Process for the preparation of remdesivir intermediates

Abstract

The application discloses a preparation method of a remdesivir intermediate. The application discloses a preparation method of a compound as shown in formula C, which comprises the following steps: (1) in an organic solvent, a compound as shown in formula C-3a or formula C-3 is subjected to a reaction as shown below in the presence of an acid, and the reaction solution is concentrated to obtain a crude product; (2) the crude product obtained in the step (1) is subjected to extraction with water and dichloromethane, and the organic phase is concentrated, and the preparation method is completed. The preparation method is simple to operate, avoids a column chromatography separation and purification mode, and is suitable for industrialized scale production.

Description

Technical Field

[0001] This invention relates to a method for preparing a remdesivir intermediate. Background Technology

[0002] Remdesivir was originally developed by Gilead Sciences in the United States for the treatment of Ebola virus. During the COVID-19 outbreak in 2020, it was used as a clinical drug for the novel coronavirus. The US FDA has approved Remdesivir for marketing to treat COVID-19. Nature (Nature, 2016, 531, 381-SI(2)) reported a method for preparing Remdesivir, which is a second-generation synthetic method for Remdesivir. The synthetic route is shown below:

[0003]

[0004] In step three above, C-3 (debenzylidene) was prepared. After the reaction, a methanol solution of methanol and triethylamine was added at low temperature, the temperature was raised to room temperature, and the mixture was concentrated under reduced pressure. After stirring with n-hexane and allowing to stand, the supernatant was poured off, and this process was repeated three times. Then, methanol was added, the temperature was raised to 45°C, water was added, and the mixture was concentrated to a certain volume of water. After cooling to room temperature, crystallization was performed, and the mixture was filtered and dried to obtain C-3. No purity was reported in the literature, and the yield was 86%. Following the post-processing method reported in Nature, the addition of methanol and triethylamine quenching poses a risk of C-3 degradation, and the color becomes very dark during prolonged concentration, which is not conducive to industrial-scale production. Furthermore, Chinese patent CN104262345B reports another post-processing method for preparing the debenzylidene, which requires preparative liquid-phase separation for purification after the reaction, yielding C-3 (debenzylidene) with a yield of 76%, which is also not conducive to industrial-scale production.

[0005] In step four above, C (propylene compound) is prepared. After the reaction is complete, the temperature is lowered and an appropriate amount of sodium bicarbonate and water are added to terminate the reaction. After stirring, the mixture is concentrated to dryness, and extracted with ethyl acetate and water. The organic layer is dried and concentrated to obtain product C (propylene compound). This product is an oily substance and can be directly proceeded to the next reaction without any further treatment. If pure C is desired, it can only be obtained by silica gel column chromatography.

[0006] According to the reaction conditions reported in Nature, if some C-3 (debenzylidene) is not completely reacted at the end of the reaction, it will remain in the oily substance after extraction and concentration with ethyl acetate. If the oily substance is not purified and directly added to the next reaction, impurities will also participate in the reaction, which is not conducive to industrial-scale production. Summary of the Invention

[0007] The technical problem this invention aims to solve is to overcome the shortcomings of existing methods for preparing remdesivir intermediates, which are limited in variety, complex in operation, and unsuitable for industrial production. This invention provides a method for preparing remdesivir intermediates that is simple to operate, avoids column chromatography separation and purification, and is suitable for large-scale industrial production.

[0008] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0009] This invention provides a method for preparing a compound as shown in Formula C, comprising the following steps:

[0010] (1) In an organic solvent, in the presence of an acid, a compound of formula C-3a or formula C-3 is reacted with 2,2-dimethoxypropane as shown below, and the reaction solution is concentrated to obtain a crude product.

[0011] (2) Extract the crude product obtained in step (1) with water and dichloromethane, and concentrate the organic phase.

[0012]

[0013] In some embodiments of the present invention, in step (1), the organic solvent may be a conventional organic solvent in the art, preferably a ketone solvent, such as acetone.

[0014] In some embodiments of the present invention, in step (1), the acid may be a conventional acid in the art or an inorganic acid. The inorganic acid may be sulfuric acid, such as concentrated sulfuric acid.

[0015] In some embodiments of the present invention, in step (1), the volume-to-mass ratio of the 2,2-dimethoxypropane and the compound as shown in formula C-3a or formula C-3 can be a conventional volume-to-mass ratio in the art, preferably 1.5 to 3 mL / g, for example 1.5 mL / g, 2.12 mL / g, 2.33 mL / g or 3 mL / g.

[0016] In some embodiments of the present invention, in step (1), the volume-to-mass ratio of the acid and the compound as shown in formula C-3a or formula C-3 can be a conventional volume-to-mass ratio in the art, preferably 0.2 to 0.5 mL / g, for example 0.2 mL / g, 0.33 mL / g or 0.5 mL / g.

[0017] In some embodiments of the present invention, in step (1), the mass-to-volume ratio of the compound of formula C-3a or formula C-3 to the organic solvent can be a conventional mass-to-volume ratio in the art, preferably 30 to 50 g / L, for example 30 g / L, 37.5 g / L, 38.5 g / L or 50 g / L.

