compound II into a solvent, adding alkali to react with perdeuterated ethanol, and performing post-treatment to obtain a compound III; adding the compound III and the compound IV into a solvent, adding a catalyst and an acid-binding agent, and after the reaction is completed, crystallizing and filtering to obtain a compound I crude product; and refining to obtain a compound I finished product. The reaction equation is shown in the specification. According to the invention, perdeuterated ethanol which is common in the market is adopted for production, and impurities are controlled within a reasonable range by adjusting the production process and conditions, so that the product purity is greatly improved, and the quality requirement of a preparation is met; the method is simple in process, convenient to operate, suitable for industrial production and low in cost, and provides a direction for production of raw material medicines of the deuterated dihydrodibenzothiazepine compound.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a preparation process for high-purity deuterated dihydrodibenzothiopyroxene compounds. Background Technology

[0002] Deuterated dihydrodibenzothiophene compounds possess excellent cap-dependent endonuclease activity and superior pharmacokinetic properties, making them suitable for the treatment and / or prevention of symptoms caused by influenza virus infection. Their pharmacokinetic and anti-influenza efficacy are significantly superior to mabaloxavir, indicating substantial future market potential.

[0003] The chemical structural formula of the deuterated dihydrodibenzothiopyroxene compound is shown below: Chinese patent CN116284048B discloses a method for preparing deuterated dihydrodibenzothiopyroxene compounds, the synthetic route of which is as follows: The preparation of high-purity deuterated dihydrodibenzothiophene compounds requires per-deuterated ethanol as a starting material, and the purity of per-deuterated ethanol directly affects the quality of the product. However, commercially available per-deuterated ethanol currently contains impurities such as deuterated methanol and incompletely deuterated ethanol. The per-deuterated methanol content in commercially available per-deuterated ethanol is currently 0.10%~0.50%, with an isotopic abundance of 99.0%~99.50%. Products prepared from per-deuterated ethanol of this quality standard will result in excessive impurities. The product obtained by the above process has a purity of less than 98%, and the chemical structural formulas of the main impurities involved are shown below: In this process, R1, R2, R3, R4, and R5 are each hydrogen or deuterium, with at least one being hydrogen. The quality of the deuterated dihydrodibenzothiopyroxene compound obtained by the above process cannot meet the requirements of the active pharmaceutical ingredient. The main impurities are a series of incompletely deuterated impurities, which are difficult to remove during the process, resulting in low product purity (product purity is less than 98.5%, with impurity V accounting for approximately 0.5-0.8%). Summary of the Invention

[0004] To overcome the shortcomings of existing technologies, the purpose of this invention is to provide a preparation process for high-purity deuterated dihydrodibenzothiopyroxene compounds. This process utilizes commercially available fully deuterated ethanol, significantly improving product purity and ensuring compliance with formulation quality requirements. The process is simple, easy to operate, suitable for industrial production, and low in cost, providing a direction for the production of deuterated dihydrodibenzothiopyroxene compounds as active pharmaceutical ingredients.

[0005] This invention provides a process for preparing high-purity deuterated dihydrodibenzothiophene compounds, comprising the following steps: Step S1: Compound II is added to a solvent, followed by the addition of a base and deuterated ethanol. The reaction proceeds, and after post-treatment, compound III is obtained. Step S2: Add compound III and compound IV to a solvent, add a catalyst and an acid-binding agent, and after the reaction is complete, add a crystallization solvent to crystallize, and filter to obtain crude compound I; Step S3: The crude compound I is purified to obtain the finished compound I; The reaction equation is as follows: .

