A chiral decomposition method for Boisstein

Abstract

This invention relates to a chiral resolution method for brivacertan, comprising the following steps: 1) in a solvent, compound (R,S)-2-((R)-2-oxo-4-propylpyrrolidine-1-yl)butyramide of formula 2 is co-crystallized with D-tartaric acid to obtain compound 3; 2) compound 3 is alkali-free to obtain compound 1; 3) the other diastereomer of formula 4 from step 1) is epimerized under the action of alkali to obtain compound 2, which is then used for the preparation of compound 1. This method allows for the simple separation of brivacertan from its diastereomers, thereby obtaining high-purity brivacertan.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals and relates to a chiral resolution method for brivacertan, specifically a chiral resolution method for brivacertan and its diastereomer (R)-2-((R)-2-oxo-4-propylpyrrolidine-1-yl)butyramide. Background Technology

[0002] Brivaracetam, chemically known as (S)-2-((R)-2-oxo-4-propylpyrrolidine-1-yl)butyramide, is a third-generation antiepileptic drug developed by UCB in Belgium. Clinically, it is primarily used to treat partial-onset epilepsy in patients aged 16 years and older, as adjunctive therapy with or without secondary generalized seizures. The structural formula of brivaracetam is shown in Formula 1 below.

[0003]

[0004] In the preparation of buvasidan, since buvasidan and its diastereomeric isomer formula 4 have similar physicochemical properties, how to easily and efficiently separate buvasidan from its diastereomeric isomer is the key technology and challenge in the preparation of buvasidan.

[0005]

[0006] The only reported separation and purification method in the literature is column chromatography (see WO2005028435), which uses a chiral stationary phase of chiralpak AD20µm and a mobile phase of n-heptane:ethanol = 45:55. While this method achieves high yields in separating brivacertan from its non-corresponding isomers, the column chromatography procedure is complex and costly, limiting its application to small-scale laboratory preparations and hindering industrial production.

[0007] Therefore, there is an urgent need in this field for a chiral separation method for Boissetan that has a high yield, high product purity, and is easy to operate and industrialize. Summary of the Invention

[0008] To overcome the cumbersome and costly nature of existing chiral resolution methods for buvasidan, and to achieve more economical industrial production using conventional chemical processes, the inventors have developed a simple process. This process involves the co-crystallization of compound (R,S)-2-((R)-2-oxo-4-propylpyrrolidine-1-yl)butyramide of formula 2 with D-tartaric acid to separate buvasidan from its diastereomers. Specifically, this invention employs the following technical solution.

[0009] A chiral decomposition method for Boiscitan includes the following steps:

[0010]

[0011] 1) In a solvent, compound (R,S)-2-((R)-2-oxo-4-propylpyrrolidine-1-yl)butyramide of formula 2 was co-crystallized with D-tartaric acid to obtain compound of formula 3;

[0012] 2) Compound of formula 3 is alkali-free to obtain compound of formula 1;

[0013] 3) In step 1), the other diastereomer of compound 4 is epimerized under the action of a base to obtain compound 2, which is then used to prepare compound 1.

[0014] There are no restrictions on the types of solvents mentioned, and they are conventional organic solvents in the art, such as alkanes, alkenes, alcohols, aldehydes, amines, esters, ethers, ketones, aromatic hydrocarbons, hydrogenated hydrocarbons, terpenes, halogenated hydrocarbons, heterocyclic compounds, nitrogen-containing compounds, and sulfur-containing compounds, etc.

[0015] Preferably, the solvent used in step 1) is selected from one or a mixture of two or more of toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tert-butyl ether, n-heptane, methanol, ethanol, and dichloromethane, with toluene being the preferred solvent; the volume ratio of the solvent used to the mass ratio of the compound of formula 2 is 10-25:1, preferably 15-20:1.

[0016] Preferably, the molar ratio of D-tartaric acid used in step 1) to the compound of formula 2 is 0.5-2:1, more preferably 0.5-0.6:1.

[0017] The reaction temperature in step 1) is 15-100℃, preferably 20-50℃. Specifically, it is carried out as follows: The compound of formula 2 and the solvent are heated to 40-45℃ and stirred until the system is clear. Then, D-tartaric acid is added, and the mixture is kept warm and stirred for 30 min. The temperature is then lowered to 35-40℃ and stirred to induce crystallization for 1 h. The temperature is then lowered to 20-25℃ and stirred for 4 h. The mixture is then filtered and washed to obtain a white solid.