[0018] In some embodiments of the present invention, in step (1), the temperature of the reaction can be a conventional temperature in the art, preferably 10 to 60°C, for example 10°C, 45°C or 60°C.

[0019] In some embodiments of the present invention, in step (1), the progress of the reaction can be monitored by conventional means in the art (e.g., TLC, HPLC, or LCMS) until the compound represented by formula C-3a or formula C-3 disappears or ceases to react. The reaction time is preferably 0.5 to 3 hours, for example 0.5 hours, 1 hour, 1.5 hours, or 3 hours.

[0020] In some embodiments of the present invention, in step (1), the concentration may be vacuum concentration.

[0021] In some embodiments of the present invention, step (1) may further include a quenching step prior to the concentration, wherein the solvent used for quenching may be an alkali and water. The alkali may be an inorganic alkali or an alkali metal bicarbonate, such as sodium bicarbonate.

[0022] In some embodiments of the present invention, the extraction operation in step (2) is the same as that conventional in the art.

[0023] In some embodiments of the present invention, step (2) may include a washing operation after the extraction. The washing reagent may be saturated saline solution.

[0024] In some embodiments of the present invention, in step (2), after the extraction, the organic phase obtained by the extraction may be dried. The drying reagent may be a reagent conventional in the art, such as anhydrous sodium sulfate and / or anhydrous magnesium sulfate.

[0025] In some embodiments of the present invention, in step (2), after the extraction, the organic phase obtained by extraction may be decolorized. The decolorizing reagent may be a conventional reagent in the art, such as activated carbon. The decolorization may be carried out under heating conditions, and the heating temperature may be the temperature at which the reagent is refluxed. The decolorization time may be 0.5-3 hours, for example, 1 hour.

[0026] In some embodiments of the present invention, after the concentration is completed in step (2), the following steps may be further included: mixing the concentrated substance with dichloromethane and n-heptane to precipitate the compound shown in formula C.

[0027] In some embodiments of the present invention, the volume ratio of the n-heptane to the dichloromethane is preferably 2:1 to 50:1, more preferably 2:1 to 5:1, for example 2:1.

[0028] In some embodiments of the present invention, the volume-to-mass ratio of the dichloromethane to the compound of formula C is preferably 2 to 50 ml / g.

[0029] In some embodiments of the present invention, the addition of n-heptane is preferably by dripping.

[0030] In some embodiments of the present invention, the temperature at which the n-heptane is added is preferably 10-40°C.

[0031] In some embodiments of the present invention, after the addition of n-heptane, the mixture is stirred, filtered, and dried to obtain the compound shown in Formula C. The stirring time can be 0.5-5 hours, for example, 0.5 hours. The drying can be oven drying.

[0032] In some embodiments of the present invention, the preparation method of the compound shown in formula C may further include the following steps: in an organic solvent, the compound shown in formula C-2 and boron trichloride are subjected to the following debenzylation reaction to obtain the compound shown in formula C-3a.

[0033]

[0034] In some embodiments of the present invention, the organic solvent may be a conventional organic solvent in the art, preferably a halogenated hydrocarbon solvent and / or an alkane solvent, such as dichloromethane and / or n-hexane.

[0035] In some embodiments of the present invention, the molar ratio of boron trichloride and the compound shown in formula C-2 may be a conventional molar ratio in the art, preferably 1:1 to 5:1, for example 1:1, 2.7:1 or 5:1.

[0036] In some embodiments of the present invention, the mass-to-volume ratio of the compound as shown in formula C-2 and the organic solvent may be a conventional mass-to-volume ratio in the art, preferably 25 to 40 g / L, for example 25 g / L, 31 g / L or 40 g / L.

[0037] In some embodiments of the present invention, the temperature of the debenzylation reaction can be a temperature conventional in the art, preferably -70 to -20°C, for example -40 to -20°C or -45°C.

[0038] In some embodiments of the present invention, the progress of the debenzylation reaction can be monitored by conventional means in the art (e.g., TLC, HPLC, or LCMS) until the compound shown in formula C-2 disappears or ceases to react. The debenzylation reaction time is preferably 2–3 hours, for example, 2 hours or 3 hours.

[0039] In some embodiments of the present invention, the boron trichloride is added in a conventional manner in the art, preferably by dripping. The temperature at which the boron trichloride is added is preferably -78 to -20°C, for example -78°C, -50°C, -48°C, -47°C, -45°C, -40°C, or -20°C.

[0040] In some embodiments of the present invention, the post-treatment of the debenzylation reaction may be either method one or method two.

[0041] Method 1 includes the following steps: mixing the reaction solution with an alcohol solvent to separate the compound as shown in formula C-3a;

[0042] Method 2 includes the following steps: mixing the reaction solution with an alcohol solvent, then slurrying the separated solid to obtain the compound shown in formula C-3a.