[0006] Preferably, in step S1, the solvent is a mixture of dichloromethane and acetonitrile; the mass ratio of dichloromethane to acetonitrile is 10:1 to 3:1; the base in step S1 is a mixture of pyridine and benzylamine, with a mass ratio of pyridine to benzylamine of 1.2:0.1 to 0.8:0.3. During the experimental process, it was found that if dichloromethane is used as the solvent in step S1, post-processing is more convenient, but the reaction rate is not fast enough and the yield is not high enough. Adding a certain proportion of acetonitrile results in a faster reaction rate, fewer impurities, and a higher yield, without affecting post-processing. However, if only acetonitrile is used as the solvent, impurities are present, and post-processing is difficult. Furthermore, during the experiment, it was found that if pyridine was used as the base, the reaction was mild and helped to reduce impurities in the reaction process, but some raw materials did not react completely, resulting in a low conversion rate. If benzylamine was used as the base, the reaction was rapid and the raw materials reacted more thoroughly, but the impurities were higher, affecting product quality. After multiple experiments, we added pyridine and benzylamine together in the above ratio for the reaction, which shortened the reaction time, ensured the complete reaction of the raw materials, produced fewer impurities, and improved product quality.

[0007] Preferably, the post-treatment in step S1 involves acid hydrolysis with hydrochloric acid or sulfuric acid followed by drying, filtration, and concentration, wherein the amount of acid used is 0.5-1.5% of the molar amount of compound II. Experiments of this invention have shown that after treatment with the above-mentioned acid, the deuterated methanol and other deuterated impurities related to compound III are hydrolyzed into the corresponding alcohols and carboxylic acids, which are then dissolved in water for removal, reducing the formation of impurities V and VI in subsequent products.

[0008] Preferably, step S1 is as follows: using dichloromethane and acetonitrile as solvents, add compound II, cool to -5~5℃, add deuterated ethanol dropwise, and after the addition is complete, add pyridine and benzylamine dropwise, maintaining the temperature at -5~5℃ throughout the process. After the addition is complete, keep the reaction at this temperature for 0.8~1h, then raise the temperature to 20~22℃ and keep the reaction at this temperature for 1.8~2h. After the reaction is complete, quench the reaction with dilute hydrochloric acid or dilute sulfuric acid solution, and stir at 18~20℃ for 1~2h. Then allow the mixture to stand and separate, collect the organic phase, wash with sodium chloride solution, add anhydrous sodium sulfate, stir, filter, and concentrate to obtain compound III.

[0009] Preferably, in step S2, the solvent is a mixed solvent of acetonitrile and N,N-dimethylacetamide, with a volume ratio of acetonitrile to N,N-dimethylacetamide of 10:1 to 3:1; the catalyst in step S2 is one or more of sodium iodide, potassium iodide, sodium bromide, or potassium bromide, preferably potassium iodide or sodium iodide; preferably, the acid-binding agent in step S2 is cesium carbonate and potassium carbonate, with an amount of cesium carbonate:potassium carbonate = 0.1:1.0 to 0.3:0.8 times the mass of compound III. This invention found that using N,N-dimethylacetamide and acetonitrile as a mixed solvent results in a faster reaction rate and fewer impurities compared to other single solvents. During experiments, it was found that using potassium carbonate as a base resulted in a long reaction time and incomplete reaction of the raw materials; while using cesium carbonate as a base was more expensive, produced more impurities, and resulted in a poor product color. This invention, following the above ratio, first adds potassium carbonate for reaction, and then adds cesium carbonate after a period of reaction, resulting in a more complete reaction, higher yield, and improved product yield and quality.

[0010] Preferably, the crystallization solvent in step S2 is sodium sulfite or sodium bisulfite solution, with sodium sulfite solution being preferred. The amount of crystallization solvent used is 1.0 to 1.5 times the molar equivalent of compound III. During the experimental process, it was discovered that iodide impurities were present in the product from this step, affecting its appearance and color. Treatment with sodium sulfite or sodium bisulfite solution reduces the iodide impurities to elemental iodine, which is then removed by washing with water. This not only removes excess impurities and improves product purity but also achieves a decolorization effect, eliminating the need for the activated carbon decolorization step.

