Key intermediate of sarolaner and preparation method for sarolaner with high chiral purity

Abstract

The present invention provides a key intermediate of sarolaner and a preparation method for sarolaner with high chiral purity, relating to the technical field of pharmaceuticals. The present invention provides a new key intermediate of sarolaner. The intermediate is obtained by means of chiral resolution of compound 5 (an R isomer accounts for 0%-20%), and has the characteristic of high chiral purity. The content of the R-isomer in the product can be effectively reduced during the preparation of sarolaner from the intermediate. The sarolaner prepared by the present invention has the characteristics of high chiral purity, few impurities, and high yield. The preparation method provided by the present invention exhibits simple operations, high yields, low costs, and good purity, and provides technical support for the industrial production of sarolaner.

Description

A key intermediate for saloran and a method for preparing saloran with high chiral purity Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a key intermediate of sarolidine and a method for preparing sarolidine with high chiral purity. Background Technology

[0002] Sarolaner is a novel isoxazoline veterinary drug that acts on γ-aminobutyric acid (GABA) receptors and is a new type of broad-spectrum insecticide. It selectively inhibits GABA receptors and glutamate-gated chloride channels (GluCl) in the parasite's nervous system, leading to loss of control of the parasite's neuromuscular system and ultimately death.

[0003] The chemical name of salorana is [1-(5'-((5S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'-hydrospirocyclic (azacyclobutane-3,10-(2)benzofuran)-1-yl)-2-(methanesulfonyl)ethyl ketone], with the molecular formula C 23 H 18 The molecular structure of Cl2F4N2O5S can be divided into four connected parts: an isoxazoline core, a benzene ring head group, a spirozyzine dibenzofuran, and a methanesulfonyl sulfoxide tail. The R enantiomer of isoxazoline drugs lacks ectoparasitic activity, while saloranar, as the S enantiomer, can be used to control ectoparasites. Adding a 4-substituted fluorine to the 3,5-dichlorobenzene unit significantly enhances the drug's ectoparasitic activity. The spirozyzine dibenzofuran moiety is a special structure that provides rigidity and potency to the molecule. The methanesulfonyl sulfoxide tail increases molecular polarity and maximizes the exposure of the target sites for killing fleas and ticks, enabling rapid killing of these ectoparasites.

[0004] Salorana, developed by Zoetis's Lincoln plant in the United States, was launched in the EU and New Zealand in 2015 and in China in 2020 (product name: Xinchongke). ® (Simparca) ® Used for the prevention and treatment of flea infestations in dogs, and for the treatment and control of tick infestations in dogs.

[0005] Currently, there are two main methods for preparing sarolane:

[0006] (1) Patent document CN103517907B mentions a method for preparing salorana (method one):

[0007]

[0008] (2) Patent document CN104918944B mentions a method for preparing salorana (method two):

[0009]

[0010] The aforementioned prior art has the following defects and problems:

[0011] Method 1: The inventors conducted multiple experiments using Method 1. The prepared compound 6 showed low purity in liquid phase analysis, was difficult to separate into solid and liquid phases, had poor chiral purity, and an ee value of approximately 80%. The prepared sarolane also showed low liquid phase purity and contained a significant amount of the R isomer, with an R isomer content of approximately 1%.

[0012] Method 2: The inventors conducted multiple experiments using Method 2, and the resulting compound 8 showed slightly improved solid-liquid separation, but still suffered from low liquid phase purity and high chiral impurities, with an ee value of approximately 80%. Therefore, the prepared sarolane still had low liquid phase purity and contained a significant amount of R isomers, with an R isomer content of approximately 1%.

[0013]

[0014] Although both Method 1 and Method 2 can yield sarolane, the resulting sarolane suffers from problems such as difficulty in solid-liquid separation, low yield, high product impurities, and high content of R-isomers. Summary of the Invention

[0015] To address the problems of high R-isomer content, low product purity, complex operation process, and low yield in the preparation of sarolanarana using existing technologies, this invention provides a method for preparing sarolanarana and intermediates with high chiral purity. This method is simple to operate, has a high yield, low cost, good purity, and low R-isomer content, making it particularly suitable for industrial production.