[0043] In both Method 1 and Method 2, the alcohol solvent can be one or more of methanol, ethanol, and isopropanol, with methanol being preferred.

[0044] In Method 1 and Method 2, the mass-to-volume ratio of the alcohol solvent to the reaction solution is preferably 40-50 g / L (e.g., 43 g / L, 46 g / L or 50 g / L), more preferably 40-46 g / L.

[0045] In both Method 1 and Method 2, the mixing can be carried out at -70 to 25°C, preferably at -50 to -20°C.

[0046] In both methods one and two, after mixing, the mixture may be further stirred and filtered. The stirring temperature is preferably 10-40℃. The stirring time is preferably 2-5 hours, for example, 2 hours. The filtration is preferably vacuum filtration.

[0047] In Method 2, the solvent used for pulping is preferably an alcohol solvent, or a mixture of an alcohol solvent and an ester solvent, such as ethanol, or a mixture of methanol and ethyl acetate. The alcohol solvent is preferably methanol and / or ethanol. The ester solvent is preferably ethyl acetate. When the solvent is a mixture of an alcohol solvent and an ester solvent, the volume ratio of the alcohol solvent to the ester solvent is preferably 1:1 to 1:3, for example, 1:2.

[0048] In Method 2, the volume-to-mass ratio of the solvent used for pulping to the solid is preferably 6 mL / g to 12 mL / g (e.g., 6.4 mL / g, 7 mL / g, 11.2 mL / g or 11.4 mL / g), more preferably 6 to 10 mL / g.

[0049] In Method 2, after the pulping process, the mixture can be further filtered and dried to obtain the compound shown in Formula C-3a. The filtration can be vacuum filtration. The drying can be oven drying. The drying time can be 35–55°C, for example, 45°C.

[0050] The present invention provides a method for preparing a compound as shown in formula C-3a, which includes the following steps: in an organic solvent, a compound as shown in formula C-2 and boron trichloride are subjected to a debenzylation reaction as shown below to obtain the compound as shown in formula C-3a.

[0051]

[0052] In some embodiments of the present invention, the organic solvent may be a conventional organic solvent in the art, preferably a halogenated hydrocarbon solvent and / or an alkane solvent, such as dichloromethane and / or n-hexane.

[0053] In some embodiments of the present invention, the molar ratio of boron trichloride and the compound shown in formula C-2 may be a conventional molar ratio in the art, preferably 1:1 to 5:1, for example 1:1, 2.7:1 or 5:1.

[0054] In some embodiments of the present invention, the mass-to-volume ratio of the compound as shown in formula C-2 and the organic solvent may be a conventional mass-to-volume ratio in the art, preferably 25 to 40 g / L, for example 25 g / L, 31 g / L or 40 g / L.

[0055] In some embodiments of the present invention, the temperature of the debenzylation reaction can be a temperature conventional in the art, preferably -70 to -20°C, for example -40 to -20°C or -45°C.

[0056] In some embodiments of the present invention, the progress of the debenzylation reaction can be monitored by conventional means in the art (e.g., TLC, HPLC, or LCMS) until the compound shown in formula C-2 disappears or ceases to react. The debenzylation reaction time is preferably 2–3 hours, for example, 2 hours or 3 hours.

[0057] In some embodiments of the present invention, the boron trichloride is added in a conventional manner in the art, preferably by dripping. The temperature at which the boron trichloride is added is preferably -78 to -20°C, for example -78°C, -50°C, -48°C, -47°C, -45°C, -40°C, or -20°C.

[0058] In some embodiments of the present invention, the post-treatment of the debenzylation reaction may be either method one or method two.

[0059] Method 1 includes the following steps: mixing the reaction solution with an alcohol solvent to separate the compound as shown in formula C-3a;

[0060] Method 2 includes the following steps: mixing the reaction solution with an alcohol solvent, then slurrying the separated solid to obtain the compound shown in formula C-3a.

[0061] In both Method 1 and Method 2, the alcohol solvent can be one or more of methanol, ethanol, and isopropanol, with methanol being preferred.

[0062] In Method 1 and Method 2, the mass-to-volume ratio of the alcohol solvent to the reaction solution is preferably 40-50 g / L (e.g., 43 g / L, 46 g / L or 50 g / L), more preferably 40-46 g / L.

[0063] In both Method 1 and Method 2, the mixing can be carried out at -70 to 25°C, preferably at -50 to -20°C.

[0064] In both methods one and two, after mixing, the mixture may be further stirred and filtered. The stirring temperature is preferably 10-40℃. The stirring time is preferably 2-5 hours, for example, 2 hours. The filtration is preferably vacuum filtration.

[0065] In Method 2, the solvent used for pulping is preferably an alcohol solvent, or a mixture of an alcohol solvent and an ester solvent, such as ethanol, or a mixture of methanol and ethyl acetate. The alcohol solvent is preferably methanol and / or ethanol. The ester solvent is preferably ethyl acetate. When the solvent is a mixture of an alcohol solvent and an ester solvent, the volume ratio of the alcohol solvent to the ester solvent is preferably 1:1 to 1:3, for example, 1:2.