[0011] Preferably, step S2 is as follows: using N,N-dimethylacetamide and acetonitrile as solvents, add compound III, sodium iodide, and potassium carbonate, heat to 48-50°C, maintain the temperature for 11-12 hours, then add cesium carbonate, continue the reaction for 1.8-2 hours, after the reaction is completed, cool to 0-10°C, slowly add sodium sulfite solution, after the addition is complete, maintain the temperature and stir for 1.8-2 hours, filter, and dry to obtain crude compound I.

[0012] Preferably, the refining process in step S3 is one of the following methods: (1) The crude compound I is dissolved in one or more solvents selected from acetone, acetonitrile, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. It is preferred to dissolve and crystallize the compound I in acetone or methanol. Then, purified water is slowly added dropwise to crystallize the compound I. After filtration and drying, the compound I product is obtained.

[0013] (2) The crude compound I is dissolved in one or more solvents selected from acetone, acetonitrile, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. A small amount of alkaline solution is then added for washing, followed by slow dropwise addition of purified water to crystallize. After filtration and drying, the final product, compound I, is obtained. The alkaline solution refers to one or more aqueous solutions of potassium carbonate, sodium hydroxide, and lithium hydroxide, preferably sodium hydroxide or lithium hydroxide. Experiments in this invention have shown that after washing with alkaline solution, impurities V and VI are preferentially hydrolyzed and removed by the mother liquor. The purity of the product obtained after alkaline washing can reach over 99.8%.

[0014] (3) The crude compound I is dissolved in one or more solvents selected from acetone, acetonitrile, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably acetone, acetonitrile, or methanol. Then, ethyl acetate or isopropyl acetate is added, followed by slow dropwise addition of purified water to crystallize the product. After filtration and drying, the finished compound I is obtained. Experiments in this invention have shown that after adding ethyl acetate or isopropyl acetate, small amounts of impurities V and VI in the solvent dissolve in the ethyl acetate and isopropyl acetate, and are carried away by the mother liquor after filtration, resulting in a product purity of over 99.5%.

[0015] (4) Add the crude compound I to one or more solvents selected from ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, tetrahydrofuran, methyl tert-butyl ether, and cyclohexane, preferably ethyl acetate and cyclohexane. Under the preferred solvent, it can be guaranteed to meet the quality requirements of the preparation (purity requirement ≥99.0%, impurity V content <0.5%, impurity VI content ≤0.1%, and have a high yield). After pulping, filtering, and drying, the finished compound I is obtained.

[0016] All four preparation methods can guarantee that the formulation quality requirements are met (purity ≥ 99.0%, impurity V content < 0.5%, impurity VI content ≤ 0.1%), and have a high yield. Among them, the second method is the best preparation method.

[0017] Compared with the prior art, the present invention has the following beneficial effects: (1) Since the preparation of high-purity deuterated dihydrodibenzothiophene compounds requires the use of fully deuterated ethanol as a starting material, the purity of fully deuterated ethanol directly affects the quality of the product. Currently, the commonly available fully deuterated ethanol contains impurities such as deuterated methanol and incompletely deuterated ethanol. The content of deuterated methanol in the commonly available fully deuterated ethanol is 0.10%~0.50%, and the isotope abundance is 99.0%~99.50%. The preparation of products using fully deuterated ethanol of this quality standard will lead to excessive impurities in the product. If a higher purity fully deuterated ethanol is customized, the price will increase exponentially, and the cost will be too high. Considering the need to control production costs in actual production, this invention uses the commonly available fully deuterated ethanol for production. By adjusting the production process and conditions, the impurities are controlled within a reasonable range, which greatly improves the purity of the product and ensures that the quality requirements of the formulation are met (purity requirement ≥99.0%, impurity V content <0.5%, impurity VI content ≤0.1%).

[0018] (2) This invention provides a variety of production methods for preparing high-purity deuterated dihydrodibenzothiopyroxene compounds. The process is simple, easy to operate, suitable for industrial production, and low in cost, providing a direction for the production of raw materials of deuterated dihydrodibenzothiopyroxene compounds. Attached Figure Description

[0019] Figure 1 Liquid phase diagram of compound I obtained in the example; Figure 2 Mass spectrum of compound I obtained from the example preparation; Figure 3 : The proton NMR spectrum of compound I obtained in the example; Figure 4 Carbon spectrum of compound I obtained from the example. Detailed Implementation

[0020] The present invention will be further illustrated below with specific embodiments. These embodiments are merely illustrative and do not limit the scope of the invention.