[0016] The inventors conducted in-depth analysis and research on the above problems and found that there was no effective process for removing the R-isomer in the previous preparation process of sarolanol. Therefore, this invention patent has prepared a new intermediate with extremely high chiral purity (ee value greater than 99.7%). As a result, the obtained sarolanol has high chiral purity (ee value greater than 99.7%), with few impurities and high yield.

[0017] The chemical formula of the intermediate is:

[0018]

[0019] R represents the resolving agent (including L-p-methyldibenzoyl tartaric acid, L-dibenzoyl tartaric acid, D-p-methyldibenzoyl tartaric acid, D-dibenzoyl tartaric acid, L-p-methoxydibenzoyl tartaric acid, and D-p-methoxydibenzoyl tartaric acid).

[0020] Using this intermediate, the inventors improved the preparation process of sarolana, obtaining sarolana products with high chiral purity and few impurities.

[0021] The reaction route of this invention is as follows:

[0022]

[0023] R represents the resolving agent (including L-p-methyldibenzoyl tartaric acid, L-dibenzoyl tartaric acid, D-p-methyldibenzoyl tartaric acid, D-dibenzoyl tartaric acid, L-p-methoxydibenzoyl tartaric acid, and D-p-methoxydibenzoyl tartaric acid).

[0024]

[0025] The main contents of the technical solution of this invention are as follows:

[0026] (1) A method for preparing a key intermediate of salorana, the specific steps of which are as follows.

[0027] Compound 5 (R isomer content of 0%~20%) was dissolved in a solvent, acid was added to remove the Boc protecting group; after the reaction was completed, sodium hydroxide solution was added, the mixture was stirred and separated, and the organic phase was removed by vacuum concentration; then a polar solvent was added, a resolving agent was added to crystallize, and after filtration and drying, high chiral purity intermediate compound 10 was obtained.

[0028] The solvents for the Boc deprotection reaction include dichloromethane, chloroform, dichloroethane, toluene, methanol, ethanol, isopropanol, and their mixtures, with dichloromethane, methanol, ethanol, and their mixtures being preferred.

[0029] The acid is p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, hydrogen chloride, and concentrated sulfuric acid, etc., preferably p-toluenesulfonic acid or benzenesulfonic acid.

[0030] The reaction time for removing the protecting group is 2 to 24 hours, preferably 6 to 12 hours.

[0031] The polar solvents selected are ethanol, methanol, isopropanol, n-butanol, acetonitrile, tetrahydrofuran, water, and combinations thereof, with ethanol, methanol, acetonitrile, water, or combinations thereof being preferred.

[0032] The resolving agent is selected from L-p-methyldibenzoyl tartaric acid, L-dibenzoyl tartaric acid, D-p-methyldibenzoyl tartaric acid, D-dibenzoyl tartaric acid, L-p-methoxydibenzoyl tartaric acid, and D-p-methoxydibenzoyl tartaric acid, with L-p-methyldibenzoyl tartaric acid and L-dibenzoyl tartaric acid being preferred.

[0033] The amount of polar solvent used is 3 to 20 times.

[0034] The crystallization temperature is 0~40℃.

[0035] (2) A method for preparing saloran with high chiral purity, the specific steps of which are as follows:

[0036] ① Dissolve compound 10 in a solvent, add an alkaline aqueous solution, stir and separate the liquids. Extract the aqueous phase once with an organic solvent, combine the organic phases, and wash the organic phase again with an alkaline aqueous solution. Dry the organic phase to obtain solution A.

[0037] ② Add compound 7 to an organic solvent and add N,N'-carbonyldiimidazole (CDI) in batches. Keep the mixture warm and stir to obtain solution B.

[0038] ③ Add solution A to solution B and stir at a certain temperature for 0.1~24h. After the reaction is complete, stir, separate the liquid, wash, dry, concentrate, and crystallize. Dry to obtain sodium salorane product.

[0039] The alkali in the alkaline aqueous solution refers to an aqueous solution of sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and ammonia, preferably an aqueous solution of sodium carbonate, potassium carbonate, or sodium hydroxide.