[0066] In Method 2, the volume-to-mass ratio of the solvent used for pulping to the solid is preferably 6 mL / g to 12 mL / g (e.g., 6.4 mL / g, 7 mL / g, 11.2 mL / g or 11.4 mL / g), more preferably 6 to 10 mL / g.

[0067] In Method 2, after the pulping process, the mixture can be further filtered and dried to obtain the compound shown in Formula C-3a. The filtration can be vacuum filtration. The drying can be oven drying. The drying time can be 35–55°C, for example, 45°C.

[0068] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0069] The reagents and raw materials used in this invention are all commercially available.

[0070] The positive and progressive effects of this invention are as follows:

[0071] (1) In the preparation method of compound C, dichloromethane is used as the extraction solvent. C-3 remains completely in the aqueous phase, and the unreacted C-3a remains in the water, reducing impurity residues and facilitating quality control in subsequent steps. After recrystallization, high-purity compound C (propionide) with a purity >99% by HPLC and a yield >80% is obtained. This avoids the column chromatography separation reported in the literature and is suitable for large-scale industrial production.

[0072] (2) In the preparation method of compound C-3a, an alcohol solvent is added to quench the reaction, precipitating stable C-3a (debenzylidene hydrochloride). High-purity C-3a (debenzylidene hydrochloride) intermediate is obtained by slurry purification. The preparation of intermediate C-3a (debenzylidene hydrochloride) avoids the cumbersome operations reported in the literature, such as alkali neutralization, concentration, repeated washing, and crystallization with methanol and water during quenching. This greatly simplifies the post-processing method, yielding stable C-3a (debenzylidene hydrochloride) solid with a purity >98% by HPLC and a yield greater than or equal to 89%. Detailed Implementation

[0073] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0074] In this invention, the preparation of compound C-1 from compounds A and B, the preparation of compound C-2 from compound C-1, the preparation of compound E from compound C, the preparation of compound F from compound E, and the preparation of compound C-3 were all carried out in accordance with the literature Nature, 2016, 531, 381-SI(2).

[0075] Example 1: Preparation of C-3a (debenzylidene hydrochloride)

[0076]

[0077] C-2 (140g) and dichloromethane (3.5L) were added to a reaction flask, and the temperature was lowered to -45℃. A 1M solution of boron trichloride in dichloromethane (1L) was added dropwise. The reaction was maintained at around -45℃ for about 2 hours until it ended. Methanol (160g) was added, and the mixture was heated to room temperature and stirred for 2 hours. The mixture was then filtered to obtain about 100g of wet product with an HPLC purity of 98.41%. The filter cake was slurried with 700ml of ethanol, filtered, and dried under vacuum at 45℃ to obtain a white solid C-3a (debenzylidene hydrochloride) (75g, 91%) with an HPLC purity of 98.6%.

[0078] 1H NMR(D2O)δ8.1(s,1H),7.37(d,J=5.1Hz,1H),7.14(d,J=4.8Hz,1H),4.94(d,J=5.4Hz,1H),4.42(app q, J=4.2Hz, 1H), 4.35 (t, J=5.1Hz, 1H), 3.86 (dd, J=12.8, 3.2Hz, 1H), 3.79 (dd, J=12.8, 4.7Hz, 1H).

[0079] 1 H NMR(DMSO)δ10.1(s,1H),9.3(s,1H),8.2(s,1H),7.49(d,1H),7.0(d,1H), 5.7(s,1H),4.5(d,1H),4.0(dd,1H),3.9(t,1H),3.6(dd,1H),3.5(dd,1H).

[0080] The chloride ion content was determined by ion chromatography (AG11-HC-4μm 4*50Guard 4*250mm Aralytrcal). The chloride ion content of C-3a (debenzylidene hydrochloride) was 13%, which means that one molecule of C-3a (debenzylidene hydrochloride) was formed by C-3 and one molecule of HCl.

[0081] Example 2: Preparation of C-3a (debenzylidene hydrochloride)

[0082]

[0083] C-2 (140 g) and dichloromethane (3.5 L) were added to a reaction flask, and the temperature was lowered to -50 °C. A 1 M boron trichloride n-hexane solution was added dropwise, with the internal temperature controlled at -40 to -20 °C, over approximately 25 minutes. The reaction was then maintained at around -45 °C for about 2 hours until the reaction was complete. Methanol (150 g) was added, and the mixture was brought to room temperature and stirred for 5 hours. The mixture was then filtered to obtain approximately 110 g of a moist product with an HPLC purity of 98.3%. The filter cake was slurried with 710 ml of ethanol, filtered, and dried under vacuum at 45 °C to obtain a white solid C-3a (77 g, 94%) with an HPLC purity of 98.5%. Its 1H NMR data were the same as in Example 1.