[0018] The alkali mentioned is a conventionally used alkali in this field.

[0019] Preferably, the free base in step 2) is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or a combination thereof, and more preferably sodium hydroxide; the mass molar ratio of the base to the compound of formula 3 is 0.5-3:1; preferably 1-2.5:1; the reaction temperature is 0-100℃, preferably 20-50℃.

[0020] The alkali release in step 2) is carried out as follows: After the compound of formula 3 and water are stirred evenly, sodium hydroxide solution is added at 20-30℃ to adjust the pH value to 6-7. Isopropyl acetate is added and stirred at below 40℃ until the solid is completely dissolved. The mixture is separated. The organic phase is washed with saturated brine and concentrated and dried under reduced pressure to obtain crude buvacertane.

[0021] Preferably, in the epimerization step 3), the base is selected from one or a combination of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide, with sodium tert-butoxide being more preferred; the reaction temperature has a very significant effect on the yield, the reaction temperature is 10-50℃, preferably 20-30℃; the reaction time is 2-10h, preferably 4-6h.

[0022] The post-processing steps 1), 2), and 3) may further include a recrystallization step, which can be performed according to conventional recrystallization methods in the art.

[0023] Compared with existing technologies, step 1) uses D-tartaric acid as a resolving agent. Brivaracetam is separated from the diastereomer by precipitating a cocrystallized compound with D-tartaric acid. The precipitated cocrystallized compound is then freed in alkaline solution to obtain brivaracetam. This separation and purification method avoids the costly column chromatography operation.

[0024] Following the separation process in step 1), in order to reuse the remaining diastereomer, namely compound (R)-2-((R)-2-oxo-4-propylpyrrolidine-1-yl)butyramide of formula 4, the compound of formula 4 is epimerized, so that the diastereomer, after the above treatment, becomes the initial starting material compound of formula 2 for further separation and purification. This cyclical reaction achieves the goal of reducing production costs.

[0025] The buvacertan prepared using the above-described technical solution not only boasts high yield and high purity, but the application of a recycling reaction avoids resource waste and improves atom economy. The entire process route is very simple and significantly reduces production costs, making it suitable for industrial production. Detailed Implementation

[0026] In this document, the term "compound of formula x" is sometimes expressed as "compound shown in formula x" or "compound x", which have the same meaning as can be understood by those skilled in the art.

[0027] The present invention is further illustrated below by way of examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the invention. Various changes or modifications made by those skilled in the art based on the concept of the present invention should fall within the protection scope of the present invention.

[0028] This article involves the addition amount, content and concentration of various substances. Unless otherwise specified, the percentage content mentioned refers to the mass percentage.

[0029] In the embodiments described herein, unless otherwise specified, the temperature generally refers to room temperature (15-30°C).

[0030] Reagents: The organic solvents used in the embodiments of this invention are all industrial grade and can be used directly. All reagents were purchased from Shanghai Suyuan Chemical Co., Ltd.

[0031] Polarimeter model: Rudolph Autopol V;

[0032] MRI scanner models: Bruker Avance HD 600MHz, Bruker Avance III 400MHz;

[0033] Mass spectrometer (LCMS), model: Agilent 6120B, detector: DAD.

[0034] HPLC detection conditions for compound 1: Column: CHIRALPAKAD-H 4.6*250mm 5μm; Column temperature: 20℃; Detection wavelength: 205nm; Mobile phase: n-hexane:isopropanol = 90:10, isocratic elution; Run time: 35min; Injection volume: 20μl; Flow rate: 1.0ml / min.

[0035] Example 1: Preparation of Compound 3

[0036] Add 2.56 L of toluene and 2128 g (0.603 mol) of the compound to a 5 L jacketed reaction flask, heat to 40-45 °C, stir until the system is clear, add 47.97 g (0.320 mol) of D-tartaric acid, keep warm at 40-45 °C and stir for 30 min, cool to 35-40 °C and stir until a solid precipitates, continue stirring to crystallize for 1 h, cool to 20-25 °C and stir for 4 h, filter, wash the filter cake with about 256 ml of toluene to obtain an off-white solid.

[0037] The solid was transferred to a 5L jacketed reaction flask, and 2.30L of toluene was added. The mixture was heated to 95-100℃ and stirred for 30 minutes. After cooling to 60-70℃ and stirring to precipitate the solid, the mixture was stirred for 1 hour. After cooling to 40℃ and stirring for 1 hour, the mixture was further cooled to 20-25℃ and stirred for 4 hours. The mixture was then filtered, and the filter cake was washed with approximately 256ml of toluene. The cake was dried at 50-60℃ (vacuum degree ≥0.095MPa) to constant weight, yielding 92.0g of compound 3, with a yield of 42.1% and a de value of 99.7%.