[0040] The organic solvent used for extraction refers to dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-butyl methyl ether, preferably ethyl acetate and dichloromethane.

[0041] The organic solvent in which compound 7 is dissolved is dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, isopropyl acetate, or methyl tert-butyl methyl ether, preferably ethyl acetate, tetrahydrofuran, and acetonitrile.

[0042] The reaction temperature is 0~60℃.

[0043] The crystallization solvent for saloranane refers to methanol, ethanol, isopropanol, tert-butanol, n-butanol and other organic alcohols with fewer than 8 carbon atoms, acetone, ethyl acetate, isopropyl acetate, n-heptane, preferably methanol, ethanol, ethyl acetate, isopropyl acetate, n-heptane and combinations thereof.

[0044] The advantages of the preparation method of the present invention are:

[0045] (1) The experimental operation is simple, the reaction conditions are mild, and it is easy to separate and purify, making it suitable for industrial production.

[0046] (2) By chiral separation of the intermediate, the operation is convenient and the content of R configuration in the intermediate can be effectively removed. The ee value of the intermediate compound 10 obtained is more than 99.7%.

[0047] (3) The key intermediate of sarolana (compound 10) has high chiral purity, which can effectively control the chiral purity of sarolana product, making the preparation of sarolana product simpler, more efficient and easier to purify, and the ee value of the final product can reach more than 99.7%. Attached Figure Description

[0048] Figure 1 shows the NMR spectrum of compound 10-a obtained in Example 1.

[0049] Figure 2 shows the NMR spectrum of compound 10-b obtained in Example 2.

[0050] Figure 3 shows the NMR spectrum of the salorana product prepared in Example 10. Detailed Implementation

[0051] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand the present invention. However, this is not a limitation on the scope of protection of the present invention. Based on the technical solution of the present invention, various modifications or variations that can be made by those skilled in the art without creative effort are still within the scope of protection of the present invention. Experimental preparation Step 1: Preparation of compound 4

[0052]

[0053] Compound 4 was prepared according to the method used in Example 28 of CN103517907B.

[0054] 600 g of compound 1, 600 g of compound 2, 1.3 L of toluene, 1.3 L of trifluorotoluene, and 60 g of cesium carbonate were added to a reaction flask. The mixture was heated to 110 °C and stirred for 20 h. After the reaction was complete, the mixture was concentrated under reduced pressure at 50–60 °C to remove the solvent. Then, a mixed solution of n-heptane and methyl tert-butyl ether (95:5) was added. The mixture was heated to 60–70 °C until dissolved, then cooled to 0–5 °C and filtered. The filter cake was washed with 1 L of n-heptane and dried under vacuum at 50–55 °C for 10 h to obtain 1084 g of a pale yellow to off-white solid, with a molar yield of 75%. Step 2: Preparation of compound 5

[0055]

[0056] Compound 5 was prepared according to the method used in Example 29 of CN103517907B.

[0057] 1 kg of compound 4 and 8 L of dichloroethane were added to a reaction flask and stirred to dissolve. The temperature was maintained at -5 to 0 °C. Then, 109 g of N-(acridin-9-ylmethyl)quinine bromide was added to the reaction. 254 g of hydroxylamine (50%) was added dropwise to a sodium hydroxide solution (165 g of sodium hydroxide dissolved in 500 mL of purified water). The mixed solution was added to the reaction, and the temperature was maintained below 5 °C for 4 h. After the reaction was complete, the mixture was washed with 10 L × 2 of purified water, and the organic phase was concentrated to approximately 3 L. Then, 15 L of methyl tert-butyl ether was added, and the mixture was filtered to remove insoluble matter. The filtrate was then concentrated to approximately 3 L, cooled to 0 °C, stirred to induce crystallization, and filtered to obtain a pale yellow solid, 929 g, with a molar yield of 90.40% and an R isomer content of 20%. Example 1

[0058]