[0084] Example 3: Preparation of C-3a (debenzylidene hydrochloride)

[0085]

[0086] C-2 (140g) and dichloromethane (3.5L) were added to a 5L reaction flask, and the temperature was lowered to -47°C. A 1M boron trichloride dichloromethane solution (1L) was added dropwise, maintaining the internal temperature at -40 to -20°C over approximately 25 minutes. The reaction was then maintained at approximately -40 to -20°C for 2-3 hours, ending after about 2 hours. Methanol (155g) was added, and the mixture was brought to room temperature and stirred for 2 hours. The mixture was then filtered to obtain approximately 105g of a moist product with an HPLC purity of 98.42%. The filter cake was mixed with methanol (400ml) and ethyl acetate (800ml), filtered, and dried under vacuum at 45°C to obtain a white solid C-3a (73g, 89%) with an HPLC purity of 98.65%. Its 1H NMR data were the same as in Example 1.

[0087] Example 4: Preparation of C-3a (debenzylidene hydrochloride)

[0088]

[0089] C-2 (140g) and dichloromethane (3.5L) were added to a 5L reaction flask, and the temperature was lowered to -48℃. A 1M boron trichloride n-hexane solution (1L) was added dropwise, with the internal temperature controlled at -40 to -20℃. The addition was completed in about 25 minutes. The reaction was maintained at -40 to -20℃ for 2-3 hours. After about 2 hours, the reaction was completed. Methanol (148g) was added, and the mixture was heated to room temperature and stirred for 2-5 hours. The mixture was filtered to obtain about 107g of moist product with an HPLC purity of 98.43%. The filter cake was mixed with methanol (400ml) and ethyl acetate (800ml), filtered, and dried under vacuum at 45℃ to obtain a white solid C-3a (74g, 90%) with an HPLC purity of 98.63%.

[0090] Example 5: Preparation of C-3a (debenzylidene hydrochloride)

[0091]

[0092] C-2 (140g) and dichloromethane (3.2L) were added to a reaction flask, and the temperature was lowered to -45℃. A 1M solution of boron trichloride in dichloromethane (1L) was added dropwise. The reaction was stopped after maintaining the temperature at around -45℃ for about 2 hours. Methanol (160g) was added, and the mixture was heated to room temperature and stirred for 2 hours. The mixture was then filtered to obtain about 100g of moist product with an HPLC purity of 98.44%. The filter cake was slurried with 700ml of ethanol, filtered, and dried under vacuum at 45℃ to obtain a white solid C-3a (debenzene hydrochloride) (75g, 91%) with an HPLC purity >98.67%.

[0093] Example 6: Preparation of C-3a (debenzylidene hydrochloride)

[0094]

[0095] C-2 (140g) and dichloromethane (3.5L) were added to a reaction flask, and the temperature was lowered to -45℃. A 1M solution of boron trichloride in dichloromethane (1L) was added dropwise. The reaction was stopped after maintaining the temperature at around -45℃ for about 2 hours. Methanol (160g) was added, and the mixture was heated to room temperature and stirred for 2 hours. The mixture was then filtered to obtain about 100g of moist product with an HPLC purity of 98.47%. The filter cake was mixed with methanol (200ml) and ethyl acetate (400ml), filtered, and dried under vacuum at 45℃ to obtain a white solid C-3a (debenzene hydrochloride) (74g, 90%) with an HPLC purity >98.7%.

[0096] Example 7: Preparation of C (propionide)

[0097]

[0098] C-3a (0.62 g) and acetone (16 ml) were added to a 100 ml reaction flask, followed by 2,2-dimethoxypropane (1.4 ml) and concentrated sulfuric acid (0.2 ml). The mixture was stirred at room temperature for 0.5 h, then heated to 45 °C. After reacting for 1 h, the temperature was lowered to room temperature, and then solid sodium bicarbonate (0.8 g) and water (1 ml) were added. The mixture was stirred for 15 min and then concentrated under reduced pressure. The crude product obtained from the concentration was added to water (10 ml) and dichloromethane (30 ml). The mixture was stirred, allowed to stand, and the organic phase was separated. The aqueous phase was then extracted with dichloromethane (10 ml). The organic phases were combined and washed with 10 ml of saturated brine. The organic layer was dried with 0.2 g of anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain an oily substance (HPLC purity 94.6%, HPLC content of C-3 0.18%). The oily substance was dissolved in 5 ml of dichloromethane, and 10 ml of n-heptane was added dropwise at room temperature. A large amount of solid precipitated during the addition. After the addition was completed, the mixture was stirred at room temperature for half an hour, filtered, and dried to obtain product C (0.55 g, 87.7%) with an HPLC purity of 99.1% and an HPLC content of C-3 of 0.12%. 1 H NMR (400MHz, DMSO) δ8.03-7.84(m,3H),6.91(q,J=4.6Hz,2H),5.38(d,J=6.6Hz,1H),5.02(t,J=5.7Hz,1H ), 4.90 (dd, J=6.6, 3.1Hz, 1H), 4.32 (td, J=5.3, 3.2Hz, 1H), 3.59-3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H).