[0038] Example 2: Preparation of Compound 1

[0039] Add 184 ml of water and 92.0 g (0.254 mol) of compound of formula 3 to a 1 L three-necked flask, stir well, and add sodium hydroxide solution (82 ml of water and 23.37 g of sodium hydroxide) dropwise at 20-30 °C. When the pH of the system is 6-7, stop adding the solution. Add 276 ml of isopropyl acetate and stir at 40 °C or below until the solid is completely dissolved. Separate the liquid from the liquid. Wash the organic phase once with 46 ml of saturated saline solution. Concentrate and dry the organic phase under reduced pressure to obtain crude buvasidan.

[0040] The crude product was transferred to a 100 ml flask, and 69 ml of isopropyl acetate was added. The mixture was heated to reflux, stirred until dissolved, and slowly cooled to 30 °C (1-1.5 h) while stirring for 0.5 h. The mixture was then cooled to 0-5 °C and stirred for 1 h. The mixture was filtered, and the filter cake was washed with 30 ml of isopropyl acetate. The cake was dried at 50-60 °C (vacuum ≥ 0.095 MPa) to constant weight to obtain 49.5 g of buvacertan (formula 1), with a total yield of 38.7%, HPLC purity of 99.9%, melting point of 76.8-77.9 °C, and [α]. D 20 -62.0° (c=1.0g / 100mL, MeOH).

[0041] Example 3 Preparation of Compound 2

[0042] In a 1L single-necked flask, 52.7g of compound of formula 4 and 472ml of isopropanol were added and stirred at room temperature until dissolved. Then, 9.72g of sodium tert-butoxide solid was added, and the mixture was stirred at 20-30℃ for 4 hours. A sample was taken, and the pH was adjusted to 6-7 with 2N hydrochloric acid. HPLC analysis showed that the buvasidan content was greater than 48%. The reaction was stopped, and the reaction solution was concentrated to dryness under reduced pressure at 45℃. Then, 378ml of isopropyl acetate and 95ml of 15% sodium chloride aqueous solution were added and stirred until dissolved. The pH was adjusted to 6-7 with concentrated hydrochloric acid. The organic layer was washed once with 48ml of 15% sodium chloride aqueous solution, and rotary evaporated at 45-50℃ to obtain a white solid.

[0043] The solid was transferred to a 250 ml reaction flask, and 130 ml of isopropyl acetate was added. The mixture was heated to reflux and stirred until dissolved. The temperature was slowly lowered (0.5 °C / min) to 50 °C and maintained at this temperature with stirring for 1 h. The temperature was then further lowered to 0-5 °C and maintained at this temperature with stirring for 1 h. The mixture was filtered, and the filter cake was washed with 86 ml of isopropyl acetate and dried at 50-60 °C to constant weight to obtain 47.6 g of compound 2, with a yield of 90.3% and an HPLC purity of 99.7%.

[0044] Example 4: Preparation of Compound 3

[0045] Add 1.28L of toluene and 2128g (0.603mol) of the compound to a 2.5L jacketed reaction flask, heat to 40-45℃, stir until the system is clear, add 47.97g (0.320mol) of D-tartaric acid, keep warm at 40-45℃ and stir for 30min, cool to 35-40℃ and stir until a solid precipitates, continue stirring to crystallize for 1h, cool to 20-25℃ and stir for 4h, filter, wash the filter cake with about 256ml of toluene to obtain an off-white solid.

[0046] The solid was transferred to a 5L jacketed reaction flask, and 2.30L of toluene was added. The mixture was heated to 95-100℃ and stirred for 30 minutes. After cooling to 60-70℃ and stirring to precipitate the solid, the mixture was stirred for 1 hour. After cooling to 40℃ and stirring for 1 hour, the mixture was further cooled to 20-25℃ and stirred for 4 hours. The mixture was then filtered, and the filter cake was washed with approximately 256ml of toluene. The cake was dried at 50-60℃ to constant weight to obtain 95.0g of compound 3, with a yield of 43.5% and a de value of 98.9%.