[0059] Add 50g of compound 5 (obtained in experimental preparation step 2), 30.68g of p-toluenesulfonic acid, 500mL of dichloromethane, and 25mL of ethanol to a reaction flask, turn on the heater, and raise the temperature to 40℃. Maintain the temperature for 12h. After the reaction is complete, add sodium hydroxide solution (10.70g sodium hydroxide, 200mL purified water) and stir for 1h. Allow to stand and separate the liquids. Extract the aqueous phase again with 250mL of dichloromethane. Combine the organic phases, concentrate under reduced pressure, and evaporate the dichloromethane. Add 410mL of acetonitrile, 125mL of anhydrous ethanol, and 34.4g of L-p-methylbenzoyl tartaric acid to the concentrated residue and heat to 70-75℃ to dissolve. Then cool to 50-55℃ and continue stirring at 50-55℃ for 2h. Cool to 0-10℃. The mixture was filtered, and the filter cake was washed with 50 mL of acetonitrile. Then, 330 mL of acetonitrile and 110 mL of anhydrous ethanol were added, and the mixture was heated to 70-75 °C to dissolve. The temperature was then lowered to 50-55 °C, and then to 0-10 °C. The mixture was filtered again, and the filter cake was washed with 40 mL of acetonitrile. After drying, 52 g of compound 10-a was obtained as a white crystalline solid, with a molar yield of 68.90% and an ee value of 99.8%. 1 H NMR, 600MHz (D6-DMSO) δppm: 10.10(s,2H), 7.92(d,1H), 7.85(d,4H), 7.82(d,2H), 7.68(d,1H), 7.66(s,1H), 7.30(d,4H), 5.68(s,2H), 5.06(s,2H), 4.33(d,2H), 4.23-4.27(m,4H), 2.35(s,6H), 2.08(s,1H). Example 2

[0060]

[0061] Add 40g of compound 5 (obtained in experimental preparation step 2), 22.50g of benzenesulfonic acid, 400mL of dichloromethane, and 20mL of methanol to a reaction flask, and heat to 35-40℃. Maintain the temperature for 12 hours. After the reaction is complete, add sodium hydroxide solution (8.54g of sodium hydroxide dissolved in 160mL of purified water) and maintain the temperature at 35-40℃ with stirring for 1 hour. Allow to stand and separate the liquids. Extract the aqueous phase again with 200mL of dichloromethane. Combine the organic phases, concentrate under reduced pressure, and remove the dichloromethane by evaporation. Add 320mL of methanol and 25.50g of L-benzoyl tartaric acid to the concentrated residue, heat to 65℃, stir to dissolve, and continue stirring at 60-65℃ for 3 hours. A large amount of solid precipitates. Then cool to 0-10℃. Filter, mix the filter cake with 200mL of methanol, heat to 60-65℃, and then cool to 0-10℃. The mixture was filtered, the filter cake was washed with 50 mL of methanol, and dried to give compound 10-b, 41 g of white solid, with a molar yield of 70.21% and an ee value of 99.8%. 1 H NMR, 600MHz (D6-DMSO) δppm: 10.05(s,2H), 7.97(d,4H), 7.93(d,1H), 7.82(d,2H), 7.69(d,1H), 7.66(s,1H), 7.37(t,2H), 7.51(t,4H), 5.73(s,2H), 5.06(s,2H), 4.33(d,2H), 4.23-4.29(m,4H). Example 3

[0062]

[0063] 40.0 g of compound 5 (obtained in experimental preparation step 2), 24.5 g of p-toluenesulfonic acid, 400 mL of dichloromethane, and 20 mL of ethanol were added to a reaction flask, and the temperature was raised to 35-40 °C. The reaction was maintained at this temperature for 12 h. After the reaction was complete, sodium hydroxide solution (8.54 g of sodium hydroxide dissolved in 160 mL of purified water) was added, and the mixture was stirred at 35-40 °C for 1 h. The mixture was allowed to stand and separated. The aqueous phase was extracted again with 200 mL of dichloromethane. The organic phases were combined, concentrated under reduced pressure, and the dichloromethane was removed by evaporation. 320 mL of ethanol and 30.0 g of L-p-methoxydibenzoyl tartaric acid were added to the concentrated residue, and the temperature was raised to 65 °C. The mixture was stirred to dissolve the solid, and the mixture was stirred at 60-65 °C for another 5 h, resulting in the precipitation of a large amount of solid. The temperature was then lowered to 0-10 °C. The filter cake was washed with 50 mL of ethanol and dried to give compound 10-c, a white solid of 41 g, with a molar yield of 70.21%. Example 4