[0099] Example 8: Preparation of C (propionide)

[0100]

[0101] C-3a (50.8 g) and acetone (1300 ml) were added to a 2 L reaction flask, followed by 2,2-dimethoxypropane (106 ml) and concentrated sulfuric acid (16.4 ml). The mixture was stirred at room temperature for 0.5 h, then heated to 45 °C. After reacting for 1 h, the temperature was lowered to room temperature, and then solid sodium bicarbonate (67.5 g) and water (100 ml) were added. The mixture was stirred for 15 min and then concentrated under reduced pressure. The crude product obtained from the concentration was added to water (400 ml) and dichloromethane (500 ml). The mixture was stirred, allowed to stand, and the lower organic phase was separated. The aqueous phase was then extracted with dichloromethane (250 ml). The organic phases were combined and washed with 250 ml of saturated brine. 10 g of anhydrous magnesium sulfate and 10 g of activated carbon were added to the organic layer, and the mixture was refluxed for 1 h. After hot filtration, the filtrate was concentrated to obtain an oily substance (HPLC purity 95.4%, HPLC content of C-3 0.14%). The oily substance was dissolved in 500 ml of dichloromethane, and 1000 ml of n-heptane was added dropwise at room temperature. A large amount of solid precipitated during the addition. After the addition was complete, the mixture was stirred at room temperature for half an hour, filtered, and dried to obtain product C (48 g, 93.5%) with an HPLC purity of 99.5% and an HPLC content of 0.06% for C-3. Its 1H NMR data were the same as in Example 7.

[0102] Example 9: Preparation of C (propionide)

[0103]

[0104] In a 100 ml reaction flask, C-3 (0.55 g) and acetone (16 ml) were added, followed by 2,2-dimethoxypropane (1.4 ml) and concentrated sulfuric acid (0.2 ml). The mixture was stirred at room temperature for 0.5 h, then heated to 45 °C. After reacting for 1 h, the temperature was lowered to room temperature, and then solid sodium bicarbonate (0.8 g) and water (1 ml) were added. The mixture was stirred for 15 min and then concentrated under reduced pressure. The crude product obtained from the concentration was added to water (10 ml) and dichloromethane (30 ml). The mixture was stirred, allowed to stand, and the lower organic phase was separated. The aqueous phase was then extracted with dichloromethane (10 ml). The organic phases were combined and washed with 10 ml of saturated brine. The organic layer was dried with 0.2 g of anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain an oily substance (HPLC purity 94.5%, HPLC content of C-3 0.18%). The oily substance was dissolved in 5 ml of dichloromethane, and 10 ml of n-heptane was added dropwise at room temperature. A large amount of solid precipitated during the addition. After the addition was completed, the mixture was stirred at room temperature for half an hour, filtered, and dried to obtain product C (0.54 g, 86.3%) with an HPLC purity of 99.3% and an HPLC content of 0.09% for C-3.

[0105] Comparative Example 1: Preparation of C (propionide)

[0106]

[0107] C-3a (0.62 g) and acetone (16 ml) were added to a 100 ml reaction flask, followed by 2,2-dimethoxypropane (1.4 ml) and concentrated sulfuric acid (0.2 ml). The mixture was stirred at room temperature for 0.5 h, then heated to 45 °C. After reacting for 1 h, the temperature was lowered to room temperature, and then solid sodium bicarbonate (0.8 g) and water (1 ml) were added. The mixture was stirred for 15 min and then concentrated under reduced pressure. The crude product obtained from the concentration was added to water (10 ml) and ethyl acetate (30 ml). The mixture was stirred, allowed to stand, and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (10 ml). The organic phases were combined and washed with 10 ml of saturated brine. The organic layer was dried with 0.2 g of anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain an oily substance (HPLC purity 93.8%, HPLC content of C-3 1.10%). The oily substance was dissolved in 5 ml of dichloromethane, and 10 ml of n-heptane was added dropwise at room temperature. A large amount of solid precipitated during the addition. After the addition was completed, the mixture was stirred at room temperature for half an hour, filtered, and dried to obtain product C (0.55 g, 87.7%) with an HPLC purity of 98.1% and an HPLC content of 1.1% for C-3.

[0108] Comparative Example 2: Preparation of C (propionide)

[0109]

[0110] C-3a (0.62 g) and acetone (16 ml) were added to a 100 ml reaction flask, followed by 2,2-dimethoxypropane (1.4 ml) and concentrated sulfuric acid (0.2 ml). The mixture was stirred at room temperature for 0.5 h, then heated to 45 °C. After reacting for 1 h, the temperature was lowered to room temperature, and then solid sodium bicarbonate (0.8 g) and water (1 ml) were added. The mixture was stirred for 15 min and then concentrated under reduced pressure. The crude product obtained from the concentration was added to water (10 ml) and ethyl acetate (30 ml). The mixture was stirred, allowed to stand, and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (10 ml). The organic phases were combined and washed with 10 ml of saturated brine. The organic layer was dried with 0.2 g of anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain an oily substance (HPLC purity 94.2%, HPLC content of C-3 1.02%). The oily substance was dissolved in 4 ml of ethyl acetate, and 8 ml of n-heptane was added dropwise at room temperature. During the addition, a solid precipitated out. After the addition was completed, the mixture was stirred at room temperature for half an hour, filtered, and dried to obtain product C (0.22 g, 35.1%), with an HPLC purity of 98.8% and an HPLC content of 0.5% for C-3.