[0047] Example 5: Preparation of Compound 1

[0048] Add 184 ml of water and 92.0 g (0.254 mol) of compound of formula 3 to a 1 L three-necked flask, stir well, and add sodium carbonate solution (100 ml of water and 31.0 g of sodium carbonate) dropwise at 20-30 °C. When the pH of the system is 6-7, stop adding the solution. Add 400 ml of isopropyl acetate and stir at 40 °C or below until the solid is completely dissolved. Separate the liquid from the liquid. Wash the organic phase once with 46 ml of saturated saline solution. Concentrate and dry the organic phase under reduced pressure to obtain crude buvasidan.

[0049] The crude product was transferred to a 100 ml flask, and 70 ml of isopropyl acetate was added. The mixture was heated to reflux, stirred until dissolved, and slowly cooled to 30 °C (1-1.5 h) while stirring for 0.5 h. The mixture was then cooled to 0-5 °C and stirred for 1 h. The mixture was filtered, and the filter cake was washed with 30 ml of isopropyl acetate. The cake was dried at 50-60 °C (vacuum ≥ 0.095 MPa) to constant weight to obtain 48.3 g of buvacertan (formula 1), with a total yield of 37.8%, HPLC purity of 99.9%, and melting point of 76.8-78.0 °C.

[0050] Example 6 Preparation of Compound 2

[0051] In a 1L single-necked flask, 52.7g of compound of formula 4 and 472ml of isopropanol were added and stirred at room temperature until dissolved. 4.05g of solid sodium hydroxide was added, and the mixture was stirred at 30-40℃ for 4 hours. A sample was taken, and the pH was adjusted to 6-7 with 2N hydrochloric acid. HPLC analysis showed that the buvasidan content was greater than 48%. The reaction was stopped, and the reaction solution was concentrated to dryness under reduced pressure at 45℃. 378ml of isopropyl acetate and 95ml of 15% sodium chloride aqueous solution were added and stirred until dissolved. The pH was adjusted to 6-7 with concentrated hydrochloric acid. The organic layer was washed once with 48ml of 15% sodium chloride aqueous solution, and rotary evaporated at 45-50℃ to obtain a white solid.

[0052] The solid was transferred to a 250 ml reaction flask, and 130 ml of isopropyl acetate was added. The mixture was heated to reflux and stirred until dissolved. The temperature was slowly lowered (0.5 °C / min) to 50 °C and maintained at this temperature with stirring for 1 h. The temperature was then further lowered to 0-5 °C and maintained at this temperature with stirring for 1 h. The mixture was filtered, and the filter cake was washed with 86 ml of isopropyl acetate and dried at 50-60 °C to constant weight to obtain 46.2 g of compound 2, with a yield of 87.6% and an HPLC purity of 99.5%.

[0053] Example 7 Preparation of Compound 3

[0054] Add 2.56 L of toluene and 2128 g (0.603 mol) of the compound to a 5 L jacketed reaction flask, heat to 40-45 °C, stir until the system is clear, add 89.6 g (0.422 mol) of D-tartaric acid, keep warm at 40-45 °C and stir for 30 min, cool to 35-40 °C and stir until a solid precipitates, continue stirring to precipitate crystals for 1 h, cool to 20-25 °C and stir for 4 h, filter, wash the filter cake with about 256 ml of toluene to obtain an off-white solid.

[0055] The solid was transferred to a 5L jacketed reaction flask, and 2.30L of toluene was added. The mixture was heated to 95-100℃ and stirred for 30 minutes. After cooling to 60-70℃ and stirring to precipitate the solid, the mixture was stirred for 1 hour, cooled to 40℃ and stirred for 1 hour, and then cooled to 20-25℃ and stirred for 4 hours. The mixture was then filtered, and the filter cake was washed with about 256ml of toluene and dried at 50-60℃ to constant weight to obtain 96.6g of compound 3, with a yield of 44.2% and a de value of 97.1%.

[0056] Example 8: Preparation of Compound 1

[0057] Add 184 ml of water and 92 g (0.254 mol) of compound of formula 3 to a 1 L three-necked flask, stir well, and add potassium carbonate aqueous solution (100 ml of water, 40.4 g) dropwise at 20-30 °C. When the pH of the system is 6-7, stop adding the solution. Add 276 ml of isopropyl acetate and stir at 40 °C or below until the solid is completely dissolved. Separate the liquid from the liquid. Wash the organic phase once with 46 ml of saturated saline solution. Concentrate and dry the organic phase under reduced pressure to obtain crude buvasidan.