[0021] The fully deuterated ethanol used in the specific implementation is a common commercially available fully deuterated ethanol, purchased from Pairui Technology Co., Ltd. Testing showed that it contained 0.10%~0.50% deuterated methanol, with an isotopic abundance of 99.0%~99.50%.

[0022] Example 1: Preparation of Compound III Add 800 ml of dichloromethane and 50 ml of acetonitrile to the reaction flask, then add 100 g of compound II. Cool to -5 to 5 °C, and slowly add 49 g of deuterated ethanol dropwise. After the addition is complete, slowly add 120 g of pyridine and 12 g of benzylamine dropwise, maintaining the temperature at -5 to 5 °C throughout the process. After the addition is complete, keep the reaction at this temperature for 1 h, then raise the temperature to 20 °C and keep the reaction at this temperature for 2 h. After the reaction is complete, slowly add dilute hydrochloric acid solution (50 g of 36% hydrochloric acid + 400 g of purified water) to quench the reaction, and stir at 20 °C for 1 to 2 h. Then allow the mixture to stand and separate the liquids. Collect the organic phase, wash it three times with 3V 10% sodium chloride solution, add 100 g of anhydrous sodium sulfate, stir at 20 °C for 20 to 30 min, filter, and concentrate to obtain compound III with a yield of 95.4% and a purity of 98.0%.

[0023] Example 2: Preparation of crude compound I Add 400 ml of N,N-dimethylacetamide and 50 ml of acetonitrile to a reaction flask, then add 100 g of compound III, 5 g of sodium iodide, and 100 g of potassium carbonate. Heat to 50 °C and maintain the temperature for 12 h. Then add 10 g of cesium carbonate and continue the reaction for 2 h. The remaining starting material is 0.3%. After the reaction is complete, cool to 0-10 °C and slowly add sodium sulfite solution (50 g sodium sulfite + 1500 g purified water). After the addition is complete, keep the mixture warm and stir for 2 h. After filtration and drying, obtain the crude white compound I with a yield of 93.9% and a purity of 98.5%.

[0024] Example 3 Preparation of Compound I as a Finished Product Add 700 ml of acetone and 100 g of crude compound I to a reaction flask. Heat to 50 °C to dissolve the compound, then cool to 40 °C and slowly add 1500 g of purified water dropwise. After the addition is complete, keep the mixture warm and stir for 1 h. Then slowly cool to 0-10 °C and keep the mixture warm to allow crystals to crystallize for 1 h. After filtration and drying, obtain the white compound I product with a yield of 95.1%, a purity of 99.0%, impurity V of 0.28%, and impurity VI of 0.10%.

[0025] Example 4: Preparation of Compound I (finished product) Add 700 ml of acetone to the reaction flask, add 100 g of crude compound I, heat to 50 °C to dissolve, cool to 40 °C, add 50 g of lithium hydroxide solution (containing 10 g of lithium hydroxide), stir for 1 h, then slowly add 1500 g of purified water dropwise. After the addition is complete, keep warm and stir for 1 h, then slowly cool to 0-10 °C and keep warm to crystallize for 1 h. After filtration and drying, obtain the white compound I product. The liquid chromatography, mass spectrum, proton NMR, and carbon NMR spectra of the compound I product prepared in Example 4 are shown below. Figure 1-4 ,pass Figure 1-4This demonstrates that the compound I product was successfully prepared in this embodiment, with high purity, a yield of 95.3%, a purity of 99.8%, impurity V of 0.05%, and impurity VI of 0.01%.