[0111] Comparative Example 3: Preparation of C (propionide)

[0112]

[0113] In a 100 ml reaction flask, C-3 (0.55 g) and acetone (16 ml) were added, followed by 2,2-dimethoxypropane (1.4 ml) and concentrated sulfuric acid (0.2 ml). The mixture was stirred at room temperature for 0.5 h, then heated to 45 °C. After reacting for 1 h, the temperature was lowered to room temperature, and then solid sodium bicarbonate (0.8 g) and water (1 ml) were added. The mixture was stirred for 15 min and then concentrated under reduced pressure. The crude product obtained from the concentration was added to water (10 ml) and ethyl acetate (30 ml). The mixture was stirred, allowed to stand, and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (10 ml). The organic phases were combined and washed with 10 ml of saturated brine. The organic layer was dried with 0.2 g of anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain an oily substance (HPLC purity 93.3%, HPLC content of C-3 1.22%). The oily substance was dissolved in 5 ml of dichloromethane, and 10 ml of n-heptane was added dropwise at room temperature. A large amount of solid precipitated during the addition. After the addition was completed, the mixture was stirred at room temperature for half an hour, filtered, and dried to obtain product C (0.54 g, 86.3%) with an HPLC purity of 98.4% and an HPLC content of 1.1% for C-3.

[0114] Comparative Example 4: Preparation of C (propionide)

[0115]

[0116] C-3a (0.6 g) and acetone (16 ml) were added to a 100 ml reaction flask, followed by 2,2-dimethoxypropane (1.4 ml) and concentrated sulfuric acid (0.2 ml). The mixture was stirred at room temperature for 0.5 h, then heated to 45 °C. After reacting for 1 h, the temperature was lowered to room temperature, and then solid sodium bicarbonate (0.8 g) and water (1 ml) were added. The mixture was stirred for 15 min and then concentrated under reduced pressure. The crude product obtained from the concentration was added to water (10 ml) and then extracted with methyl tert-butyl ether, isopropyl ether, ethyl acetate, and toluene, respectively. The results showed that methyl tert-butyl ether, isopropyl ether, ethyl acetate, and toluene extracted product C and unreacted C-3 together, making subsequent separation difficult. The HPLC purity of C was ≤95%, and the HPLC content of C-3 was 1%.

[0117] Comparative Example 5: Preparation of C (propionide)

[0118]

[0119] C-3a (0.6 g) and acetone (16 ml) were added to a 100 ml reaction flask, followed by 2,2-dimethoxypropane (1.4 ml) and concentrated sulfuric acid (0.2 ml). The mixture was stirred at room temperature for 0.5 h, then heated to 45 °C. After reacting for 1 h, the temperature was lowered to room temperature, and then solid sodium bicarbonate (0.8 g) and water (1 ml) were added. The mixture was stirred for 15 min and then concentrated under reduced pressure. The crude product obtained from the concentration was added to water (10 ml) and dichloromethane (30 ml). The mixture was stirred, allowed to stand, and the lower organic phase was separated. The aqueous phase was then extracted with dichloromethane (10 ml). The organic phases were combined and washed with 10 ml of saturated brine. The organic layer was dried with 0.2 g of anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain an oily substance (HPLC purity 94.5%, HPLC content of C-3 0.17%). The oily substance was dissolved by heating with 3 ml of methyl tert-butyl ether at 55 °C. A small amount of solid precipitated at room temperature. After filtration and drying, product C (0.1 g, 14.5%) was obtained with an HPLC purity of 99.3% and an HPLC content of C-3 of 0.08%.

Claims

1. A method for preparing a compound as shown in Formula C, characterized in that, It includes the following steps: (1) In an organic solvent, in the presence of an acid, a compound of formula C-3a or C-3 is reacted with 2,2-dimethoxypropane as shown below, and the reaction solution is concentrated to obtain a crude product. (2) Extract the crude product obtained in step (1) with water and dichloromethane to concentrate the organic phase; In step (2), after the concentration is completed, the following steps are further included: mixing the concentrated substance with dichloromethane and n-heptane to precipitate the compound shown in formula C; 。 2. The method for preparing the compound of formula C as described in claim 1, characterized in that, In step (1), the organic solvent is a ketone solvent; And / or, in step (1), the acid is an inorganic acid; And / or, in step (1), the volume-to-mass ratio of the 2,2-dimethoxypropane and the compound as shown in formula C-3a or formula C-3 is 1.5 to 3 mL / g; And / or, in step (1), the volume-to-mass ratio of the acid to the compound of formula C-3a or formula C-3 is 0.2 to 0.5 mL / g; And / or, in step (1), the mass-to-volume ratio of the compound of formula C-3a or formula C-3 to the organic solvent is 30-50 g / L; And / or, in step (1), the temperature of the reaction is 10~60℃; And / or, in step (1), the reaction time is 0.5 to 3 h; And / or, in step (1), the concentration is reduced pressure concentration; And / or, in step (1), prior to the concentration, a quenching step is further included; And / or, in step (2), after the extraction, a washing operation is also included; And / or, in step (2), after the extraction, the organic phase obtained from the extraction is dried; And / or, in step (2), after the extraction, the organic phase obtained from the extraction is decolorized.