[0058] The crude product was transferred to a 100 ml flask, 70 ml of isopropyl acetate was added, the mixture was heated to reflux, stirred until dissolved, slowly cooled to 30 °C (1-1.5 h), and kept warm and stirred for 0.5 h. The mixture was then cooled to 0-5 °C, kept warm and stirred for 1 h, filtered, and the filter cake was washed with 30 ml of isopropyl acetate. The mixture was dried at 50-60 °C (vacuum degree ≥0.095 MPa) to constant weight to obtain 48.1 g of compound buvacertan of formula 1, with a total yield of 37.6%, an HPLC purity of 99.8%, and a melting point of 76.8-77.9 °C.

[0059] Example 9 Preparation of Compound 2

[0060] In a 1L single-necked flask, 52.7g of compound of formula 4 and 470ml of isopropanol were added and stirred at room temperature until dissolved. Then, 11.3g of potassium tert-butoxide solid was added, and the mixture was stirred at 20-30℃ for 4 hours. A sample was taken, and the pH was adjusted to 6-7 with 2N hydrochloric acid. HPLC analysis showed that the buvasidan content was greater than 48%. The reaction was stopped, and the reaction solution was concentrated to dryness under reduced pressure at 45℃. Then, 378ml of isopropyl acetate and 95ml of 15% sodium chloride aqueous solution were added and stirred until dissolved. The pH was adjusted to 6-7 with concentrated hydrochloric acid. The organic layer was washed once with 48ml of 15% sodium chloride aqueous solution, and rotary evaporated at 45-50℃ to obtain a white solid.

[0061] The solid was transferred to a 250 ml reaction flask, and 130 ml of isopropyl acetate was added. The mixture was heated to reflux and stirred until dissolved. The temperature was slowly lowered (0.5 °C / min) to 50 °C and maintained at this temperature with stirring for 1 h. The temperature was then further lowered to 0-5 °C and maintained at this temperature with stirring for 1 h. The mixture was filtered, and the filter cake was washed with 86 ml of isopropyl acetate and dried at 50-60 °C to constant weight to obtain 46.9 g of compound 2, with a yield of 89.0% and an HPLC purity of 99.7%.

[0062] To further demonstrate the superior effects of the present invention, the following comparative examples are provided. In the comparative examples, buvacertan cannot form co-crystal compounds with common organic acids such as malic acid, mandelic acid, and glutamic acid. This application uses D-tartaric acid as a resolving agent, which not only enables the preparation of co-crystal compounds of buvacertan and D-tartaric acid but also achieves high yield and purity, making it suitable for large-scale industrial production.

[0063] Preparation of the buvacertane eutectic compound in Comparative Example 1

[0064] 400 ml of toluene and 220.0 g (0.0942 mol) of the compound were added to a 5 L jacketed reaction flask. The temperature was raised to 40-45 °C and stirred until the system was clear. 6.7 g (0.0499 mol) of D-malic acid was added. The mixture was kept at 40-45 °C and stirred for 30 min. The temperature was lowered to 35-40 °C and stirred for 1 h. The temperature was then lowered to 10-15 °C and stirred for 24 h. No solid precipitated from the reaction solution, and a eutectic compound of buvasidan and D-malic acid was not obtained.

[0065] Preparation of the buvacertane eutectic compound in Comparative Example 2

[0066] 400 ml of toluene and 220.0 g (0.0942 mol) of the compound were added to a 5 L jacketed reaction flask. The temperature was raised to 40-45 °C and stirred until the system was clear. 6.7 g (0.0499 mol) of L-malic acid was added. The mixture was kept at 40-45 °C and stirred for 30 min. The temperature was lowered to 35-40 °C and stirred for 1 h. The temperature was lowered to 10-15 °C and stirred for 24 h. No solid precipitated from the reaction solution, and a eutectic compound of buvasidan and L-malic acid was not obtained.

[0067] Preparation of the buvacertane eutectic compound in Comparative Example 3

[0068] Add 400 ml of toluene and 220.0 g (0.0942 mol) of the compound to a 5 L jacketed reaction flask, heat to 40-45 °C, stir until the system is clear, add 7.6 g (0.0499 mol) of D-mandelic acid, keep warm at 40-45 °C and stir for 30 min, cool to 35-40 °C and stir for 1 h, cool to 10-15 °C and stir for 24 h. No solid precipitates from the reaction solution, and no eutectic compound of buvastan and D-mandelic acid is obtained.