[0064]

[0065] 10.0 g of compound 5 (obtained in experimental preparation step 2), 5.7 g of benzenesulfonic acid, 100 mL of dichloromethane, and 5 mL of methanol were added to a reaction flask, and the temperature was raised to 35–40 °C. The reaction was maintained at this temperature for 14 h. After the reaction was complete, sodium hydroxide solution (4.2 g of sodium hydroxide dissolved in 40 mL of purified water) was added, and the mixture was stirred at 35–40 °C for 1.5 h. The mixture was allowed to stand and separated. The aqueous phase was extracted again with 50 mL of dichloromethane. The organic phases were combined, concentrated under reduced pressure, and the dichloromethane was evaporated. 160 mL of methanol and 6.89 g of D-p-methylbenzoyl tartaric acid were added to the concentrated residue, and the temperature was raised to 60 °C, then lowered to 0–10 °C. The mixture was filtered, and the filter cake was washed with 20 mL of methanol and dried to give compound 10-d, a white solid of 9.25 g, with a molar yield of 61.27% and an ee value of 99.7%. Example 5

[0066]

[0067] 10.0 g of compound 5 (obtained in experimental preparation step 2), 5.7 g of benzenesulfonic acid, 100 mL of dichloromethane, and 5 mL of methanol were added to a reaction flask, and the temperature was raised to 35–40 °C. The reaction was maintained at this temperature for 16 h. After the reaction was complete, sodium hydroxide solution (4.2 g of sodium hydroxide dissolved in 40 mL of purified water) was added, and the mixture was stirred at 35–40 °C for 0.5 h. The mixture was allowed to stand and separated. The aqueous phase was extracted again with 50 mL of dichloromethane. The organic phases were combined, concentrated under reduced pressure, and the dichloromethane was evaporated. 60 mL of acetonitrile and 6.4 g of D-dibenzoyl tartaric acid were added to the concentrated residue, and the temperature was raised to 70 °C, then lowered to 0–10 °C. The mixture was filtered, and the filter cake was washed with 10 mL of acetonitrile and dried to give compound 10-e, a white solid of 8.21 g, with a molar yield of 56.26% and an ee value of 99.7%. Example 6

[0068]

[0069] 10.0 g of compound 5 (obtained in experimental preparation step 2), 5.7 g of benzenesulfonic acid, 100 mL of dichloromethane, and 5 mL of methanol were added to a reaction flask, and the temperature was raised to 35-40 °C. The reaction was maintained at this temperature for 12 h. After the reaction was complete, sodium hydroxide solution (4.2 g of sodium hydroxide dissolved in 40 mL of purified water) was added, and the mixture was stirred at 35-40 °C for 1 h. The mixture was allowed to stand and separated. The aqueous phase was extracted again with 50 mL of dichloromethane. The organic phases were combined, concentrated under reduced pressure, and the dichloromethane was removed by evaporation. 160 mL of methanol and 7.46 g of D-p-methoxydibenzoyl tartaric acid were added to the concentrated residue, and the temperature was raised to 65 °C, then lowered to 0-10 °C. The mixture was filtered, and the filter cake was washed with 20 mL of methanol and dried to give compound 10-f, a white solid of 9.26 g, with a molar yield of 59.12% and an ee value of 99.8%. Example 7

[0070]

[0071] Add 8.00 g of compound 10-a and 80 mL of dichloromethane to a reaction flask. Dissolve 3.91 g of potassium carbonate in 80 mL of purified water and add it to the reaction flask. Incubate at 35–40 °C with stirring for 1 h, then allow to stand and separate the phases. Extract the aqueous phase once more with 40 mL of dichloromethane and combine the organic phases. Wash the organic phase three times with 10% sodium hydroxide solution. Dry the organic phase with anhydrous magnesium sulfate and filter to obtain solution A.