[0026] Example 5: Preparation of Compound I (finished product) Add 700 ml of acetone and 100 g of crude compound I to a reaction flask. Heat to 50 °C to dissolve the compound, then cool to 40 °C and add 100 ml of ethyl acetate. Then slowly add 1500 g of purified water dropwise. After the addition is complete, keep the mixture warm and stir for 1 h. Then slowly cool to 0-10 °C and keep the mixture warm to allow crystals to precipitate for 1 h. After filtration and drying, obtain the white compound I product with a yield of 88.6%, a purity of 99.5%, impurity V of 0.19%, and impurity VI of 0.06%.

[0027] Example 6 Preparation of Compound I as a Finished Product Add 800 ml of ethyl acetate and 200 ml of cyclohexane to the reaction flask, add 100 g of crude compound I, heat to 50 °C and stir for 1 h, then slowly cool to 0-10 °C and keep warm to allow crystallization to occur for 1 h. After filtration and drying, obtain white compound I product with a yield of 85.0%, purity of 99.7%, impurity V of 0.08%, and impurity VI of 0.02%.

[0028] Comparative Example 1 Preparation of compound III: Comparative Example 1 is basically the same as Example 1, except that 120g of pyridine and 12g of benzylamine are replaced with 132g of pyridine.

[0029] Results: The reaction was incomplete, with many impurities, and compound III was obtained with a yield of 85.6% and a purity of 95.5%.

[0030] Comparative Example 2 Preparation of compound III: Comparative Example 2 is basically the same as Example 1, except that 800 ml of dichloromethane and 50 ml of acetonitrile are replaced with 850 ml of dichloromethane.

[0031] Results: Compound III was obtained in 87.1% yield and 97.5% purity.

[0032] Comparative Example 3 Preparation of crude compound I: Comparative Example 3 is basically the same as Example 2, except that 10g of cesium carbonate is replaced with 10g of potassium carbonate.

[0033] Results: After 20 hours of reaction, 1.5% of the raw material remained in the reaction solution, and the reaction ended. The subsequent processing was the same as in Example 2, and the crude product of compound I was finally obtained with a yield of 87.76% and a purity of 95.9%.

[0034] Comparative Example 4 Preparation of crude compound I: Comparative Example 4 is basically the same as Example 2, except that the sodium sulfite solution is replaced with purified water.

[0035] Results: The crude product of compound I was finally obtained with a yield of 94.1% and a purity of 97.6%. The product was light yellow in color and contained residual iodine ions.

[0036] Comparative Example 5 Preparation of Compound I product: Comparative Example 5 is basically the same as Example 4, except that lithium hydroxide is replaced with potassium hydroxide.

[0037] Results: White compound I was obtained with a yield of 87.5% and a purity of 98.4%. Impurity V was 0.58% and impurity VI was 0.31%.

[0038] Comparative Example 6 Preparation of Compound I product: Comparative Example 6 is basically the same as Example 6, except that ethyl acetate is replaced with tetrahydrofuran.

[0039] Results: White compound I was obtained with a yield of 65.2% and a purity of 99.8%. Impurity V was 0.01%, and impurity VI was not detected.

Claims

1. A process for preparing high-purity deuterated dihydrodibenzothiophene compounds, characterized in that, Includes the following steps: Step S1: Compound II is added to a solvent, followed by the addition of a base and deuterated ethanol. The reaction proceeds, and after post-treatment, compound III is obtained. Step S2: Add compound III and compound IV to a solvent, add a catalyst and an acid-binding agent, and after the reaction is complete, add a crystallization solvent to crystallize, and filter to obtain crude compound I; Step S3: The crude compound I is purified to obtain the finished compound I; The reaction equation is as follows: 。 2. The preparation process of the high-purity deuterated dihydrodibenzothiophene compound according to claim 1, characterized in that: In step S1, the solvent is a mixture of dichloromethane and acetonitrile, with a mass ratio of 10:1 to 3:1; in step S1, the base is a mixture of pyridine and benzylamine, with a mass ratio of pyridine to benzylamine of 1.2:0.1 to 0.8:0.