[0069] Preparation of the buvacertane eutectic compound in Comparative Example 4

[0070] Add 400 ml of toluene and 220.0 g (0.0942 mol) of the compound to a 5 L jacketed reaction flask, heat to 40-45 °C, stir until the system is clear, add 7.6 g (0.0499 mol) of L-mandelic acid, keep warm at 40-45 °C and stir for 30 min, cool to 35-40 °C and stir for 1 h, cool to 10-15 °C and stir for 24 h. No solid precipitates from the reaction solution, and no eutectic compound of buvastan and L-mandelic acid is obtained.

[0071] Preparation of the buvaciran eutectic compound in Comparative Example 5

[0072] 400 ml of toluene and 220.0 g (0.0942 mol) of the compound were added to a 5 L jacketed reaction flask. The temperature was raised to 40-45 °C and stirred until the system was clear. 7.3 g (0.0499 mol) of D-glutamic acid was added. The mixture was kept at 40-45 °C and stirred for 30 min. The temperature was lowered to 35-40 °C and stirred for 1 h. The temperature was lowered to 10-15 °C and stirred for 24 h. No solid precipitated from the reaction solution, and a co-crystal of brivacertan and D-glutamic acid was not obtained.

[0073] Preparation of the buvacertane eutectic compound in Comparative Example 6

[0074] 400 ml of toluene and 220.0 g (0.0942 mol) of the compound were added to a 5 L jacketed reaction flask. The temperature was raised to 40-45 °C and stirred until the system was clear. 7.3 g (0.0499 mol) of L-glutamic acid was added. The mixture was kept at 40-45 °C and stirred for 30 min. The temperature was lowered to 35-40 °C and stirred for 1 h. The temperature was then lowered to 10-15 °C and stirred for 24 h. No solid precipitated from the reaction solution, and a co-crystal of brivacertan and L-glutamic acid was not obtained.

Claims

1. A chiral resolution method for Boissetan, characterized in that, The following steps are involved: 1) In a solvent, compound (R,S)-2-((R)-2-oxo-4-propylpyrrolidine-1-yl)butyramide of formula 2 was co-crystallized with D-tartaric acid to obtain compound of formula 3; 2) Compound of formula 3 is alkali-free to obtain compound of formula 1; 3) In step 1), the other diastereomer of compound 4 is epimerized under the action of a base to obtain compound 2, which is then used to prepare compound 1.

2. The chiral decomposition method as described in claim 1, characterized in that, The solvent mentioned in step 1) is selected from one or more of the following solvents: toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tert-butyl ether, n-heptane, methanol, ethanol, and dichloromethane; the volume ratio of the solvent used to the mass ratio of the compound of formula 2 is 10-25:

1.

3. The chiral decomposition method as described in claim 2, characterized in that, The solvent used in step 1) is selected from toluene; the volume ratio of the solvent used to the mass ratio of the compound of formula 2 is 15-20:

1.

4. The chiral decomposition method as described in claim 1, characterized in that, The molar ratio of D-tartaric acid used in step 1) to the compound of formula 2 is 0.5-2:1; And / or, the reaction temperature is 15-100℃.

5. The chiral decomposition method as described in claim 1, characterized in that, Step 1) is carried out as follows: Mix the compound of formula 2 with the solvent, heat and stir until the system is clear, then add D-tartaric acid, keep warm and stir, cool down to crystallize, filter and wash.

6. The chiral decomposition method as described in claim 1, characterized in that, The alkali mentioned in step 2) is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or a combination thereof; the mass molar ratio of the alkali to the compound of formula 3 is 0.5-3:

1. And / or, the reaction temperature is 0-100℃.

7. The chiral decomposition method as described in claim 1, characterized in that, The alkali release in step 2) is carried out as follows: After the compound of formula 3 and water are stirred evenly, sodium hydroxide solution is added to adjust the pH value to 6-7, isopropyl acetate is added, and the mixture is stirred until the solid is completely dissolved. The mixture is then separated into liquid and liquid phases. The organic phase is washed with saturated brine and concentrated and dried under reduced pressure to obtain crude buvasidan.

8. The chiral separation method as described in claim 1, characterized in that, The alkali mentioned in step 3) is selected from one or a combination of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide; the reaction temperature is 10-50℃; And / or, the reaction time is 2-10 hours.

9. The chiral separation method as described in claim 8, characterized in that, The reaction temperature described in step 3) is 20-30℃; And / or, the reaction time is 4-6 hours.

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