[0072] Add 2.61 g of compound 7 and 40 mL of dichloromethane to a reaction flask, heat to 35–40 °C, stir to dissolve, then add 2.15 g of CDI in portions, and maintain the reaction at 35–40 °C for 3 hours. Then add solution A to the reaction mixture and maintain the temperature. After the reaction is complete, add 40 mL of purified water, stir and separate the layers; add 40 mL of sodium chloride aqueous solution, stir and separate the layers. Dry the organic phase with anhydrous magnesium sulfate, filter and concentrate.

[0073] After concentration, 48 mL of a mixed solvent of anhydrous ethanol / n-heptane / ethyl acetate (44% / 50% / 6%, V / V / V) was added. The mixture was heated to 50-60°C and stirred to dissolve. Then, the temperature was lowered to 0-10°C, then raised to 25-35°C and stirred while maintaining the temperature. Finally, the temperature was lowered to 0-10°C, filtered, and dried to obtain salorana, a white solid, 3.55 g, with a molar yield of 64.70% and an ee value of 99.7%. Example 8

[0074]

[0075] Add 8.00 g of compound 10-a and 80 mL of dichloromethane to a reaction flask. Dissolve 3.91 g of potassium carbonate in 80 mL of purified water and add it to the reaction flask. Incubate at 35–40 °C with stirring for 1 h, then allow to stand and separate the liquids. Extract the aqueous phase once more with 40 mL of dichloromethane and combine the organic phases. Wash the organic phase three times with 10% sodium hydroxide solution. Dry the organic phase with anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and after concentration, add 40 mL of ethyl acetate and stir to obtain solution A.

[0076] Add 2.61 g of compound 7 and 40 mL of ethyl acetate to a reaction flask, heat to 35–40 °C, stir to dissolve, then add 2.15 g of CDI in portions, and maintain the reaction temperature at 10–30 °C for 4 hours. Then add solution A to the reaction mixture and maintain the temperature. After the reaction is complete, add 40 mL of purified water, stir and separate the layers; add 40 mL of sodium chloride aqueous solution, stir and separate the layers. Dry the organic phase with anhydrous magnesium sulfate, filter and concentrate.

[0077] After concentration, 35 mL of methanol and 70 mL of isopropanol were added, the temperature was raised to 60-70°C, and the mixture was stirred to dissolve. Then the temperature was lowered to 0-10°C, filtered, washed, and dried to obtain salorana, a white solid, 3.40 g, with a molar yield of 61.96% and an ee value of 99.8%. Example 9

[0078]

[0079] Add 8.00 g of compound 10-b and 80 mL of ethyl acetate to a reaction flask. Dissolve 3.10 g of sodium carbonate in 80 mL of purified water and add it to the reaction flask. Incubate at 35–40 °C with stirring for 0.5 h, then allow to stand and separate the phases. Extract the aqueous phase once more with 40 mL of ethyl acetate and combine the organic phases. Wash the organic phase twice with 10% sodium hydroxide solution. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and after concentration, add 40 mL of acetonitrile and stir to obtain solution A.

[0080] 1.62 g of compound 7 and 40 mL of acetonitrile were added to a reaction flask, heated to 35–40 °C, and stirred to dissolve. Then, 1.90 g of CDI was added in portions, and the reaction was maintained at 45–60 °C for 2 hours. Solution A was then added to the reaction mixture, and the reaction was maintained at this temperature. After the reaction was complete, the acetonitrile was removed by concentration. 80 mL of dichloromethane and 40 mL of purified water were added, and the mixture was stirred and separated. 40 mL of sodium chloride aqueous solution was added, and the mixture was stirred and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.