3. The method for preparing the compound as shown in formula C according to claim 2, characterized in that, In step (1), the organic solvent is acetone; And / or, in step (1), the acid is sulfuric acid.

4. The method for preparing the compound of formula C as described in claim 1, characterized in that, In step (1), prior to the concentration, a quenching step is further included, wherein the solvent used for quenching is an aqueous solution of alkali.

5. The method for preparing the compound of formula C as described in claim 4, characterized in that, The alkali mentioned is an inorganic alkali.

6. The method for preparing the compound of formula C as described in claim 5, characterized in that, The alkali is a bicarbonate of an alkali metal.

7. The method for preparing the compound of formula C as described in claim 1, characterized in that, In step (2), after the concentration is completed, the concentrated substance is mixed with dichloromethane and n-heptane to precipitate the compound shown in formula C. In this step, the volume ratio of n-heptane to dichloromethane is 2:1 to 50:

1. And / or, the method of adding the n-heptane is dropwise; And / or, the temperature at which the n-heptane is added is 10-40°C; And / or, after adding the n-heptane, stirring, filtering, and drying, the compound shown in formula C is obtained.

8. The method for preparing the compound of formula C as described in claim 7, characterized in that, In step (2), after the concentration is completed, the concentrated substance is mixed with dichloromethane and n-heptane to precipitate the compound shown in formula C. In this step, the volume ratio of n-heptane to dichloromethane is 2:1 to 5:

1.

9. The method for preparing the compound of formula C as described in claim 1, characterized in that, It further includes the preparation step of the compound shown in formula C-3a: in an organic solvent, the compound shown in formula C-2 and boron trichloride are subjected to the debenzylation reaction shown below to obtain the compound shown in formula C-3a. 。 10. The method for preparing the compound of formula C as described in claim 9, characterized in that, In the preparation steps of the compound shown in formula C-3a, The organic solvent is a halogenated hydrocarbon solvent and / or an alkane solvent; And / or, the molar ratio of the boron trichloride and the compound shown in formula C-2 is 1:1 to 5:1; And / or, the mass-to-volume ratio of the compound of formula C-2 to the organic solvent is 25-40 g / L; And / or, the temperature for the debenzylation reaction is -70 to -20°C; And / or, the debenzylation reaction takes 2-3 hours; And / or, the boron trichloride is added dropwise; And / or, the temperature at which the boron trichloride is added is -78 to -20°C.

11. The method for preparing the compound of formula C as described in claim 9 or 10, characterized in that, The post-treatment of the debenzylation reaction is performed using either Method 1 or Method 2. Method 1 includes the following steps: mixing the reaction solution with an alcohol solvent to separate the compound as shown in formula C-3a; Method 2 includes the following steps: mixing the reaction solution with an alcohol solvent, then slurrying the separated solid to obtain the compound shown in formula C-3a.

12. The method for preparing the compound of formula C as described in claim 11, characterized in that, In both Method 1 and Method 2, the alcohol solvent is one or more of methanol, ethanol, and isopropanol. And / or, in Method 1 and Method 2, the mass-to-volume ratio of the alcohol solvent to the reaction solution is 40-50 g / L; And / or, in Method 1 and Method 2, the mixing is carried out at -70~25°C; And / or, in Method 1 and Method 2, after mixing, the mixture is further stirred and filtered; And / or, in Method 2, the solvent used for pulping is an alcohol solvent, or a mixture of an alcohol solvent and an ester solvent; And / or, in Method 2, the volume-to-mass ratio of the solvent used for pulping to the solid is 6 mL / g to 12 mL / g; And / or, in method two, after the pulping is completed, the compound is further filtered and dried to obtain the compound shown in formula C-3a.

13. The method for preparing the compound of formula C as described in claim 12, characterized in that, In both Method 1 and Method 2, the alcohol solvent is methanol; And / or, in Method 1 and Method 2, the mass-to-volume ratio of the alcohol solvent to the reaction solution is 40~46 g / L; And / or, in Method 1 and Method 2, the mixing is carried out at -50 to -20°C; And / or, in Method 2, the solvent for pulping is ethanol, or a mixture of methanol and ethyl acetate; And / or, in Method 2, when the solvent is a mixture of alcohol solvent and ester solvent, the volume ratio of the alcohol solvent to the ester solvent is 1:1 to 1:3; And / or, in Method 2, the volume-to-mass ratio of the solvent used for pulping to the solid is 6-10 mL / g.

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