3.

3. The preparation process of the high-purity deuterated dihydrodibenzothiophene compound according to claim 1, characterized in that: In step S1, the post-treatment involves acid hydrolysis with hydrochloric acid or sulfuric acid followed by drying, filtration, and concentration. The amount of acid used is 0.5-1.5% of the molar amount of compound II.

4. The preparation process of the high-purity deuterated dihydrodibenzothiopyroxene compound according to any one of claims 1-3, characterized in that: Step S1 is as follows: Using dichloromethane and acetonitrile as solvents, add compound II, cool to -5~5℃, add deuterated ethanol dropwise, and after the addition is complete, add pyridine and benzylamine dropwise, maintaining the temperature at -5~5℃ throughout the process. After the addition is complete, keep the reaction at this temperature for 0.8~1h, then raise the temperature to 20~22℃ and keep the reaction at this temperature for 1.8~2h. After the reaction is complete, quench the reaction with dilute hydrochloric acid or dilute sulfuric acid solution, and stir at 18~20℃ for 1~2h. Then allow the mixture to stand and separate, collect the organic phase, wash with sodium chloride solution, add anhydrous sodium sulfate, stir, filter, and concentrate to obtain compound III.

5. The preparation process of the high-purity deuterated dihydrodibenzothiophene compound according to claim 1, characterized in that: In step S2, the solvent is a mixture of acetonitrile and N,N-dimethylacetamide, with a volume ratio of acetonitrile to N,N-dimethylacetamide of 10:1 to 3:1; the catalyst in step S2 is one or more of sodium iodide, potassium iodide, sodium bromide, or potassium bromide; the acid-binding agent in step S2 is cesium carbonate and potassium carbonate, with the amount of acid-binding agent being cesium carbonate:potassium carbonate = 0.1:1.0 to 0.3:0.8 times the mass of compound III.

6. The preparation process of the high-purity deuterated dihydrodibenzothiophene compound according to claim 1, characterized in that: In step S2, the crystallization solvent is sodium sulfite or sodium bisulfite solution, and the amount of crystallization solvent used is 1.0 to 1.5 times the molar equivalent of compound III.

7. The preparation process of high-purity deuterated dihydrodibenzothiophene compounds according to claim 5 or 6, characterized in that: Step S2 is as follows: Using N,N-dimethylacetamide and acetonitrile as solvents, add compound III, sodium iodide and potassium carbonate, heat to 48~50℃, keep the temperature for 11~12h, then add cesium carbonate, continue the reaction for 1.8~2h, after the reaction is completed, cool to 0~10℃, slowly add sodium sulfite solution, after the addition is complete, keep the temperature and stir for 1.8~2h, filter and dry to obtain crude compound I.

8. The preparation process of the high-purity deuterated dihydrodibenzothiophene compound according to claim 1, characterized in that: The refining process described in step S3 employs one of the following methods: (1) The crude compound I is dissolved in one or more solvents selected from acetone, acetonitrile, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. Then purified water is slowly added dropwise to crystallize the product. After filtration and drying, the finished compound I is obtained. (2) The crude compound I is dissolved in one or more solvents selected from acetone, acetonitrile, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. Then, an alkaline solution is added for washing. Then, purified water is slowly added dropwise to crystallize the product. After filtration and drying, the finished compound I is obtained. (3) Dissolve the crude compound I in one or more solvents selected from acetone, acetonitrile, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, then add ethyl acetate or isopropyl acetate, and slowly add purified water to crystallize the product. After filtration and drying, the finished compound I is obtained. (4) Add the crude compound I to one or more solvents selected from ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, tetrahydrofuran, methyl tert-butyl ether, and cyclohexane, and perform pulping treatment. After filtration and drying, the finished compound I is obtained.

9. The preparation process of the high-purity deuterated dihydrodibenzothiophene compound according to claim 1, characterized in that: In method (2), the alkaline solution is one or more aqueous solutions of potassium carbonate, sodium hydroxide, and lithium hydroxide.

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