[0081] After concentration, 24 mL of methanol was added, the temperature was raised to 50-60℃, and the mixture was stirred to dissolve. Then the temperature was lowered to 0-10℃, filtered, washed, and dried to obtain 3.63 g of sarolana, with a molar yield of 63.96% and an ee value of 99.8%. Example 10

[0082]

[0083] Add 8.00 g of compound 10-a and 80 mL of methyl tert-butyl ether to a reaction flask. Dissolve 1.13 g of sodium hydroxide in 80 mL of purified water and add it to the reaction flask. Incubate at 35–40 °C with stirring for 0.5 h, then allow to stand and separate the phases. Extract the aqueous phase once more with 40 mL of methyl tert-butyl ether and combine the organic phases. Wash the organic phase twice with 10% sodium hydroxide solution. Dry the organic phase with anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and after concentration, add 40 mL of tetrahydrofuran and stir to obtain solution A.

[0084] Add 2.61 g of compound 7 and 40 mL of tetrahydrofuran to a reaction flask, heat to 35–40 °C, stir to dissolve, then add 2.15 g of CDI in portions, and maintain the reaction at 35–40 °C for 2 hours. Then add solution A to the reaction mixture and maintain the reaction temperature. After the reaction is complete, concentrate to remove acetonitrile, add 80 mL of ethyl acetate and 40 mL of purified water, stir and separate the layers; add 40 mL of sodium chloride aqueous solution, stir and separate the layers. Dry the organic phase with anhydrous magnesium sulfate, filter and concentrate.

[0085] After concentration, 48 mL of a mixed solvent of anhydrous ethanol / n-heptane / ethyl acetate (44% / 50% / 6%, V / V / V) was added. The mixture was heated to 50-60°C and stirred to dissolve. Then, the temperature was lowered to 0-10°C, then raised to 25-35°C and stirred while maintaining the temperature. Finally, the temperature was lowered to 0-10°C, filtered, and dried to obtain salorana, a white solid, 3.55 g, with a molar yield of 64.70% and an ee value of 99.7%. 1 H NMR, 600MHz (D6-DMSO) δppm: 7.82(s,1H), 7.81(s,1H), 7.76(d,1H), 7.70(s,1H), 7.69(d,1H), 5.13(s,2H), 4.58(s,2H), 4.35-4.36(m,2H), 4.25(s,2H), 4.23(s,2H), 3.15(s,3H). Example 11

[0086]

[0087] Add 8.00 g of compound 10-a and 80 mL of dichloromethane to a reaction flask. Dissolve 3.91 g of potassium carbonate in 80 mL of purified water and add it to the reaction flask. Incubate at 35–40 °C with stirring for 1 h, then allow to stand and separate the liquids. Extract the aqueous phase once more with 40 mL of dichloromethane and combine the organic phases. Wash the organic phase three times with 5% potassium carbonate solution. Dry the organic phase with anhydrous magnesium sulfate and filter to obtain solution A.

[0088] 2.61 g of compound 7 and 40 mL of dichloromethane were added to a reaction flask, heated to 35–40 °C, and stirred to dissolve. Then, 2.15 g of CDI was added in portions, and the reaction was maintained at 35–40 °C for 4 hours. Solution A was then added to the reaction mixture, and the reaction was maintained at this temperature. After the reaction was complete, 40 mL of purified water was added, and the mixture was stirred and separated. 40 mL of sodium chloride aqueous solution was then added, and the mixture was stirred and separated. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated.

[0089] After concentration, 24 mL of methanol was added, the temperature was raised to 50-60℃, and the mixture was stirred to dissolve. Then the temperature was lowered to 0-10℃ and stirred while maintaining the temperature. The mixture was filtered, washed, and dried to obtain sarolana, a white solid, 3.47 g, with a molar yield of 63.24% and an ee value of 99.8%. Example 12

[0090]

[0091] Add 8.00 g of compound 10-f and 80 mL of dichloromethane to a reaction flask. Dissolve 3.77 g of potassium carbonate in 80 mL of purified water and add it to the reaction flask. Incubate at 35–40 °C with stirring for 1 h, then allow to stand and separate the phases. Extract the aqueous phase once more with 40 mL of dichloromethane and combine the organic phases. Wash the organic phase twice with 5% potassium carbonate solution. Dry the organic phase with anhydrous magnesium sulfate and filter to obtain solution A.

[0092] Add 2.01 g of compound 7 and 40 mL of dichloromethane to a reaction flask, heat to 35–40 °C, stir to dissolve, then add 2.07 g of CDI fractionally, and maintain the reaction at 35–40 °C for 3 hours. Then add solution A to the reaction mixture and maintain the temperature. After the reaction is complete, add 40 mL of purified water, stir and separate the layers; add 40 mL of sodium chloride aqueous solution, stir and separate the layers. Dry the organic phase with anhydrous magnesium sulfate, filter and concentrate.

[0093] After concentration, 24 mL of methanol was added, the temperature was raised to 50-60℃, and the mixture was stirred to dissolve. Then the temperature was lowered to 0-10℃ and stirred while maintaining the temperature. The mixture was filtered, washed, and dried to obtain sarolana, a white solid, 3.02 g, with a molar yield of 57.16% and an ee value of 99.7%.

Claims

1. A key intermediate for salorana, characterized in that, The intermediate is compound 10, wherein R is a resolving agent. 。 2. The intermediate according to claim 1, wherein, The resolving agent is selected from L-p-methyldibenzoyl tartaric acid, L-dibenzoyl tartaric acid, D-p-methyldibenzoyl tartaric acid, D-dibenzoyl tartaric acid, L-p-methoxydibenzoyl tartaric acid, and D-p-methoxydibenzoyl tartaric acid, with L-p-methyldibenzoyl tartaric acid and L-dibenzoyl tartaric acid being preferred.

3. A method for preparing a key intermediate of salorana, characterized in that, The specific steps of the preparation method are as follows: Compound 5 (R isomer content of 0%~20%) is dissolved in a solvent, acid is added to remove the Boc protecting group; after the reaction is completed, sodium hydroxide solution is added, the mixture is stirred and separated, and the organic phase is concentrated and evaporated; then a polar solvent is added, a resolving agent is added to crystallize, and after filtration and drying, compound 10 with high chiral purity is obtained. 。 4. The preparation method according to claim 3, wherein, The solvents for the Boc deprotection reaction include dichloromethane, chloroform, dichloroethane, toluene, methanol, ethanol, isopropanol, and their mixtures, with dichloromethane, methanol, ethanol, and their mixtures being preferred.

5. The preparation method according to claim 3, wherein the acid is p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, hydrogen chloride, sulfuric acid, etc., preferably p-toluenesulfonic acid or benzenesulfonic acid.

6. The preparation method according to claim 3, wherein, The polar solvents selected are ethanol, methanol, isopropanol, n-butanol, acetonitrile, tetrahydrofuran, water, and combinations thereof, with ethanol, methanol, acetonitrile, water, or combinations thereof being preferred.

7. The preparation method according to claim 3, wherein, The amount of polar solvent used is 3 to 20 times.

8. A method for preparing salorana with high chiral purity, characterized in that, The specific steps of the preparation method are as follows: ① Dissolve compound 10 according to claim 1 in a solvent, add an alkaline aqueous solution, stir and separate the liquids. Extract the aqueous phase once with an organic solvent, combine the organic phases, and wash the organic phase again with an alkaline aqueous solution. Dry the organic phase to obtain solution A. ② Add compound 7 to an organic solvent and add N,N'-carbonyldiimidazole (CDI) in batches. Keep the mixture warm and stir to obtain solution B. ③ Add solution A to solution B, stir at a certain temperature for 0.1~24h, and after the reaction is complete, stir, separate the liquids, wash, dry, concentrate, crystallize, and dry to obtain sodium salorane product. 。 9. In the preparation method according to claim 8, the saroranone crystallization solvent refers to methanol, ethanol, isopropanol, tert-butanol, n-butanol and other organic alcohols with fewer than 8 carbon atoms, acetone, ethyl acetate, isopropyl acetate, n-heptane, preferably methanol, ethanol, ethyl acetate, isopropyl acetate, n-heptane and combinations thereof.

10. The preparation method according to claim 8, wherein, The aforementioned high purity refers to a product ee value of 99.7% or higher.

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